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Vitamin D is classically recognized for its role in calcium homeostasis and skeletal metabolism. Over the last few decades, vitamin D deficiency has increased in prevalence in adults and children. Potential extraskeletal effects of vitamin D have been under investigation for several diseases. Several cross-sectional studies have associated lower vitamin D status with decreased lung function. This finding has prompted investigators to examine the association of vitamin D deficiency with several chronic lung diseases. One major focus has been the link between maternal vitamin D status and childhood asthma. Vitamin D deficiency has also been associated with increased risk of respiratory infection from influenza A and Mycobacterium tuberculosis. Other chronic respiratory diseases associated with vitamin D deficiency include cystic fibrosis, interstitial lung disease, and chronic obstructive pulmonary disease. This review will examine the current clinical literature and potential mechanisms of vitamin D in various pulmonary diseases.
Vitamin D is a seco-steroid hormone important in bone mineralization and calcium homeostasis. Recently, research has found that vitamin D may play a role in multiple chronic diseases such as cancer, autoimmune diseases, infections, and cardiovascular disorders (1, 2). Vitamin D may also have a role in several diseases involving the respiratory system. Higher vitamin D concentrations, assessed by 25-hydroxyvitamin D [25(OH)D],7 have been associated with better lung function as measured by forced expiratory volume in 1 s (FEV1) in a large cross-sectional study of the U.S. population in the NHANES III. (3) Although the precise connection between vitamin D status and lung function is unclear at this point, the mechanism by which vitamin D improves lung function may be through its action on regulating inflammation (4–6), inducing antimicrobial peptides (7), and/or its action on muscle (8, 9).
There have been numerous studies looking at vitamin D status in association with various lung diseases focusing on asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and respiratory infections. These studies have demonstrated a high prevalence of vitamin D deficiency in their participants (10–19). Furthermore, several studies have reported that lower maternal vitamin D status during pregnancy or during early childhood increases the risk of asthma and wheezing in the offspring and later childhood, respectively (20–24). Vitamin D deficiency has been associated with lower lung function in COPD and CF patients (3, 13, 16, 17, 25). Other studies have shown an association between vitamin D deficiency and infections such as Mycobacterium tuberculosis (TB) (14, 15, 26–33) and upper respiratory tract infections (18, 19, 34–36). The principal limitation is that the majority of these studies have been cross-sectional by design, with only a limited number of prospective randomized clinical trials. The purpose of this review is to examine the current evidence for a protective role of vitamin D in the following lung diseases: asthma, CF, interstitial lung disease (ILD), COPD, and respiratory infections.
Cholecalciferol (vitamin D3) is synthesized upon exposure of the skin to UVB (290–315 nm), resulting in the conversion of endogenous 7-dehydrocholesterol to previtamin D3, which isomerizes to vitamin D3. After entering the circulation, it is transported by the vitamin D binding protein or albumin. Vitamin D3 is hydroxylated in the liver by 25-hydroxylase to its major circulating metabolite, 25(OH)D3, which is converted to the biologically active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], in the kidney and other tissues by the 1α-hydroxylase (37) (Fig. 1).
The prevalence of vitamin D deficiency has been increasing in the general population in recent decades. The majority of circulating 25(OH)D is derived from sun exposure, with a limited dietary contribution. The increased prevalence of vitamin D deficiency is attributed to sun avoidance, indoor lifestyle, use of sunscreen, and decreased intake of vitamin D-containing foods (1). Because vitamin D is sequestered in adipose tissue, the increasing prevalence of obesity also increases the prevalence of vitamin D deficiency (1).
Recent epidemiologic data suggest an association between vitamin D deficiency and asthma (20, 38). Asthma is a disorder characterized by varying and recurring symptoms of airflow obstruction and bronchial hyper-responsiveness in the setting of inflammation (39). Vitamin D deficiency has been found to increase the risk of severe asthma exacerbation defined as the need for emergency department evaluation or hospitalization (40). Analysis of the NHANES III data reported that patients with asthma and vitamin D deficiency [(25(OH)D < 10 μg/L] had higher rates of recent upper respiratory tract infections compared to those with serum 25(OH)D concentrations > 30 μg/L (59 vs. 22%; P < 0.001) (18). Several other cross-sectional studies conducted in adults and children have found that vitamin D deficiency was associated with lower lung function, wheezing, and asthma control (Table 1).
A cross-sectional study on 616 asthmatic Costa Rican children found that higher serum 25(OH)D concentrations were associated with a reduction in the need for antiinflammatory medications and hospitalization during the previous year (10). However, several studies from other countries have demonstrated mixed results in the association of vitamin D deficiency and asthma (Table 1) (11, 41–44). Sutherland et al. (24) reported that in patients with asthma, higher serum 25(OH)D concentrations were associated with higher FEV1. Higher serum 25(OH)D concentrations were also associated with reduced airway hyper-responsiveness and improved in vitro responsiveness to glucocorticoids (24). Others have demonstrated an inverse correlation between serum 25(OH)D concentrations and the amount of steroid medication prescribed to asthmatic patients (45) and a positive correlation with FEV1 (42), FEV1% predicted (42), and FEV1/forced vital capacity (FVC). (42, 45) Searing et al. (45) also reported a decreased inflammatory response in the combination dexamethasone and vitamin D treatment group compared to the dexamethasone treatment group alone by in vitro analysis of MKP-1 and IL-10 levels. This suggests that vitamin D may potentiate the effects of steroids in asthmatic patients. The childhood asthma management program study randomized children with mild to moderate persistent asthma to commonly used controller medications. They found that vitamin D-deficient children were at increased risk for a severe exacerbation defined as a hospitalization or emergency department visit (40). Finally, Chinellato et al. (46) reported higher prevalence of exercise induced bronchoconstriction in asthmatic children who were vitamin D deficient.
The effects of vitamin D deficiency on asthma pathophysiology are not completely understood. Many researchers have focused on the potential of vitamin D to dampen the inflammatory immune response in patients with asthma, although other mechanisms may be involved. Studies conducted in a murine model of asthma found that the hormonal form of vitamin D shifted the T-regulatory lymphocyte response from a T helper cell 1 to a less inflammatory T helper cell 2 dominant phenotype (4, 5).
In vivo studies suggest that vitamin D increases the production of IL-10, an antiinflammatory cytokine involved in the pathogenesis of asthma, from T cells in both steroid-sensitive and -resistant asthma patients (6). In contrast, Hypponen et al. (47) demonstrated a U-shaped relationship between serum 25(OH)D and IgE concentrations in adults from the UK. This finding may suggest increased risk of allergic disease such as asthma with low or high serum concentrations of 25(OH)D. The current working hypothesis is that vitamin D potentially reduces the inflammatory response in asthma, leading to a decrease in the amount of antiinflammatory medications such as glucocorticoids that are used by patients.
Vitamin D may also regulate matrix metalloproteinases (MMP) that are involved in airway remodeling. Song et al. (48) found that pretreatment of human airway smooth muscle cells with 1,25(OH)2D3 decreased the in vitro production of MMP-9 and a disintegrin and metalloprotease 33 (ADAM33) when these cells were exposed to serum from asthmatic patients. This inhibitory effect on MMP-9 and ADAM33 may indicate that vitamin D sufficiency prevents further airway narrowing in asthmatic patients. In summary, vitamin D may have a beneficial role in the pathology of asthma by shifting the Th1 and Th2 balance, reducing inflammation, regulating MMP, and reducing airway remodeling.
Studies of ~5000 pregnant women from the United States, Finland, Scotland, and Japan demonstrated an inverse association between maternal intake of vitamin D and the rate of wheezing in their offspring (20–23) (Table 1). In children, a vitamin D-deficient diet was associated with a decreased response to bronchodilators (22), increased incidence of allergic rhinitis (23), and increased incidence of asthma (23). Other studies have found that maternal diets poor in vitamin D lead to an increased risk of reactive airways in the offspring (20–23). An additional study has reported that the cord-blood 25(OH)D concentrations in children were inversely associated with risk of wheezing at 15 mo, 3 y, and 5 y, yet no association was observed between cord-blood 25(OH)D concentrations and incidence of asthma in children at 5 y (49).
In a prospective cohort study, Hypponen et al. (50) reported that children receiving vitamin D supplementation (2000 IU/d) in the first year of life had a nonsignificant increase risk of developing asthma (P = 0.08). A limitation of this study was that vitamin D status was not confirmed by serum testing of 25(OH)D. A similar study from the UK of 596 pregnant women demonstrated that higher serum 25(OH)D concentrations during pregnancy conferred increased risk of asthma in their offspring by 9 y of age (51). The major limitation of this study was a dropout rate of ~60% at 9 y (51, 52). These seemingly conflicting findings will be further examined in a large, randomized, multi-center trial, the Vitamin D Antenatal Asthma Reduction Trial, which will test the hypothesis that vitamin D supplementation can prevent or reduce asthma, wheezing, and other allergic illnesses (53).
CF is the most common inherited respiratory disorder in the Western world. The CF transmembrane conductance regulator mutation leads to thick secretions that are retained in the airways, preventing adequate bacterial killing by antibacterial factors from the lining of the lung, excessive inflammation, and eventual respiratory failure (54). As the median lifespan of CF patients has reached almost 40 y, the effect of the high prevalence of vitamin D deficiency has become more apparent (55, 56). The causes of vitamin D deficiency in CF are: inadequate intake of vitamin D, diminished body fat, pancreatic exocrine insufficiency causing vitamin D malabsorption, limited sun exposure (57), and decreased serum vitamin D binding protein (58). At large CF centers, >90% of the patients have 25(OH)D concentrations < 30 μg/L (59, 60).
There is a limited understanding of the extraskeletal functions of vitamin D such as the production of antimicrobial peptides in CF. These peptides, cathelicidins and defensins, play a role in the innate host defenses against airway pathogens. LL-37, a cathelicidin, is cleaved from the full-length hCAP18 protein and is the only cathelicidin present in humans. The LL-37 antimicrobial peptide has antimicrobial activity against Gram-positive, Gram-negative bacteria, fungi, and some viruses (7). In vitro studies have demonstrated that 1,25(OH)2D3 is necessary for pathogens to induce cathelicidin mRNA expression in both normal and CF bronchial epithelial cells (61). Vitamin D status has been associated with higher levels of circulating LL-37 in septic patients (62). Given the potential of vitamin D to induce antimicrobial peptides, optimizing vitamin D status may decrease the frequency of pulmonary exacerbations in CF patients. However, no studies published to date have tested this hypothesis.
Numerous studies have demonstrated a correlation between decreased bone mineral density in CF and decreased FEV1% predicted (16, 63–67) (Table 2). Low bone mineral density places these patients at increased risk for fractures of thoracic vertebrae and ribs, leading to an ineffective cough and/or impairment in airway clearance (58). Two other retrospective studies found a positive correlation between serum 25(OH)D concentrations and lung function indicators FEV1% predicted (16) and FEV1 (17). Another study in Scandinavian CF patients demonstrated that IgG levels were inversely correlated with serum 25(OH)D concentrations, suggesting there is an association between vitamin D status and the degree of inflammation in CF patients (67). Future randomized trials will attempt to determine how vitamin D effects lung function, reduces the rate of CF exacerbations, and improve bacterial clearance during pulmonary exacerbations (68).
ILD is a heterogeneous set of disorders that is characterized by damage of the lung parenchyma (69) and has been ineffectively treated with corticosteroids (70). Recently, vitamin D status has been associated with the severity of ILD (Table 2). Olson et al. (71) found the highest mortality in the IPF population was in the winter months, even after accounting for infectious etiologies, suggesting a potential link between vitamin D and ILD. Mascitelli et al. (72) speculated that increased mortality due to infection in the winter months may due to vitamin D deficiency. Hagaman et al. (12) reported that ILD patients in Cincinnati had a high prevalence of vitamin D deficiency [38% of patients had 25(OHOD < 20 μg/L]. Those with connective tissue disease ILD were more likely to have diminished 25(OH)D concentrations compared to the other forms of ILD (deficient 52 vs. 20%; P < 0.0001). Most importantly, the connective tissue disease-ILD group with reduced levels of 25(OH)D had a clinically significant decline in their lung function [FVC, P = 0.015; diffusing capacity of the lung for carbon monoxide (DLCO), P = 0.004].
The pathophysiology of vitamin D deficiency in ILD has been studied by Ramirez et al. (73) using a murine model. They demonstrated that 1,25(OH2)D3 inhibits TGFβ1 stimulation of profibrotic phenotypes in lung fibroblasts and epithelial cells. In summary, there is early epidemiologic evidence demonstrating an association between vitamin D deficiency and ILD; however, the mechanism by which vitamin D may be protective in ILD remains unclear and not well studied in vitro or in clinical studies.
By 2020 COPD may become the 3rd leading cause of death worldwide (74). COPD is a lung disease associated with significant and progressive irreversible airflow obstruction (75). Recently, a number of studies have shown an association between vitamin D deficiency and severity of COPD (13, 25). Lower vitamin D status in COPD may be due to diminished production of pre-vitamin D3 associated with skin aging caused by smoking and limited UVB exposure (1, 76).
Studies have shown that the degree of vitamin D deficiency correlates with the severity of the disease as measured by the reduction of FEV1 (3, 13, 25) (Table 2). The difference in FEV1 between the highest and lowest quintiles of serum 25(OH)D was greater in those with a diagnosis of chronic bronchitis (248 mL) or emphysema (344 mL) than in the other participants. When evaluating the interaction between emphysema and chronic bronchitis in regards to serum 25(OH)D concentrations, the results were not significant (3). Ferrari et al. (25) also demonstrated that the maximal exercise capacity and carbon monoxide transfer in the single breath method were both positively correlated with serum 25(OH)D concentrations (r = 0.247, P < 0.05; and r = 0.496, P < 0.001). Impairment of exercise capacity in COPD may be related to a reduction in muscle strength (8); however, it is unclear whether vitamin D may play a role in exercise capacity. One longitudinal study of current smokers with mild to moderate COPD evaluated vitamin D status in participants with rapid and slow lung function decline over a 6-y period. It found no difference in the serum 25(OH)D concentrations of the rapid decliners compared to the slow decliners (25.0 and 25.9 μg/L, respectively; P = 0.54) (77). Patients with COPD are at risk for vitamin D deficiency; however, it remains to be seen if correction of vitamin D deficiency leads to a slower decline in lung function and improvement in exercise capacity.
The effects of vitamin D on respiratory infections have been studied in a variety disease processes ranging from TB to upper respiratory tract infections. One of the mechanisms by which vitamin D improves recovery from infection appears to be by enhancing innate immunity by upregulation of antimicrobial peptides, as discussed earlier.
TB is a global epidemic, with an incidence of 8.9–9.9 million cases in 2008 (78). Before the etiologic cause of TB was determined in 1903 by Robert Koch, cod liver oil and sun exposure, both sources of vitamin D, were commonly used to treat patients infected with TB (79, 80).
Several studies across ethnic backgrounds have demonstrated a positive association between prevalence of TB and vitamin D deficiency (14, 15, 26–33, 81, 82) (Table 3). However, two smaller studies did not find an association between vitamin D status and risk of TB infection (83, 84). A recent meta-analysis of trials involving TB patients demonstrated that participants with TB had significantly lower serum 25(OH)D concentrations compared to matched controls (0.68; 95% CI = 0.43–0.93) (85).
Early clinical trials have been conducted to test whether vitamin D therapy improves TB outcomes. One study demonstrated that participants who were exposed to TB and who were treated with a single dose of 100,000 IU of vitamin D2 had increased in vitro activity of Mycobacterium bovis bacille Calmette-Guerin-lux luminescence compared to the healthy controls at 24 h (0.57 vs. 0.71; 95% CI = 0.01–0.25; P = 0.03), suggesting an enhanced innate immune response (86). Another study by Morcos et al. (87) found that children diagnosed with TB and treated with conventional therapy plus vitamin D compared to placebo for 2 mo did have clinical improvement characterized by less febrile episodes, resolution of cachexia, and reduction in lymph node enlargement. However, there was no evidence of radiographic improvement, which may be related to the short follow-up. Nursyam et al. (88) demonstrated that pulmonary TB patients treated with conventional TB therapy plus 100,000 IU of vitamin D daily had a significantly higher sputum conversion rate at 6 wk compared to TB patients treated with conventional TB therapy alone. A similar trial reported no difference in sputum conversion rate in participants who received 100,000 IU of cholecalciferol or placebo on 3 different occasions at 14, 28, and 42 d. However, the sputum conversion rate was statistically higher only in those in the vitamin D group with the tt genotype TaqI vitamin D receptor polymorphism (89). In contrast, an African study, in which participants received traditional therapy plus 100,000 IU of vitamin D at baseline and 5 and 8 mo or placebo, did not show any effect of vitamin D therapy (90). However, serum 25(OH)D concentrations in the vitamin D group did not differ from the placebo group, raising questions about the sufficiency and frequency of the vitamin D dosing regimen (90). Overall, these initial clinical associations and early trials suggest that vitamin D may be beneficial as an adjunctive treatment to the traditional therapy in patients with TB; however, additional randomized trials need to be conducted to clarify the role of vitamin D.
Ecological studies have suggested that an environmental factor such as vitamin D could explain the seasonality of influenza (91–95). This has been observed in several epidemiologic studies (3 case controls, 1 observational, 1, prospective cohort, and 1 cross sectional) showing an association between vitamin D deficiency and increased risk of respiratory infection (18, 19, 34–36, 49) (Table 4). An NHANES III analysis was the largest of these studies (~18,000 patients) and demonstrated an association between vitamin D deficiency and upper respiratory tract infections (18). Three smaller case control studies did not reveal an association between vitamin D deficiency and respiratory infections (96–98). However, 95% of the participants in the acute lower respiratory tract infection group received some form of vitamin D supplementation, thereby increasing the serum 25(OH)D in the placebo group (96). An additional possibility is that the association of vitamin D deficiency with increased respiratory infection occurs only in those patients with the most severe pulmonary illnesses (35). Approximately 50% of the patients admitted to the pediatric intensive care unit with respiratory illness were vitamin D deficient (<20 μg/L) compared to only 20% on the general medical floor (OR = 8.23; 95% CI = 1.4–48; P = 0.02) (97). The inconsistencies in these reports illustrate the need to evaluate the effects of vitamin D on respiratory infection with randomized control trials.
There are only a few published randomized controlled trials evaluating the effects of vitamin D on infectious outcomes. In a post hoc analysis of women participating in a vitamin D trial for osteoporosis, Aloia et al. (99) found improved upper respiratory tract symptoms in participants receiving vitamin D. A study by Urashima et al. (100) determined that wintertime vitamin D supplementation decreased the risk of influenza A infection diagnosed by nasal swab in school age children. Similarly, a trial conducted in Afghanistan reported a decreased risk of recurrent pneumonia with a single dose of 100,000 IU of vitamin D over the next 3 mo (101). Other trials evaluating the effects of vitamin D supplementation on reducing the rate of respiratory illness did not demonstrate a significant decrease in the occurrence of respiratory illnesses (Table 3). These studies may not have had achieved adequate serum 25(OH)D concentrations or the dosage of vitamin D was too small to be effective (102, 103). At this time, further studies need to be conducted to determine if higher doses of vitamin D are able to prevent and/or treat respiratory infections.
At this time, there is a considerable amount of evidence that implicates vitamin D as a factor associated with various chronic lung diseases. The question remains whether vitamin D deficiency contributes to the etiology of lung disease or if vitamin D deficiency is simply a manifestation of the lung disease and/or its treatment. As research in this field unfolds, vitamin D supplementation will need to be evaluated in larger trials focused on specific respiratory diseases. More research is needed studying the potential mechanisms by which vitamin D may be protective in respiratory diseases. Currently, there are 26 trials listed on clinicaltrials.gov that involve vitamin D and various lung diseases. These future randomized prospective controlled trials will shed light on the true benefits of vitamin D and potential mechanisms in both preventing and treating chronic lung diseases.
JDF and VT analyzed data; JDF, RG, and VT wrote the paper. VT had primary responsibility for final content. All authors read and approved the final manuscript.
1Supported by NIH K23 AR054334 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH T32DK007734 from The National Institute of Diabetes and Digestive and Kidney Diseases, NIH 5UL1RR025008 from the National Center for Research Resources, and by a Cystic Fibrosis Foundation Center Grant to the Emory Cystic Fibrosis Center.
2 Author disclosures: J. D. Finklea, R. E. Grossmann, and V. Tangpricha, no conflicts of interest.
7Abbreviations used: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FEV1/FVC, forced expiratory volume in 1 s/forced vital capacity; ILD, interstitial lung disease; MMP, matrix metalloproteinase; 25(OH)D, 25-hydroxyvitamin D; 25(OH)D3, 25-hydroxyvitamin D3; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; TB, Mycobacterium tuberculosis.