A systematic review of the role of vitamin insufficiencies and supplementation in COPD

Background Pulmonary inflammation, oxidants-antioxidants imbalance, as well as innate and adaptive immunity have been proposed as playing a key role in the development of COPD. The role of vitamins, as assessed either by food frequency questionnaires or measured in serum levels, have been reported to improve pulmonary function, reduce exacerbations and improve symptoms. Vitamin supplements have therefore been proposed to be a potentially useful additive to COPD therapy. Methods A systematic literature review was performed on the association of vitamins and COPD. The role of vitamin supplements in COPD was then evaluated. Conclusions The results of this review showed that various vitamins (vitamin C, D, E, A, beta and alpha carotene) are associated with improvement in features of COPD such as symptoms, exacerbations and pulmonary function. High vitamin intake would probably reduce the annual decline of FEV1. There were no studies that showed benefit from vitamin supplementation in improved symptoms, decreased hospitalization or pulmonary function.


Introduction
COPD in all stages of severity is a very prevalent disease and a great burden for patients and society [1]. In affluent countries COPD is related to smoking over a long period of time, whereas in many other countries it is also related to indoor and outdoor air pollution [1]. The pathology of chronic obstructive pulmonary disease include pulmonary inflammation, oxidants-antioxidants imbalance, protease-antiprotease imbalance, and both innate and adaptive immunity [2,3]. Smoking cessation has been proven to be effective in stopping further deterioration of pulmonary function, reducing symptoms and improving overall health [4]. Smoking cessation however, seems to have only limited influence on the inflammatory process that is associated with COPD. This inflammatory process is probably initiated by oxidative stress and forms the basis of the pathophysiology of COPD [5][6][7][8]. Thus the inflammatory process that is associated with COPD seems to be triggered by noxious gasses such as smoking and serious indoor or outdoor air pollution. Oxidative stress caused by these noxious gasses at the level of the epithelium of the bronchial tree might have play a key role in this inflammatory process. It is therefore possible that anti oxidant therapy or an intensive anti oxidant diet could have an influence on the inflammatory process and the progression of COPD. Over the last two decades a number of studies have suggested that COPD risk is associated with vitamins that all have antioxidant properties and with an anti oxidant diet. Low diet-intake of vitamins has been reported to reduce natural defenses and increase the possibility of airway inflammation [9]. Furthermore, a higher intake of fruits and vegetables was associated with a lower risk of COPD, lower mortality and an improvement of spirometric values [10][11][12][13][14][15][16][17].
When levels of vitamins were measured in the serum they were found to be significantly lower in COPD patients than in control subjects [18]. The association of vitamins with pulmonary diseases is further supported by a meta-analysis of 40 studies in patients with asthma. This meta-analysis revealed that relatively low dietary intake of vitamins A and C were associated with statistically significant increased odds of asthma and wheezing [19].
Although for vitamin D the role in respiratory diseases has been clarified through its implication in immunity, for most other vitamins the mechanism of action is less clear [38][39][40][41][42]. Indeed we know that 1,25-dihydroxyvitamin D stimulates both innate and adaptive immunity, in addition to mineralization and calcium homeostasis. Further support on the important role of Vitamin D is given by the fact that it regulates genes that are implicated in apoptosis and cellular proliferation [39], known to be an important step in COPD pathogenesis [42]. Vitamin D has both immunomodulatory and antiiflammatory properties [43]. For vitamin A, B, C, and E, studies highlight their role in COPD risk as well as their connection with COPD outcomes such as symptoms and improvement in spirometric values, without a clear mechanism of action. This article aims to update the knowledge we have about the association between vitamin intake and COPD in outcome measures, as well as to assess the potential role of vitamin supplements.

Methods
A systematic literature search was performed from 1989 until June 2010 in Pubmed, Embase and Cochrane Collaboration containing the following keywords: COPD in conjunction with smoking, gene polymorphisms, vitamins, FEV1, vitamin C, vitamin E, vitamin D, vitamin A, b-carotene, and vitamin supplements. Further articles were identified from the reference lists of the included articles. In order to be as accurate as possible we included in the present review only studies that have measured serum vitamin levels or used validated food frequency questionnaires to assess the role of vitamins.
Other dietary factors -cured meats, fish, whole grains and alcohol-that have been reported to be associated with the risk of chronic obstructive pulmonary disease or with an increase in symptoms were not included in this review [44][45][46][47][48][49][50][51]. Further we did not examine the influence of caloric intake on COPD. Weight loss and muscle wasting, considered complications of COPD strongly associated with diet, are also not included in the review.

Methods of assessing vitamin status: which is best?
The literature reports two essentially different ways to measure vitamins: Serum levels and Food Frequency Questionnaires (FFQ). Both measures have their advantages and disadvantages.

Serum levels of vitamins
The assessment of serum levels of vitamins can have the advantage of being more objective than patient's reported intake. However, serum level assessment of vitamins has the disadvantage that they represent the more recent intake, and for some vitamins such as vitamin C, the levels in peripheral blood are not representative of intake and do not change accordingly [19,52].

Food Frequency questionnaire
Food frequency questionnaires on the other hand present a large heterogeneity with differences in assessing periods (from 1 day to two years), number of items on food questionnaires (ranging from 44 to 350) and use of portion size questions [53]. Further, it has been suggested that FFQs do not always detect weak associations [54]. Regarding vitamin C intake large differences were found between FFQs that used portion size questions instead of using standard portions [53]. Another problem regarding FFQ use is that it is difficult to determine which particular vitamin is associated with COPD and if it is the vitamins in fruits and vegetables that are associated with COPD, or another confounding nutrient. Resveratrol for example, a phenolic antioxidant is present in many fruits and is associated with anti-inflammatory activity [55,56]. Therefore it is not clear if in some cases, the vitamins have the beneficial effect, or other nutrients such as resveratrol with antioxidant and anti-inflammatory properties.
Another important obstacle in FFQ is that an assessment of vitamin D from food intake would lead to an incorrect estimation in for example Mediterranean countries where there is a high skin synthesis because of the sunlight.

Food intake patterns: Effect of vitamins on the risk of developing COPD and associated mortality
Varraso et al in a study of 72,043 women identified 754 cases of newly diagnosed COPD [44]. In this study a healthy diet (fruit, vegetables, fish, whole-grain products) was compared with a Western diet (refined grains, cured and red meats, desserts, French fries). The healthy diet was associated with a lower risk of COPD [44]. This could be considered to be due to the overall diet, or indicate a possible positive effect of vitamins on COPD risk, as fruits are considered sources rich with vitamins. From the same author another study comparing the same patterns of diet showed the same results in 111 self-reported cases of newly diagnosed COPD in men [46]. Celik et al used a food frequency questionnaire and found that the consumption of fruits and vegetables was significantly lower in COPD patients compared to the control group [77]. Fruit intake was related to a lower 25-year incidence of chronic bronchitis and emphysema [57] as well as spirometry improvement [78]. A recent randomized controlled trial has shown that a dietary shift to more anti-oxidant foods such as fruits and vegetables is associated with improvement in lung function [25].
These studies showed a protective role of vitamins against COPD but did not measure vitamins in serum or with a FFQ. Therefore conclusions about the special role of any vitamin in COPD could not be obtained.

Vitamin D and COPD
Vitamin D is extremely important for the human body. It has a significant role in bone mineralization, in calcium and phosphorous absorption, and is important in the immune system [39,40]. It's most important role however is in bone structure development and bone turn over, as a low vitamin D level is directly associated with osteoporosis. The main sources of vitamin D are skin synthesis and diet. The precursor form is 7-dehydrocholesterol which with UVB is transformed to vitamin D3. Vitamin D3 is transported via the D-binding protein (DBP) to the liver where with hydroxylation reactions transforms to 25(OH)D3 and which is transported again by DBP to the kidneys where it takes its active form of 1,25(OH)2D3. 25OHD3 can also be transformed in 1,25(OH)2D3 in the immune cells [42]. Some studies showed a DBP Gc-1F allele presence that was higher in COPD patients [79,80] and Schellenberg et al found that the Gc2 homozygous genotype was protective for COPD [81]. Other polymorphisms associated with vitamin D binding protein gene are related to clinical differences in families with alpha-1-antitrypsin deficiency [82].
COPD is characterized by inflammation induced by macrophages and neutrophils (innate immunity). COPD is considered a disease where proinflammattory cytokines are increased and has a Th2 response with a predominance of CD8 lymphocytes (adaptive immunity). 1,25-dihydroxyvitamin D stimulates innate immunity probably due to activation of cathelicidin (antimicrobial peptides) to enhance the bacterial killing via Toll-like receptors [83,84]. Vitamin D receptors (VDR) are present in various cells of both innate (ie.macrophages) and adaptive immunity (i.e.T and B cells). Vitamin D is able to modulate both types of immunity therefore minimizing inflammation [85]. Vitamin D in general is involved in modulating cellular proliferation, suppressing TH cells, [86], downregulating cytokines such as IL-2 [87], as well as in the inhibition of dendritic cells [88], all of which are known to be important in the COPD pathway. Regarding respiratory function, vitamin D plays a significant role in airway remodeling through the inhibition of TNFa and enhancement of Il-10 in immune cells [39]. Vitamin D also seems to play a role as an alternative treatment strategy to reverse glucocorticoid resistance through its ability to restore IL-10 response [89]. This is important since glucorticoid resistance is a pivotal barrier to the anti inflammatory treatment of COPD.
Black et al reported that higher vitamin D levels were associated with better lung function [72]. In this study that used cross-sectional data from the Third National Health and Nutrition Examination Survey 14.091 people aged >20 years were included. The mean difference between the highest and the lowest quintile of 25-hydroxyvitamin D serum concentration was 126 ml in FEV 1, and 172 ml for FVC after adjustment for factors that affect lung function (age, gender, smoking, etc) [72] (Table 1).
Vitamin D insufficiency has been reported to be associated with an increased incidence of chronic respiratory infections [29,[33][34][35]. There are some studies that also suggest that low serum 25-hydroxy vitamin D levels are associated with upper and lower respiratory tract infection [33][34][35]. In one large cross sectional study with 18.883 participants, this association was stronger in COPD patients [33] (Table 1). Ebstein Barr virus infection, which is often found in COPD patients, is also associated with low levels of vitamin D [98,99]. Liou et al reported a relation between Toll-like receptors, external triggers and vitamin D-mediated innate immunity, and suggested that differences in the ability of human populations to produce vitamin D may contribute to susceptibility to microbial infections [100].
Finally, Vitamin D could play an important role as an antioxidant therapy, not only for the significant improvement in spirometric values, but also because it has been proposed as a novel treatment to cachexia and sarcopenia in COPD patients [101].

Vitamin C and E
The role of vitamin C (also known as ascorbate or L-ascorbic acid) in the human body is essential. It has antioxidant properties, is involved in various metabolic reactions, and some studies report it also plays a role in the immune system [102,103]. It is considered important for the maintenance of the connective tissue and bone remodeling [102]. Vitamin E has antioxidant properties as well, and has been reported to have a protective role in the prevention of atherosclerosis and carcinogenesis [104].
In one study that included 3 European Countries a trend (P < 0.05) of lower COPD mortality was observed with vitamin E intake, while no trend was found with vitamin C after adjustment for age, smoking and country [16]. Higher levels of vitamin C and E in both serum and FFQ in healthy subjects were associated with an increase in FEV1 and FVC [31,32,[58][59][60][61][62][63][64][65][66]69,70]. More details are depicted in Table 2. In one study an increase of 20 micromol/Lt in plasma vitamin C concentration was associated with a 13% reduction in the risk of developing obstructive airway disease OR: 0.87 (CI:0.77-0.98) [75].
Studies regarding the role of vitamin C and E in respiratory symptoms showed that low levels were associated with more wheezing, phlegm production and dyspnea [28,31,32,36,37]. Tug et al found both vitamin E and vitamin A levels were significantly lower during exacerbations of COPD than in patients with stable COPD [30].
Takkouche et al, in 1667 cases of the common cold in the general population suggested that intake of vitamin C and zinc was not related to the occurrence of common cold [105]. Nevertheless vitamin C decreases the duration of common cold symptoms which might be important in patients with COPD [106].

Vitamin A and B
Vitamin A (retinol and carotens) plays an important role in several functions of the human body including vision, bone and skin health, and further has an innate antioxidant activity. Vitamin B is involved in various steps of metabolism and enhances immunity. High levels of vitamin A, b-carotene and/or alpha-carotene were associated with increase in FEV1 and FVC in most of the studies [31,32,63,65,66,[69][70][71]76] although there are some exceptions [57,61,68]. More details are presented in Table 2. High serum beta carotene levels in a general population sample of 523 subjects were associated with the expression of a gene polymorphism that connected with a slower FEV1 decline [107].
Hirayama et al reported that the highest level of intake of vitamin A resulted in a 52% (p = 0.008) reduction in COPD risk [108] while in another study the risk for COPD was associated with lower levels of plasma vitamin A (p < 0.01) [108].
Fimognari et al reported lower levels of folate and vitamin B12 in COPD patients, resulted in an increased  plasma level of total homocysteine, a known cardiovascular risk factor [109].
Regarding the role of b-carotene in respiratory symptoms, two studies showed a beneficial association with cough [32,36] and one study showed no correlation with symptoms, except for wheezing [31].

Vitamin supplementation
Antioxidant supplementation has been proposed to be helpful in patients with COPD as a way to reduce oxidative stress and inflammation, and improve spirometric values [24]. Multivitamin supplementation has been reported to be popular for patients with COPD especially among older patients [110].
Seven studies reported the effect of vitamin supplements on several outcomes of COPD [18,36,[111][112][113][114][115]. All these studies showed a large heterogeneity regarding: which vitamins had been supplemented, the dosage and the duration of the vitamin supplementation, ranging from 4 weeks to 5 years [111][112][113][114][115]. Secondly, different outcomes were measured such as spirometric values, symptoms and exercise capacity. A randomized controlled trial in high-risk individuals for cardiovascular events that received antioxidant vitamins (vitamin C, E and b-carotene) supplementation for 5 years failed to identify any improvement in 5-year mortality and in spirometric values or hospitalization due to COPD. However this study excluded patients with severe COPD [115]. More details are depicted in Table 3. Also a cohort study of 77,719 participants using multi-vitamin supplements was not related to the total mortality [116].
Little is known regarding the prevention of upper respiratory tract infections after supplementation of Vitamin D although some studies report a trend for improvement [117] but some others do not confirm that (ranges of OR = 0.77-0.95) [118,119]. The supplementation did not affected the reccurence or incidence of chronic cough, phlegm or dyspnea. Relative risk for the above mentioned symptoms arround 1 with or without supplementation.
[111] Vit E supplementation. 400 IU daily for 12 weeks. 30 COPD patients Spirometric measurements. Changed not significant either on day 1 or after 12 weeks of vitamin E supplementation. [112] Vit E supplementation Patients were divided into two groups: group A-placebo group (n = 14), receiving only standard therapy, and group Bvitamin E-supplemented group (n = 10), receiving 400 IU of vitamin E capsules twice daily in addition to standard therapy, for 8 weeks.

COPD patients.
There was a similar degree of lung function and clinical improvement in both groups.

COPD patients
No improvement in lung function after 12 weeks of supplementation.
[115] Supplementation 600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene daily 5-year treatment period. All participants randomly allocated to receive vitamin supplementation or placebo.

Conclusion
The results of this review show that intake of various vitamins are associated with improvement in features of COPD such as symptoms, exacerbations and pulmonary function. Increased vitamin intake could probably reduce the annual decline of FEV1. Although the mechanisms behind these effects are often not clear, this might open possibilities to develop drugs that modify or prevent COPD. Dietary interventions directed towards high vitamin intake might be an additional approach towards COPD management. Although there are many studies that associate vitamins with improvement in lung function tests, there is no clear evidence of the benefit of vitamin supplements. Most studies regarding supplements showed no benefit of multivitamin supplemention in symptoms, spirometric function or hospitalization for COPD. This review suggests that future work is needed with prospective randomized controlled trials, that would explore the role of vitamins as well as the effectiveness of vitamin supplements on outcomes such as symptoms spirometric values, health status, risk of development of COPD and exacerbations rates.