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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.i6583 (Published 15 February 2017) Cite this as: BMJ 2017;356:i6583

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Alternatives to Vitamin D supplementation of food

Though endorsing Professor Martineau’s finding from his re-analysis of data from multiple trials of Vitamin D in acute respiratory disease (1) I am sure, given the Government Scientific Advisory Group on Nutrition (SACN) 2016 report on Vitamin D after five years' deliberation not actively coming out in favour of food supplementation, it would take quite a time to initiate change in that direction after further deliberation.

What is needed now is for a short term study to give practical evidence of Vitamin D’s wider benefits while waiting for the VIDAL long term population Vitamin D trial to report (http://www.isrctn.com/ISRCTN46328341). This should aim to address the wide ranging degrees of uncertainty about Vitamin D’s value. The continued pleading for the GPs to reduce antibiotic prescriptions because of increased antibiotic resistance (https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...) , could be one area with real clinical and economic benefit for exploration of Professor Martineau’s strong data (1) taken with laboratory data showing Vitamin D rapidly improves measures of immune enhancement (2). Such a study would be a pilot randomised placebo controlled trial of vitamin D 800 vs 4,000 iu as first line of treatment (or supplement to standard of care if antibiotics are obviously required such as in acute urinary infection) verses early use of antibiotics alone in GP practices with high winter use of antibiotics. The primary target would be patients presenting with acute symptoms of respiratory infections, though other areas of high antibiotic use like acute urinary tract infection could be included. The end point would be the reduction in antibiotic use achieved over eight weeks trial and days of sick note if applicable. The aim would be to recruit the trial from 1st November 2017 to 1st March 2018 using a dried blood spot assay (3) to stratify into less than 30 and 30-60 Vitamin D levels and whether or not had flu vaccination.

Two other heavy loads in winter GP practice might also benefit from such a short term trial with similar drug usage and quality of life endpoints over 8 weeks. The first would be new acute lumbar/cervical spine problems or muscle/tendon injuries leading to time off work, and the second patients requiring off work certification for new acute neuro-psychiatric problem (4-6).

A final trial also worth considering would be to initiate all suspected cancer diagnoses entered into 2 weeks wait appointments between 1st November and 1st of March into a similar randomisation and continue those who are subsequently diagnosed with cancer for 1 year, given the 8-14% worse survival in such winter diagnosed patients at 1 year (7) and increasing evidence for a role of anaerobe promotion of inflammation associated with cancers as potential Vitamin D target to reduce (8). Given increasing evidence for mental health influencing cancer survival (9, 10) and currently unexplained association between periodontal disease and an increased Cancer risk (11, 12), inclusion of standardised short mood questionnaire and recording the impact of treatment on bleeding gums could expand our understanding of the short term benefits of Vitamin D.

Clearly with the current complexity of ethics and trial approval it would be a tough call to get through but where there is a will, a way can be found. There is clearly a need for a simplification of the process for implementing short trials of practice improvement with known safe and well tolerated drugs that is different to long term trials with potentially lethal drugs or well-known serious side effects. These trial suggestions would be a good way to start developing such a process as well as a test of whether the Department of Health is really as interested in cutting costs as it was in increasing budget spend on Tamiflu.

1. 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.
2. Martineau AR, Wilkinson KA, Newton SM, Floto RA, Norman AW, Skolimowska K, et al. IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol. 2007;178(11):7190-8.
3. Hoeller U, Baur M, Roos FF, Brennan L, Daniel H, Fallaize R, et al. Application of dried blood spots to determine vitamin D status in a large nutritional study with unsupervised sampling: the Food4Me project. Br J Nutr. 2016;115(2):202-11.
4. Gloth FM, 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging. 1999;3(1):5-7.
5. Head J, Ferrie JE, Alexanderson K, Westerlund H, Vahtera J, Kivimaki M. Diagnosis-specific sickness absence as a predictor of mortality: the Whitehall II prospective cohort study. BMJ. 2008;337:a1469.
6. Oliver T. Whitehall sickness absence and Cancer: ?Due to Sunlight deficiency http://wwwbmjcom/content/337/bmja1469?tab=responses [Internet]. 2008; 337. Available from: http://www.bmj.com/content/337/bmj.a1469/reply#bmj_el_202937?sid=096094e....
7. Lim HS, Roychoudhuri R, Peto J, Schwartz G, Baade P, Moller H. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer. 2006;119(7):1530-6.
8. Oliver R. Meta-analysis of impact of circumcision and vitamin D on occurrence of prostate cancer: Could they act by suppressing anaerobes colonizing areas of prostatic proliferative inflammatory atrophy? J Clin Oncol. 2012;30(5_suppl):259.
9. Oliver RTD. Psychological support for cancer patients. Lancet. 1989;2(8673):1209-10.
10. Stagl JM, Lechner SC, Carver CS, Bouchard LC, Gudenkauf LM, Jutagir DR, et al. A randomized controlled trial of cognitive-behavioral stress management in breast cancer: survival and recurrence at 11-year follow-up. Breast Cancer Res Treat. 2015;154(2):319-28.
11. Maisonneuve P, Amar S, Lowenfels AB. Periodontal Disease, Edentulism and Pancreatic Cancer: A Meta Analysis. Ann Oncol. 2017.
12. Momen-Heravi F, Babic A, Tworoger SS, Zhang L, Wu K, Smith-Warner SA, et al. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study. Int J Cancer. 2017;140(3):646-52.

Competing interests: No competing interests

24 February 2017
Tim R Oliver
Professor Emeritus in Oncology
Queen Mary University of London
Barts Cancer Institute Office of the Director, Charterhouse Campus, London EC1M 6BQ