February 15, 2017

expert reaction to study investigating the impact of vitamin D supplements on acute respiratory infections

In a systematic review and meta-analysis published in the British Medical Journal, scientists report that daily or weekly vitamin D supplementation was safe and reduced the risk of acute respiratory infections overall, but particularly in individuals with low levels of vitamin D.

Dr Benjamin Jacobs, Consultant Paediatrician, Royal National Orthopaedic Hospital, said:

“Martineau’s study is a major step forward. It shows strong evidence of benefit and safety of vitamin D supplements from a rigorous analysis of 25 clinical trials. The benefits of Vitamin D for bone health are already widely accepted, but many sceptics still deny other health benefits.
“Martineau’s study shows a clear reduction in respiratory infection in people taking vitamin D, including patients of all age groups. The main caveat is the finding that vitamin D was only effective if given daily or weekly.  Large doses given once a month, or even less frequently, did not show benefit and may even be harmful.

“Bolland and other sceptics try, but fail, to find weaknesses in Martineau’s analysis. Martineau’s data is strong, from 11,000 patients in good quality clinical trials around the world. The case for universal vitamin D supplements, or food fortification with vitamin D, is now undeniable. Governments and health professionals need to take Martineau’s study into account when setting Vitamin D policy now.”

Ms Catherine Collins, Registered Dietitian & Spokesperson for The British Dietetic Association, said:

“Vitamin D has the most complex backstory of all the nutrients we need. It isn’t a vitamin – it’s a prohormone we make following bare skin exposure to sunlight. But ‘sunsafe’ messages about sun exposure and skin cancer, lifestyle and cultural demands means that for many people dietary intake is now their main source of Vitamin D. And as many people don’t like oily fish or liver our dietary intake is inadequate and deficiency increasingly common.

“Blood tests for Vitamin D deficiency measure the inactive pro-hormone, as ‘active’ Vitamin D is made ‘on demand’ from parathyroid gland responding to blood calcium levels.  Measuring ‘active’ 1,25 Vitamin D is merely a marker of parathyroid gland activity, not vitamin sufficiency. Add to this the difficulty in interpreting blood levels based on predicted dietary intake and bioavailability, with vitamin status complicated by sunlight exposure, and status influenced by skin colour, age and body fat stores, then Vitamin D becomes a difficult nutrient to investigate. Yet Vitamin D has important functions beyond bone health, and the effect on the immune system overall has been the subject of many research studies.

“This paper confirms the established role of Vitamin D on the immune system, and confirms that for the Vitamin D deficient, supplements have an important role in supporting immune function. It appears to show that ‘less is more’ when it came to supplement choice, reinforcing Department of Health and the European Food Safety Authority (EFSA) guidelines that a 10μ daily supplement is optimal for those taking few vitamin D rich foods and who avoid sun exposure.

“Large-dose supplements appeared less effective than lower dose versions in this review. Whilst study numbers were small, this makes physiological sense. Our bodies prefer smaller amounts akin to normal food exposure, rather than large, pharmacological nutrient doses. To put into context, the definition of a large dose in this study – one providing at least 30,000 IU/ 750mcg – provided a vitamin D equivalent of eating 75 salmon fillets, or 750 egg yolks, or 20 tubs of margarine in one sitting.

“The researchers attempted to unravel the impact of vitamin D supplement across age groups, respiratory conditions, and supplement options. They showed a modest but significant 12% reduction in symptoms (OR 0.88; 95% CI 0.81-0.96) across almost 11,000 people studied.   Effect of supplements was most striking in those with confirmed deficiency (42% reduction: OR 0.58; 95% CI 0.40 to 0.82, p <0.002).  Children also seemed to benefit, with a summary of 8 trials confirming a 40% reduction in symptoms (OR 0.60; CI 0.46-0.77).  They didn’t find any protective effect in babies, although with breast milk, infant formula, baby vitamin drops and some weaning foods already providing Vitamin D this is perhaps not unexpected given the small number of studies available for review.

“Nutrient research is usually conducted in a very defined group to limit the impact of natural variation on outcomes evaluated. A valid criticism of this study suggested the outcome was compromised by the variety of age groups and health issues studied. But when it comes to population messages we live in a similar ‘heterogenous’ society exposed to ‘one size fits all’ health messages, and so dietetically this meta-analysis is relevant.”

Prof. Martin Hewison, Professor of Molecular Endocrinology, University of Birmingham, and member of the Society for Endocrinology, said:

“This is an important study that matches the previous study by Bolland and colleagues in terms of the rigour and breadth of the systematic review, but it includes several significant advances on the previous publication.  Firstly, in contrast to the previous study, the authors of the current BMJ article stratified their data to show that the greatest benefit was observed for subjects who were vitamin D-deficient prior to vitamin D supplementation. Thus trials where supplemented subjects are vitamin D sufficient at the start are much less likely to show positive effects. This may explain some of the negative data published in the previous BMJ article.  Secondly, the current study shows that vitamin D supplementation is only effective when given as a daily or weekly dose, rather than the large dose bolus supplements given less frequently. This strongly suggests that although bolus vitamin D supplements are convenient (easier to confirm compliance), this approach may hinder vitamin D efficacy, possibly by triggering feedback control mechanisms that attenuate vitamin D responses. Whatever the case it is clear that some types of vitamin D supplementation are more likely to be effective than others, and this may cause further confusion when analysing multiple trials.  One final important point to make is that the current study of vitamin D supplementation and respiratory infection in human subjects is strongly supported by many pre-clinical publications describing multiple mechanisms by which vitamin D can induce antibiotic immune responses. These extensive mechanistic studies provide a clear explanation for how vitamin D can achieve the protective effects described in the current BMJ article.

“The implications of this study are as striking as the previous paper. I agree with the authors that this study supports a new indication for vitamin D (beyond its established benefits for bone health).  This may be particularly important for people in the UK who are at high risk of vitamin D-deficiency, particularly in the winter.  The Science Advisory Council on Nutrition (SACN) recently recommended intake of additional vitamin D for the whole UK population to prevent vitamin D-deficiency. SACN indicated that their recommendations were particularly relevant for people who are at increased risk of vitamin D-deficiency: those with darker skin from African, Afro-Caribbean and South Asian backgrounds; people who are confined indoors, and people who cover up their skin while outdoors.  The current study endorses SACN’s advice, but we also have to consider that antibiotic effects of vitamin D may require higher doses than currently recommended by SACN. Further trials to assess the effects of vitamin D on respiratory infection are essential.”

Prof. Catherine Hawrylowicz, British Society for Immunology spokesperson, and Professor at King’s College London, and Deputy Director of the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma said:

“Observational and experimental studies predict that vitamin D supplementation will reduce susceptibility to acute respiratory tract infections, but clinical trials, which vary greatly in design, have not consistently shown benefit.

“This meta-analysis and systematic review is the largest yet performed and is important because it begins to tease out why this might be so. Whilst the effects across the whole population were modest, the authors highlight that giving vitamin D frequently and to individuals who are profoundly vitamin D deficient has a much greater benefit.

“These findings are likely to be particularly important in individuals for whom acute respiratory tract infections are life-threatening, such as those with asthma and COPD, who are frequently profoundly vitamin D deficient. Since the authors conclude that vitamin D is safe, further targeted studies in such ‘at risk’ populations seem highly desirable.”

Prof. Louis Levy, head of nutrition science at Public Health England, said:

“Based on evidence reviewed by the Scientific Advisory Committee on Nutrition (SACN), we recommend that certain population groups take a daily 10 micrograms Vitamin D supplement year round and everyone considers taking one during the autumn and winter months to protect musculoskeletal health.

“The evidence on Vitamin D and infection is inconsistent and this study does not provide sufficient evidence to support recommending Vitamin D for reducing the risk of respiratory tract infections.”

Background:

• Current advice on Vitamin D is based on the recommendations of the Scientific Advisory Committee on Nutrition (SACN) following its review of the evidence on Vitamin D and health.
• In order to protect musculoskeletal health, SACN recommended that the blood concentration of all individuals in the UK should not fall below 25 nmol/L at any time of the year and gave advice on the Vitamin D intake required to support this.
• In its report on Vitamin D and Health, SACN concluded that evidence on Vitamin D and infection is inconsistent.

Current recommendations on Vitamin D:

• PHE advises that in spring and summer, the majority of the population get enough Vitamin D through sunlight on the skin and a healthy, balanced diet. During autumn and winter everyone will need to rely on dietary sources of Vitamin D.  Since it is difficult for people to meet the 10 microgram recommendation from consuming foods naturally containing or fortified with Vitamin D, people should consider taking a daily supplement containing 10 micrograms of Vitamin D in autumn and winter.
• People whose skin has little or no exposure to the sun, like those in institutions such as care homes, or who always cover their skin when outside,  risk Vitamin D deficiency and need to take a supplement throughout the year.  Ethnic minority groups with dark skin, from African, Afro-Caribbean and South Asian backgrounds, may not get enough Vitamin D from sunlight in the summer and therefore should consider taking a supplement all year round.
• Children aged one to four years should have a daily 10 microgram Vitamin D supplement. PHE recommends that babies are exclusively breastfed until around six months of age. As a precaution, all babies under one year should have a daily 8.5-10 microgram Vitamin D supplement to ensure they get enough. Children who have more than 500ml of infant formula a day do not need any additional Vitamin D as formula is already fortified.

* ‘Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data” by Martineau et al. published in The BMJ on Wednesday 15th February. 

Declared interests

Dr Benjamin Jacobs: No conflicts of interest.

Ms Catherine Collins: No conflicts of interest.

Prof. Martin Hewison: No conflicts of interest.

Prof. Catherine Hawrylowicz: She has received peer-reviewed funding (MRC, Asthma UK) to study the immunological mechanisms by which vitamin D may improve respiratory health, and benefit patients with asthma.

Prof. Louis Levy: None received.