Is there sufficient evidence to support the use of vitamin supplements in the asthmatic patient?

KEYWORDS:

• Vitamin
• dietary supplements
• asthma
• therapeutics
• safety

1. Introduction

Asthma is the most common chronic inflammatory disorder of the airways manifesting with recurrent wheezes and breathlessness as early as in childhood, worldwide [1]. Globally, it is estimated that more than 300 million people suffer from asthma; that puts it as one of the major public health issues worldwide [1]. This figure is estimated to increase to 400 million in 2025 with the prevalence of 9–16.4% in various countries [1]. Environmental factors such as air pollution, industrialization, and Western lifestyle, as well as nutrition transition, play an important role in the increased prevalence of asthma [1,2]. While smoking and occupational asthmagens account for 16.5% of disability-adjusted life years due to asthma, other contributing factors are not well identified [1]. Vitamins are a group of nutritional factors that may play a role in pathogenesis and possibly in the treatment of asthma [3]. Fresh fruits are an important source of dietary vitamins, and a UK-based study on 515 patients with asthma showed that patients with asthma had a lower intake of fresh fruits compared to healthy controls [4]. More importantly, citrus fruit consumption, vitamin C, and magnesium were inversely associated with symptomatic asthma [4]. Magnesium sulfate has a role in the management of severe asthma exacerbation, but the role of the vitamins such as vitamin C in the treatment of asthma has not yet established. Downregulation of oxidative stress, suppressing inflammation and T-helper 2 immune responses, prevention from aeroallergen sensitization, enhanced steroid responsiveness, and positive effects on lung development and function are some of the possible mechanisms of vitamins in the treatment of asthma [3,5]. Here we summarize the current evidence about the usefulness of supplementation of the most studied vitamins (C, E, and D) in the treatment of adult asthma to find the answer of the following question: Is there sufficient evidence to support the use of vitamin supplements in patients with asthma?

2. Mechanism of action

It is postulated that combination of vitamin C and vitamin E has a beneficial effect in asthmatic patients in part due to their synergistic antioxidant activity [6]. Vitamin E is a lipophilic antioxidant, a potent peroxyl radical scavenger, that reacts with peroxyl radicals and forms tocopheroxyl radical, and vitamin C is a hydrophilic antioxidant that transforms tocopheroxyl radicals to their reduced forms [6]. The ways that vitamins C and E may help asthmatics include an increase in metabolism of histamine, increased rate of reactive oxygen species removal, decrease in production of bronchoconstrictor inflammatory markers like prostaglandins, and decrease in contracture of airway smooth muscle cells [3]. Vitamin D – another popular vitamin that may help vitamin D-deficient asthmatics – has extra-skeletal health benefits. Vitamin D supplementation might reduce the risk of asthma exacerbations by enhancing innate immune system function and preventing from acute respiratory tract infections (for instance, by an increase in the production of cathelicidin, an antimicrobial peptide, in airways) [7,8]. In addition, Vitamin D supplementation enhances responsiveness to steroid therapy and helps function of regulatory T cells in steroid-resistant asthmatics [9]. In allergic asthma that usually starts from childhood and marches into adulthood, vitamin D deficiency is associated with aeroallergen sensitization [5].

3. Vitamin C and vitamin E

To date, 10 randomized clinical trials (RCTs) compared vitamin C supplementation with placebo for the treatment of adults with mild-to-severe asthma and only 1 of these 10 studies published during the last decade [10,11]. The dosage of vitamin C was varying from 1, 1.5 to 5 g once daily for about 2 weeks to 6 months [10]. Vitamin C supplementation did not improve either asthma symptoms or lung function [10]. Unfortunately, there was no report on asthma exacerbation requiring hospital admission or health-related quality of life of the patients treated with vitamin C supplementation. Moreover, the overall quality of the included studies in this meta-analysis is not high enough to reach a consensus about presence or absence of positive effect of vitamin C supplementation in the treatment of adult patients with asthma [10]. In addition, it is not clear whether vitamin C supplementation in cold seasons or during the hospitalization benefits patients with asthma or not. A total of three RCTs assessed the usefulness of vitamin C supplementation in the treatment of exercise-induced asthma (EIA). Patients on vitamin C supplementation had significant attenuation in forced expiratory volume in 1 s (FEV1) following exercise and a greater increase in FEV1 in post-bronchodilator pulmonary function tests [10]. Similarly, there was no report on asthma exacerbation requiring hospital admission or health-related quality of life patients with exercise-induced asthma treated with vitamin C supplementation [10]. Reviewing studies published so far reveal that we have no idea about the effect of vitamin C supplementation on health-related quality of life and asthma exacerbations [10]; however, there are some obvious benefits for lung function in patients with exercise-induced asthma [11]. It looks like a neglected field of study that researchers found no significant improvement in asthma symptoms and lung function in patients with asthma by supplementation of vitamin C, and stopped doing more research. Current evidence shows that vitamin C supplementation with dosage as high as 5 g per day for 6 months, when added to routine medications, cannot do anything more for patients with mild or severe asthma [10].

The number of RCT studies that investigated the effect of vitamin E supplementation in asthmatic patients is limited. Pearson et al. found that 500 mg vitamin E supplementation for 6 weeks did not have any beneficial effect on asthma symptoms, lung function, or immunoglobin-E levels in 72 adults with asthma [12]. Some hypothesized that vitamin E not only may synergize the antioxidant activity of vitamin C but also increase its absorption; therefore, the coadministration of these two vitamins may be of more benefit in the treatment of asthma [13]. The most recent Cochrane systematic review on the efficacy of combination treatment with vitamin C and E supplementation in adult patients with asthma found only three RCTs with 46 participants with different severities of asthma and one RCT on patients with exercise-induced asthma with only eight participants [14]. The dosage of combination treatments varied from 0.5 to 2 g vitamin C and 0.267 to 0.5 g once daily for 5–12 weeks [14]. None of them reported the efficacy of this treatment on health-related quality of life and asthma exacerbations. No significant improvement in asthma symptoms or lung function was observed [14]. These studies provided no data on health-related quality of life of the participants and asthma exacerbations [14]. A recent crossover RCT on eight adult patients with exercise-induced asthma revealed that 0.5 g vitamin C and 300 IU vitamin E once daily for 3 weeks attenuates FEV1 following exercise [13]. What is evident from these studies is that currently there is no evidence to support the use of vitamin C and E in the treatment of asthma, whether mild or severe, but the biggest problem to accept this conclusion is that the low number of participants and thereby low power of these studies puts this conclusion at high risk of type 2 error.

4. Vitamin D

Vitamin D has been one of the most interesting topics for researchers studying new nutritional modalities to manage asthma. The most recent Cochrane systematic review meta-analysis found two RCTs that studied the efficacy of vitamin D supplementation in the treatment of adults with mild-to-moderate asthma [15]. Vitamin D supplementation with oral vitamin D3, 100,000 IU bolus once, then 4000 IU/day for 28 weeks in VIDA study [16] and bimonthly 6 mL Vigantol oil containing 120,000 IU vitamin D3 for 12 months (total of six doses) in ViDiAs study [17] did not reduce asthma exacerbations. None of these powerful high-quality RCTs support the usefulness of vitamin D supplementation in the treatment of asthma in order to reduce the number of exacerbations or improve the health-related quality of life of patients. Vitamin D3 supplementation resulted in about 25% reduction of the original inhaled corticosteroid dose which is of value not only to taper corticosteroids but also to prevent other add on treatments such as long-acting β-agonists and anticholinergics [16]. However, one of the obstacles to determine the exact efficacy of vitamin D3 supplementation is the variable response of participants to the treatment [16]. After 28 weeks supplementation with 100,000 IU bolus dose, and then 4,000 IU/day, a wide-range of serum of vitamin D was detected [16]. Another problem is the long-term adverse effects of vitamin D3 supplementation and the concern of possible toxicity [16]. Moreover, nutritional status of patients with asthma should be taken into account when interpreting the results since supplementation of vitamins like D may be of no value for populations with sufficient status. However, ViDiAs study found that vitamin D3 supplementation in the study population with a high prevalence of vitamin D insufficiency at baseline does not reduce asthma exacerbations [17]. Hence, current evidence does not support that vitamin D3 supplementation help reduce asthma symptoms or exacerbations.

5. Conclusion

Deficiency of vitamins C, E, and D may be a part of the puzzle of asthma pathogenesis, but what we can do to improve the current care is not to simply add them to the regimen of the patients. These vitamins exert their role in the interaction of genetic factors and environmental factors. Deficiency in these vitamins may be a bystander effect of asthma pathogenesis and progression. Currently, there is not enough evidence to support the usefulness of vitamin C, E, or D supplementation in patients with asthma in order to reduce asthma exacerbations.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.