Skip Navigation


Age and Ageing Advance Access originally published online on August 15, 2007
Age and Ageing 2007 36(5):574-577; doi:10.1093/ageing/afm091
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
36/5/574    most recent
afm091v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (10)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Avenell, A.
Right arrow Articles by MacPherson, G. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Avenell, A.
Right arrow Articles by MacPherson, G. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438)

SIR—There is increasing interest in the influence of vitamin D on tissues other than bone [1]. Active vitamin D (1,25-dihydroxyvitamin D3) is an important regulator of the immune system and has been most studied with regard to autoimmunity, where it acts as an immunosuppressant [2]. The influence of 1,25-dihydroxyvitamin D3 on infection in vitro and in animal models has been little studied [3]. Mouse studies have suggested that 1,25-dihydroxyvitamin D3 enhances Mycobacterium bovis killing [4], but increases the susceptibility to Toxoplasma gondii [5]. 1,25-dihyroxyvitamin D3 directly regulates antimicrobial peptide gene expression, which could enhance host defence against infection [6–8].

Case control studies have found associations between vitamin D deficiency and tuberculosis in Asians in the UK [9] and severe acute lower respiratory and gastrointestinal infections in children in Ethiopia, Turkey, India and Jordan [10–13]. Peripheral blood T lymphocytes were significantly decreased in Turkish children with rickets [14], and children with rickets were found to have reduced neutrophil motility [15] and phagocytosis [16].

We have been unable to find any randomised controlled trials of vitamin D supplementation, which have examined the incidence of infection in at-risk groups. Rehman [17] reported reductions in respiratory infections and febrile illnesses in a group of Indian children with high alkaline phosphatase levels, but no clinical evidence of rickets as a result of vitamin D and calcium supplementation. A randomised trial of co-administration of intramuscular 1,25-dihydroxyvitamin D3 with influenza vaccine was not found to enhance humoral immunity in healthy young volunteers, whose vitamin D status was not described [18].

At a conservative estimate, at least 8% of UK community-dwelling older people, and 32% of older people living in institutions have vitamin D deficiency (serum 25-hydroxyvitamin D3 levels below 25 nmol/l) [19, 20]. However, there is some evidence that the optimal serum 25-hydroxyvitamin D3 level for health could be as high as 90–100 nmol/l [21].

As an adjunct to the RECORD trial [22], a blinded, randomised, placebo-controlled trial of oral vitamin D3 and/or calcium supplementation for the secondary prevention of osteoporotic fractures, we examined whether vitamin D was associated with a reduction in self-reported infections and antibiotic use.

Methods

Five thousand two hundred and ninety-two participants were randomised within a factorial design to 800 IU (20 µg) daily vitamin D3, 1,000 mg calcium (calcium carbonate), both, or placebo, and followed up for 24–62 months. The trial was based in 21 centres in England and Scotland. Ethical approval was obtained from the Multicentre Research Ethics Committee for Scotland and each centre's Local Research Ethics Committee. Participants gave written informed consent. Full details and main results of the trial are reported elsewhere [22].

In March 2002, when 25-hydroxyvitamin D3 levels are lowest in older people in the northern hemisphere [19], all trial participants who were alive, or had not withdrawn from filling in questionnaires were sent a reply-paid postal questionnaire. This asked if they had had an infection or received antibiotics in the previous week.

We compared all participants who had been randomised to take vitamin D3 with all participants who had not been randomised to D3 (i.e. intention-to-treat analysis), using multiple logistic regression (adjusted for the trial minimisation factors of gender, age, type of enrolling fracture and time since fracture).

Results

Three thousand four hundred and forty-four participants responded to the questionnaire at a median (interquartile range) time of 18 (11–25) months since randomisation. Based on questionnaire responses, at least 55% of trial participants were still taking their tablets. Of the respondents randomised to vitamin D3, 17.2% (300/1,740) reported an infection, compared with 18.8% (321/1,704) on placebo (adjusted odds ratio 0.90, 95% confidence interval 0.76 to 1.07, P = 0.23) (Table 1). A percentage of 6.4 (111/1,737) randomised to vitamin D3 reported antibiotic use compared with 7.5% (128/1,703) on placebo (adjusted odds ratio 0.84, 95% CI 0.64 to 1.09, P = 0.18).


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline characteristics and reported infections and antibiotic use during window week

 
‘Per protocol’ analyses, based on tablet taking when completing the questionnaire, showed smaller odds ratios for infection (0.80, 95% CI 0.64 to 1.01, P = 0.06) and antibiotic use (0.74, 95% CI 0.52 to 1.06, P = 0.10).

Adverse events such as hypercalcaemia, renal stones and renal impairment were rare and did not differ between those people receiving vitamin D3 or not.

Discussion

Although the observed differences were consistent with vitamin D reducing the risk of infection, the results were not statistically significant. ‘Per protocol’ analyses showed smaller odds ratios for infection and antibiotic use, but the concern about such ‘per protocol’ analyses is that they are prone to bias, however, rates of tablet taking were similar for vitamin D3 and placebo groups. Non-compliance may therefore have reduced the protective effect. Our questions may also have been too crude, and it might have been preferable to ask participants to keep diaries for longer and to record the length, type and severity of infections.

Only 6% of the RECORD trial participants could not walk out-doors unaccompanied: hence, our participants were likely to have had higher sunlight exposure for vitamin D manufacture in the skin than less mobile older people and be less likely to benefit. The 25-hydroxyvitamin D3 level from a small sample of 60 trial participants in Southampton and Newcastle, measured from February to July before supplementation averaged 38 (SD 16) nmol/l by high-performance liquid chromatography [22], similar to the mean level for older people in institutions in recent UK surveys [19, 20]. After 1 year of supplementation in these participants 25-hydroxyvitamin D3 was 62 (SD 16) nmol/l.

Based on data from studies of bone mineral density, lower-extremity function, falls, fractures, colorectal cancer and dental health, Bischoff-Ferrari and colleagues have argued that serum concentrations of 25-hydroxyvitamin D3 should be 75 nmol/l or more, with optimal levels at least 90–100 nmol/l [21]. In older people, an intake of >=1000 IU (25 µg) vitamin D3 could bring 25-hydroxyvitamin D3 to 75 nmol/l in more than 50% of the population [21]. However, the studies contributing these data used different methods for determining serum 25-hydroxyvitamin D3 and rarely reported compliance. Currently available assays for 25-hydroxyvitamin D3 do not agree well, so that assay-specific decision limits have been suggested for assessing compliance and 25-hydroxyvitamin D3 status [23]. Further research is needed to assess the effect of a higher dose of vitamin D on infections in populations at high risk of insufficiency.

Key points

  • 1,25-dihyroxyvitaminD3 is an important regulator of the immune system.
  • Vitamin D deficiency is common in older people in the UK, particularly in people living in institutions.
  • Daily supplementation with 800 IU vitamin D3 (20 µg) was well tolerated by older people living in the community, with no detectable adverse effects.
  • Supplementation was associated with fewer self-reported infections and antibiotics, but the estimated 10–15% reduction was not statistically significant.
  • Further randomised trials of vitamin D and infections are warranted in at-risk populations.

Conflict of interest statement

None declared for the authors. Conflict of interest statements for other members of the RECORD Trial Group are given in reference number 22.

Record Trial Group

Record Trial Management Group
Health Services Research Unit, University of Aberdeen, Aberdeen, UK (AM Grant, A Avenell, MK Campbell, AM McDonald, GS MacLennan, GC McPherson); University of Southampton, UK (FH Anderson); MRC Epidemiology Resource Centre, University of Southampton, UK (C Cooper); Freeman Hospital, Newcastle-Upon-Tyne (RM Francis); Centre for Health Services Research and Business School—Economics, University of Newcastle-Upon-Tyne, UK (C Donaldson); The Hull York Medical School, Hull, UK (WJ Gillespie); Royal Infirmary of Edinburgh, UK (CM Robinson); Department of Health Sciences, York, UK (DJ Torgerson); Queens Medical Centre, Nottingham, UK (WA Wallace).

Record Trial Biochemical Analyses
WD Fraser, Royal Liverpool University Hospital, Liverpool.

Further members of the RECORD Trial Group are listed in reference 22

Acknowledgements

We thank the patients who took part in the RECORD study, without whose help this study would not have been possible. The MRC funded the central organisation of RECORD, and Shire Pharmaceuticals funded the drugs, which were co-funded and manufactured by Nycomed. Shire Pharmaceuticals and Nycomed were given the opportunity to comment on the penultimate version of this trial report. However, the trial was conducted, analysed and reported independently of all the funding parties.

Alison Avenell*, Jonathan A. Cook, Graeme S. MacLennan and Gladys C. MacPherson

Health Services Research Unit, Third Floor, Applied Health Sciences Building, School of Medicine, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK

* To whom correspondence should be addressed E-mail: a.avenell{at}abdn.ac.uk

References

  1. Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr (2003) 89:552–72.[CrossRef][Web of Science][Medline]
  2. Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (2003) 49:277–300.[Web of Science][Medline]
  3. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr (2004) 80:1717S–20.[Abstract/Free Full Text]
  4. Waters WR, Palmer MV, Nonnecke BJ, Whipple DL, Horst RL. Mycobacterium bovis infection of vitamin D-deficient NOS2–/– mice. Microb Pathog (2004) 36:11–7.[CrossRef][Web of Science][Medline]
  5. Rajapakse R, Mousli M, Pfaff AW, et al. 1,25-dihydroxyvitamin D3 induces splenocyte apoptosis and enhances BALB/c mice sensitivity to toxoplasmosis. J Steroid Biochem Mol Biol (2005) 96:179–85.[CrossRef][Web of Science][Medline]
  6. Wang T-T, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol (2004) 173:2909–12.[Abstract/Free Full Text]
  7. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide CAMP gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J (2005) 19:1067–77.[Abstract/Free Full Text]
  8. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin-D mediated human antimicrobial response. Science (2006) 311:1770–3.[Abstract/Free Full Text]
  9. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet (2000) 355:618–21.[CrossRef][Web of Science][Medline]
  10. Beser E, Cakmakci T. Factors affecting the morbidity of vitamin D deficiency rickets and primary protection. East Afr Med J (1994) 71:358–62.[Web of Science][Medline]
  11. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet (1997) 349:1801–4.[CrossRef][Web of Science][Medline]
  12. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory tract infection in Indian children under 5y. Eur J Clin Nutr (2004) 58:563–7.[CrossRef][Web of Science][Medline]
  13. Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Paed (2004) 50:364–8.[CrossRef]
  14. Yener E, Coker C, Cura A, Keskinoglu A, Mir S. Lymphocyte subpopulations in children with vitamin D deficient rickets. Acta Paed Japon (1995) 37:500–2.
  15. Lorente F, Fontan G, Jara P, Casas C, Garcia-Rodriguez MC, Ojeda JA. Defective neutrophil motility in hypovitaminosis D rickets. Acta Paediatr Scand (1976) 65:695–9.[Web of Science][Medline]
  16. Stroder J, Kasal P. Evaluation of phagocytosis in rickets. Acta Paediatr Scand (1970) 59:288–92.[Web of Science][Medline]
  17. Rehman PK. Sub-clinical rickets and recurrent infection. J Trop Paed (1994) 40:58.
  18. Kriesel JD, Spruance J. Calcitriol 1,25-dihydroxy-vitamin D3 coadministered with influenza vaccine does not enhance humoral immunity in human volunteers. Vaccine (1999) 17:1883–8.[CrossRef][Web of Science][Medline]
  19. Finch S, Doyle W, Lowe C, et al. National Diet and Nutrition Survey: People aged 65 Years and Over. (1998) London: The Stationery Office. Volume 1: Report of the Diet and Nutrition Survey.
  20. Hirani V, Primatesta P. Vitamin D concentrations among people aged 65 years and over living in private households and institutions in England: population survey. Age Ageing (2005) 34:485–91.[Abstract/Free Full Text]
  21. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr (2006) 84:18–28.[Abstract/Free Full Text]
  22. The RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people Randomised Evaluation of Calcium and/OR vitamin D, RECORD: a randomised placebo-controlled trial. Lancet (2005) 365:1621–8.[CrossRef][Web of Science][Medline]
  23. Glendenning P, Taranto M, Noble JM, et al. Current assays overestimate 25-hydroxyvitamin D3 and underestimate 25-hydroxyvitamin D2 compared with HPLC: need for assay-specific decision limits and metabolite-specific assays. Ann Clin Biochem (2006) 43:23–30.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Age AgeingHome page
A. Avenell, J. A. Cook, G. S. MacLennan, and G. C. McPherson
Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438)
Age Ageing, September 1, 2009; 38(5): 606 - 609.
[Full Text] [PDF]

Home page
 Arch Intern MedHome page
A. A. Ginde, J. M. Mansbach, and C. A. Camargo Jr
Vitamin D Level, Respiratory Tract Infections, and Controlled Trials--Reply
Arch Intern Med, August 10, 2009; 169(15): 1443 - 1444.
[Full Text] [PDF]

Home page
 Arch Intern MedHome page
A. A. Ginde, M. C. Liu, and C. A. Camargo Jr
Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004
Arch Intern Med, March 23, 2009; 169(6): 626 - 632.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
A. A. Ginde, J. M. Mansbach, and C. A. Camargo Jr
Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey
Arch Intern Med, February 23, 2009; 169(4): 384 - 390.
[Abstract] [Full Text] [PDF]

Home page
 Age AgeingHome page
W. B. Grant and C. F. Garland
The role of vitamin D3 in preventing infections
Age Ageing, January 1, 2008; 37(1): 121 - 122.
[Full Text] [PDF]

This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
36/5/574    most recent
afm091v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (10)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Avenell, A.
Right arrow Articles by MacPherson, G. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Avenell, A.
Right arrow Articles by MacPherson, G. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?