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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Martineau AR, Jolliffe DA, Hopper RL et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. British Medical Journal 2017;356:i6583.
The authors of the study undertook an individual participant data (IPD) meta-analysis based on 25 randomised control trials, in order to determine whether vitamin D supplementation can decrease the risk of acute respiratory tract infections. As acute respiratory tract infections are a major cause of global morbidity and mortality, many studies have reported association between low serum concentrations of 25-hydroxyvitamin D and susceptibility to such infections.
The study included randomized, double-blind, placebo controlled trials of supplementation with vitamin D3 or D2 of any duration. The studies were reanalyzed separately. Random effects model was performed for IPD meta-analysis. The heterogeneity was assessed by calculation of the standard deviation of random effects and using the I2 statistic. Further subgroup analyses was done to explore the cause of heterogeneity and identify modifying factors.
The aim of subgroup analyses was to investigate whether effects of vitamin D supplementation on risk of acute respiratory tract infection differed according to baseline vitamin D status, dosing frequency, dose size, age, body mass index, presence or absence of comrbidity and influenza vaccination status. Race or ethnicity was not investigated as a potential effect modifier, as data for this was missing for 4% of participants.
The researchers found statistically significant protective effects of vitamin D for one step analysis of acute respiratory tract infection. Two step analysis also showed steady effects for the proportion of participants experiencing at least one acute respiratory tract infection. Subgroup analysis revealed a strong protective effect of vitamin D supplementation among those with baseline circulating 25-hydroxyvitamin D levels less than 25 nmol/l and no statiscally significant effect among those with baseline levels of 25 nmol/l. When vitamin D was administered using a daily or weekly regimen the protective effect was seen in comparison to when administered as a bolus dose. Also the protective effects of daily or weekly administration was greater in both groups with baseline levels of 25-hydroxyvitamin D both above or below 25 nmol/l. P values for interaction were more than 0.05 for all other potential effect modifiers investigated. Only two factors modified the influence of vitamin D supplementation on risk of acute respiratory tract infection (i.e. baseline vitamin D status and dosing frequency).
The authors have been successful in reporting that vitamin D supplementation shows a protective effect against acute respiratory tract infections. The main benefit is seen in individuals with deficient serum 25-hydroxyvitamin D and those receiving daily or weekly supplement without any additional bolus dose. The authors state that age did not modify the effect of vitamin D supplementation. In our view, in the study a very wider age range of 0-95yrs is considered. It is proper to consider a subgroup analysis for age and other specific group should be studied separately.
Dr. Sumedha Mohan
MDS (Periodontology and Oral Implantology)
Dr. L Satyanarayana
Scientist 'G' (Epidemiology & Biostatistics)
Dr. Smita Asthana
Scientist 'D' (Epidemiology & Biostatistics)
Competing interests: No competing interests
Patently, our paper does not state that vitamin D reduces the risk of respiratory infections by 12%, either in the abstract or in the main body of the text (1). The only place that this figure appears in the BMJ is in the editorial by Avenell and Bolland (2); I am not responsible for the content of this piece. Neither does our abstract imply ‘that the benefits of vitamin D supplementation are universal and apply to all people.’ On the contrary, we highlight that the magnitude of protective effects of vitamin D against acute respiratory infection vary according to baseline vitamin D status.
It is statistically invalid to calculate relative risk reduction by halving the difference between the adjusted odds ratio and 1, as Prof Hemilä appears to do.
I questioned Prof Hemilä’s sensitivity analysis primarily on the basis that he excluded one trial from Afghanistan, seemingly because it was conducted in a ‘less developed country’, but retained another study that was conducted in the same country. This seemed inconsistent to me. I am struck by further inconsistencies in his latest response: why, for example, are findings from a trial conducted in university students more ‘relevant for ordinary people’ than findings of a trial conducted in young men undergoing military training?
I agree with Prof Hemilä that the overall estimate of the protective effect of vitamin D against acute respiratory infection is unlikely to apply to all populations similarly. This in fact was the basis for undertaking individual participant data meta-analysis in the first place. Rather than overlooking the ‘apples and oranges problem’, our paper specifically addresses it, for example by showing that protective effects of vitamin D against ARI are stronger in individuals with baseline 25(OH)D levels <25 nmol/L vs. ≥25 nmol/L.
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. Epub 2017/02/17.
2. Bolland MJ, Avenell A. Do vitamin D supplements help prevent respiratory tract infections? BMJ. 2017;356:j456. Epub 2017/02/17.
Competing interests: I am corresponding author for the paper on which Prof Hemila has commented.
The results reported by Martineau et al could be practice changing to all family physicians around the world, if the results were valid. Indeed, much effort has been invested in performing a decent, formally valid systematic review. Nevertheless, systematic reviews do not always eliminate bias in the primary research.
Suspecting bias in the primary trials included in this systematic review, I have chosen to read the trial which stands out due to its large positive effect size combined with a relatively large sample size.
This is the trial by Camargo et al [2] which indeed has a significant impact on the meta-analysis final results. This clustered randomized controlled trial allocated school classrooms in Mongolia to receive either vitamin D or non-fortified milk.
Unfortunately, randomizing whole classrooms (and not individuals) exposes this trial to very large random errors or biases. There were only 104 children in the control group, and although the authors do not report the number of classrooms, one can guess that the control group consisted of 3-5 classrooms. Since acute respiratory infection (ARI) is contagious (!), a high correlation among children in the same classroom is expected. In such a trial with this specific outcome, The real "n" in the control group is therefore not 104, but 3-5 (classrooms).
Even one classroom with special characteristics at baseline or during the study (eg respiratory viral epidemic in the classroom during the study, problems in blinding in one classrom, etc) could divert the outcome of many individuals in the same direction. This would cause a "significant" result if "n" is the number of individuals and not the number of classrooms.
To add a possible bias toward positive results of this trial, Camargo reports (table 1 in the original article) that children from classsrooms randomized to the control group were somewhat more prone to respiratory tract infection (ARI) even before intervention (P=0.16). Considering this possible selection bias, one could think that even one classroom more prone to ARI and allocated to the control arm might be the explanation of this trial's positive results.
Returning to the current meta-analysis, Martineau admits that the funnel plot was "asymetric" but interprets this as "…the possibility that small trials showing adverse effects of vitamin D might not have been included". My alternative interpretation is that negative trials, small AND large ones, might have been excluded from this meta-analysis due to significant publication bias.
In conclusion, the effort of the authors is admirable and the results are very interesting, but before testing vitamin D levels and prescribing it to every person around the globe, I wait for a decent well conducted randomized controlled trial or for a meta-analysis [3] that excluded all trials with high risk of large bias.
References
1. http://www.bmj.com/content/356/bmj.i6583
2. https://www.ncbi.nlm.nih.gov/pubmed/22908115
3. https://www.ncbi.nlm.nih.gov/pubmed/27826955
Competing interests: No competing interests
Professor Martineau claims (27 Feb) that I was not correct when I stated (17 Feb) that they had interpreted the odds ratio (OR) as an approximation for the relative risk (RR). However, anyone can read from their abstract that ”vitamin D supplementation reduced the risk of acute respiratory infection among all participants (adjusted odds ratio 0.88 ...” [1].
Given that in the medical literature OR is routinely used as an approximation of RR, their abstract states that vitamin D reduces the risk of respiratory infections by 12%. In my comment, I showed from the study-level data that the OR exaggerated the percentage effect of vitamin D more than two-fold. Thus, if we assume that the same ratio of two is also valid for the adjusted OR calculated by Martineau, then the correct estimate of the vitamin D effect would be a 6% reduction in the incidence of acute respiratory infections, which is substantially less than their abstract indicates. Martineau’s comments on the absolute effect size and NNT do not address my point.
I showed that the statistical significance of the pooled effect was not robust (17 Feb). The exclusion of two studies [2,3] led the pooled estimate to become nonsignificant. Martineau dismisses my sensitivity analysis on the basis that there are more than those two studies that have found a statistically significant benefit from vitamin D and he listed five [4-8]. However, four of those five trials he listed were conducted with quite special populations and therefore their findings cannot be directly extrapolated to the general population.
Majak (2011) restricted their trial to children with newly diagnosed asthma [4], Marchisio (2013) to children with a history of recurrent acute otitis media [5], Bergman (2012) to patients with antibody deficiency or increased susceptibility to respiratory tract infections [6], and Laaksi (2010) to young men undergoing military training [7]. Vitamin D may decrease the incidence of respiratory infections in children with asthma or in children with recurrent ear infections, etc. However, findings from those particular studies cannot be extrapolated to the population of ordinary children nor to the population of ordinary adults.
The only study in Martineau’s list [4-8] that appears potentially relevant for ordinary people is the Goodall (2014) trial which was carried out with university students in Canada [8]. However, the difference in clinical upper respiratory infections between the vitamin D and placebo groups in that study was not significant (P = 0.09, Table 2 in [8]). Thus, the 5th study in the list, that seems most relevant for ordinary people, was negative.
Martineau overlooks the ‘apples and oranges’ problem. When there is a highly significant heterogeneity among a set of trials, the existence of that heterogeneity indicates that no single estimate of effect, such as a 6% decrease in incidence, is applicable to all conditions of the included studies. Instead, different estimates should be examined for different conditions. Pooling heterogeneous studies to a single uniform estimate such as 6% does not guide further research, instead, considering the particular characteristics of the positive studies may suggest paths for future investigations.
Martineau investigated the potential role of certain variables such as vitamin D status. However, the selection of participants is also a highly relevant variable that may explain divergence between studies, but that source of variation was not considered [1]. Positive effects in certain special population groups indicates that the effects of vitamin D should be further studied in conditions close to those positive studies [2-7]. In any case, it does not seem appropriate to imply in the abstract that the benefits of vitamin D supplementation are universal and apply to all people [1].
References
[1] http://www.bmj.com/content/356/bmj.i6583
[2] https://www.ncbi.nlm.nih.gov/pubmed/22908115
[3] https://www.ncbi.nlm.nih.gov/pubmed/20723187
[4] https://www.ncbi.nlm.nih.gov/pubmed/21315433
[5] https://www.ncbi.nlm.nih.gov/pubmed/23694840
[6] https://www.ncbi.nlm.nih.gov/pubmed/23242238
[7] https://www.ncbi.nlm.nih.gov/pubmed/20632889
[8] https://www.ncbi.nlm.nih.gov/pubmed/24885201
Competing interests: No competing interests
Martineau et al. have demonstrated a clear association between incidence of acute respiratory illness and vitamin D deficiency in the 1.1-15.9 years age group (1). However, their subsequent assertion that “Vitamin D supplementation was safe” and that “These findings support the introduction of public health measures such as food fortification to improve vitamin D status” are potentially open to misinterpretation by the general public and need to be viewed with caution.
UK media coverage of this scientific study was accompanied by extrapolative quotes that “daily or weekly vitamin D supplements will mean 3.25 million fewer people would get at least one acute respiratory infection a year” (2,3). The study’s recommendations were widely re-interpreted in the national press with headlines including “Vitamin D supplements 'the key to beating colds and flu'” (Independent) and “Vitamin D 'proved to cut risk of colds and flu'“ (The Guardian).
Well intentioned but inadvertent hypervitaminosis D is not a new phenomenon. It has occurred previously in both agricultural and human nutritional interventions. In captive animals, providing vitamin supplementation is often essential in order to mimic the wild environment (4,5,6). The use of UVB light as a source of vitamin D is ideal in that it does not carry any risk of toxicity, however, over supplementation with dietary vitamin D does, and vitamin D toxicosis has been observed in mammalian breeding groups (5,7,8,9,10). Pet food has also had to be recalled due to extreme levels of certain nutrients including, but not limited to, vitamin D3 (11). The problems of dietary supplementation invariably occur when supplements are either provided in addition to a diet that is already sufficient or when the supplementary dose is too high, as is often the case in large groups, in which requirements may not be homogenous. Notably, during the 1940s and 1950s there was widespread fortification of human foodstuffs aimed at preventing rickets. However, in 1957 the Ministry of Health Joint Subcommittee on Welfare Foods needed to take action to halve infantile intake of vitamin D to tackle the increase in incidence of infantile hypercalcaemia (12,13).
In 2012-13 the UK Teratology Information Service reported concerns relating to vitamin D were in the top 15 most frequent telephone enquiries that year, reflecting an increased consumption of dietary supplements (14). An online search for “vitamin D supplement” reveals a range of easily available non-prescription preparations containing daily doses of 400 – 10,000 IU. Adoption of some of these daily supplements would supply well above the current Scientific Advisory Committee on Nutrition (SACN) recommended reference nutrient intake (RNI) from all dietary sources of 10 mcg (400 IU) vitamin D per day for the general population aged 4 years and older (15).
Whilst controlled and targeted dietary fortification may indeed be of benefit, it is important that scientific advice be carefully worded so as not to be taken out of context where it might be misconstrued to be of generalized benefit for all and indeed cause as much harm as good.
References
(1) Martineau AR et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583. doi: https://doi.org/10.1136/bmj.i6583
(2) Pickover E. Independent – 2017 February 16th. http://www.independent.co.uk/life-style/health-and-families/health-news/...
(3) Boseley S. Health Editor: The Guardian – 2017 February 15th. https://www.theguardian.com/science/2017/feb/15/adding-vitamin-d-to-food...
(4) Lopez I, Pineda C, Muñoz L, et al. Chronic vitamin D intoxication in captive Iberian lynx (Lynx pardinus). PLoS One 2016;11:1–10. doi:10.1371/journal.pone.0156331
(5) Wallach JD. Hypervitaminosis D Green Iguanas. Veterinary Medical Association 1966;149:912–4
(6) Ferguson GW, Brinker AM, Gehrmann WH, et al. Voluntary exposure of some Western-Hemisphere snake and lizard species to ultraviolet-B radiation in the field: How much ultraviolet-B should a lizard or snake receive in captivity? Zoo Biol 2010;29:317–34. doi:10.1002/zoo.20255
(7) Ferguson GW, Jones JR, Gehrmann WH, et al. Indoor husbandry of the panther chameleon Chamaeleo Furcifer pardalis: Effects of dietary vitamins A and D and ultraviolet irradiation on pathology and life‐history traits. Zoo Biology 1996;15:279–99. doi:10.1002/(SICI)1098-2361(1996)15:3<279::AID-ZOO7>3.3.CO;2-T
(8) Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. The American Journal of Clinical Nutrition 2004;79:362–71. doi:14985208
(9) Webb AR, Decosta BR, Holick MF. Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation. Journal of Clinical Endocrinology and Metabolism 1989;68:882–7. doi:10.1210/jcem-68-5-88
(10) Martínez F, Manteca X, Pastor J. Retrospective study of morbidity and mortality of captive Iberian Lynx (Lynx pardinus) in the ex situ conservation programme (2004-June 2010). Journal of Zoo and Wildlife Medicine 2013;44:845–52. doi:10.1638/2011-0165R4.1
(11) Rumbeiha W, Morrison J. A Review of Class I and Class II Pet Food Recalls Involving Chemical Contaminants from 1996 to 2008. Journal of Medical Toxicology 2011;7:60–6. doi:10.1007/s13181-010-0123-5
(12) Bransby ER, Berry WTC, Taylor DM. Study of the Vitamin-D Intakes of Infants in 1960. BMJ 1964;1:1661–3. doi:10.1136/bmj.1.5399.1661
(13) British Paediatric Association. Infantile Hypercalcaemia, Nutritional Rickets, and Infantile Scurvy in Great Britain. A British Paediatric Association Report. BMJ 1964;1:1659. doi: https://doi.org/10.1136/bmj.1.5399.1659
(14) National Poisons Information Service Report 2012/13. Public Health England. http://www.npis.org/NPISAnnualReport2012-13.pdf
(15) SACN vitamin D and health report. Public Health England (21st July 2016) https://www.gov.uk/government/publications/sacn-vitamin-d-and-health-report
Competing interests: No competing interests
I thank Professor Hemilä and Dr Holmes for taking the time to comment on our work.
Professor Hemilä implies that we have interpreted the odds ratio as an approximate relative risk – but this is not the case. I draw his attention to the methods section of our paper (1), where we highlight that absolute effect sizes were calculated from odds ratio data using the Visual Rx NNT calculator (www.nntonline.net/visualrx/). The resultant absolute risk reductions are presented in the Summary of Findings Table, and these were used to calculate NNTs presented in the manuscript. With respect to exploration of potential causes of heterogeneity: understanding these causes was the very reason why we felt it necessary to conduct an individual participant data meta-analysis as opposed to an aggregate data meta-analysis, and our pre-specified sub-group analyses were specifically conducted to address this issue (Tables 2 and 3). We identified two potential factors: baseline vitamin D status and dosing interval. Prof Hemilä’s rationale for wishing to exclude trials by Camargo et al (2) and Manaseki et al (3) is not clear to me: what is so ‘very special’ about Mongolian schoolchildren or 1-36 month old children in Afghanistan that justifies their post hoc exclusion from the meta-analysis? If the issue relates to ‘development’ of countries, why exclude a trial conducted in Mongolia (2) (which is ranked as a lower-middle income country by the World Bank), but retain another study conducted in Afghanistan (4) (ranked as Low Income)? The fact that many trials conducted in higher-income settings reported protective effects of vitamin D against ARI (5-9), while other trials conducted in lower-income settings reported no protective effects (4, 10), goes against the hypothesis that the degree of ‘development’ of a country influences vitamin D responsiveness. Furthermore, the biological explanation for such a phenomenon is not proposed: just like higher income countries, lower income countries are heterogeneous with respect to potential effect modifiers such as baseline vitamin D status and nutritional status.
In response to Dr Holmes: we pre-specified that we would use random effects modelling in the protocol of the meta-analysis, on the grounds that this is the most appropriate approach to take when results of trials are heterogeneous. The adjusted OR that Dr Holmes generates using fixed-effect modelling of data presented in Figure 2 (0.88, 95% CI 0.81 to 0.96) is in fact identical to the adjusted OR that we obtained in the one-step IPDMA using random effects modelling. The choice of modelling method does not therefore appear to have major effects on the estimate of effect size.
I acknowledge that there is a degree of asymmetry in the funnel plot, indicating that some small trials showing adverse effects of vitamin D might have escaped our attention. However, I reiterate the point made in the Discussion that if one or two small trials showing large adverse effects of vitamin D were to emerge, we do not anticipate that they would greatly alter the results of the one step IPD meta-analysis, since any negative signal from a modest number of additional participants would likely be diluted by the robust protective signal generated from analysis of data from nearly 11,000 participants. The rationale for excluding smaller trials post hoc is not clear to me, as there is no reason to suppose that bigger trials are necessarily more methodologically sound than smaller ones. Indeed, the largest RCT included in our meta-analysis (4) utilised an intermittent bolus dosing regimen, which sub-group analyses suggest may be less effective than daily or weekly supplementation regimens for reducing ARI risk (1).
References
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. Epub 2017/02/17.
2. Camargo CA, Jr., Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130(3):e561-7. Epub 2012/08/22.
3. Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health. 2010;15(10):1148-55. Epub 2010/08/21.
4. 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):1419-27. Epub 2012/04/13.
5. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamaki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis. 2010;202(5):809-14. Epub 2010/07/17.
6. Bergman P, Norlin AC, Hansen S, Rekha RS, Agerberth B, Bjorkhem-Bergman L, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2(6):e001663. Epub 2012/12/18.
7. Marchisio P, Consonni D, Baggi E, Zampiero A, Bianchini S, Terranova L, et al. Vitamin D supplementation reduces the risk of acute otitis media in otitis-prone children. Pediatr Infect Dis J. 2013;32(10):1055-60. Epub 2013/05/23.
8. Goodall EC, Granados AC, Luinstra K, Pullenayegum E, Coleman BL, Loeb M, et al. Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial. BMC infectious diseases. 2014;14:273. Epub 2014/06/03.
9. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 2011;127(5):1294-6. Epub 2011/02/15.
10. Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, Arora H, et al. Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India up to age 6 months: randomised controlled trial. BMJ. 2011;342:d2975. Epub 2011/06/02.
Competing interests: I am the corresponding author of the article on which these authors have commented.
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
Rather than attacking the press for hyped, fashionably called "fake" news, as do several of the rapid responders, missed are the important issues raised in (1).
1. There is a highly significant benefit in respiratory tract infections in those with the lowest baseline level, <25nmol/L hydroxyvitamin D, which is a clear deficiency never found in those who regularly expose their skin to >45º above the horizon sun, an angle needed for the required UV-B to reach ground level, or in those regularly taking above minimal amounts of supplements.
2. The presence of such low common deficiency levels(2) alone is worthy of extensive press and medical world attention.
Regardless of a putative benefit in infections in some, all cell types have vitamin D receptors, indicating a system wide need that also includes bone health. Clearly we need more studies and I would propose one inspired by the cheapest and most creative ones ever by Trividi, Doll and Khaw(3), using the mail system and Freepost response cards. Supplied were 800 IU/d of D3 (as 100,000 IU 3x/year) and a 30% reduction of fractures of the "main osteoporotic sites" was found after 5 years, with other main events trending in the right direction. Unfortunately there was no question about respiratory illness.
For some perspective and while the experts debate, here in North America bottles with 1000 (25 mcg) or 2000 IU daily doses are on store shelves. However without that daily bother, 50,000 IU pills, a small bolus, taken in the order of monthly are available on-line at about $0.30 each, a consumer decision based on season and on personal risk, all over-the-counter thus indicating safety, as reported in (1).
1. A.R. Martineau et al. doi: https://doi.org/10.1136/bmj.i6583
2. 2. K.D. Cashman et al http://ajcn.nutrition.org/content/103/4/1033.long
3. Trivedi, Doll & Khaw. http://www.bmj.com/content/326/7387/469.long
Competing interests: No competing interests
The meta-analysis on vitamin D and respiratory infections by Martineau et al. [1] has two major problems: 1) the use of the odds ratio (OR) as the effect measure and 2) not exploring potential causes for the highly significant heterogeneity between the trials.
Altman et al. pointed out that “The odds ratio should not be interpreted as an approximate relative risk [RR] unless the events are rare in both groups (say, less than 20-30%)”[2]. Acute respiratory infections are not rare. In Figure 2 of the Martineau et al. meta-analysis, only 2 of the 24 trials had event rates less than 20% in both groups [1]. I reproduced their Figure 2 using the random effects Mantel-Haenszel approach and calculated OR=0.82 (95% CI 0.72 to 0.95) for the 24 trials. The minor discrepancy with their published OR is explained by adjustments [1]. The Figure 2 data gives RR=0.92 (95% CI 0.87 to 0.98). Thus, the OR suggests that the incidence of respiratory infections might be reduced by 18%, but the RR shows that 8% reduction is the valid estimate. Thus, OR exaggerates the effect of vitamin D by over two times.
When there is highly significant heterogeneity, researchers should explore causes for the heterogeneity. Of the included studies, Camargo et al. [3] and Manaseki et al. [4] found significant effect of vitamin D on the risk of respiratory infections. However, the former was carried out with Mongolian schoolchildren and the latter with 1-36 months old children in Afghanistan. If those two trials are removed from the meta-analysis in a sensitivity analysis, the evidence of heterogeneity decreases substantially (from P=0.001 to P=0.04) and the evidence of benefit from vitamin D vanishes to RR=0.95 (95% CI 0.90 to 1.00; P = 0.07; based on 4157 infections among 10202 participants in the remaining 22 trials).
Thus, the positive overall finding in the meta-analysis of all the 24 trials depends on the inclusion of the two trials carried out in Mongolia and in Afghanistan, with very special participants [3,4]. Panagiotou et al. showed that for many treatments, the efficacy was substantially greater in less developed compared with more developed countries [5]. It is possible that the effects in the two trials were genuine [3,4], but their findings should not be extrapolated to populations of more developed countries, neither to adults and not even to children.
References
[1] http://www.bmj.com/content/356/bmj.i6583
[2] http://www.bmj.com/content/317/7168/1318.1
[3] https://www.ncbi.nlm.nih.gov/pubmed/22908115
[4] https://www.ncbi.nlm.nih.gov/pubmed/20723187
[5] http://www.bmj.com/content/346/bmj.f707
Competing interests: No competing interests
Re: Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data
It is good to read this research article, “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data”. [1] The investigators said the evidence contributing to these analyses was assessed as being of high quality, but the 2% absolute risk reduction reported (from 42% to 40%) is not a sufficient justification for taking supplements.
Although Vitamin D supplementation was safe and effective in patients who were vitamin D deficient, manufacturers have been taking advantage of these findings to target health conscious consumers for health benefits because of wide coverage of this report in the media. This is not a good trend.
Regards.
Dr. Rajiv Kumar
Faculty, Deptt. of Pharmacology, Government Medical College & Hospital,
Chandigarh160030. India. DRrajiv.08@gmail.com
References:
1. BMJ 2017;356:i6583
Competing interests: No competing interests