Plasma vitamin D levels of patients with allergic rhino-conjunctivitis with positive skin prick test Alper Yenigun, M.D.,1 Zeynep Dadaci, M.D.,2 and Mufide Oncel, M.D.3
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ABSTRACT
Background: Allergic rhino-conjunctivitis (ARC) and allergic rhinitis are inflammatory diseases that develop through immunoglobulin E in the rhino-ocular mucosa due to allergy. The main symptoms are runny nose, nasal congestion, sneezing, itchy nose, and conjunctivitis. Objective: This study was designed to evaluate plasma 25-hydroxyvitamin D levels in patients with ARC. Study design: This study was planned as a prospective and cross sectional study. This study was performed in a tertiary referral center. Methods: This observational study involved 42 patients with ARC and 35 consecutive, age- and sex-matched healthy subjects. Patients in both groups underwent skin-prick test. Plasma 25-hydroxyvitamin D levels of all subjects were quantified with electrochemiluminescence technique. Results were compared between the groups and p ⬍ 0.05 was considered as statistically significant. Results: Group one included 42 ARC patients (15 male, 27 female, ages between 12 and 43, average age 25.7 ⫾ 8.6); group two included 35 healthy people (15 male, 20 female, ages between 12 and 44, average age 26.9 ⫾ 9.1). Plasma 25-hydroxyvitamin D levels of the subjects with ARC group (7.33 ⫾ 3.61 ng/mL, standard error mean: 0.55, range 3.17–13.68 ng/mL) were significantly lower than the control group (13.37 ⫾ 5.42 ng/mL, standard error mean: 0.91, range 6.84 –25.92 ng/mL) (p ⫽ 0.010, Independent-Samples test). Conclusions: We found lower plasma vitamin D levels in patients with ARC when compared with the control group. (Am J Rhinol Allergy 29, e46 –e49, 2015; doi: 10.2500/ajra.2015.29.4164)
A
llergic rhinitis is defined clinically by the symptoms caused by immunologically mediated (most often immunoglobulin E dependent) inflammation after the exposure of the nasal mucous membranes to offending allergens. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction or blockage, nasal itching, sneezing, and postnasal drip that reverse spontaneously or after treatment. Allergic conjunctivitis often accompanies allergic rhinitis.1 The prevalence of allergic rhinitis in the general population of Europe has been reported to be around 25%.2,3 Allergic conjunctivitis is inflammation of the conjunctiva (the mucous membrane that lines the inner surface of the eyelids and is continued over the forepart of the eyeball) due to allergy.4 Allergic conjunctivitis is also frequently associated with other allergic diseases, especially allergic rhinitis.5 When combined with rhinitis, the condition is termed as allergic rhino-conjunctivitis (ARC). ARC is an inflammatory disease that develops through immunoglobulin E in the rhino-ocular mucosa. ARC is a frequently encountered and chronic disease with an increasing incidence.6 Besides physical complaints, it has an adverse effect on quality of life by causing social and psychological distresses.7 Because 25-hydroxy vitamin D serum levels are low in allergic individuals and vitamin D influences allergy-mediating immune cells such as T cells and the immune functions of cells forming the barriers against allergens such as epithelial cells, one might speculate that vitamin D plays a role in allergy development.8 In 2004, Zitterman et al. suggested that vitamin D deficiency has an effect on allergy risk depending on their observation of the association between low vitamin D status and low cord blood levels of the tolerogenic cytokine interleukin-10 (IL-10).9 Furthermore, Camargo et al. suggested that regional differences in vitamin D status were responsible for the strong north-south gradient for the prescription of EpiPens as emergency treatment for severe allergic reactions in the United States.10
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1 Konya Hospital, Otorhinolaryngology Clinic, Konya, Turkey, 2Department of Ophthalmology, Faculty of Medicine, Mevlana University, Konya, Turkey, and 3Department of Biochemistry, Faculty of Medicine, Mevlana University, Konya, Turkey The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Alper Yenigun, M.D., Otorhinolaryngology Clinic, Konya Hospital, Semsi Tebrizi District, Serafettin Street, No. 95, 42080, Karatay-Konya, Turkey E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
e46
Thacher et al. suggested that increased vitamin D levels affect the incidence and the course of allergic disease.11 Although clinical findings are essential for diagnosis, skin tests are the most common methods for determining the allergy and identifying the responsible allergen, and they have become the golden standard for diagnosis.12 We aimed to investigate plasma vitamin D levels of patients with ARC and compare with normal subjects.
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MATERIALS AND METHODS This is a prospective study, the approval dated 07/05/2013, and decision number 2013/153 was received from the Ethical Board for Clinical Research at Selcuk University, Faculty of Medicine. Written informed consents of all patients were obtained. The study included a total of 77 consecutive patients (42 patients with ARC and 35 control subjects), who applied to the Ear Nose and Throat and Ophthalmology Outpatient Clinics during May and June, 2013. Criteria for excluding subjects from this study were as follows: presence of a disorder with the potential to interfere with the blood vitamin D levels (rickets, osteoporosis, etc.); immune system disease potentially modifying blood cytokine levels; usage of steroids in the last one month and antihistamines in the last 15 days; upper respiratory tract infection; acute airway disease like nonallergic eosinophilic rhinitis or drug-induced rhinitis; drug intake with the potential to interfere with the vitamin D levels (anticonvulsants, antacids, ketoconazole, etc.); asthma; and presence of unilateral, isolated polyp. Cases were divided into two different groups: ARC group and healthy subjects (control group). ARC group consisted of 42 ARC patients (15 male, 27 female, range 12–43, average age 25.7 ⫾ 8.6), who have allergic rhinitis symptoms and active allergic conjunctivitis (conjunctival hyperaemia, itching, tearing, chemosis or lid edema) and identified to have an allergy against at least one active agent at skin-prick test were included. Control group consisted of 35 healthy people of similar age and gender (15 male, 20 female, ages between 12 and 44, average age 26.9 ⫾ 9.1), who have normal ocular examination except refractive disorders, without any history of allergic disorders, systemic diseases, or drug consumption and with negative skin-prick test results.
March–April 2015, Vol. 29, No. 2
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Table 1. Demographic of the groups Variables
Allergic Rhino-Conjunctivitis Group
Control Group
15 27 25.7 ⫾ 8.6 12–43
15 20 26.9 ⫾ 9.1 12–44
Sex Male Female Age (median) Age (range)
p Value
Table 2. Allergens variance of the allergic rhino-conjunctivitis group
(0.241) (0.669)
Independent-Samples T-Test, *p ⬍ 0.05 and **p ⬍ 0.01.
Skin-Prick Test Standard allergen extracts of the brand Alyostal ST-IR (Staller Genes S.A., Paris, France) were used for skin-prick tests. Allergen extracts were drawn into Quick test applicators with eight heads and were applied to the skin at the ventral side of the forearm, after the testing site was cleansed with alcohol. We used histamine (1 mg/mL) as a positive control and isotonic NaCl as a negative control. The results were read at the 15th minute after application. Test validity criteria were set as more than 3 mm for positive controls and less than 3 mm for negative controls. A skin reaction with an induration of 3 mm or more was accepted as positive.13 Fourteen common allergens (Dermatophagoides pteronyssinus, Dermatophagoides farina, cockroach, trees mix, grasses mix, pine, cat feather, nuts, penicillium mix, cladosporium, cacao, egg, wheat, alterina) plus a negative and a positive control were applied to the skin of the forearm with two eight-headed applicators.
Biochemical Analysis
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Statistical Analysis
The Number Cruncher Statistical System 2007 and Power Analysis and Sample Size 2008 Statistical Software (Utah) program was employed for evaluating the data gathered in the study. Besides using descriptive statistics (median, standard deviation) in evaluating the data, the Independent-Samples T-Test was used for comparing the quantitative data, for comparing the normally distributed parameters in between groups. The significance level was set at p ⬍ 0.001 and p ⬍ 0.05.
RESULTS
Forty-two patients with ARC (15 male, 27 female) and 35 control subjects (15 male, 20 female) were enrolled in our study. The mean ages of patients with ARC and control subjects were 25.7 ⫾ 8.6 years (range 12–43 years) and 26.9 ⫾ 9.1 years (range 12–44 years), respectively. Independent-Samples test results comparing the mean ages and sex of the two groups did not reveal any statistically significant difference (p ⫽ 0.669 and p ⫽ 0.241, respectively) (Table 1). Forty-two (54.5%) of the 77 patients in groups tested positive for at least one allergen (allergy group), whereas 35 (45.5%) showed no positive skin reaction to any of the allergens (control group) (Table 2). In our cases, symptoms of patients with ARC were listed as redness of the eye (100%), runny nose (50.0%), sneeze (52.3%), stuffiness (38.1%), itching of the nose (33.3%), and nasal discharge (7.1%) (Table 3).
Allergic Rhinitis Group
D. pteronyssinus D. farinae Cockroach Trees mix Grasses mix Pine Cat feather Nuts Penicillium mix Cladosporium Cacao Egg Wheat Alterina
21 (50%) 15 (35.7%) 19 (45.2%) 20 (47.6%) 16 (38.1%) 5 (11.9%) 5 (11.9%) 3 (7.1%) – 2 (4.7%) 5 (11.9%) 8 (19.0%) 5 (11.9%) 2 (4.7%)
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Table 3. Allergic rhinitis symptoms of the allergic rhinoconjunctivitis group Symptoms
Runny nose Sneeze Stuffiness Itching of the nose Nasal discharge
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Fasting venous blood sample was obtained from each subject from the antecubiteal vein into EDTA anticoagulated tubes and serum separator tubes. After centrifugation at 2000 ⫻ g for 15 minutes, plasma samples were aliquoted, labeled and stored at ⫺80°C for a maximum of 30 days until analysis. When we reached the targeted sample size, plasma samples were thawed, and plasma 25-hydroxyvitamin D levels were quantified with electrochemiluminescence technique on Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany). Detection limit for 25-hydroxyvitamin D was 3 ng/mL (7.5nM).
Allergens
Allergic Rhinitis Group 21 (50.0%) 22 (52.3%) 16 (38.1%) 14 (33.3%) 3 (7.1%)
Plasma vitamin D levels of the subjects with ARC group (7.33 ⫾ 3.61 ng/mL, standard error mean: 0.55 range 3.17–13.68 ng/mL) were significantly lower than the control group (13.37 ⫾ 5.42 ng/mL, standard error mean: 0.91, range 6.84– 25.92 ng/mL) (p ⫽ 0.010, Independent-Samples test) (Fig. 1).
DISCUSSION To the best of our knowledge, this is the first study evaluating the relationship between ARC and vitamin D status. Plasma levels of vitamin D in patients with ARC group were significantly lower than the control group (p ⫽ 0.010). These results imply a possibly important role of vitamin D in the pathogenesis of allergic diseases, and its possible role in the treatment of allergic diseases. Skin-prick test is the most commonly used test method for its convenience, easy to use, cheap, reliable features, and low systemic reaction risks.6,12 Therefore, in our study, we chose to use skin-prick tests. Pollens are the most common allergens detected in patients with allergic rhinitis. Studies conducted in different regions of our country supports this finding.14 In our study, the most common allergens found by skin-prick test were D. pteronyssinus (50%), trees mix (47.6%), and cockroach (45.2%), respectively (Table 2). We demonstrated these allergens at the ARC in our region for the first time in the literature. Allergic rhinitis symptoms, such as nasal itching, sneezing, watery nasal discharge, and nasal obstruction, are reversible either spontaneously or with treatment. Headache and olfactory disorders can be seen in patients with allergic rhinitis but may also be related to other diseases. The positive predictive value of symptoms for patients with ARC in our cases were listed as redness of the eye (100%), sneeze (52.3%), runny nose (50.0%), and stuffiness (38.1%), respectively (Table 3). Vitamin D regulates the functions of effector T lymphocytes besides its effect on natural immunity. In in vitro studies, 1, 25-dihydroxyvitamin D3 was shown to inhibit T-cell proliferation and production of
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Figure 1. Plasma vitamin D levels of ARC and control group.
cytokines IL-2 and interferon-␥ by Th1 cells. The effect of vitamin D on the production of cytokines IL-4, IL-5, and IL-13 by Th2 cells is less known. Some studies demonstrate an inhibitory effect of 1, 25-dihydroxyvitamin D3 on CD4⫹ T cells that produce interferon-␥, cause increment of IL-4, IL-5, and IL-10 production and resulting in Th2 response, but other studies demonstrate an inhibitory or no effect of 1, 25-dihydroxyvitamin D3 on IL-4-producing cells, in other words not causing Th2 response. In in vitro studies, it was suggested that the concentration of 1, 25-dihydroxyvitamin D3 may be important in Th2 response and too much or too less vitamin D might initiate an allergic immune response.15 Asthma and allergic diseases are characterized with inflammation, in which Th2-type lymphocyte reaction dominates. Vitamin D deficiency leads smooth muscle contraction, increases airway inflammation, and causes disturbance of prostaglandin regulation by affecting the balance of Th1-Th2.16 It was reported that the risk of asthma and development of allergic rhinitis in children decreased by increasing the intake of vitamin D.17 Vitamin D was reported to both enhance and inhibit the functions of Th2 cells, in different studies.18,19 Also, there is evidence that vitamin D can influence the function of other immunocytes such as B cells and regulatory T cells, which may explain the epidemiologic association between vitamin D deficiency with both autoimmune and allergic diseases.18,19 Supportively, we found an association between low vitamin D levels and ARC in this present study. There are several studies in the literature describing the relationship between allergic diseases and vitamin D. Sharief et al. investigated the link between vitamin D deficiency and allergy in children and adolescents. The authors reported a correlation between vitamin D deficiency and increased risk of allergy.20 Ehlayel et al. reported an increased prevalence of vitamin D deficiency among children with asthma, allergic rhinitis, atopic dermatitis, acute urticaria, or food allergy.21 Wjst et al. reported an increased prevalence of allergic rhinitis in vitamin D-deficient subjects in a study, including 18,224 adults.22 Wang et al. reported a significantly lower vitamin D level was found in chronic rhino sinusitis with nasal polyposis in Taiwan.23 Ryoo et al. reported Serum 25-hydroxy vitamin D concentrations are inversely associated with the waning of pneumococcal antibody titers over time, especially individuals with asthma and other atopy conditions.24
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Also, there are several case-control studies demonstrating lower vitamin D levels in allergic patients when compared with controls.25,26 In a previous study of us, we found lower vitamin D levels in patients with seasonal allergic conjunctivitis.25 In another case-control study, vitamin D was reported to be effective on Th1/Th2 balance in patients with allergic rhinitis, and vitamin D deficiency was found to be related with allergy.26 Ours is a preliminary study describing the relationship between vitamin D status and ARC. The results of our study suggest that the vitamin D deficiency is related with the ARC response. In our study, the sample size was small, so studies with larger number of patients are needed to confirm our findings. Accordingly, supplementation of vitamin D might be considered for the treatment of patients with ARC, in case of vitamin D deficiency.
CONCLUSION We demonstrated lower plasma vitamin D levels in patients with ARC when compared with the control group. To the best of our knowledge, this is the first study demonstrating the relationship between low vitamin D levels and ARC. Further studies are necessary to determine the effects of vitamin D administration for treatment of ARC, as well as the dose and duration of treatment. Also, more advanced studies are necessary to fully clarify the mechanism of action of vitamin D in ARC.
REFERENCES 1.
2. 3. 4. 5.
Brozek JL, Bousquet J, Baena-Cagnani CE, et al., Global Allergy and Asthma European Network, Grading of Recommendations Assessment, Development and Evaluation Working Group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 126:466–476, 2010. Bauchau V, and Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J 24:758–764, 2004. Bauchau V, and Durham SR. Epidemiological characterization of the intermittent and persistent types of allergic rhinitis. Allergy 60:350–353, 2005. Bielory L, and Friedlaender MH. Allergic conjunctivitis. Immunol Allergy Clin North Am 28:43–58, vi, 2008. Rosario N, and Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin Allergy Clin Immunol 11:471–476, 2011.
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Delivered by Ingenta to: Economics Dept IP: 79.110.18.229 On: Tue, 28 Jun 2016 19:33:48 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
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Bousquet J, Van Cauwenberge P, and Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy ClinImmunol 108:148–334, 2001. Majani G, Baiardini I, Giardini A, et al. Health-related quality of life assessment in young adults with seasonal allergic rhinitis. Allergy 56:313–317, 2001. Wjst M, and Dold S. Genes, factor X, and allergens: What causes allergic diseases? Allergy 54:757–759, 1999. Zittermann A, Dembinski J, and Stehle P. Low vitamin D status is associated with low cord blood levels of the immunosuppressive cytokine interleukin-10. Pediatr Allergy Immunol 15:242–246, 2004. Camargo CA Jr, Clark S, Kaplan MS, et al. Regional differences in EpiPen prescriptions in the United States: The potential role of vitamin D. J Allergy Clin Immunol 120:131–136, 2007. Thacher TD, and Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 86:50–60, 2011. Li JT, Andrist D, Bamlet WR, and Wolter TD. Accuracy of patient prediction of allergy skin test results. Ann Allergy Asthma Immunol 85:382–384, 2000. Cakır Edis E, Tabakog˘lu E, Caglar T, et al. Skin prick test results in patients from Thrace region presenting with pulmonary symptoms. Balkan Med J 24:12–16, 2007. Cingi C, Topuz B, Songu M, et al. Prevalence of allergic rhinitis among the adult population in Turkey. Acta Otolaryngol 130:600– 606, 2010. Dimeloe S, Nanzer A, Ryanna K, and Hawrylowicz C. Regulatory T cells, inflammation and the allergic response-The role of glucocorticoids and vitamin D. J Steroid Biochem Mol Biol 120:86–95, 2010. Sutherland ER, Goleva E, and Jackson LP. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med 181:699–704, 2010.
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Erkkola M, Kaila M, and Nwaru B. Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children. Clin Exp Allergy 39:875–882, 2009. Litonjua AA, and Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 120:1031–1035, 2007. Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 76:315–325, 2012. Sharief S, Jariwala S, Kumar J, et al. Vitamin D levels and food and environmental allergies in the United States: Results from the National Health and Nutrition Examination Survey 2005–2006. J Allergy Clin Immunol 127:1195–1202, 2011. Ehlayel MS, Bener A, and Sabbah A. Is high prevalence of vitamin D deficiency evidence for asthma and allergy risks? Eur Ann Allergy Clin Immunol 43:81–88, 2011. Wjst M, and Hyppo¨nen E. Vitamin D serum levels and allergic rhinitis. Allergy 62:1085–1086, 2007. Wang LF, Lee CH, Chien CY, et al. Serum 25-hydroxyvitamin D levels are lower in chronic rhinosinusitis with nasal polyposis and are correlated with disease severity in Taiwanese patients. Am J Rhinol Allergy 27:162–165, 2013. Ryoo E, Kumar R, Kita H, and Juhn YJ. Serum 25-hydroxyvitamin D concentrations and waning pneumococcal antibody titers among individuals with atopy. Allergy Asthma Proc 34:370–377, 2013. Dadaci Z, Borazan M, Kiyici A, et al. Plasma vitamin D and serum total immunoglobulin E levels in patients with seasonal allergic conjunctivitis. Acta Ophthalmol 92:443–446, 2014. Ozkara S, Keles E, Ilhan N, et al. The relationship between Th1/Th2 balance and 1a, 25- dihydroxyvitamin D3 in patients with nasal polyposis. Eur Arch Otorhinolaryngol 269:2519–2524, 2012. e
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American Journal of Rhinology & Allergy
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e49
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ABSTRACT
Background: Allergic rhino-conjunctivitis (ARC) and allergic rhinitis are inflammatory diseases that develop through immunoglobulin E in the rhino-ocular mucosa due to allergy. The main symptoms are runny nose, nasal congestion, sneezing, itchy nose, and conjunctivitis. Objective: This study was designed to evaluate plasma 25-hydroxyvitamin D levels in patients with ARC. Study design: This study was planned as a prospective and cross sectional study. This study was performed in a tertiary referral center. Methods: This observational study involved 42 patients with ARC and 35 consecutive, age- and sex-matched healthy subjects. Patients in both groups underwent skin-prick test. Plasma 25-hydroxyvitamin D levels of all subjects were quantified with electrochemiluminescence technique. Results were compared between the groups and p ⬍ 0.05 was considered as statistically significant. Results: Group one included 42 ARC patients (15 male, 27 female, ages between 12 and 43, average age 25.7 ⫾ 8.6); group two included 35 healthy people (15 male, 20 female, ages between 12 and 44, average age 26.9 ⫾ 9.1). Plasma 25-hydroxyvitamin D levels of the subjects with ARC group (7.33 ⫾ 3.61 ng/mL, standard error mean: 0.55, range 3.17–13.68 ng/mL) were significantly lower than the control group (13.37 ⫾ 5.42 ng/mL, standard error mean: 0.91, range 6.84 –25.92 ng/mL) (p ⫽ 0.010, Independent-Samples test). Conclusions: We found lower plasma vitamin D levels in patients with ARC when compared with the control group. (Am J Rhinol Allergy 29, e46 –e49, 2015; doi: 10.2500/ajra.2015.29.4164)
A
llergic rhinitis is defined clinically by the symptoms caused by immunologically mediated (most often immunoglobulin E dependent) inflammation after the exposure of the nasal mucous membranes to offending allergens. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction or blockage, nasal itching, sneezing, and postnasal drip that reverse spontaneously or after treatment. Allergic conjunctivitis often accompanies allergic rhinitis.1 The prevalence of allergic rhinitis in the general population of Europe has been reported to be around 25%.2,3 Allergic conjunctivitis is inflammation of the conjunctiva (the mucous membrane that lines the inner surface of the eyelids and is continued over the forepart of the eyeball) due to allergy.4 Allergic conjunctivitis is also frequently associated with other allergic diseases, especially allergic rhinitis.5 When combined with rhinitis, the condition is termed as allergic rhino-conjunctivitis (ARC). ARC is an inflammatory disease that develops through immunoglobulin E in the rhino-ocular mucosa. ARC is a frequently encountered and chronic disease with an increasing incidence.6 Besides physical complaints, it has an adverse effect on quality of life by causing social and psychological distresses.7 Because 25-hydroxy vitamin D serum levels are low in allergic individuals and vitamin D influences allergy-mediating immune cells such as T cells and the immune functions of cells forming the barriers against allergens such as epithelial cells, one might speculate that vitamin D plays a role in allergy development.8 In 2004, Zitterman et al. suggested that vitamin D deficiency has an effect on allergy risk depending on their observation of the association between low vitamin D status and low cord blood levels of the tolerogenic cytokine interleukin-10 (IL-10).9 Furthermore, Camargo et al. suggested that regional differences in vitamin D status were responsible for the strong north-south gradient for the prescription of EpiPens as emergency treatment for severe allergic reactions in the United States.10
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1 Konya Hospital, Otorhinolaryngology Clinic, Konya, Turkey, 2Department of Ophthalmology, Faculty of Medicine, Mevlana University, Konya, Turkey, and 3Department of Biochemistry, Faculty of Medicine, Mevlana University, Konya, Turkey The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Alper Yenigun, M.D., Otorhinolaryngology Clinic, Konya Hospital, Semsi Tebrizi District, Serafettin Street, No. 95, 42080, Karatay-Konya, Turkey E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
e46
Thacher et al. suggested that increased vitamin D levels affect the incidence and the course of allergic disease.11 Although clinical findings are essential for diagnosis, skin tests are the most common methods for determining the allergy and identifying the responsible allergen, and they have become the golden standard for diagnosis.12 We aimed to investigate plasma vitamin D levels of patients with ARC and compare with normal subjects.
T
O N
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MATERIALS AND METHODS This is a prospective study, the approval dated 07/05/2013, and decision number 2013/153 was received from the Ethical Board for Clinical Research at Selcuk University, Faculty of Medicine. Written informed consents of all patients were obtained. The study included a total of 77 consecutive patients (42 patients with ARC and 35 control subjects), who applied to the Ear Nose and Throat and Ophthalmology Outpatient Clinics during May and June, 2013. Criteria for excluding subjects from this study were as follows: presence of a disorder with the potential to interfere with the blood vitamin D levels (rickets, osteoporosis, etc.); immune system disease potentially modifying blood cytokine levels; usage of steroids in the last one month and antihistamines in the last 15 days; upper respiratory tract infection; acute airway disease like nonallergic eosinophilic rhinitis or drug-induced rhinitis; drug intake with the potential to interfere with the vitamin D levels (anticonvulsants, antacids, ketoconazole, etc.); asthma; and presence of unilateral, isolated polyp. Cases were divided into two different groups: ARC group and healthy subjects (control group). ARC group consisted of 42 ARC patients (15 male, 27 female, range 12–43, average age 25.7 ⫾ 8.6), who have allergic rhinitis symptoms and active allergic conjunctivitis (conjunctival hyperaemia, itching, tearing, chemosis or lid edema) and identified to have an allergy against at least one active agent at skin-prick test were included. Control group consisted of 35 healthy people of similar age and gender (15 male, 20 female, ages between 12 and 44, average age 26.9 ⫾ 9.1), who have normal ocular examination except refractive disorders, without any history of allergic disorders, systemic diseases, or drug consumption and with negative skin-prick test results.
March–April 2015, Vol. 29, No. 2
Delivered by Ingenta to: Economics Dept IP: 79.110.18.229 On: Tue, 28 Jun 2016 19:33:48 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm
Table 1. Demographic of the groups Variables
Allergic Rhino-Conjunctivitis Group
Control Group
15 27 25.7 ⫾ 8.6 12–43
15 20 26.9 ⫾ 9.1 12–44
Sex Male Female Age (median) Age (range)
p Value
Table 2. Allergens variance of the allergic rhino-conjunctivitis group
(0.241) (0.669)
Independent-Samples T-Test, *p ⬍ 0.05 and **p ⬍ 0.01.
Skin-Prick Test Standard allergen extracts of the brand Alyostal ST-IR (Staller Genes S.A., Paris, France) were used for skin-prick tests. Allergen extracts were drawn into Quick test applicators with eight heads and were applied to the skin at the ventral side of the forearm, after the testing site was cleansed with alcohol. We used histamine (1 mg/mL) as a positive control and isotonic NaCl as a negative control. The results were read at the 15th minute after application. Test validity criteria were set as more than 3 mm for positive controls and less than 3 mm for negative controls. A skin reaction with an induration of 3 mm or more was accepted as positive.13 Fourteen common allergens (Dermatophagoides pteronyssinus, Dermatophagoides farina, cockroach, trees mix, grasses mix, pine, cat feather, nuts, penicillium mix, cladosporium, cacao, egg, wheat, alterina) plus a negative and a positive control were applied to the skin of the forearm with two eight-headed applicators.
Biochemical Analysis
O D
Statistical Analysis
The Number Cruncher Statistical System 2007 and Power Analysis and Sample Size 2008 Statistical Software (Utah) program was employed for evaluating the data gathered in the study. Besides using descriptive statistics (median, standard deviation) in evaluating the data, the Independent-Samples T-Test was used for comparing the quantitative data, for comparing the normally distributed parameters in between groups. The significance level was set at p ⬍ 0.001 and p ⬍ 0.05.
RESULTS
Forty-two patients with ARC (15 male, 27 female) and 35 control subjects (15 male, 20 female) were enrolled in our study. The mean ages of patients with ARC and control subjects were 25.7 ⫾ 8.6 years (range 12–43 years) and 26.9 ⫾ 9.1 years (range 12–44 years), respectively. Independent-Samples test results comparing the mean ages and sex of the two groups did not reveal any statistically significant difference (p ⫽ 0.669 and p ⫽ 0.241, respectively) (Table 1). Forty-two (54.5%) of the 77 patients in groups tested positive for at least one allergen (allergy group), whereas 35 (45.5%) showed no positive skin reaction to any of the allergens (control group) (Table 2). In our cases, symptoms of patients with ARC were listed as redness of the eye (100%), runny nose (50.0%), sneeze (52.3%), stuffiness (38.1%), itching of the nose (33.3%), and nasal discharge (7.1%) (Table 3).
Allergic Rhinitis Group
D. pteronyssinus D. farinae Cockroach Trees mix Grasses mix Pine Cat feather Nuts Penicillium mix Cladosporium Cacao Egg Wheat Alterina
21 (50%) 15 (35.7%) 19 (45.2%) 20 (47.6%) 16 (38.1%) 5 (11.9%) 5 (11.9%) 3 (7.1%) – 2 (4.7%) 5 (11.9%) 8 (19.0%) 5 (11.9%) 2 (4.7%)
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Table 3. Allergic rhinitis symptoms of the allergic rhinoconjunctivitis group Symptoms
Runny nose Sneeze Stuffiness Itching of the nose Nasal discharge
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Fasting venous blood sample was obtained from each subject from the antecubiteal vein into EDTA anticoagulated tubes and serum separator tubes. After centrifugation at 2000 ⫻ g for 15 minutes, plasma samples were aliquoted, labeled and stored at ⫺80°C for a maximum of 30 days until analysis. When we reached the targeted sample size, plasma samples were thawed, and plasma 25-hydroxyvitamin D levels were quantified with electrochemiluminescence technique on Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany). Detection limit for 25-hydroxyvitamin D was 3 ng/mL (7.5nM).
Allergens
Allergic Rhinitis Group 21 (50.0%) 22 (52.3%) 16 (38.1%) 14 (33.3%) 3 (7.1%)
Plasma vitamin D levels of the subjects with ARC group (7.33 ⫾ 3.61 ng/mL, standard error mean: 0.55 range 3.17–13.68 ng/mL) were significantly lower than the control group (13.37 ⫾ 5.42 ng/mL, standard error mean: 0.91, range 6.84– 25.92 ng/mL) (p ⫽ 0.010, Independent-Samples test) (Fig. 1).
DISCUSSION To the best of our knowledge, this is the first study evaluating the relationship between ARC and vitamin D status. Plasma levels of vitamin D in patients with ARC group were significantly lower than the control group (p ⫽ 0.010). These results imply a possibly important role of vitamin D in the pathogenesis of allergic diseases, and its possible role in the treatment of allergic diseases. Skin-prick test is the most commonly used test method for its convenience, easy to use, cheap, reliable features, and low systemic reaction risks.6,12 Therefore, in our study, we chose to use skin-prick tests. Pollens are the most common allergens detected in patients with allergic rhinitis. Studies conducted in different regions of our country supports this finding.14 In our study, the most common allergens found by skin-prick test were D. pteronyssinus (50%), trees mix (47.6%), and cockroach (45.2%), respectively (Table 2). We demonstrated these allergens at the ARC in our region for the first time in the literature. Allergic rhinitis symptoms, such as nasal itching, sneezing, watery nasal discharge, and nasal obstruction, are reversible either spontaneously or with treatment. Headache and olfactory disorders can be seen in patients with allergic rhinitis but may also be related to other diseases. The positive predictive value of symptoms for patients with ARC in our cases were listed as redness of the eye (100%), sneeze (52.3%), runny nose (50.0%), and stuffiness (38.1%), respectively (Table 3). Vitamin D regulates the functions of effector T lymphocytes besides its effect on natural immunity. In in vitro studies, 1, 25-dihydroxyvitamin D3 was shown to inhibit T-cell proliferation and production of
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Figure 1. Plasma vitamin D levels of ARC and control group.
cytokines IL-2 and interferon-␥ by Th1 cells. The effect of vitamin D on the production of cytokines IL-4, IL-5, and IL-13 by Th2 cells is less known. Some studies demonstrate an inhibitory effect of 1, 25-dihydroxyvitamin D3 on CD4⫹ T cells that produce interferon-␥, cause increment of IL-4, IL-5, and IL-10 production and resulting in Th2 response, but other studies demonstrate an inhibitory or no effect of 1, 25-dihydroxyvitamin D3 on IL-4-producing cells, in other words not causing Th2 response. In in vitro studies, it was suggested that the concentration of 1, 25-dihydroxyvitamin D3 may be important in Th2 response and too much or too less vitamin D might initiate an allergic immune response.15 Asthma and allergic diseases are characterized with inflammation, in which Th2-type lymphocyte reaction dominates. Vitamin D deficiency leads smooth muscle contraction, increases airway inflammation, and causes disturbance of prostaglandin regulation by affecting the balance of Th1-Th2.16 It was reported that the risk of asthma and development of allergic rhinitis in children decreased by increasing the intake of vitamin D.17 Vitamin D was reported to both enhance and inhibit the functions of Th2 cells, in different studies.18,19 Also, there is evidence that vitamin D can influence the function of other immunocytes such as B cells and regulatory T cells, which may explain the epidemiologic association between vitamin D deficiency with both autoimmune and allergic diseases.18,19 Supportively, we found an association between low vitamin D levels and ARC in this present study. There are several studies in the literature describing the relationship between allergic diseases and vitamin D. Sharief et al. investigated the link between vitamin D deficiency and allergy in children and adolescents. The authors reported a correlation between vitamin D deficiency and increased risk of allergy.20 Ehlayel et al. reported an increased prevalence of vitamin D deficiency among children with asthma, allergic rhinitis, atopic dermatitis, acute urticaria, or food allergy.21 Wjst et al. reported an increased prevalence of allergic rhinitis in vitamin D-deficient subjects in a study, including 18,224 adults.22 Wang et al. reported a significantly lower vitamin D level was found in chronic rhino sinusitis with nasal polyposis in Taiwan.23 Ryoo et al. reported Serum 25-hydroxy vitamin D concentrations are inversely associated with the waning of pneumococcal antibody titers over time, especially individuals with asthma and other atopy conditions.24
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Also, there are several case-control studies demonstrating lower vitamin D levels in allergic patients when compared with controls.25,26 In a previous study of us, we found lower vitamin D levels in patients with seasonal allergic conjunctivitis.25 In another case-control study, vitamin D was reported to be effective on Th1/Th2 balance in patients with allergic rhinitis, and vitamin D deficiency was found to be related with allergy.26 Ours is a preliminary study describing the relationship between vitamin D status and ARC. The results of our study suggest that the vitamin D deficiency is related with the ARC response. In our study, the sample size was small, so studies with larger number of patients are needed to confirm our findings. Accordingly, supplementation of vitamin D might be considered for the treatment of patients with ARC, in case of vitamin D deficiency.
CONCLUSION We demonstrated lower plasma vitamin D levels in patients with ARC when compared with the control group. To the best of our knowledge, this is the first study demonstrating the relationship between low vitamin D levels and ARC. Further studies are necessary to determine the effects of vitamin D administration for treatment of ARC, as well as the dose and duration of treatment. Also, more advanced studies are necessary to fully clarify the mechanism of action of vitamin D in ARC.
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