Vitamin D for prevention of respiratory tract infections

Commentary

Introduction

Respiratory tract infections are conditions that affect the air passages. These include acute infections that affect the lower respiratory tract and lungs, such as pneumonia and influenza (1), which are among the leading causes of death in children worldwide (2). In 2015, 16% of all deaths in children under five years of age were attributed to pneumonia (2). These conditions may also have an impact on quality of life (3). Therefore, it is important to find interventions that could prevent respiratory conditions.

Vitamin D is a fat-soluble-vitamin, different from others in that a major source derives from UV light-induced conversion of its precursor under the skin. Dietary sources include fortified foods and supplements. Studies have indicated that there is a high prevalence of vitamin D deficiency worldwide (4–5). Vitamin D deficiency may affect the immune system as vitamin D plays an immunomodulation role (6), enhancing innate immunity by up-regulating the expression and secretion of antimicrobial peptides (7–8), which boosts mucosal defences. Furthermore, recent meta-analyses have reported a protective effect of vitamin D supplementation on respiratory tract infections (9–12). Therefore, in this commentary we reviewed the applicability of such intervention and implementation in settings with limited resources based on these four systematic reviews and meta-analyses.

Methodology summary

This commentary provides an overview of four systematic reviews and meta-analyses (9–12). Yakoob et al. (9) conducted a Cochrane review of individually- or cluster-randomized controlled trials assessing synthetic oral vitamin D supplementation and the incidence rate of respiratory tract infection in children under five years of age. This review included trials of vitamin D supplementation at different doses and frequencies compared to a control group. The control group included placebo of propylene glycol or olive oil, or no intervention. The outcomes included in this review were incidence rate, duration, and severity of infections, particularly, pneumonia and diarrhoea. Pneumonia was confirmed by chest radiograph.

Bergman et al. (10) conducted a systematic review and meta-analysis of randomized controlled trials assessing vitamin D and incidence of respiratory tract infection, defined by each author as primary or secondary outcomes, including upper or lower infections in children and in adults; they excluded tuberculosis and fungal infections. The randomized trials compared vitamin D supplementation group to a control (no treatment or placebo) group. In this review, there were no limitations with regard to participant’s characteristics, vitamin D doses, and treatment duration.

Charan et al. (11) assessed the effect of vitamin D supplementation on the prevention of respiratory tract infections through a meta-analysis of randomized placebo controlled clinical trials in children and in adults. The outcome of this systematic review and meta-analysis was the episode of respiratory tract infection (pneumonia, influenza, common cold) in those randomized to the intervention compared to controls.

Martineau et al. (12) completed a systematic review and meta-analysis of randomized controlled trials with individual’s participant data. This review assessed the effect of vitamin D supplementation on acute respiratory tract infections in children and in adults.

These reviews used standard procedure of search terms and strategies, and presented clear search criteria and data analyses for conducting systematic reviews and meta-analyses.

Evidence summary

Yakoob et al. (9) included four trials with a total of 3198 children from Afghanistan, Spain, and the USA. Pneumonia episodes (two trials reported this) were similar between those supplemented with vitamin D compared to controls (Rate Ratio [RR]: 1.06; 95% CI: 0.89, 1.26). The trial from Afghanistan found an increase in repeat episodes of pneumonia with vitamin D supplementation (RR 1.69; 95% CI: 1.28, 2.21) but not when confirmed or unconfirmed pneumonia was combined (RR 1.06; 95% CI: 1.00, 1.13). No study reported on duration of pneumonia or severity of infection.

Bergman et al. (10) included 11 randomized placebo-controlled trials with 5660 individuals (average age was 16 years, ranging from 6 months to 75 years). The summarized results showed that vitamin D supplementation significantly decreased the risk of respiratory tract infections (odds ratio [OR]: 0.64; 95% CI: 0.49, 0.84; p=0.0014). Also, this review found that the protective effect of vitamin D was greater in studies using daily single doses (300-2000 IU/day) (OR 0.51; 95% CI: 0.39, 0.67) compared to large doses given at certain intervals (100,000 or 200,000 IU per month or every 3 months) (OR 0.86; 95% CI: 0.62, 1.20). However, there was evidence of heterogeneity and publication bias among studies.

Five clinical trials were included in the review conducted by Charan et al. (11). The reduction of episodes of respiratory tract infections was significantly lower in vitamin D supplementation group compared to the control group (OR=0.58; 95% CI: 0.42, 0.81; p=0.001). When analysed by age using fixed models, the protective effect of vitamin D supplementation was found among two trials reporting this in children (OR 0.58; 95% CI: 0.42, 0.81; P=0.001 in two trials) and among three trials reporting this in adults (OR 0.65; 95% CI: 0.47, 0.90; P=0.01). However, when using random models, the effect remained significant in children (OR 0.58; 95% CI: 0.42, 0.81; P=0.001) and it was marginal in adults (OR 0.54; 95% CI: 0.28, 1.06; P=0.08). This difference could be attributed to publication bias, low number of trials, different vitamin D doses and heterogeneity of participants.

Martineau et al. (12) included 25 randomized controlled trials, with a total of 10,933 participants aged 0-95 years from 14 different countries. Overall, there was a significant beneficial effect of vitamin D supplementation in decreasing the risk of experiencing at least one acute respiratory tract infection (OR 0.88; 95% CI: 0.81, 0.96; P=0.003). This protective effect was seen in those not receiving bolus doses (OR 0.81; 95% CI: 0.72, 0.91) vs those receiving bolus doses of ≥30000 IU (OR 0.97; 95% CI: 0.86, 1.10). Also, this effect was seen among those receiving doses <800 IU (OR 0.80; 95% CI: 0.68, 0.94; P=0.006) but not those receiving doses 800–2000 IU or >2,000 IU. Furthermore, this protective effect was seen in children 1–16 years (OR 0.60; 95% CI: 0.46, 0.77; P<0.001) but not in those aged 16-65 years or those older than 65 years. In general, there was significant heterogeneity of effect between primary trials.

Discussion

Applicability of the results

Three of the reviews consistently showed a benefit of vitamin D supplementation for preventing respiratory tract infection mainly in children younger than 16 years (10–12). Two of the reviews also reported that the protective effect is observed only when single daily doses are used but not when bolus doses are given (10, 12). One review further showed that doses of 800 IU or less were protective of respiratory tract infections, but not higher doses (12). However, this protective role was not seen for pneumonia, as reported by Yakoob et al. (9) from only two trials.

It is important to note that most reviews reported significant heterogeneity, which may make the generalizability of the results difficult. This heterogeneity may be due to several reasons, including some publication bias, but also methodological issues, such as low numbers of trials, vitamin D supplementation regime used and heterogeneity of participants’ characteristics. With respect of vitamin D supplementation regime, these reviews showed that the size of the dose and the administration intervals might modify the effects of vitamin D supplementation on respiratory tract infections. Daily smaller doses were more effective than single large boluses of vitamin D. In fact, studies have shown that large boluses may in some cases increase the risk of adverse outcomes, such as increased risk of pneumonia, suppressed proliferative responses of peripheral blood monocytes, suppressed inflammation, and greater positive sputum cultures (13–16). With respect to participant’s characteristics, body mass index as well as baseline vitamin D status may modify the 25-hydroxyvitamin D response to vitamin D supplementation (15, 17, 18).

Implementation in settings with limited resources

Vitamin D supplementation for preventing respiratory tract infection is not routinely done. For this intervention to be effective, it should be done continuously, before the respiratory tract infection starts. This could be a major challenge in many under-resourced settings, as programme managers and policy-makers will have to plan for procurement of the preparation, storage, distribution, quality-control, and compliance assurance of vitamin D supplements for children on a routine basis. Failures in implementation of this intervention have been attributed in many instances to inadequate infrastructure and poor compliance, particularly in developing countries. Intermittent vitamin D supplementation would reduce some of these challenges, although results from these trials show that bolus doses are not effective. Future studies could evaluate the effectiveness of different dosing schemes on respiratory tract infections, such as once a week, which may be easier to implement.

Further research

Additional trials testing different dosing regimen (level of dose and intervals) are needed before implementing this at a population level. Also, trials should follow up participants long enough to understand if vitamin D is still effective once vitamin D status is optimal, as once vitamin D deficiency is corrected, giving more vitamin D supplementation may not provide additional benefits. Currently, there are other randomized controlled trials testing the effects of vitamin D on risk of acute respiratory tract infection, which could help elucidate some of these issues. In addition, future studies need to report adherence to the intervention to better understand if inclusion of non-adherent participants would bias the results reported so far.

References

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2. WHO. Pneumonia. Geneva: World Health Organization; 2016. (http://www.who.int/mediacentre/factsheets/fs331/en/)

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7. Wang TT, Dabbas B, Laperriere D, Bitton AJ, Soualhine H, Tavera-Mendoza LE, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. Journal of Biological Chemistry. 2010;285(4):2227-31.

8. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1, 25-dihydroxyvitamin D3. The FASEB Journal. 2005; 19(9):1067-1077.

9. Yakoob MY, Salam RA, Khan FR, Bhutta ZA. Vitamin D supplementation for preventing infections in children under five years of age. Cochrane Database Systematic Reviews. 2016;11:CD008824.

10. Bergman P, Lindh ÅU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS one. 2013;8(6):e65835.

11. Charan J, Goyal JP, Saxena D, Yadav P. Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis. Journal of Pharmacology and Pharmacotherapeutics. 2012;3(4):300-303.

12. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.

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14. Coussens AK, Wilkinson RJ, Hanifa Y, Nikolayevskyy V, Elkington PT, Islam K, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proceedings of the National Academy of Sciences. 2012;109(38):15449-15454.

15. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Annals of Internal Medicine. 2012;156(2):105–114.

16. Manaseki-Holland S, Maroof Z, Bruce J, Mughal MZ, Masher MI, Bhutta ZA, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet. 2012;379(9824):1419-1427.

17. Martineau AR, James WY, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. The Lancet Respiratory Medicine. 2015;3(2):120-30.

18. Drincic AT, Armas LAG, van Diest EE, Heaney RP. Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity. 2012;20(7):1444-1448.

Disclaimer

The named authors alone are responsible for the views expressed in this document.

Declarations of interests

Conflict of interest statements were collected from all named authors and no conflicts were identified.