A Review on the Role of Vitamin D in Asthma

Asthma, a major public health issue, is one of the most common diseases affecting millions of population globally. It is a chronic respiratory disease characterized by increased airway inflammation and hyper-responsiveness. Vitamin D is of particular interest in asthma due to its immunomodulatory effects. Serum 25-hydroxyvitamin D is found to be associated with a wide range of pulmonary diseases, including viral and bacterial respiratory infections, asthma, and cancer. Several researches have reported positive associations between vitamin D and asthma. On the other hand, others have reported contrasting effects of vitamin D on asthma. This review provides an examination of current epidemiologic and experimental evidence of a causal association between vitamin D status and asthma or asthma exacerbations, including its probable protective mechanism. Most of the evidence regarding vitamin D and asthma is reported by observational studies. Therefore, results from the experimental trials of vitamin D supplementation are important as they can provide evidence for future recommendations about the significance of vitamin D for asthma. Moreover, the trials can be effective in assessing the correct dosage and safety of vitamin D supplementation when given in diverse age groups such as children, teenagers, and adults for prevention and treatment of asthma.

Several dietary hypotheses have been proposed in context with asthma [7][8] and among them vitamin D status is of particular interest. Studies suggest that there is a probable relationship between vitamin D status and asthma-related symptoms presumably via the immunemodulatory effects of vitamin D [5,8].

Risk factors of asthma
Numerous risk factors of asthma can be divided into host and environmental factors.

Host Factors
Genetic: Several genes can be related to the pathogenesis of asthma. Four major areas have been focused in this regard; production of IgE antibodies, airway hyper-responsiveness, and inflammatory mediators (cytokines, chemokines), growth factors and the ratio between Th1 and Th2 immune responses [5][6][7][8].
Obesity: Obesity has been associated with the development of asthma. However, the biologic causality has not been yet proven [7,9].
Gender: Prevalence rates of asthma are different among males and females [8][9]. Childhood asthma is found to be common in boys than girls and by adulthood, this is reversed [10]. Reasons for this gender differences are not clear. However, the lung size is smaller in males than in females at birth but larger in adulthood [8][9].

Environmental Factors
Allergens: The role of allergens in the development of asthma in children is still unclear. It relies on the allergen, the dose, the time of exposure and the age of the child, and genetics can also play a role [10].
Infections: Evidence suggests that respiratory infections in early childhood may have a protective role against the development of asthma and studies have shown that they may develop asthma in later life [8,11].
Tobacco smoke: Studies reveal that exposure to tobacco both prenatally or after birth can increase the risk of developing asthma-like symptoms in early childhood [12].
Outdoor/Indoor pollutants: The role of pollutants in the development of asthma is less well defined. It has been observed that increased levels of outdoor or indoor pollutions can aggravate asthma symptoms [12][13].
Diet: Studies have shown that infants fed with commercial cow's milk formula etc. have a higher frequency of wheezing illnesses in early childhood as compared to breast milk feeding infants [11,13].

Pathophysiology
Narrowing of airway causes asthma and its symptoms [2]. Following are the factors which contribute to the development of this physiologic change [9][10].
In response to multiple broncho-constrictor, mediators and neurotransmitters the airway smooth muscle gets contracted and this leads to narrowing of the airway; this can be retreated by bronchodilators [10].

Diagnosis of asthma
It involves a careful process of history taking, physical examination, and diagnostic testing. The family history of asthma and atopic disease can also assist in diagnosing asthma [12,14].

Physical Examination
The common abnormal physical finding on the examination is wheezing on chest auscultation. In severe cases, a silent chest can be found because of limitation of airflow and ventilation [2]. However, the other symptoms include: difficulty in speaking, drowsiness, tachycardia, cyanosis and use of accessory muscles and intercostal recession [14]. Confirmation of asthma is based on two additional elements [2,14].
Spirometry: It is the preferred method of diagnosis of airflow obstruction. Peak flow measurements alone should not be used to diagnose asthma due to wide variability in predicted peak expiratory reference values. It may be more useful in monitoring patient's symptoms and response to therapy [14].
Exclusion of alternative diagnosis: Common acute causes of wheezing in children must be omitted before diagnosing asthma in children [14].

Management
The management of asthma involves controlling the clinical symptoms and maintaining it for a long term.

Pharmacologic Treatment
It can be divided into two categories: controllers and relievers.
Controllers: They are basically a preventive measure to keep asthma under control and taken daily on long term basis. Sometimes to reach clinical control add-on therapy with another class of controller is preferred over increasing the dose of inhaled corticosteroids [15][16].
Relievers: They are fast acting beta2 agonists and are the most effective medication for quick relief of bronchospasm in adults and children [15][16].

Review Vitamin D
Vitamin D is a fat-soluble nutrient which is a modulator of calcium absorption and bone health. It also plays an important role in immune regulation and in respiratory infections [10,17]. Serum 25OHD is the top indicator of overall vitamin D status since it reflects the intake of vitamin D from dietary sources intake as well as sun exposure; it also accounts for the adaptation of vitamin D from adipose stores in the liver [17]. Though, there are no guidelines on optimum levels of serum 25OHD. However, vitamin D deficiency is defined as 25OHD level of less than 50 nmol/L (20 ng per millilitre) [18]. When 25OH D levels are between 50 and 75 nmol/L (20-30 ng per millilitre) it is an indicator of vitamin D insufficiency [18]. Moreover, 25OHD levels of 75 nmol/L (30 ng per millilitre) to 100 nmol/L suggest normal vitamin D levels. Vitamin D intoxication is defined as, serum levels of 25(OH) D are greater than 150 ng/ml [18].

Vitamin D epidemiology
Vitamin D deficiency has a high incidence worldwide. It is estimated that almost half of the healthy people population are 25-hydroxy-vitamin D (25-OH D) deficient [19]. Insufficient sun exposure or pigmented skin and inadequate dietary intake are the main causes of these low levels of 25-OH D [19]. A study conducted in the US on 9,757 subjects found that approximately 9% of participants had vitamin D deficiency and 61% had vitamin D insufficiency [20]. The common factors of vitamin D deficiency are increasing age, being female, Mexican-American ethnicity, obesity, and reduced dairy intake [19][20].

Vitamin D deficiency in South Asia
Sunlight exposure helps vitamin D production and in South Asia, almost all the days are sunny [21][22]. However, still, there is a high prevalence of vitamin D deficiency in these countries due to other underlying factors such as lack of proper diet, inadequate calcium intake, social culture and customs that require the elderly, children and females to be confined in the house, limiting their exposure to sunlight [20][21]. It has been reported that the prevalence of this deficiency ranges from 69% to 82% in Indian population [23][24]. This is not limited to the Asians living in India and Pakistan [5,9], but even the immigrants (UK, Denmark, and Norway) have this deficiency [23][24].

Vitamin D and immune system
Vitamin D plays a significant part in inborn and adaptive immunity; however, it is not completely understood [9,25]. It is reported that over 900 genes are regulated by vitamin D [26]. This action of vitamin D has gained immense acceptance after the discovery of vitamin D receptor (VDR). Several studies have shown that vitamin D prevents the increase of CD41 Tcells [25][26] and decreases the creation of Th1 cytokines IL-17 [10,[25][26][27]. However, due to alterations in target cells timing and quantity of vitamin administration, studies have shown contrasting results. Evidence suggests that innate immunity is activated by the production of anti-microbial peptide LL-37 by macrophages [25][26][27]. The adaptive immune system increases the production of T-cells and modifies the functions of antigen-presenting cells (APCs), of dendritic cells. In addition, vitamin D has been revealed to improve and inhibit IL-4 production by naive T-cells [25][26][27].

Vitamin D and asthma
It has been suggested that modernization and westernization have led to vitamin D deficiency among world population. Since, the majority of the population spends time indoors away from sun exposure, leading to vitamin D deficiency [21,27].
The role of vitamin D in asthma is not yet clear. Few cross-sectional surveys had suggested a probable link between asthma and vitamin D [27][28]. Studies have concluded that decreased level of serum 25(OH)D is correlated with an increased prevalence, hospitalization, and increased emergency visits along with declined lung function and increased airway hyperresponsiveness in asthmatic children [27,29]. Clinical trials conducted in recent times have shown the protective influence of vitamin D supplementation among asthmatic patients [30][31][32]. In addition, increased intake of vitamin D during pregnancy has an influence on asthma in children and adults [33][34].

Evidence from Observational Studies
A cross-sectional survey on 75 Italian asthmatic children found that the prevalence of vitamin D-deficiency was 53.3% [28]. In another survey from North America, 17% of asthmatics had vitamin D deficiency and a positive correlation was observed between vitamin D levels and lung function [29]. A study conducted by Thuesen, et al. on 4,999 Danish adults reported contrasting results and concluded that 25(OH)D levels do not have any effect on the development of asthma and allergic symptoms [35]. A cohort study revealed that low serum 25(OH)D levels at the age of 6 years predicted asthma-associated symptoms (uncontrolled asthma and lung function) at 14 years of age [36].
The data from observational studies has shown a parallel relation between vitamin D and asthma outcomes [36][37][38][39]. Although, it is challenging to formulate a relationship between them due to certain limitations of these studies such as the presence of bias (selection bias), confounders (physical activity, sex, age, etc.) and small sample size. All of the abovementioned limitations might have caused a spurious relation between vitamin D and asthma.
Cohort studies suggest that lower maternal dietary intake of vitamin D can result in the development of asthma morbidity and wheeze in children [40][41][42]. However, a major limitation of these studies was that they assessed vitamin D intake using food frequency questionnaires rather than directly measuring serum concentrations.
A study conducted by Gale, et al. shared that children whose mothers had serum 25(OH)D concentrations above 75 nmol/L had five times more risk of developing asthma at 9 years [33]. Studies conducted in Finland and Japan on more than 750 mother-child pair have found that dietary vitamin D intake during pregnancy is inversely related to the incidence of wheeze among children [41][42]. Another study concludes that serum 25(OH)D during late pregnancy was not related with maternal vitamin D status and risk of childhood asthma [43]. A study conducted by Zosky, et al. found that maternal vitamin D deficiency was positively related with asthma at 6 years in males (OR: 3.03; 95% CI: 1.02-9.02) [40].
Comparison between the results of the studies should be done with caution, as these studies had a number of limitations, for instance, short follow-up duration, significant rates of attrition, and lack of validated measures for measuring serum vitamin D.
A study done in New Zealand revealed that low blood 25(OH) D levels were not associated with asthma incidence [44].
The relation between higher 25(OH)D levels and reduction in the incidence of asthma is contradictory and studies depicting a direct role for vitamin D in the development of asthma are required.

Vitamin D and asthma pathogenesis
A study conducted by Gupta, et al. was the pioneer research in concluding that serum vitamin D levels were found to be lowest among children with steroid resistant asthma (STRA) [45] with reduced lung function, increased corticosteroid use, and asthma exacerbations. The probable reason for this is because low vitamin D levels increase the airway smooth muscle (ASM) and reduce lung function in severe asthma [45].

Evidence from Observational Studies
Vitamin D is only used for primary prevention for asthma but it also has a role in asthma exacerbation. A cross-sectional study of 616 asthmatic children in Costa Rica between the ages of 6 and 14 years, reported that vitamin D deficiency/insufficiency was prevalent in 28% of the children and increased levels of vitamin D were related with reduction in asthma exacerbations and reduced visits to emergency department (OR: 0.05; 95% CI: 0.004-0.71) [20]. A 4-year longitudinal study was conducted by Brehm, et al. to establish causal relations between serum vitamin D levels and asthma exacerbations in 1024 North American asthmatic children with mild to moderate asthma [25]. This study confirmed that less levels of vitamin D (<30 ng/mL) had increased risk of asthma exacerbations (OR: 1.5; 95% CI: 1.1-1.9) [25]. In addition, the study also concluded that children with vitamin D insufficiency had higher chances of asthma exacerbation [25].
Another cross-sectional study conducted on 560 children ages between 6 and 14 years with asthma in Puerto Rico reported that children with vitamin D insufficiency were 2.6 times more at risk of developing asthma exacerbations (OR: 2.6; 95% CI: 1.5-4.9) [37]. A recent study conducted on 70 adult asthmatic patients and 20 healthy controls by Shahin, et al. [46], concluded that serum vitamin D level was significantly decreased in asthmatic patients (19.88 ± 9.6 ng/ml) as compared to the control group (33.5 ± 6.1 ng/ml) [46] ( Table 1).   [30]. Other trial on 100 asthmatic children revealed that monthly doses of 60,000 IU of vitamin D can significantly decrease the number of exacerbations (p = 0.011) and it also resulted in the reduction of steroids (p = 0.013) and emergency visits (p = 0.015) [32]. A study conducted in 2016 in which Japanese schoolchildren with asthma (n = 89) were randomly assigned to either receive vitamin D (n = 54) or placebo (n = 35). At 2 months, asthma control was significantly more improved in the vitamin D group as compared to the placebo group (p = 0.015) [47].  These data certainly are suggestive of a relation of vitamin D in asthma and can be useful as an adjunct therapy to overcome steroid resistance in severe asthma. There are many studies on the influence of vitamin D on responses to infection, but there are none or limited studies to determine the causal role of vitamin D deficiency during acute asthma exacerbation.

Future perspectives
Most of the observational researches have demonstrated the benefit of vitamin D supplementation in asthmatic patients. Nevertheless, to address the limitation of temporality in the observational studies, clinical trials are required to establish the association between vitamin D and asthma.
Trials with larger sample sizes are needed to provide the evidence of causality for vitamin D and asthma. These trials will also be helpful in establishing the appropriate route, dose, and safety of vitamin D supplementation for prevention and treatment of asthma.
It is also imperative to realize the protective mechanism of vitamin D against asthma. The suppression of Th2 immune response explains the protective effect of vitamin D alongside asthma. Nonetheless, there is a need to identify evidence between vitamin D and atopic reactions.
There is no evidence to suggest that asthmatic patients should be screened for vitamin D deficiency or insufficiency. However, the high-risk group (obese patients and elderly of African-American ethnicity who have limited sun exposure) must be screened for this deficiency.
Further researches are needed on the molecular level of vitamin D receptor to explain the role of dietary vitamin D in the prevention and management of asthma.

Conclusions
Vitamin D can be effective as an adjunct therapy in the management of asthma. The higher levels of vitamin D, in fact, are needed to prevent various health problems. Regardless of the growing evidence about the association of vitamin D with asthma and asthma exacerbation, the results of the studies are not reliable. Several studies have supported the view that vitamin D deficiency is the cause of the global asthma epidemic. On the other hand, another set of studies has proposed that vitamin D supplements are responsible for the asthma epidemic.
However, larger trials with huge sample sizes are required to define the role of vitamin D in asthma and answer questions that whether vitamin D supplementation will be more effective in the high-risk vitamin D deficient group or not.

Conflicts of interest:
The authors have declared that no conflicts of interest exist.