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Rapid Responses: Rapid Responses published:
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multivitamins! do they help?
- girish chawla, kusum chawla (7 April 2005)
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Re: multivitamins! do they help?
- Don E Greenwood (8 April 2005)
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Response to Dr. Greenwood
- George A Heckman (15 April 2005)
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Test for essential nutrient deficiencies
- Ellen C G Grant (15 April 2005)
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Analysis may be flawed
- Kamran Abbasi (15 April 2005)
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Multivitamins probably do help
- Damien Downing (15 April 2005)
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Competing interests?
- John P. Heptonstall (16 April 2005)
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Multivitamins shorten infections
- Kevin RH Smith (17 April 2005)
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Why spoil the dream?
- Dr. Rajesh Chauhan (17 April 2005)
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Author’s response to Deputy Editor of the BMJ’s posting
- Alexander J Sutton, Alia El-Kadiki (17 April 2005)
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Supplements in Ophthalmology
- Michael A Williams, Tanya Moutray (17 April 2005)
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Concerns about studies included in review
- Susan D Shenkin, Martha C Whiteman, Alison Pattie, and Ian J Deary (20 April 2005)
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Authors' response to various postings
- Alexander J Sutton, Alia El-Kadiki (26 April 2005)
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Comment related to the importance of the specific nutrition status at baseline
- María G Joyanes, Jose M Arias de Saavedra (26 April 2005)
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Specific nutrition status at baseline, especially of zinc and copper
- Ellen C G Grant (28 April 2005)
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The effect of zinc and vitamin A on immunity was translated into similar effects on infections in elderly people
- Cristina Fortes, Shah Ebrahim, Department of Social Medicine, University of Bristol, BS8 BPR-S, England (25 May 2005)
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The Questions About Chandra (2002) and Jain (2002)
- Saul Sternberg, Seth Roberts (30 July 2005)
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girish chawla, sho intensive care walsgrave hospital, coventry cv2 2hz, kusum chawla
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Dear sir, We would like to thank the editorial committee for publishing this article. It was a great article and the fact that they looked at eight studies which showed that the role of multivitamins in elderly for prevention of infectious diseases is not clear was very impressive. We are surprised to see that these multivitamins are so extensively used in geriatric units and in community. Actually many of them are available over the counter and many elderly patients buy them thinking that it will help them. In today's era of evidence based medicene, we think it is very important that this message is passed to doctors in general practice and hospital pharmacists so that we can cut down on the unnecessary use of these multivitamins. It would have a huge cost benifit as well. It is a great article as it will change practice and save elderly people, who are already on a load of medications to have one less tablet. We hope that patients would love not to have tablets if they don`t need them. Kind Regards
Competing interests: None declared |
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Don E Greenwood, psychologist private practice
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Unfortunately no information is given about types and amounts of vitamins used, which can make a big difference. For example, synthetic vitamin E is likely to be notably less effective than natural-source mixed -tocopherol vitamin E, so we need to know which was used. If practice is to be "evidence-based", we must know what the "evidence" is in a replicable way (which we don't); so I don't see that this article has told us anything. Competing interests: None declared |
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George A Heckman, Assistant Professor McMaster University, Box 2000 Station A, Hamilton, ON, CAN L8N 3Z5
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Dear Dr. Greenwood: To be consistent with your desire for care to be "evidence-based", you would need to be able to support the claim that "synthetic vitamin E is likely to be notably less effective than natural-source mixed - tocopherol vitamin E". Such evidence, using clinically relevant outcomes assessed in a well-designed trial, does not exist. In fact, the HOPE-TOO trial used "natural" vitamin E, and found that it had no health benefits. There is no medical equivalent to "habeas corpus", "effective until proven otherwise". Regards, Competing interests: None declared |
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Ellen C G Grant, physician and medical gyanecologist Kingston, KT2 7JU, UK
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David Bender wrote that neither identifying biomarkers of optimum nutritional status, rather than the absence of deficiency; or epidemiological studies to identify nutrients associated with a lower incidence of chronic diseases, followed by intervention studies has yet provided satisfactory evidence for the benefits of a daily multivitamin supplement.1 Currently, not enough evidence exists to recommend the routine use of micronutrient supplements for an elderly population but further and more expansive studies are warranted.2 What is wrong with actually using tests which measure concentrations and functions of minerals, vitamins and essential fatty acids to see which supplemets are actually needed? I have been practising Nutritional Medicine for 35 years but never, if at all possible, without using tests of nutritional status. The commonest deficiencies impairing the immune system are of zinc and magnesium and often copper. Such deficiencies usually also impair the function of B vitamins and block essential fatty acid production. On average, healthy preconception couples taking a multivitamin and mineral supplement have a better nutritional status than non-supplemented couples, but only nutritional tests can confirm if the supplements used are being absorbed in doses needed to treat individual deficiencies in individuals. I have never been able to use a single daily multi vitamin and mineral pill to accomplish this obviously desired goal. No one would expect a single daily dose of insulin to be given to all diabetics. High wheat diets, smoking, alcohol drinking, use of hormones and exposures to toxic metals, all cause nutritional deficiencies which are seldom diagnosed and repleted. 1 Bender DA. Daily doses of multivitamin tablets BMJ 2002; 325: 173- 174. 2 El-Kadiki A. Sutton AJ. Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. BMJ 2005;330:871 (16 April), doi:10.1136/bmj.38399.495648.8F (published 31 March 2005) Competing interests: None declared |
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Kamran Abbasi, Deputy editor BMJ
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This systematic review and meta-analysis by El-Kadiki and Sutton includes a study by Ranjit K Chandra (Effect of vitamin and trace-element supplemention on immune responses and infection in elderly subjects. Lancet 1992;340:1124-7). The validity of this study has been questioned (BMJ 2004;328:67). A follow up report to this study was recently retracted, also because of concerns about its validity (Nutrition 2005;21:286). The review by Kadiki and Sutton includes a second paper by Chandra (Influence of micronutrient supplement on immune responses and infection- related illness in 50-65 year old individuals. Nutr Res 2002;22:5-11). We are further investigating the inclusion criteria for this systematic review and the data analysis. Kamran Abbasi
Competing interests: None declared |
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Damien Downing, Ecological physician, journal editor Integrative Healthcare144 Harley Street W1G 7LE
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Greenwood is certainly right to question the evidence base in this article. The authors state that only 8 of 36 potentially relevant studies met their inclusion criteria (which are not, as is claimed, specified on bmj.com that I can see). If one of their criteria had been adequate duration of study period they would not have included Chavance 1993 [1], which studied subjects for only 4 months, whereas the other 3 studies considered under the 3rd outcome all continued for 1-2 years. Excluding this paper would, on a quick calculation, have changed the incidence rate ratio from 0.89 to 0.73. The 3rd outcome result is therefore distorted by the inclusion of a single inadequate study. Under the 1st outcome, it is not readily discerned from this paper that the treatment effect (to reduce the number of days of infection by a mean of 17.45 days) amounts to a reduction of over 50% in each study. The importance of this significant outcome is thus played down. The 2nd outcome is in effect an outlying subset of the 3rd, in that it considers the change in probability of experiencing no infections during the study period (1 to 2 years), while the incidence rate ratio considers those having 1, 2, 3 infections and so on, and the change in these numbers. The odds ratio notwithstanding, in the studies considered the actual difference is 2.50% in favour of placebo — about 9 people out of 360. Outcome 2 is therefore of less clinical relevance than outcome 3. Omitting the 2nd outcome and the inadequate Chavance study would thus have yielded a very different overall finding — that multivitamin and mineral supplementation led to a significant reduction in incidence and duration of infections. Put another way, this is a poor use of meta-analysis that arrives at a questionable conclusion. 1. Chavance M, Herbeth B, Lemoine A, Zhu BP. Does multivitamin supplementation prevent infections in healthy elderly subjects?. Int J Vitam Nutr Res 1993;63: 11-6 Competing interests: Practising nutritional medicine |
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John P. Heptonstall, Director of The Morley Acupuncture Clinic and Complementary Therapy Centre. Practitioner of TCM -acu LS27 8EG
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I am at a loss in trying to understand why this “systematic review and meta-analysis of RCTs” was ever published or why the authors seem to feel their attempt to elucidate on what is a very complex subject, that they virtually admits has failed to do so, was worth publishing. The authors admit that.. 1. They analysed to reach their conclusion that “the evidence for routine use of multivitamin and mineral supplements to reduce infections in elderly people is weak and conflicting” only a “modest” number of relevant studies, that is 8. 2. They found that “considerable variability existed in the outcome definitions used to report infections” in those 8 studies. 3. “Disappointingly no more than 4 studies reported any one outcome”. 4. “The potentially conflicting results of the 3 different outcome measures could potentially be attributed to the selection of the specific trials that report that outcome”. 5. “In an attempt to obtain more comprehensive data, we contacted authors of 6 of the trials and requested further information, and sent a reminder….unfortunately no additional data were supplied for any of the trials”. 6. “No previous systematic review or meta-analysis of the use of micronutrients in preventing infections in elderly people has ever been undertaken”. 7. “Study results are heterogeneous and this particularly confounded outcome measures”. 8. “3 trials individually show a significant reduction in days of infection for the multivitamin and mineral group and the pooled estimate of a benefit of approximately 17.5 days”……after “an extreme sensitivity analysis….the pooled estimate remained similar and still significant, 14 days benefit”. Based on those observations alone I would question the integrity of their conclusion. I believe a better conclusion would have been that there could be no conclusion. What responsibility do the authors feel to elderly people, and what do elderly people gain, from the message in their conclusion? I think that informing elderly people their choice to use micronutrients and minerals, of whatever type they believe assists them to prevent and survive infections, is probably flawed (my experience is that people tend to identify supplements that benefit them - why would elderly people waste money when they do not work?) without compelling evidence of efficacy or safety one way or the other is irresponsible. Then why publish? The University of Leicester, Alexander Sutton being a member of the Department of Health sciences there, has very recently (2003) been involved in research into Influenza prevention/treatments (1) involving Alexander Sutton and others, including K. Nicholson of the Department of Microbiology and Immunology of the University of Leicester, who has numerous listed pharmaceutical interests (GSK, Wyeth, Chiron, Hoffman La Roche, Aventis Pasteur, Johnson & Johnson) all of whom offer various forms of drug based influenza and avian influenza interventions from vaccines to anti-viral drugs (such as the neuraminidase inhibitor drug Tamiflu the Blair government is said to have just spent £200 millions of public funds on, coincident with high profile media borne ‘scare mongering’ until ‘a vaccine is available for avian flu). The study in part included children and elderly, and considered prevention of, and reduction in time spent with, flu-like illnesses. Being cynical, I can see the advantage to pharmaceutical companies involved in providing vaccines and anti-virals to elderly people that might be gained if the latter loose confidence in their supplements, that may be safely and effectively inhibiting flu and other infections, due to the perhaps misguided conclusion of Sutton and El-Kadiki. Should Alexander Sutton declare a competing interest in view of the very recent involvement in research into drug therapies that could be construed as being in competition with supplements an elderly person might prefer to drug therapies? Regards John H. Reference 1. “Systematic review and economic decision modelling for the prevention and treatment of influenza A and B”, D. Turner, A Wailoo, K Nicholson, N Cooper, A Sutton, K Abrams, 2003. Competing interests: None declared |
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Kevin RH Smith, Specialist Registrar in Occupational Medicine. WellWork Ltd., Westbrooke House, Allendale Road, Hexham. NE46 2DE
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Editor, It was disappointing that El-Kadiki and Sutton(1) did not discuss the possibility that multivitamins and minerals reduce the severity, especially in terms of duration, of infections as a possible explanation for the differing results of the different parts of their meta-analysis. Their results show a statistically significant reduction in summed duration of infection (days of infection) but statistically insignificant reductions in risk of having at least one infection and infection rate. As Damien Downing points out(2), the reduced summed duration is not only statistically significant but is also significant in amounting to a reduction of 50%. Occam’s razor demands a single hypothesis that explains all results in preference to multiple hypotheses. A single hypothesis that explains these results is that maintaining good vitamin and mineral intake enables the body to respond more rapidly, and or effectively, to infections, thus shortening at least some infection episodes. The possibility that clinical infection rate is also reduced is compatible with the outcomes of their second and third outcome meta- analyses. It is biologically plausible that a rapid and effective response to infection, when extreme, leads to sub-clinical infection and thus influences measurable infection incidence. As a majority of people, regardless of age, will have at least one episode of infection in a year, the dichotomous data in the second analysis is inevitably weak, resulting in wide confidence intervals and an inability to show an effect of less than a 20% reduction in the odds ratio of at least one infection. I would take a daily multivitamin for as little as a 10% increase in the odds of having no infections for a year. The third outcome meta-analysis has data of an inherently intermediate quality: better than dichotomous but not as powerful as the recording of annual number of infection days. The 95% confidence interval is again sufficiently wide to be compatible with a 20% reduction in infection incidence. The most important outcome sought in taking supplements, I would suggest, would be reduced summed duration and severity of infection(s.) I suggest that future research be designed to test the various hypotheses that multivitamins and minerals reduce the duration, the incidence or the severity of infections. Studies designed to detect a change in incidence will need to recruit larger numbers of participants than those designed to detect a change in summed duration. Authors should be clear which hypothesis or hypotheses their statistics relate to and tailor their discussions accordingly. Dr Kevin RH Smith BSc, MB, ChB, FRCS, DTM&H, AFOM. References 1. “Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials” Alia El-Kadiki & Alexander J Sutton, BMJ 2005;330:871-4. 2. “Multivitamins probably do help” Damien Downing, BMJ rapid response 15th April 2005. Competing interests: I take vitamin C and zinc upplements with apparent good effect. |
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Dr. Rajesh Chauhan, Consultant Family Medicine & Communicable Diseases 309/9 AV Colony Sikandra, AGRA -282007. INDIA
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Where is the harm? We keep wasting a lot of money for some dreams and vague ideas. Well if oldies can pay to enjoy a multivitamin pill, must we spoil their dream? I have been a practicing physician for over 21 years and I am sure as professionals we all know what El-Kadiki A and Sutton AJ have reiterated in their “Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials”. BMJ 2005;330:871. From the experience I have gained on consumption of multivitamins by geriatric population is definitely not for enhanced longitivity. Perhaps with the regular use of these pills there may be a subconscious desire to remain healthy enough to fend for themselves till their very end, with no one to support them or their pride would not let them seek out support. Regards. Dr. Rajesh Chauhan MBBS, DFM, FCGP, ADHA, FISCD. Competing interests: None declared |
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Alexander J Sutton, Senior Lecturer in Medical Statistics Department of Health Sciences, University of Leicester, Leicester, LE1 6TP, Alia El-Kadiki
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This is, in most part, a response to the rapid response by Kamran Abbasi, Deputy Editor of the BMJ, “Analysis may be flawed”, from the authors of the original article.1 Since Dr Abbasi’s posting, we have been in telephone contact with him and following discussions, he encouraged us to write a response here. The concern of Dr Abbasi is that the systematic review and meta- analysis includes studies for which there has been concern about their validity raised publicly. We, the authors, were unaware of this controversy until we very recently received correspondence from people who had read the web-based early view version of the paper (published 31 March 2005). In light of this situation, we are currently producing a further document, for publication in the BMJ, to describe how the results and conclusions of the systematic review and meta-analysis would change if evidence from the studies under scrutiny were discounted. This will be done as quickly as possible. On the telephone, Dr Abbasi also encouraged us to write and clarify our concern with the title of his posting, “Analysis may be flawed”. Both Dr Abbasi and the authors are in agreement that the analysis may contain flawed data, but Dr Abbasi had no intention to suggest that we had used flawed methodology in conducting and reporting our systematic review and meta-analysis. We would also like to thank all people who have taken the time to post responses to our article. We intend to write a response here to these other postings in the near future. Regards, Alex Sutton ajs22@le.ac.uk Alia El-Kadiki alia@elkadiki.fsnet.co.uk Reference: 1. El-Kadiki A, Sutton AJ. Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. BMJ 2005;330:870 (16 April) Competing interests: None declared |
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Michael A Williams, SpR, Ophthalmology Royal Victoria Hospital, Belfast, Northern Ireland, Tanya Moutray
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We were interested in the paper analysing the role of supplements in preventing infection in the elderly.[1] Occasionally patients in Ophthalmology clinics ask about the use of supplements to prevent age- related macular degeneration (AMD), a disease which affects about 420 000 people in the UK.[2] Several treatments are available, such as argon laser and photodynamic therapy. However only a minority of cases are suitable for laser treatment, and treatment generally does not improve vision; rather we counsel patients that it may slow, delay or prevent deterioration. New therapies are under investigation. These include surgery such as macular translocation, injections of intravitreal steroids or intravitreal anti-growth factor antibodies, specifically anti-Vascular Endothelial Growth Factor antibodies. The ‘baby-boom’ generation are said to attack rather than wait for the inevitable effects of ageing.[3] Prevention of AMD is therefore of pertinent interest. The pathogenesis of AMD is uncertain, and so it is difficult to identify, never mind measure and compare, possible risk factors. The exposure to risk factors may be too long ago, the patients may be too ill or elderly to cooperate and the power may be limited by the low incidence of putative risk factors. The Age-Related Eye Disease Study (AREDS) investigated the role of anti-oxidant and Zinc supplements in AMD.[4] These were vitamin C (500mg per day), vitamin E (400 IU per day) and beta-carotene (15mg per day); many times the recommended daily allowance. Zinc was also given (80 mg per day) in response to a small randomised trial showing its benefit.[5] AREDS showed a consistent trend in certain patients, mostly not reaching statistical significance, towards the benefit of anti-oxidants and zinc in preventing progression of specific cases of early ‘dry’ AMD to advanced AMD (choroidal neovascularisation or geographic atrophy). What can be said to patients about supplements for AMD?[3] Typical over the counter supplements would not provide the dosages used in AREDS, and the quality control is said to be uncertain. The long-term toxic effects of such treatment are unknown, and beta-carotene may even be harmful in smokers.[6] The groups of patients who benefited from supplements in AREDS had ocular signs that would probably not cause visual symptoms. Should everybody therefore be screened, and high dose supplement prescribed when AREDS criteria are met? Should screening be targeted to those with a family history of AMD, or only one eye? It is unoriginal to end with a clarion call to encourage further studies. As is the case for treatment of infections, it may be tempting to suggest supplements for all, even though evidence is weak or lacking. Until further work is done however, our advice to patients will therefore be based on our experience and the patient’s expectations. 1. El-Kadiki A, Sutton AJ. Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. BMJ 2005;330: 871-3. 2. Owen CG, Fletcher AE, Donaghue M et al. How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? Br J Ophthalmol 2003;87:312-7. 3. Jampol LM. Antioxidants, Zinc and Age-Related Macular Degeneration. Arch Ophthalmol 2001;119: 1533-4. 4. AREDS report number 8. A randomised placebo-controlled clinical trial of high-dose supplementation with vitamins C and E, beta carotene and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol 2001;119:1417-36. 5. Newsome DA, Swartz M, Leone NC et al. Oral zinc in macular degeneration. Arch Ophthalmol 1988;106:192-8. 6. Omenn GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Eng J Med 1996;334:1150-5 Competing interests: None declared |
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Susan D Shenkin, SpR Geriatric Medicine Royal Victoria Hospital, Edinburgh, EH4 2DN, Martha C Whiteman, Alison Pattie, and Ian J Deary
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Dear Editor, We were interested to read the systematic review and meta-analysis by El- Kadiki and Sutton[1]. As with all systematic reviews and meta-analyses, the conclusions are only as good as the studies included, and we have concerns about the inclusion of three studies in the meta-analysis, on two main counts. Firstly, in the methodology, the exact age considered “elderly” is not defined, but the authors state in the discussion that, for the Barringer et al[2] (2003) study, those aged <65 years were excluded from the analysis. However, Jain[3] (2002) recruited subjects aged 51-78, and Chandra's[4] (2002) subjects were aged 50-65. Were those aged <65 in these studies excluded from the analysis? Indeed, for the Chandra[4] (2002) paper, should this have been included at all, given that all subjects were <=65? Secondly, as is now clear from the recent rapid responses, the authors (and presumably the reviewers of the paper) were not aware of the correspondence5 that ensued from Chandra’s 1992 paper[6] which is included in the meta-analysis. This letter raised questions about the methodology and statistical reporting of this study, including the point that the standard errors were implausible. Chandra’s reply[7] stated that these are standard deviations, but does not fully deal with other serious points made. We became aware of this study due to our concerns about a subsequent publication by Chandra in the journal Nutrition[8] (it is not included in the meta-analysis as it deals with the effects of supplements on cognition). These concerns have been reported and discussed at length in the BMJ[9]. Our concerns[10,11], and those of Roberts and Sternberg[12], were felt to be so serious, and Chandra’s reply to them sufficiently inadequate, that Nutrition has retracted this paper[13]. It is surprising, given the BMJ’s involvement in the investigation, that this was not raised during the review process. We feel that inclusion of Chandra’s data in a meta-analysis should mention these relevant concerns so that readers can be fully informed. Given the striking disparity between the first cluster of results (Chandra, Chandra and Jain) and the others, it might have been wise at least to run the meta-analyses with and without these data. We look forward to seeing El-Kadiki and Sutton’s proposed future publication. Yours sincerely,
1. El-Kadiki A, Sutton AJ. Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomized controlled trials. BMJ 2005; 330: 871-4. 2. Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R. Effect of multivitamin and mineral supplement on infection and quality of life. Ann Intern Med 2003; 138:365-71. 3. Jain AL. Influence of vitamins and trace elements on the incidence of respiratory infection in the elderly. Nutr Res 2002; 22: 85-7. 4. Chandra RK. Influence of multinutrient supplement on immune responses and infection-related illness in 50-65 year old individuals. Nutr Res 2002; 22:5-11. 5. Carpenter KJ, Roberts S, Sternberg S. Nutrition and immune function: a 1992 report. Lancet 2003; 361(9376): 2247 6. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992; 340: 1124-27. 7. Chandra RK Author reply to Nutrition and immune function: a 1992 report. Lancet 2003; 361(9376): 2247-8. 8. Chandra RK. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 2001; 17: 709-12. 9. White C. Three journals raise doubts on validity of Canadian studies. BMJ 2004;328: 67. 10. Shenkin SD, Whiteman MC, Pattie A, Deary IJ. Supplementation and the elderly: dramatic results? Nutrition 2002;18:364 11. Shenkin SD, Whiteman MC, Pattie A, Deary IJ. Continued concern about nutritional supplements and cognitive function in the elderly. 2004; 20(3):336 12. Roberts S, Sternberg S. Do nutritional supplements improve cognitive function in the elderly? Nutrition 2003;19:976-978. 13 Meguid MM. Retraction. Nutrition 2005;21:286. Competing interests: SS’s father is European editor of Nutrition, but has had no input into the composition of this letter. |
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Alexander J Sutton, Senior Lecturer in Medical Statistics Department of Health Sciences, University of Leicester, Leicester, LE1 6TP, Alia El-Kadiki
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Thank you to everyone who has contributed a rapid response to our article. We have addressed Dr Abbasi, the Deputy Editor of the BMJ’s concerns in a separate posting to this list. We would like to make the following points in response to other postings on our paper. Responding to Dr Greenwood’s comments. We do supply details of types and amounts of vitamins used in Table 2 of the long version of the paper although we acknowledge that “unpicking” effects of individual vitamins and minerals is beyond the scope of the meta-analysis. Responding to Dr Downings’ post. The 8 trials were selected from 36 potential relevant studies because the 28 studies were not relevant to our study question. The inclusion criteria, as explained in the paper, are: 1. Had to be a randomised controlled trial; 2. Participants had to be elderly; 3. Had to evaluate a combination of multivitamins and mineral supplements; and 4. Had to report an infection-based outcome. The 28 excluded studies were either epidemiological studies, investigated children, or looked only at "immune markers" rather than clinical infection outcomes. Dr Downing is correct in observing that the Chavance 1993 [1] study does have a shorter follow-up period than the other trials. However, meta-analysis often includes studies with differential follow-up periods since relative effects are being measured between study arms. This does make the assumption that the intervention effect is constant over time, but this is routinely assumed in meta-analysis. If more studies were available, the effect of follow-up on effect could have been investigated using meta-regression techniques. We are struggling to understand Mr Heptonstall’s objections to our paper. We do not believe that presenting a summary of a conflicting literature equates to failure, nor to us acting irresponsibly. Mr Heptonstall also questions whether Dr Sutton should declare a competing interest. This claim is made on the basis on Dr Sutton having worked with Professor Nicholson of the Department of Microbiology and Immunology of the University of Leicester, who declared interests relating to several companies developing influenza interventions, on a project evaluating the effectiveness and cost-effectiveness of prevention and treatment strategies for influenza [2]. Mr Heptonstall suggests that it may be of benefit to pharmaceutical companies developing such interventions for persons to loose confidence in the effect of multivitamins. Dr Sutton would like to clarify that the work he conducted on influenza was funded by the British government through the Health Technology Appraisal initiative and through NICE. He has no financial interest in any influenza intervention or multivitamin supplement. We thank Dr Kevin Smith for his thoughtful comments regarding the various outcomes considered. We will not comment on this here as it overlaps with our sensitivity analysis addressing concerns with the validity of certain studies that we included in the meta-analysis. We believe this will be published in the BMJ shortly. We thank Dr Chauhan for his thoughts. We agree that taking supplements may have beneficial psychological effects. However, there is a limit of vitamin intake beyond which some vitamins have been shown to cause toxicity. [3] We also wish to stress multivitamin and mineral supplements may be clinically beneficial for other clinical outcomes we did not consider in our review. We thank Dr Grant for her discussion of a test for essential nutrient deficiencies, but have nothing to add regarding this issue. Dr Shenkin and colleagues make some astute observations regarding age ranges in the studies. They are correct in suggesting they were not all the same. We did not exclude participants who were less than 65 years of age from the analysis. In an ideal world, we would have had access to the individual study data and could have made consistent age groups over which to do our analysis (in fact this was done in a meta-analysis published in the BMJ recently that Dr Sutton was involved in [4]). Alternatively, with more studies we could have looked at the influence of age using meta- regression. Unfortunately, neither of these strategies was possible here. Since Barringer et al [5] did report sub-grouped data for those less than or greater than 65 years, and they included persons as young as 45 years, we decided to use only the >=65 subgroup from this study. We believe this gave us the most homogeneous age ranges possible across studies, given the summary data available, however, we acknowledge this is a difficult issue and others may have taken different decisions. References: 1. Chavance M, Herbeth B, Lemoine A, Zhu BP. Does multivitamin supplementation prevent infections in healthy elderly subjects?. Int J Vitam Nutr Res 1993;63: 11-6 2. Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technology Assessment. 2003; 7(35):1-182. (Version also published as report 67 for National Institute for Clinical Excellence (NICE)) 3. Donnelly JG (1996) vitamins, in (eds) Kaplan LA, Pesce AJ, Kazmierczak SC. Clinical Chemistry: Theory, Analysis, and Correlation. 4th edition, Mosby. Table 39-1 4. Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in the treatment and prevention of influenza A and B: Systematic review and meta-analysis of randomised controlled trials. BMJ 2003; 326:1235-1238 5. Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R. Effect of multivitamin and mineral supplement on infection and quality of life. Ann Intern Med 2003; 138:365-71. Competing interests: None declared |
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María G Joyanes, Specialist CNA-AESA Carretera Majadahonda-Pozuelo, 28220-Majadahonda (Madrid) Spain, Jose M Arias de Saavedra
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One of the ways that epidemiological studies can obtain better results is to use more and better defined groups, which allows the specific cause of an effect to be identified. The effectiveness of the use of multivitamins and mineral supplements to prevent infections is poorly understood and remains a controversial subject. Their underlying mechanisms are still uncertain, as was described and compiled by the author: · related to improvement in immunity
Also, the authors included as potential explanation of this heterogeneity of the results the nutritional status at baseline of the study participants, among others. Beyond this possible reason, the importance of this question remains in essence the need to give supplements. If there is not a primary deficiency, is it necessary to give supplements? In addition, another separate group should be considered if there exits a secondary malnutrition that is due to the infection itself. Because of this, this criteria of separating the target populations must be contribute to clarify the result and as consequence to take measures in the assessment for supplements. If the nutritional status is good, why take supplements? Joyanes M & Lema L. Criteria for optimizing the food composition tables in relation to studies of habitual food intakes. Crit Rev Food & Nutr Sci. 18.12.2005. In press. G Arbonés A Carbajal, M González-Gross, B Gonzalvo, Mª Joyanes, I Marqués, Mª L Martín, A Martínez, P Montero, C Núñez, I Puigdueta, J Quer, M Rivero, Mª A Roset, F Sánchez-Muniz. Grupo de trabajo “Salud pública” de la Sociedad Española de Nutrición (SEN) Recomendaciones dietéticas para personas mayores. Nutr Hospital. XVIII, 3:109-137, 2003. Mª Joyanes, M GGross & A Marcos. The need of reviewing of Spanish recommended dietary energy and nutrients intakes. Eur J of Clin Nutr 56 (9):899-905, 2002. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston KT2 7JU, UK
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"Millions of people worldwide take multivitamin and mineral supplements, hoping to promote health, but few studies have documented their benefits." Why does the effectiveness of supplements in preventing infections remain controversial and poorly understood? The importance of maintaining a normal balance of copper and zinc to ensure a normally functioning immune system has been recognised for many decades but is not usually assessed. Fraker and King write that in humans and higher animals thymic atrophy, lymphopenia, and compromised cell- and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency. As the deficiency advances, a reprogramming of the immune system occurs, beginning with the activation of the stress axis and chronic production of glucocorticoids that accelerate apoptosis among pre-B and -T cells. This reduces lymphopoiesis and causes atrophy of the thymus and impairs lymphocytic production of cytokines.1,2 Deficiencies in zinc, copper and iron lead to marked immune dysfunction.3 Copper deficiency in rodents reduced the production of interleukin-2 from type 1 helper T-cells by 50% and by 75% in an in vitro human model, which also demonstrated reduced abundance of mRNA. Copper deficiency alters gene expression.4 Zinc and immunity brings up 2,610 references in Pub Med and copper and immunity brings up 1668 references. How much evidence more evidence is needed before tissue assessments of zinc and copper status become routine? 1 Fraker PJ. King LE. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr. 2004;24:277-98. 2 King JC. Specific nutrient requirements: trace elements. In: Gershwin ME, German JB, Keen CL, eds. Nutrition and Immunology; Principles and Practice. Totowa N J:Humana Press,Inc.,2000: 65-74. 3 Sherman AR. Immune dysfunction in iron, copper, and zinc deficiencies. In: Bodgen JD, Klevay LM, eds. Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals. Totawa, NJ: Humana Press Inc., 2000: 309-331. 4 Scholl TO, Reilly TM. Trace element and mineral nutrition in human pregnancy. In Bodgen JD, Klevay LM, eds. Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals. Totawa, NJ: Humana Press Inc., 2000: 115-138. Competing interests: None declared |
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Cristina Fortes, Researcher in Epidemiology Clinical Epidemiology Unit, IDI/IRCCS ; via monti di Creta, 104, 00167, Rome, Italy, Shah Ebrahim, Department of Social Medicine, University of Bristol, BS8 BPR-S, England
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Elderly people show clinical and laboratory evidence of decreased T- lymphocyte function, suffering an increased morbidity and mortality due to infections diseases. There is also evidence linking poor intake of some nutrients with impaired immunity in elderly people [1,2] Theoretically, the risk of infections could be reduced by enhanced cellular immunity, which might be improved by adequate nutrient intake. El -Kadiki and Sutton’s evaluation showed that the use of multivitamins and mineral supplements were associated with a reduction of the mean annual number of days spent with infection, but with no reduction in infection rate [3]. “Cocktail” supplementation may have little effect on infection rate owing to opposing effects of constituents [4, 5], variation in nutritional requirements, and do not allow identification of those specific nutrients that are effective. Clarifying the influence of single nutrients on the health of older people using RCTs may be a more productive way forward. We conducted a three-month double-blinded, randomised 2x2 factorial design, controlled trial of supplementation with vitamin A (800 ug) and zinc (25 mg as zinc sulphate) on 178 elderly people living in an Italian residential home. The objective of this study was evaluate if zinc and/or vitamin A supplementation improved immune response and decreased the incidence of infections in relatively fit elderly people. Infections were documented by an infection questionnaire completed by a care home doctor, by checking clinical records, and use of antibiotic therapy. Zinc treatment was associated with an increase in the absolute number of CD4+DR+T-cells (p=0.016) and cytotoxic T-lymphocytes (p=0.012). Conversely, those subjects who received vitamin A experienced a reduction in the number of CD3+ T-cells (P=0.012) and CD4+ T-cells (p=0.012) [6]. Zinc treatment was also associated with a decreased plasma lipid peroxides (TBA-RS) (beta= -0.19; 95% CI:-0.37, -0.002; p=0.05) while vitamin A had no effect [7]. By the end of one-year surveillance a total of 56 clinical infections occurred of which 14 were acute respiratory infections. The overall rate of infection was 45.9 cases per 100 person-years. There was weak evidence of a reduced risk of infection in the zinc group (RR:0.86; 95%CI:0.45 -1.6), and stronger evidence of a reduction in the duration of episodes (16 days vs. 31 days, p= 0.08) in keeping with El -Kadiki and Sutton’s findings (see Table). The effect of zinc on acute exacerbations in the small sub-set of people with chronic bronchitis was much greater but confidence intervals were wide. There were no differences between vitamin A and non-vitamin A groups in incidence rate but duration of episodes was somewhat longer in those treated with vitamin A (31 days vs. 18 days, p=0.20). The suggestive effects of zinc on infections may reflect their role in increasing CD4+ and cytotoxic T-cells [6] since both T-cells subsets play a pivotal role in controlling viral infections. The positive effect of zinc on duration of infection episodes may be explained by its antioxidant action as diminished inflammation and mucus production occurs through decreased lipid peroxidation [8]. Our findings, while imprecise, are supported by other trials demonstrating beneficial effects of zinc and no benefit from vitamin A. Future studies should attempt to avoid the limitations of our small trial. Confirmation of microbiological diagnosis of infections, and a sample size of at least 360 subjects would be needed to detect a decrease of 15% in incidence of infections (alpha=0.05 and beta=80%). Focusing on people at greater risk of infections, particularly those with chronic bronchitis, would also seem worthwhile. References 1. Lesourd BM. Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. Am J Clin Nutr 1997; 66:478- 484. 2. Namanjeet A, Jianqin S, Krause D, Mastro A, Handte. Immune function is impaired in iron deficient, homebound, older women. Am J Clin Nutr 2004; 79:516-21. 3. El-Kadiki A, Sutton AJ Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. BMJ. 2005pr 16;330:871- 877. 4. Sandstead HH Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Am J Clin Nutr. 1995; 61:621S- 624S. 5. Yadrick MK, Kenney MA, Winterfeldt EA. Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult females. Am J Clin Nutr. 1989;49:145-50. 6. Fortes C, Forastiere F, Agabiti N, Fano V, Pacifici R, Virgili F, Piras G, Guidi L, Bartoloni C, Tricerri A, Zuccaro P, Ebrahim S, Perucci CA.The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc. 1998 Jan;46:19-26. 7. Fortes C, Agabiti N, Fano V, Pacifici R, Forastiere F, Virgili F, Zuccaro P, Perruci CA, Ebrahim S. Zinc supplementation and plasma lipid peroxides in an elderly population. Eur J Clin Nutr. 1997 ;51:97-101. 8. Ohtsuka Y, Kobayashi K, Hirano T, Furukawa S, Nagano S, Takahashi T. Involvement of lipoproteins in suppression of interleukin 2-dependent cell proliferation by sera from aged humans. Gerontology. 1990;36(5-6):268 -75. Competing interests: None declared |
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Saul Sternberg, Professor of Psychology University of Pennsylvania, Philadelphia PA 19104, Seth Roberts
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In a manuscript submitted to NUTRITION RESEARCH, we question the accuracy of the Chandra (2002) and Jain (2002) articles in that journal. The manuscript, entitled "Nutritional supplements and human immune function: Did Chandra (2002) and Jain (2002) replicate Chandra (1992)?", is available at: http://www.psych.upenn.edu/~saul/chandra.replication.html Competing interests: We are coauthors of a letter in The Lancet criticizing Chandra (1992), and authors of a letter in Nutrition criticizing Chandra (2001). |
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