Document Type : Review
1 Departments of Pediatrics, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
2 Departments of Pediatric Asthma and Allergy, Ghaem Hospital,School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
3 Departments of Pediatrics, Emam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
The active form of vitamin D is synthesized in some body organs following sun exposure and dietary intake. Vitamin D exhibits its major and critical effects not only through regulation of calcium and phosphate metabolism but also by influencing on respiratory and immune system. Serum concentrations of 25-hydroxyvitamin D below the optimum limit lead to vitamin D insufficiency or maybe deficiency. These inappropriate concentrations of vitamin D lead to different types of pulmonary diseases such as viral and bacterial respiratory infection, asthma, chronic obstructive pulmonary disease, and cancer. In this review we described the association between vitamin D deficiency and severe therapy resistant asthma. We also reviewed the underlying molecular mechanism of vitamin D deficiency in children with severe- therapy resistant asthma. Based on current information, future clinical trial are needed to study the role of vitamin D supplementation on different groups of patients with severe asthma including infants, children of school age, and ethnic minorities.
The association between steroid hormone vitamin D insufficiency and different diseases including cancers, autoimmune diseases, metabolic diseases, cardiovascular and respiratory abnormalities, has been studied in various articles (1-4). Asthma, allergy and respiratory infections draw the attention of researchers and showed an increasing trend due to huge number of related publication. Sunlight exposure will supply almost 90% of the human needed vitamin D and the rest is provided via appropriate food ingredients. 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase) is known as a responsible enzyme for producing active form of vitamin D; 1,25-dihydroxvitamin D (1,25(OH)(2)D) from vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferal) in the liver and kidney (5).
The active form of vitamin D is attached to vitamin D receptors (VDRs) and affects not only the calcium absorption, bone cell differentiation and activation, but also the immune responses (6). In this study, we tried to briefly review the association between serum concentration of vitamin D and pulmonary diseases such as allergy and asthma.
The active form of vitamin D
Serum concentration of vitamin D prohormone (25(OH)D), which has a half-life of almost 3 weeks, is the most appropriate yardstick of vitamin D status. The concentrations of serum 25(OH)D as the vitamin D status index, lower than the optimum limit, which is still under consideration, is proposed as vitamin D deficiency or insufficiency, which might be diagnosed with no clinical presentation. According to Dietary Reference Intake (DRI), serum levels of 25(OH)D lower than 30 nmol/L lead to vitamin D deficiency (7).
The photosynthesis and bioavailability of 25(OH)D concentrations is under the influence of various factors such as race, vitamin D intake, sunlight exposure rate, obesity, age, some chronic diseases and physical activity (8). Both vitamin D2 and D3 are provided through sunlight exposure and transformation into 25(OH)D in the liver due to the function of 25-hydroxylases. Eventually, they convert to 1,25-dihydroxyvitamin D [1,25(OH)2D] under the activity of 1α-hydroxylase in the kidney. Although vitamin D deficiency or insufficiently can be determined based on 25(OH)D concentrations, it does not reveal the clinical and biochemical consequences, which are under the influence of vitamin D insufficiency time span, vitamin D receptor function, calcium intake, individual needs for calcium and individual variations (9).
Radioimmunoassay is the most prevalent technique in the assessment of 25(OH)D level, but it varies based on the method and different laboratories. Liquid chromatography–tandem mass spectrometry is also used to evaluate the total 25(OH)D (the level of both 25-hydroxylated D2 and D3).
Nutritional rickets and osteomalacia are significant presentations of vitamin D deficiency. Although vitamin Deficiency results in diseases, various skeletal and none-skeletal beneficial effects are proposed due to applying vitamin D supplementations. Increased bone mineral density, reduction of bone fracture rate, decreased mortality rate, reduced risk of colon and breast cancers, obesity, lower cardiovascular, metabolic, diabetes mellitus, multiple sclerosis, infection, mental illness, musculoskeletal pain, renal disease, allergy and asthma risks are other advantages of vitamin D (10).
The association of vitamin D and asthma
Based on some epidemiologic studies, maternal vitamin D situation during the prenatal period is negatively associated with childhood allergy and asthma. Vitamin D affects the immune system function and diminishes autoimmune diseases, but the relation between vitamin D levels and indices of allergy and asthma such as serum total and specific Immunoglobulin E (IgE) is not certainly indicated (11).
The efficacy of vitamin D in decreasing the prevalence of asthma is an attractive area of research. During the pregnancy, vitamin D is influential on the lung development and the immune system. Thus, pre-birth cohort and clinical trials are the preferred types of studies (12). It is showed that increased administration of vitamin D during pregnancy can reduce the possibility of recurrent wheeze in the Northeastern United States (13).
Although asthma is manageable with low doses of steroids, almost 5-10% of patients are resistant to treatments and need intense healthcare (14). The involvement of vitamin D deficiency and insufficiency in some pulmonary diseases has been studied. Several studies revealed low vitamin D concentrations in children with various levels of asthma, which can lead to decreased lung function, increased exacerbation and drug application (15).
Brehm et al. in a cross-sectional study, showed that circulating concentrations of 25-hydroxyvitamin D had a statistically significant negative association with the total IgE and eosinophil counts in children of Costa Rica between the age 6-14. They proposed that vitamin D insufficiency could occur even in sun-replete regions (15). Another research group conducted a cross-sectional study revealed that vitamin D deficiency could attenuate the immune function and led to the respiratory infections, which were the main risk factors of asthma exacerbation (16).
Despite the effect of vitamin D on embryonic lung development, various sources can relate vitamin D concentration to different levels of asthma and allergy, which will be mentioned below. Due to the effect of Vitamin D on the immune system, it is suggested that T helper type 1, T helper type 2 and regulatory T cells are under the influence of vitamin D (17). In some articles, vitamin D is related to lung function, which can be proposed as an another source to affect the asthma and allergy (18). Another study, used microarray technique, showed that vitamin D could affect the expression of responsible genes for morphogenesis, cell growth and airway remodeling in bronchial smooth muscle cells (19). Different regulations of vitamin D receptor responsible genes are suggested to be involved in occurrence of asthma phenotype in two studies (20,21).
Severe-therapy-resistant asthma and serum vitamin D
Limited number of studies has investigated the effect of different concentrations of vitamin D on children with therapy-resistant asthma (STRA). Table 1 summarized cross-sectional studies conducted on children to investigate the association of vitamin D with respiratory disorder. It has been indicated that significant reduced concentrations of vitamin D (Gupta et al. suggested that reduced concentrations of vitamin D in children with STRA, was related with more intense manifestations such as lung function and inflammation (23). Based on their findings, the level of vitamin D has been significantly low in children with STRA, compared with the moderate asthmatic children.
Hypertrophy and hyperplasia have been detected in children with STRA, which lead to airway smooth muscle remodeling. According to in-vitro studies, calcitriol might be able to inhibit thrombin and platelet-derived growth factor that induced ASM cell proliferation through hyperphosphorylation of retinoblastoma protein and activation of checkpoint kinase 1 (Chk1). In these studies, vitamin D was suggested as an effective therapeutic agent in asthmatic patients acting through airway remodeling (24,25). Gupta et al. mentioned that airway smooth muscle hypertrophy was a structural impairment following embryonic vitamin D shortcoming which led to asthma. Moreover, negative association has been identified between vitamin D level and airway smooth muscle mass remodeling (26). Reticular basement membrane thickness, epithelial shedding or airway smooth muscle cells proliferation are other risk factors of remodeling that have not shown any relation with vitamin D concentrations.
The relation between serum concentrations of vitamin D and other factors such as treatment rate with inhaled corticosteroid (ICS) and asthma exacerbation and control were studied in other investigations.
During 2009 to 2010, a group of researchers showed a significant negative relation between vitamin D concentration and asthma exacerbation. Based on their results, children with lower serum vitamin D levels had a higher rate of hospitalization or emergency department visit (odds ratio, 1.5; 95% CI, 1.1-1.9) (15,27). Other studies showed that a lower level of circulating vitamin D was related with significantly higher rate of corticosteroids administration. Based on in-vitro studies, vitamin D could increase the corticosteroids action and suppression of cell proliferation (15,28).
Molecular mechanism of vitamin D deficiency in patients with SRTA
Based on investigations, vitamin D can induce the production of interleukin (IL)-10 by regulatory T cells, which regulates lymphocyte and monocyte responses to glucocorticoids. The underlying mechanism might be based on up-regulation of forkhead box P3 (FOXP3) in T regulatory cells. In this regard, applying vitamin D supplement might be useful in increasing the efficacy of dexamethasone in patients with steroid-resistant asthma (35).
Another mechanism of vitamin D might be due to decreasing the airway smooth mass through changing the expression of responsible genes. Vitamin D administration might be able to affect the cell cycle; decrease the airway smooth mass in S phase by diminishing the cells transition from G0/G1 to S phase through modulating phosphorylation of retinoblastoma and checkpoint kinase 1 proteins (25). In addition, regulating transcription of responsible genes in airway remodeling is another possible mechanism. The responsible function might be through the reduction of the mRNA and protein expression of metalloproteinase 9 (MMP9) and ADAM metallopeptidase domain 33 (ADAM33) genes and decreasing the ADAMD33 protein expression (36).
The regulation effect of vitamin D on eosinophil migration increases the viability of isolated eosinophil (37). Another noticeable proposed role of vitamin D in patients with severe asthma is to diminish the proliferation and stimulation of transforming growth factor beta 1 (TGF-β1)-treated fibroblasts and to decrease the expression of extracellular matrix proteins (38).
Based on in-vitro experiments, 1,25(OH)2D3 can inhibit nuclear factor-kappa B function and can eventually attenuate inflammatory responses following respiratory syncytial virus, which is known as a major pathogen respiratory tract (39).
Although significant negative relation has been detected between serum vitamin D and allergy indicators, future double-blind and placebo-control clinical trials on various types of population are needed to establish the role of vitamin D.
We would like to thank Clinical Research Development Unit of Ghaem Hospital for their assistant in this manuscript.
Conflict of Interest
The authors declare no conflict of interest.
- Mann JF, Lonn EM, Yi Q, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int. 2004;65:1375-1380.
- Montero-Arias F, Sedo-Mejia G, Ramos-Esquivel A. Vitamin d insufficiency and asthma severity in adults from costa rica. Allergy Asthma Immunol Res. 2013;5:283-288.
- Egan KM, Signorello LB, Munro HM, et al. Vitamin D insufficiency among African-Americans in the southeastern United States: implications for cancer disparities (United States). Cancer Causes Control. 2008;19:527-535.
- Di Rosa M, Malaguarnera M, Zanghi A, et al. Vitamin D3 insufficiency and colorectal cancer. Crit Rev Oncol Hematol. 2013;88:594-612.
- Flanagan JN, Wang L, Tangpricha V, et al. Regulation of the 25-hydroxyvitamin D-1alpha-hydroxylase gene and its splice variant. Recent Results Cancer Res. 2003;164:157-167.
- Hewison M, Zehnder D, Bland R, et al. 1alpha-Hydroxylase and the action of vitamin D. J Mol Endocrinol. 2000;25:141-148.
- Ross AC, Manson JE, Abrams SA, et al. The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. J Am Diet Assoc. 2011;111:524-527.
- Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm Venereol. 2011;91:115-124.
- Binkley N, Krueger D, Cowgill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab. 2004;89:3152-3157.
- Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86:50-60.
- Bonanno A, Gangemi S, La Grutta S, et al. 25-Hydroxyvitamin D, IL-31, and IL-33 in children with allergic disease of the airways. Mediators Inflamm. 2014;2014:520241.
- Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol. 2007;120:1031-1035.
- Camargo CA, Jr., Rifas-Shiman SL, Litonjua AA, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr. 2007;85:788-795.
- Bush A, Zar HJ. WHO universal definition of severe asthma. Curr Opin Allergy Clin Immunol. 2011;11:115-121.
- Brehm JM, Celedon JC, Soto-Quiros ME, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009;179:765-771.
- Chinellato I, Piazza M, Sandri M, et al. Vitamin D serum levels and markers of asthma control in Italian children. J Pediatr. 2011;158:437-441.
- Cantorna MT, Zhu Y Fau - Froicu M, Froicu M Fau - Wittke A, et al. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004;80:1717S-1720S.
- Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 2005;128:3792-3798.
- Bosse Y, Maghni K Fau - Hudson TJ, Hudson TJ. 1alpha,25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol Genomics. 2007;29:161-168.
- Raby BA, Lazarus R Fau - Silverman EK, Silverman Ek Fau - Lake S, et al. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med. 2004;170:1057-1065.
- Poon AH, Laprise C Fau - Lemire M, Lemire M Fau - Montpetit A, et al. Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med. 2004;170:967-973.
- Foong RE, Zosky GR. Vitamin D deficiency and the lung: disease initiator or disease modifier? Nutrients. 2013;5:2880-2900.
- Gupta A, Bush A, Richards D, et al. Serum vitamin D levels and severe therapy resistant asthma in children. Arch Dis Child. 2011;96:A13-A13.
- Clifford RL, Knox AJ. Vitamin D–a new treatment for airway remodelling in asthma? Br J Pharmacol. 2009;158:1426-1428.
- Damera G, Fogle H, Lim P, et al. Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. Br J Pharmacol. 2009;158:1429-1441.
- Gupta A, Sjoukes A Fau - Richards D, Richards D Fau - Banya W, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184:1342-1349.
- Brehm JM, Schuemann B, Fuhlbrigge AL, et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126:52-58.
- Searing DA, Zhang Y, Murphy JR, et al. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol. 2010;125:995-1000.
- Erkkola M, Kaila M, Nwaru B, et al. Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children. Clin Exp Allergy. 2009;39:875-882.
- Camargo CA, Ingham T, Wickens K, et al. Vitamin D status of newborns in New Zealand. Br J Nutr. 2010;104:1051-1057.
- Morales E, Romieu I, Guerra S, et al. Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring. Epidemiology. 2012;23:64-71.
- Pike KC, Inskip HM, Robinson S, et al. Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes. Thorax. 2012;67:950-956.
- Brehm JM, Acosta-Pérez E, Klei L, et al. Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med. 2012;186:140-146.
- Alyasin S, Momen T, Kashef S, et al. The relationship between serum 25 hydroxy vitamin d levels and asthma in children. Allergy Asthma Immunol Res. 2011;3:251-255.
- Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116:146-155.
- Foley SC, Mogas AK, Olivenstein R, et al. Increased expression of ADAM33 and ADAM8 with disease progression in asthma. J Allergy Clin Immunol. 2007;119:863-871.
- Hoshino M, Aoike N, Takahashi M, et al. Increased immunoreactivity of stromal cell-derived factor-1 and angiogenesis in asthma. Eur Respir J. 2003;21:804-809.
- Ramirez AM, Wongtrakool C, Welch T, et al. Vitamin D inhibition of pro-fibrotic effects of transforming growth factor β1 in lung fibroblasts and epithelial cells. J Steroid Biochem Mol Biol. 2010;118:142-150.
- Falsey AR, Hennessey PA, Formica MA, et al. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med. 2005;352:1749-1759.