Vitamin D Supplements Could Protect from the Common Cold and Flu

The NHS recommends that everyone considers taking a vitamin D supplement, particularly in the autumn and winter months, to optimise musculoskeletal health. However, a recent review by Martineau et al. [1] made the headlines by suggesting that this guidance could also help combat the common cold and flu. After assessing the findings of this study within the limited scope of current research it has been concluded that vitamin D offers some immunomodulatory effects, but there is not enough scientific evidence to advise supplementation for protection against respiratory tract infections.

Recent headlines have stated that increasing vitamin D status could combat the common cold or flu, suggesting the benefits of population-wide supplementation [2]. Such action is already recommended by Public Health England during autumn and winter for those whose diet is not sufficient in either foods naturally containing vitamin D, such as oily fish, liver and egg yolks, or those fortified with it [3]. This is aimed at ensuring average intake meets the RNI of 10μg/day, an amount proposed by SACN to ensure that the majority of the population avoids deficiency disease, which is serum vitamin D <25nmol/L [4].

A systematic review and meta-analysis by Martineau et al. has investigated the potential benefits of vitamin D in addition to the proven association between intake and enhanced bone and muscle health, by considering its potential immunomodulatory effects [1]. More specifically, it relates vitamin D status to the incidence of acute respiratory tract infections such as rhinovirus and influenza, aka the common cold and flu. There is some belief that vitamin D induces the innate immune system [5], and it has been shown to be important in the activation of 1α-hydroxylase, and the subsequent induction of cathelicidin production by macrophages, which is an antimicrobial peptide for Mycobacterium tuberculosis [6]. However, beyond this the causative mechanisms are not well understood. General thought surrounding the immunomodulatory effects involve polymorphism of vitamin D receptor (VDR) genes. Vitamin D acts through VDRs to stimulate transcription of antimicrobial peptides such as ẞ-defensin and cathelicidin, which are able to inactivate viral pathogens and increase phagocyte recruitment in the respiratory system [7]. It has also been shown to decrease the pulmonary inflammatory response without jeopardising viral defence mechanisms by downregulating expression of pro-inflammatory cytokines including IL-1, IL-6, IL-8, and TNF-α [8]. It is therefore believed that vitamin D supplements, particularly during the winter months when plasma vitamin D concentration in individuals in the UK is at its lowest, may provide a protective ‘seasonal stimulus’ against respiratory tract infections [9].

This review will evaluate the importance of the outcomes of the research by Martineau et al., determining whether there is sufficient evidence to confidently establish a correlation between incidence of respiratory tract infections and vitamin D status. It will then discuss the conclusions in relation to the impacts on public health advice, specifically the potential for recommending vitamin D supplementation.   

Method

Data extraction

An individual participant data (IPD) meta-analysis was conducted on prospective randomised double blind placebo controlled trials that assessed incidence of acute respiratory tract infection based on supplementation with either vitamin D₃ or vitamin D₂. Study characteristics, IPD and follow-up data were extracted.

Outcome definition

The primary outcome was incidence of acute respiratory tract infections, with secondary outcomes as incidence of upper and lower respiratory tract infections, emergency department or hospital attendance, use of antimicrobials, absence from work or school, incidence of serious adverse events, incidence of adverse reactions to vitamin D, and mortality.

IPD meta-analysis

One and two step IPD meta-analyses were performed for each outcome, adjusting for age, sex and study duration. The causes of heterogeneity were investigated by specifying subgroups based on baseline vitamin D status (<25nmol/L or ≥25nmol/L), vitamin D dosing regime (daily/weekly or bolus), dose size (daily equivalent <800IU, 800-1999 IU or ≥2000 IU), age, BMI and presence or absence of asthma, COPD and influenza vaccination.

Results

Overall results

By one and two-step analysis there was a statistically significant reduction in the number of individuals having at least one acute respiratory tract infection but not in time to first acute respiratory tract infection. There was a protective effect observed for acute respiratory tract infection rate.

There was a statistically significant reduction in the odds of having at least one acute respiratory tract infection for those with baseline serum vitamin D concentration of <25nmol/L, but not in those with baseline serum vitamin D concentration of ≥25nmol/L.

Daily or weekly vitamin D supplementation reduced the odds of having at least one acute respiratory tract infection whereas the bolus dose showed no effect.

Results of secondary outcomes

There was no statistically significant association with the secondary outcomes.

Vitamin D did not increase risk of adverse events with potential reactions rare. Hypercalcaemia was found in 0.5% and renal stones in 0.2% but evenly distributed between intervention and control groups.

Discussion

The IPD meta-analysis and systematic review by Martineau et al. showed vitamin D supplementation to offer a 12% reduction in the risk of suffering at least one acute respiratory tract infection [1]. These findings are not well backed up within current literature due to the limited scope of research. Avenell et al. found that the 10-15% reduction in self-reported infections and antibiotic use within a group of elderly subjects in response to regular vitamin D supplementation at 800IU was not statistically significant [10]. 

However, it has been reported by SACN that deficiency of vitamin D results in macrophages being unable to produce sufficient calcitriol, the hormonally active form of vitamin D, to upregulate cathelicidin production [4], which would impair the immune response to infectious diseases. The results by Martineau et al. also correlate with the early theory by Hope-Simpson that respiratory tract infections caused by influenza and rhinovirus have features of ‘seasonality’ due to a physiological link to solar radiation. It has been shown that exposure to UV radiation reduces the incidence of viral respiratory tract infections [11], which is biologically plausible as UVB radiation converts cutaneous 7-dehydrocholesterol to vitamin D, modifying the innate immune response. The temperature climate of the UK means that winter serum vitamin D concentration in adults in England is half that of summer, at 33.1nmol/L compared to 60.1nmol/L. During these months 42% of the population are said to have a vitamin D status that classes them as ‘deficient’ [4]. Combining this with physiological principles, it could be deemed unsurprising that epidemic outbreaks are seasonal, suggesting that the UK recommendation of vitamin D supplementation during the winter months may be beneficial to ensure serum concentration is sufficient for immunomodulatory effects to be observed.

The greatest effect of supplementation in the meta-analysis by Martineau et al. was seen within those considered vitamin D deficient, with baseline serum vitamin D concentration of <25nmol/L [1]. As a fat soluble molecule, it is stored in adipose tissue, slowly released then converted to calcitriol for use [12]. This suggests there are limitations in the effectiveness of vitamin D intake in excess of that needed to maintain serum concentration. This indicates that supplementation may be unnecessary in those with adequate dietary intake and sun exposure. However, despite the findings by Martineau et al. that there is no statistically significant effect between incidence of acute respiratory tract infections and vitamin D status based on age, the required exposure time to sunlight for the elderly is two to ten-fold that of younger adults meaning for the older age group it may remain essential [13].

Although vitamin D storage occurs, it was found by Martineau et al. that daily or weekly supplementation can have offer more protection than bolus doses [1]. A similar effect was also found by Kearns et al. where a high bolus dose was able to sustain serum vitamin D concentration in the short term but, after 90 days, this was not the case, implying regular dosing regimes would be most successful [14].This contrasts research that found that doses of ≥300,000 IU can be effective at improving vitamin D status and suppressing parathyroid hormone (PTH) concentrations for up to 3 months [10] due to the long half-life of vitamin D and slow release from fat in response to physiological requirements. If immune system modulation was proven to be maintained similar to PTH suppression the recommendation for vitamin D supplementation could be for a bolus dose at the beginning of winter. As poor compliance can result in vitamin D supplementation being accused as being inadequate at treating deficiency [15] and larger doses tend to have better adherence rates [16], this could increase the likelihood of observance and provide a more population-wide effect.

Importantly, Martineau et al. found that vitamin D supplementation caused no increase in adverse events such as hypercalcaemia and renal stones [1]. As vitamin D has a key role in regulating calcium homeostasis, it is thought that an increased intake of vitamin D may stimulate kidney stone formation. However, the magnitude of the effect is still unclear [17]. To reinforce the conclusion from the study by Martineau et al., no detectable adverse effects were found by Avenell et al. from daily supplementation with 800IU vitamin D [9], a dose is twice that currently recommended in the UK [18]. Immunomodulatory effects are thought to require higher serum vitamin D concentrations than thought to be ideal for musculoskeletal health, requiring more aggressive dosing schemes [7] meaning this research suggests there may be potential to increase UK recommendations so the desired benefits are achieved.   

Impacts

Although the mechanisms are uncertain and require more research, evaluation of the IPD meta-analysis by Martineau et al. has let it be concluded that vitamin D offers some immunomodulatory effects [1]. The greatest response was observed in those considered vitamin D deficient suggesting the benefits of supplementation for such individuals. In contrast to current public health advice, there is little evidence to suggest that vitamin D supplements are required for those with adequate vitamin D status, although this relies on dietary intake and cutaneous synthesis from UV irradiation being sufficient to maintain adequate vitamin D levels. Moreover, those ‘at risk’ such as the elderly, who make only 25% of the vitamin D of younger adults after the exposure to equivalent amounts of sunlight [10], and those consuming a diet low in oily fish, eggs and fortified dairy products or cereal, should perhaps consider supplementation. It could also be argued that current UK recommendations of all adults taking a regular vitamin D supplement during the winter months, when sunlight exposure is low, may be advantageous.  

It has been shown that there is little scientific basis for the ideal dose for immunomodulatory effects to be observed, although the most effective regime seems to be taking a low daily dose, raising vitamin D concentration sufficiently and then managing it without adverse effects. Consideration of compliance is essential in this suggestion meaning further research into the efficacy of bolus doses would be beneficial. Without clear evidence for an optimum dose, initial advice should perhaps focus on ensuring winter serum vitamin D concentration is similar to that achieved by sun exposure during the summer [10], reducing the seasonal disparity in the incidence of respiratory tract infections.

Whilst the conclusions from the meta-analysis and systematic review by Martineau et al. made the headlines, there does not seem to be enough scientific research to result in changes in recommendations regarding vitamin D supplementation on the basis of its contribution to reducing incidence of acute respiratory tract infections. However, publicity of the study may have been beneficial in the promotion of adequate vitamin D intake in the population, which would enhance calcium and phosphorous regulation and optimise musculoskeletal health [3].

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[1] Martineau, A.R. et al. (2017) Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMI, 356, 16583.

[2] Gallagher, J. (2017) Vitamin D pills ‘could stop colds or flu’. URL: http://www.bbc.co.uk/news/health-38988982 [22nd February 2017]

[3] Public Health England (2016) PHE publishes new advice on vitamin D. URL: https://www.gov.uk/government/news/phe-publishes-new-advice-on-vitamin-d [22nd February 2017]

[4] SACN (2016) Vitamin D and health. [pdf] SACN. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf [22nd February 2017]

[5] Hewison, M. (2011) Vitamin D and innate and adaptive immunity. Vitamins and Hormones, 86, 23-62.

[6] Talat, N., Perry, S., Parsonnet, J., Dawood, G., Hussain, R. (2010) Vitamin D deficiency and tuberculosis progression. Emerging Infectious Diseases, 16(5), 853-855.

[7] Yamschikowv, A.V., Desai, N.S., Blumberg, H.M., Ziegler, T.R., Tangpricha, V. (2009) Vitamin D for treatment and prevention of infectious diseases: A systematic review of randomized controlled trials. Endocrine Practice, 15(5), 438-449.

[8] Sun, J. (2010) Vitamin D and mucosal immune function. Current Opinion in Gastroenterology, 26(6), 591-595. 

[9] Dini, C., Bianchi, A. (2012) The potential role of vitamin D for prevention and treatment of tuberculosis and infectious diseases. Annali dell’Istituto Superiore di Sanitá, 48(3), 319-327.

[10] Avenell, A., Cook, J.A., Maclennan, G.S., Macpherson, G.C. (2007) Vitamin D supplementation to prevent infections: A sub-study of a randomised placebo-controlled trial in older people. Age Ageing, 36(5), 574-577.

[11] Cannell, J.J., Vieth, R., Umhau, J.C., Holick, M.F., Grant, W.B., Madronich, S., Garland, C.F., Giovannucci, E. (2006) Epidemic influenza and vitamin D. Epidemiology and Infection, 134(6), 1129-1140.

[12] Heaney, R.P., Armas, L.A.G., Shary, J.R., Bell, N.H., Binkley, N., Hollis, B.W. (2008) 25-Hydroxylation of vitamin D₃: Relation to circulating vitamin D₃ under various input conditions. The American Journal of Clinical Nutrition, 87(6), 1738-1742.

[13] NHS Cumbria (2013) Guidelines for the prescribing of vitamin D in adults. [pdf] NHS. Available at: http://www.cumbria.nhs.uk/ProfessionalZone/MedicinesManagement/Guidelines/Cumbria-Vitamin-D-Clinical-Guideline-final.pdf [28th February 2017]

[14] Kearns, M.D., Binongo, J.N.G., Watson, D., Alvarez, J.A., Lodin, D., Ziegler, T.R., Tangpricha, V. (2015) The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: A randomized, double-blind, placebo-controlled trial. European Journal of Clinical Nutrition, 69, 193-197.

[15] Segal, E., Zinman, C., Raz, B., Ish-Shalom, S. (2009) Low patient compliance – A major negative factor in achieving vitamin D adequacy in elderly hip fracture patients supplemented with 800IU of vitamin D3 daily. Archives of Gerontology and Geriatrics, 49(3), 346-367.

[16] Kearns, M.D., Alvarez, J.A., Tangpricha, V. (2014) Large, single-dose, oral vitamin D supplementation in adult populations: A systematic review. Endocrine Practice, 20(4), 341-351.

[17] Tang, J., Chonchol, M.B. (2013) Vitamin D and kidney stone disease. Current Opinion in Nephrology and Hypertension, 22(4), 383-389.

[18] NHS (2015) Vitamins and minerals – Vitamin D. URL: http://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-D.aspx [28th February 2017]