==== Front Dent J (Basel) Dent J (Basel) dentistry Dentistry Journal 2304-6767 MDPI 33096916 10.3390/dj8040121 dentistry-08-00121 Article Association between Vitamin D and Candida-Associated Denture Stomatitis Muhvić-Urek Miranda 12* Saltović Ema 2 Braut Alen 23 Kovačević Pavičić Daniela 24 1 Department of Oral Medicine and Periodontology, Faculty of Dental Medicine, University of Rijeka, Kresimirova 40, 51 000 Rijeka, Croatia 2 Dental Clinic, Clinical Hospital Center Rijeka, Kresimirova 40, 51 000 Rijeka, Croatia; ema.saltovic@medri.uniri.hr (E.S.); alen.braut@fdmri.uniri.hr (A.B.); daniela.kovacevic@fdmri.uniri.hr (D.K.P.) 3 Department of Restorative Dentistry and Endodontics, Faculty of Dental Medicine, University of Rijeka, Kresimirova 40, 51 000 Rijeka, Croatia 4 Department of Prosthodontics, Faculty of Dental Medicine, University of Rijeka, Kresimirova 40, 51 000 Rijeka, Croatia * Correspondence: miranda.muhvic.urek@fdmri.uniri.hr 21 10 2020 12 2020 8 4 12121 7 2020 14 10 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Candida-associated denture stomatitis (CADS) is a fungal infection affecting 60–65% of denture wearers. Its etiology is complex and multifactorial and often associated with host immunodeficiency. Evidence exists that vitamin D has potential immunomodulatory and anti-inflammatory effects. The aim of this case–control study was to assess the association between vitamin D levels and CADS. The study included 32 complete denture wearers with CADS and 32 sex- and age-matched complete denture wearers without CADS. The patients were clinically examined, and the severity of denture stomatitis was assessed according to Newton’s classification scale. The serum vitamin D level was determined via the use of an electrochemiluminescence assay. The vitamin D level in the CADS group and control group was 54.68 ± 17.07 and 56.82 ± 17.75 nmol/L, respectively. There was no significant difference between the groups (p = 0.622). Univariate logistic regression analysis showed that the presence of CADS was not associated with hypovitaminosis D (odds ratio (OR) = 1.44; 95% confidence interval (CI) = 0.37–5.54). It can be concluded that vitamin D is not associated with CADS and does not play a significant role in host susceptibility to CADS. This finding suggests that vitamin D screening is not indicated routinely in patients with Candida-associated denture stomatitis. 25-hydroxyvitamin Dcandidiasisoralstomatitisdenturevitamin D ==== Body 1. Introduction Candida-associated denture stomatitis (CADS) is a fungal infection of the oral mucosa occurring beneath dentures [1]. It is considered a Candida-associated lesion, together with angular cheilitis and median rhomboid glossitis [2,3]. Its main feature is that antifungal therapy alone does not cure this condition, and the removal/treatment of predisposing factors must be included [2]. CADS has been found to occur in 60–65% of denture wearers [4]. Although Candida (C.) albicans has been identified as the primary pathogen of CADS, other species such as C. glabrata, C. tropicalis, and C. parapsilosis have been found less frequently [5,6]. According to published data, CADS is the most common form of candidiasis [7]. It presents itself as erythema and inflammatory hyperplasia of the mucosa. Newton [8] classified denture stomatitis in 1962 into three types: punctiform hyperemia (Type I), diffuse hyperemia (Type II), and granular hyperemia (Type III). The changes can be manifested in the partial and complete denture wearers and occur more often in the maxilla. The etiology of CADS is complex and multifactorial. Several local and systemic predisposing factors may convert Candida from normal commensal flora (saprophytic stage) to a pathogenic form, leading to disease onset [4,9,10]. Local factors such as dry mouth, local trauma, complete denture wearing, poor denture hygiene, continuous denture wearing, ill-fitting dentures, carbohydrate-rich diets, and acidic salivary pH favor biofilm accumulation in the oral environment and promote the growth of Candida species (spp.), and affect the immune response of oral mucosa [3,4,9,11,12]. On the other hand, systemic factors such as diabetes mellitus, immunosuppression (e.g., chemotherapy, corticosteroids, immunosuppressive drugs, and biological therapies), immunodeficiencies (e.g., HIV infection, acute leukemia and agranulocytosis), nutrition and hematinic deficiencies (e.g., iron, folate, and B12) can have an impact on host defense mechanisms [3,4]. In some cases, despite antimycotic drug use and the removal or treatment of predisposing factors, CADS persists or reactivates [13]. More research pertaining to the identification of potential new local and systematic predisposing factors is, therefore, needed. Apart from having a major role in mineral metabolism (calcium and phosphate) and bone health, vitamin D plays a role in preventing malignancies, infectious diseases, and chronic inflammatory diseases [14,15,16]. It maintains oral health by controlling bone loss, decreasing bone resorption, as well as preventing infectious and inflammatory disease [14]. Vitamin D has immunomodulatory effects and affects both the innate and adaptive immune systems [15]. Its antimicrobial (antibacterial, antiviral, and antifungal) effects are achieved through various immune cells such as lymphocytes B, lymphocytes T, monocytes, macrophages, and neutrophils [15,17,18], as well as the stimulation of antimicrobial protein secretion [17]. The amount of available data related to vitamin D and fungal infection is low when compared to how it is involved in bacterial and viral infections [17]; furthermore, the clinical data pool concerning these matters is small. The aim of this case–control study was to assess the association between vitamin D levels and Candida-associated denture stomatitis. 2. Materials and Methods 2.1. Subjects The study comprised 32 Caucasian complete denture wearers with CADS and 32 sex- and age-matched control subjects (complete denture wearers without any signs of CADS). All participants were patients at the Department of Oral Medicine and at the Department of Prosthodontics at the Dental Clinic, Clinical Hospital Center Rijeka. The inclusion criteria were presence of upper complete denture and first dental visit to our departments. The exclusion criteria were vitamin D replacement therapy, systemic or topical anti-fungal therapy, and/or oral mouthwashes received in the preceding month. The sample size calculation was based on previous study that evaluated the serum vitamin D level in patients with periodontitis [19], where the vitamin D levels in experimental and control groups were 41.9 ± 16.3 and 56.9 ± 14.2 ng/L, respectively. A total of 19 patients in each group were necessary to reach 80% of statistical power and alpha 0.05. 2.2. Questionnaire The participants were interviewed using a questionnaire that included information about age, gender, and prescribed medications. 2.3. Clinical Examination The clinical data were collected while the patient was seated in a dental chair illuminated with professional dental light and using a set of standard dental instruments. The intraoral examinations were performed by the one of the authors (M.M.-U.). A diagnosis of CADS was made on the basis of clinical features stated in World Health Organization guidelines [20], Burket’s Oral Medicine textbook [3], and microbiological analyses. The clinical severity of denture stomatitis was graded according the Newton’s classification scale into Type I, Type II, and Type III [8]. 2.4. Cultivation and Identification of Candida spp. Swabs were taken from participants’ palatal mucosa using sterile swab sticks. The material was cultivated on Sabouraud dextrose agar for 72 h at 37 °C. Candida spp. was identified based on germ-tube formation, chlamydospore production, and carbohydrate assimilation using the API ID 32C system (bioMerieux, Marcy l’Etoile, France) [21,22,23]. 2.5. Serum Vitamin D Measurement Venous blood sample (3.5 mL) was collected in serum separator tubes in the hospital laboratory by a medical professional. After clotting, the serum was centrifuged at 2000× g for 10 min. The total vitamin D level was determined using a Roche Elecsys Vitamin D total electrochemiluminescence assay and a Cobas e601 analyzer (Roche Diagnostics GmbH, Manheim, Germany). The measuring range of the test was 7.50–175 nmol/L. Intra-assay and inter-assay coefficients of variation were below 5%. According to vitamin D levels, participants were categorized into four groups: vitamin D sufficient (>75 nmol/L), vitamin D insufficient (>50–≤75 nmol/L) and moderately (>25–≤50 nmol/L) or severely (≤25 nmol/L) vitamin D deficient [24]. 2.6. Ethical Considerations The study protocol was approved by the Ethics Committee of the Clinical Hospital Center Rijeka (Ethical approval code 003-05/20-1/41, Project identification code uniri-biomed-18-65, approval date 10 April 2020). Ethical guidelines set forth in the Declaration of Helsinki were followed. All participants gave their informed consent prior to being included in the study. 2.7. Statistical Analysis Statistical analysis of data was performed using Statistica for Windows, version 12.7 (StatSoft, Inc., Tulsa, OK, USA). The Kolmogorov–Smirnov normality test was applied to data. The Student’s t- and Kruskal–Wallis ANOVA tests were applied to analyze age and vitamin D level differences between groups. Chi-square and Fisher’s exact tests were used to compare the differences for categorical values. In order to establish the association between the hypovitaminosis D and CADS, the odds ratio (OR) and its 95% confidence interval (CI) were calculated using a logistic regression model. A p value of <0.05 was considered statistically significant. 3. Results 3.1. Demographic Data The demographic data of participants are shown in Table 1. There were no differences based on gender and age between the groups (p > 0.05 each). Women were more represented than men (female:male ratio, 3.6:1). 3.2. Candidal Infection and the Severity of Denture Stomatitis C. albicans was isolated in 30 (93.73%) patients, while C. glabrata was isolated in two (6.26%) patients with CADS. Clinically, according the Newton’s classification scale, Type II was the most prevalent type and presented in 17 (53.12%) patients, followed by Type III and Type I (Figure 1). 3.3. Serum Vitamin D Level The mean value (±standard deviation) of vitamin D level in patients with CADS was 54.68 (±17.07) nmol/L and in control subjects it was 56.82 (±17.75) nmol/L. There was no significant difference between groups (p = 0.622). In both groups, female participants had lower vitamin D levels than the male participants, but no statistically significant difference was found (Table 2). Furthermore, there was no statistically significant difference between the groups in terms of vitamin D level being affected by denture stomatitis severity (Table 3). 3.4. Vitamin D Status Table 4 presents data related to vitamin D status for both of the investigated groups. In the group of patients with CADS, hypovitaminosis D was found in 27 (84.37%) participants. In the control group, hypovitaminosis D was found in 26 (81.25%) participants. Univariate logistic regression analysis showed that the presence of CADS was not associated with hypovitaminosis D (OR = 1.44; 95% CI = 0.37–5.54). According to gender, in CADS group three women (12%) had normal levels of vitamin D; eight women (32%) had insufficient levels; and 14 (56%) had a deficiency. In the control group, three women (12%) had normal levels of vitamin D, 10 (40%) had insufficient levels, and 12 (48%) had a deficiency. No statistically significant difference was found in terms of vitamin D status between female participants depending on the presence of fungal infection (p = 0.83). In the group of men with CADS, two (28.57%) men had normal levels, three (42.86%) had an insufficient level, and two (28.57%) had a vitamin D deficiency. In the control group of men, three (42.86%) men had normal levels, two (28.57%) had insufficient levels, and two (28.57%) had a vitamin D deficiency. No significant difference in vitamin D status was found between these groups (p = 0.82). 4. Discussion Vitamin D deficiency is associated with numerous adverse health outcomes [25,26]. Patients with vitamin D deficiency have an increased risk of developing skeletal diseases (e.g., rickets, osteopenia, and osteoporosis) [26,27], cardiovascular diseases (e.g., hypertension, myocardial infarction, and stroke) [25,28,29], autoimmune diseases (e.g., inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes mellitus Type I) [25,30,31,32], cancers (e.g., leukemia, squamous cell carcinoma, breast cancer, and bowel carcinoma) [25,33,34] and infectious diseases (e.g., tuberculosis, viral respiratory infections, and sepsis) [17,25,35,36]. Nowadays, many ongoing studies have set their aim on discovering the association between vitamin D and Coronavirus disease 2019 (COVID-19), i.e., its possible role in the prevention and risk of development this disease [37,38]. However, no clear correlation was found yet on the association between hypovitaminosis D and COVID-19. In the oral cavity, vitamin D plays an important role in the maintenance of oral health by maintaining bone mass, preventing gingivitis, periodontitis, dental caries and tooth loss, and preventing the onset of malignant and infectious diseases by stimulating immunity and through its antimicrobial properties [39,40,41,42]. Antonoglou et al. [19] presented a low serum level of 1.25(OH)2D in patients with chronic periodontitis. The same group of researchers demonstrated that periodontal therapy increases the serum levels of vitamin D in patients with diabetes mellitus Type 1 [43]. It is considered that vitamin D reduces the likelihood of gingivitis, due to its anti-inflammatory action [39]. Vitamin D insufficiency through its negative influences on the density of alveolar bone and the immune system, contributes to infection and inflammation, which lead to periodontitis. Studies have shown that vitamin D has an antifungal effect by stimulating keratinocytes and macrophages [44] and via the production of antimicrobial proteins such as cathelicidin [45,46] and beta-defensins [47]. Candidiasis is the most common oral fungal infection, particularly in immunocompromised patients, the elderly, and denture wearers. Sroussi et al. [48] determined that vitamin D deficiency is an important predictor for the onset of oral candidiasis in patients with HIV infection. They also determined that vitamin D inversely affects calprotectin, an antimicrobial and immune regulatory protein complex that influences neutrophil function and inhibit its oxidative functions. A recently published study by Lim et al. [18] suggests that candidemic patients have lower vitamin D concentrations than hospitalized patients and healthy subjects. The hypothesis for this study was that the hypovitaminosis D in patients with dentures is one of predisposing factors for onset of CADS. To the best of our knowledge, this is the first study that investigated serum vitamin D level in patients with CADS. We determined that patients with CADS do not have significantly lower vitamin D serum levels compared to control subjects. However, the female subjects of both groups had lower vitamin D serum levels than their male counterparts, a finding supported by other authors [49,50,51]. We also found a trend toward lower serum vitamin D level with increasing CADS severity. This finding is suggestive of an immunomodulatory role of vitamin D in severe types of CADS. In order to confirm this finding, a larger sample size is needed. There are contradictory data for the influence of vitamin D in the treatment of fungal infections. Bonilla [52] described, in 1954, three clinical cases of severe refractory chromoblastomycosis, where treatment with 600,000 IU of calciferol led to the significant improvement of cutaneous lesions. Cantorna et al. [53] published data showing that vitamin D had no effect on systemic candidiasis. In an experimental study using a mouse model, Lim et al. [18] indicated the therapeutic effect of vitamin D in the treatment of systematic candidiasis, depending on dose. A low dosage had the best results, while high doses were not effective and even suppressed the mice’s immune responses. The limitation of this study is small number of participants especially male participants. Studies with a larger sample size may clarify the association of lower vitamin D level and severe types of CADS and bring up more accurate findings. Future studies are still warranted for discovering other predisposing factors for CADS occurrence, as well as the role of vitamin D in other types of Candida infections. 5. Conclusions It can be concluded that vitamin D has no significant role in terms of being a systemic, predisposing factor in fungal infection that occurs among denture wearers. This indicates that vitamin D determination during the diagnostics and treatment of Candida-associated denture stomatitis is not necessary. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author Contributions Conceptualization, M.M.-U. and D.K.P.; methodology, M.M.-U. and D.K.P.; investigation, M.M.-U. and E.S.; data curation, E.S.; writing—original draft preparation, M.M.-U. and A.B.; writing—review and editing, M.M.-U. and E.S.; supervision, D.K.P. and A.B. All authors have read and agreed to the published version of the manuscript. Funding This work has been fully supported by the University of Rijeka under the project number uniri-biomed-18-65. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Severity of denture stomatitis in patients with Candida-associated denture stomatitis. dentistry-08-00121-t001_Table 1Table 1 Demographic data of subjects in Candida-associated denture stomatitis and control groups. Demographic Data Groups p Value CADS Control Gender Female/n (%) 25 (78.13) 25 (78.13) p = 1 * Male/n (%) 7 (21.87) 7 (21.87) Age/years Average 68.9 68.9 p = 1 ** Standard deviation 8.4 8.4 Min. 53 53 Max. 83 83 CADS, Candida-associated denture stomatitis. * Chi-square test. ** Student’s t-test. dentistry-08-00121-t002_Table 2Table 2 Serum vitamin D level according the groups and gender. Groups CADS Control p Value (n = 32) (n = 32) Vitamin D/nmol/L mean ± SD 54.68 ± 17.07 56.82 ± 17.75 p = 0.622 * 95% CI 48.53–60.83 50.49–63.14 median female male female male (5th–95th percentile) (n = 25) (n = 7) (n = 25) (n = 7) 48.2 69.7 51.2 66.57 p = 0.16 ** (30.4–78.8) (42.1–83.7) (30.4–78.5) (41–98.2) CADS, Candida-associated denture stomatitis; CI, confidence interval. * Student’s t-test. ** Kruskal–Wallis ANOVA test. dentistry-08-00121-t003_Table 3Table 3 Serum vitamin D level depending on denture stomatitis severity. Groups p Value Type I DS Type II DS Type III DS Control (n = 7) (n = 17) (n = 8) (n = 32) Vitamin D/nmol/L median 57.4 50.3 43.4 54.35 p = 0.601 * (5th–95th percentile) (33.50–78.80) (36.50–83.70) (26.80–74.80) (30.40–80.60) DS, denture stomatitis. * Kruskal–Wallis ANOVA test. dentistry-08-00121-t004_Table 4Table 4 Vitamin D status in Candida-associated denture stomatitis and control groups. Vitamin D Status Groups CADS Control p Value n (%) n (%) sufficiency (>75 nmol/L) 5 (15.63) 6 (18.75) insufficiency (>50–≤75 nmol/L) 11 (34.77) 13 (40.625) p = 0.75 * moderate deficiency (>25–≤50 nmol/L) 16 (50) 13 (40.625) severe deficiency (≤25 nmol/L) 0 0 CADS, Candida-associated denture stomatitis. * Chi-square test. ==== Refs References 1. Webb B.C. Thomas C.J. Willcox M.D. Harty D.W. Knox K.W. Candida-associated denture stomatitis. Aetiology and management: A review. Part 1. Factors influencing distribution of Candida species in the oral cavity Aust. Dent. J. 1998 43 45 50 10.1111/j.1834-7819.1998.tb00152.x 9583226 2. Samaranayake L. Oral mucosal and salivary gland infections Essential Microbiology for Dentistry 4th ed. Samaranayake L. Churcill Livnigstone Elsivier Edinburg, UK 2012 307 321 3. Jontell M. Holmstrup P. Red and white lesion of oral mucosa Burkets Oral Medicine 11th ed. Greenberg M.S. Glick M. Ship J.A. BC Decker, Inc. Hamilton, ON, Canada 2008 77 106 4. Salerno C. Pascale M. Contaldo M. Esposito V. Busciolano M. Milillo L. Guida A. Petruzzi M. Serpico R. Candida-associated denture stomatitis Med. Oral Patol. Oral Cir. Bucal. 2011 16 139 143 10.4317/medoral.16.e139 20711156 5. Coco B.J. Bagg J. Cross L.J. Jose A. Cross J. Ramage G. Mixed Candida albicans and Candida glabrata populations associated with the pathogenesis of denture stomatitis Oral Microbiol. Immunol. 2008 23 377 383 10.1111/j.1399-302X.2008.00439.x 18793360 6. Sanitá P.V. Pavarina A.C. Giampaolo E.T. Silva M.M. Mima E.G. Ribeiro D.G. Vergani C.E. Candida spp. prevalence in well controlled type 2 diabetic patients with denture stomatitis Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2011 111 726 733 10.1016/j.tripleo.2011.02.033 21569989 7. Webb B.C. Thomas C.J. Willcox M.D. Harty D.W. Knox K.W. Candida-associated denture stomatitis. Aetiology and management: A review. Part 2. Oral diseases caused by Candida species Aust. Dent. J. 1998 43 160 166 10.1111/j.1834-7819.1998.tb00157.x 9707778 8. Newton A.V. Denture sore mouth Br. Dent. J. 1962 112 357 359 9. Sardi J.C. Scorzoni L. Bernardi T. Fusco-Almeida A.M. Mendes Giannini M.J. Candida species: Current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options J. Med. Microbiol. 2013 62 10 24 10.1099/jmm.0.045054-0 23180477 10. Bilhan H. Sulun T. Erkose G. Kurt H. Erturan Z. Kutay O. Bilgin T. The role of Candida albicans hyphae and Lactobacillus in denture-related stomatitis Clin. Oral Investig. 2009 13 363 368 10.1007/s00784-008-0240-6 11. Compagnoni M.A. Souza R.F. Marra J. Pero A.C. Barbosa D.B. Relationship between Candida and nocturnal denture wear: Quantitative study J. Oral Rehabil. 2007 34 600 605 10.1111/j.1365-2842.2007.01754.x 17650170 12. Santos A.L.S. Carvalho I.S. Prata J.M. Martins M.B. Souza L.O.P. Galdono A.C.M. Braga-Silva L.A. Branquinha M.H. Rodrigues S.M. Sousa L.V.N.F. Candida Albicans Involvement in Denture-Related Stomatitis: A Serious and Real Clinical Concern J. Infect. Dis. Diagn. 2016 1 104 10.4172/2576-389X.1000104 13. Darwazeh A.M.G. Darwazeh T.A. What makes oral candidiasis recurrent infection? A clinical view J. Mycol. 2014 10.1155/2014/758394 14. Stein S.H. Tipton D.A. Vitamin D and its impact on oral health--an update J. Tenn. Dent. Assoc. 2011 91 30 33 21748977 15. Prietl B. Treiber G. Pieber T.R. Amrein K. Vitamin D and immune function Nutrients 2013 5 2502 2521 10.3390/nu5072502 23857223 16. Basit S. Vitamin D in health and disease: A literature review Br. J. Biomed. Sci. 2013 70 161 172 10.1080/09674845.2013.11669951 24400428 17. Youssef D.A. Miller C.W. El-Abbassi A.M. Cutchins D.C. Cutchins C. Grant W.B. Peiris A.N. Antimicrobial implications of vitamin D Derm. Endocrinol. 2011 3 220 229 10.4161/derm.3.4.15027 18. Lim J.H. Ravikumar S. Wang Y.M. Thamboo T.P. Ong L. Chen J. Goh J.G. Tay S.H. Chengchen L. Win M.S. Bimodal influence of vitamin D in host response to systemic Candida infection-vitamin D dose matters J. Infect. Dis. 2015 212 635 644 10.1093/infdis/jiv033 25612733 19. Antonoglou G.N. Knuuttila M. Niemelä O. Raunio T. Karttunen R. Vainio O. Hedberg P. Ylöstalo P. Tervonen T. Low serum level of 1,25(OH)2 D is associated with chronic periodontitis J. Periodontal Res. 2015 50 274 280 10.1111/jre.12207 25039942 20. Kramer I.R. Pindborg J.J. Bezroukov V. Infirri J.S. Guide to epidemiology and diagnosis of oral mucosal diseases and conditions. World Health Organization Community Dent. Oral Epidemiol. 1980 8 1 26 6929240 21. McKenzie D.W. Serum germ tube identification of Candida albicans J. Clin. Pathol. 1962 15 563 565 10.1136/jcp.15.6.563 16810991 22. Joshi K.R. Solanki A. Prakash P. Morphological identification of Candida species on glucose agar, rice extract agar and corn meal agar with and without Tween-80 Indian J. Pathol. Microbiol. 1993 36 48 52 8354555 23. Durán-Valle M.T. Sanz-Rodríguez N. Muñoz-Paraíso C. Almagro-Moltó M. Gómez-Garcés J.L. Identification of clinical yeasts by Vitek MS system compared with API ID 32 C Med. Mycol. 2014 52 342 349 10.1093/mmy/myt036 24782106 24. Holick M.F. Vitamin D deficiency N. Engl. J. Med. 2007 357 266 281 10.1056/NEJMra070553 17634462 25. Khadilkar V.V. Khadilkar A.V. Use of vitamin D in various disorders Indian J. Pediatr. 2013 80 215 218 10.1007/s12098-012-0877-7 22956345 26. Holick M.F. Chen T.C. Vitamin D deficiency: A worldwide problem with health consequences Am. J. Clin. Nutr. 2008 87 1080 1086 10.1093/ajcn/87.4.1080S 18400738 27. Turner A.G. Anderson P.H. Morris H.A. Vitamin D and bone health Scand. J. Clin. Lab. Invest. Suppl. 2012 243 65 72 10.3109/00365513.2012.681963 22536765 28. Wang T.J. Pencina M.J. Booth S.L. Jacques P.F. Ingelsson E. Lanier K. Benjamin E.J. D’Agostino R.B. Wolf M. Vasan R.S. Vitamin D deficiency and risk of cardiovascular disease Circulation 2008 117 503 511 10.1161/CIRCULATIONAHA.107.706127 18180395 29. Nadir M.A. Szwejkowski B.R. Witham M.D. Vitamin D and cardiovascular prevention Cardiovasc. Ther. 2010 28 5 12 10.1111/j.1755-5922.2010.00192.x 20074253 30. Griz L.H. Bandeira F. Gabbay M.A. Dib S.A. Carvalho E.F. Vitamin D and diabetes mellitus: An update 2013 Arq. Bras. Endocrinol. Metabol. 2014 58 1 8 10.1590/0004-2730000002535 24728158 31. Pappa H.M. Grand R.J. Gordon C.M. Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease Inflamm. Bowel Dis. 2006 12 1162 1174 10.1097/01.mib.0000236929.74040.b0 17119391 32. Mesliniene S. Ramrattan L. Giddings S. Sheikh-Ali M. Role of vitamin D in the onset, progression, and severity of multiple sclerosis Endocr. Pract. 2013 19 129 136 10.4158/EP12152.RA 23186958 33. Feldman D. Krishnan A.V. Swami S. Giovannucci E. Feldman B.J. The role of vitamin D in reducing cancer risk and progression Nat. Rev. Cancer 2014 14 342 357 10.1038/nrc3691 24705652 34. Ordóñez Mena J.M. Brenner H. Vitamin D and cancer: An overview on epidemiological studies Adv. Exp. Med. Biol. 2014 810 17 32 25207358 35. Miragliotta G. Miragliotta L. Vitamin D and infectious diseases Endocr. Metab. Immune Disord. Drug Targets 2014 14 267 271 10.2174/1871530314666141027102627 25386893 36. Dini C. Bianchi A. The potential role of vitamin D for prevention and treatment of tuberculosis and infectious diseases Ann. Ist. Super. Sanita 2012 48 319 327 10.4415/ANN_12_03_13 23007057 37. Hastie C.E. Mackay D.F. Ho F. Celis-Morales C.A. Katikireddi S.V. Niedzwiedz C.L. Jani B.D. Welsh P. Mair F.S. Gray S.R. Vitamin D concentrations and COVID-19 infection in UK Biobank Diabetes Metab. Syndr. 2020 14 561 565 10.1016/j.dsx.2020.04.050 32413819 38. Meltzer D.O. Best T.J. Zhang H. Vokes T. Arora V. Solway J. Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence medRxiv 2020 13 2020.05.08.20095893 10.1101/2020.05.08.20095893 39. Amano Y. Komiyama K. Makishima M. Vitamin D and periodontal disease J. Oral Sci. 2009 51 11 20 10.2334/josnusd.51.11 19325195 40. Zhan Y. Samietz S. Holtfreter B. Hannemann A. Meisel P. Nauck M. Völzke H. Wallaschofski H. Dietrich T. Kocher T. Prospective Study of Serum 25-hydroxy Vitamin D and Tooth Loss J. Dent. Res. 2014 93 639 644 10.1177/0022034514534985 24828383 41. Jimenez M. Giovannucci E. Krall Kaye E. Joshipura K.J. Dietrich T. Predicted vitamin D status and incidence of tooth loss and periodontitis Public Health Nutr. 2014 17 844 852 10.1017/S1368980013000177 23469936 42. Fathi N. Ahmadian E. Shahi S. Roshangar L. Khan H. Kouhsoltani M. Maleki Dizaj S. Sharifi S. Role of vitamin D and vitamin D receptor (VDR) in oral cancer Biomed. Pharmacother. 2019 109 391 401 10.1016/j.biopha.2018.10.102 30399574 43. Antonoglou G. Knuuttila M. Niemelä O. Hiltunen L. Raunio T. Karttunen R. Vainio O. Ylöstalo P. Tervonen T. Serum 1,25(OH)D level increases after elimination of periodontal inflammation in T1DM subjects J. Clin. Endocrinol. Metab. 2013 98 3999 4005 10.1210/jc.2013-1906 23940127 44. Adams J.S. Liu P.T. Chun R. Modlin R.L. Hewison M. Vitamin D in defense of the human immune response Ann. N. Y. Acad. Sci. 2007 1117 94 105 10.1196/annals.1402.036 17656563 45. Benincasa M. Scocchi M. Pacor S. Tossi A. Nobili D. Basaglia G. Busetti M. Gennaro R. Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts J. Antimicrob. Chemother. 2006 58 950 959 10.1093/jac/dkl382 17023499 46. Lee W.J. Cha H.W. Sohn M.Y. Lee S.J. Kim D.W. Vitamin D increases expression of cathelicidin in cultured sebocytes Arch. Dermatol. Res. 2012 304 627 632 10.1007/s00403-012-1255-z 22695798 47. Tomalka J. Azodi E. Narra H.P. Patel K. O’Neill S. Cardwell C. Hall B.A. Wilson J.M. Hise A.G. β-Defensin 1 plays a role in acute mucosal defense against Candida albicans J. Immunol. 2015 194 1788 1795 10.4049/jimmunol.1203239 25595775 48. Sroussi H.Y. Burke-Miller J. French A.L. Adeyemi O.M. Weber K.M. Lu Y. Cohen M. Association among vitamin D, oral candidiasis, and calprotectinemia in HIV J. Dent. Res. 2012 91 666 670 10.1177/0022034512446342 22538413 49. Van der Wielen R.P. Löwik M.R. Van den Berg H. De Groot L.C. Haller J. Moreiras O. Van Staveren W.A. Serum vitamin D concentrations among elderly people in Europe Lancet 1995 346 207 210 10.1016/S0140-6736(95)91266-5 7616799 50. Jacques P.F. Felson D.T. Tucker K.L. Mahnken B. Wilson P.W. Rosenberg I.H. Rush D. Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample Am. J. Clin. Nutr. 1997 66 929 936 10.1093/ajcn/66.4.929 9322570 51. Spiro A. Buttriss J.L. Vitamin D: An overview of vitamin D status and intake in Europe Nutr. Bull. 2014 39 322 350 10.1111/nbu.12108 25635171 52. Bonilla E. Treatment of chromoblastomycosis with calciferol; report of three cases AMA Arch. Derm. Syphilol. 1954 70 666 667 10.1001/archderm.1954.01540230115015 13206410 53. Cantorna M.T. Yu S. Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity Mol. Asp. Med. 2008 29 369 375 10.1016/j.mam.2008.04.004 18561994