Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Peter Bergman, Asa U Lindh, Linda Björkhem-Bergman, Jonatan D Lindh, Peter Bergman, Asa U Lindh, Linda Björkhem-Bergman, Jonatan D Lindh
Abstract
Background: Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI.
Methods: Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochran's Q and I(2). Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530.
Findings: Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohran's Q p<0.0001, I(2) = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias.
Interpretation: Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, et al. (2013) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095–2128.
- Pfeffer PE, Hawrylowicz CM (2012) Vitamin D and lung disease. Thorax 67: 1018–1020.
- Gombart AF, Borregaard N, Koeffler HP (2005) 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 19: 1067–1077.
- Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, et al. (2011) Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 6: e25333.
- Rivas-Santiago B, Rivas Santiago CE, Castaneda-Delgado JE, Leon-Contreras JC, Hancock RE, et al. (2012) Activity of LL-37, CRAMP and antimicrobial peptide-derived compounds E2, E6 and CP26 against Mycobacterium tuberculosis. Int J Antimicrob Agents
- Liu PT, Stenger S, Li H, Wenzel L, Tan BH, et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773.
- Liu PT, Stenger S, Tang DH, Modlin RL (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179: 2060–2063.
- Hewison M (2011) Antibacterial effects of vitamin D. Nat Rev Endocrinol 7: 337–345.
- Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, et al. (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181: 7090–7099.
- Ginde AA, Mansbach JM, Camargo CA Jr (2009) Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 169: 384–390.
- Jolliffe DA, Griffiths CJ, Martineau AR (2012) Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J Steroid Biochem Mol Biol
- Charan J, Goyal JP, Saxena D, Yadav P (2012) Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J Pharmacol Pharmacother 3: 300–303.
- Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, et al. (2011) The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343: d5928.
- Chinn S (2000) A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 19: 3127–3131.
- Lipsey MW, Wilson DB (2001) Practical Meta-analysis: Sage.
- Brok J, Thorlund K, Wetterslev J, Gluud C (2009) Apparently conclusive meta-analyses may be inconclusive–Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol 38: 287–298.
- Aloia JF, Li-Ng M (2007) Re: epidemic influenza and vitamin D. Epidemiol Infect 135: 1095–1096 author reply 1097–1098.
- Avenell A, Cook JA, Maclennan GS, Macpherson GC (2007) Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 36: 574–577.
- Bergman P, Norlin AC, Hansen S, Rekha RS, Agerberth B, et al. (2012) Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open 2.
- Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, Orav EJ, Stahelin HB, et al. (2010) Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med 170: 813–820.
- Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, et al. (2012) Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics 130: e561–567.
- Choudhary N, Gupta P (2012) Vitamin D supplementation for severe pneumonia–a randomized controlled trial. Indian Pediatr 49: 449–454.
- Jorde R, Witham M, Janssens W, Rolighed L, Borchhardt K, et al. (2012) Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials. Scand J Infect Dis 44: 126–132.
- Kumar GT, Sachdev HS, Chellani H, Rehman AM, Singh V, et al. (2011) 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 342: d2975.
- Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, et al. (2010) Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis 202: 809–814.
- Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, et al. (2012) High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 156: 105–114.
- Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, et al. (2009) A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 137: 1396–1404.
- Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I (2011) Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 127: 1294–1296.
- Manaseki-Holland S, Maroof Z, Bruce J, Mughal MZ, Masher MI, et al. (2012) Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet 379: 1419–1427.
- Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, et al. (2010) Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health 15: 1148–1155.
- Murdoch DR, Slow S, Chambers ST, Jennings LC, Stewart AW, et al. (2012) Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA 308: 1333–1339.
- Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, et al. (2010) Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 91: 1255–1260.
- Heaney RP (2012) Vitamin D–baseline status and effective dose. N Engl J Med 367: 77–78.
- Martineau AR (2012) Bolus-dose vitamin D and prevention of childhood pneumonia. Lancet 379: 1373–1375.
- Hollis BW (2011) Short-term and long-term consequences and concerns regarding valid assessment of vitamin D deficiency: comparison of recent food supplementation and clinical guidance reports. Curr Opin Clin Nutr Metab Care 14: 598–604.
- Kimball S, Vieth R, Dosch HM, Bar-Or A, Cheung R, et al. (2011) Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J Clin Endocrinol Metab 96: 2826–2834.
- Khoo AL, Chai LY, Koenen HJ, Kullberg BJ, Joosten I, et al. (2011) 1,25-dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: impact of seasonal variation of immune responses. J Infect Dis 203: 122–130.
- Coussens AK, Wilkinson RJ, Hanifa Y, Nikolayevskyy V, Elkington PT, et al. (2012) Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci U S A 109: 15449–15454.
- Nielsen NO, Skifte T, Andersson M, Wohlfahrt J, Soborg B, et al. (2010) Both high and low serum vitamin D concentrations are associated with tuberculosis: a case-control study in Greenland. Br J Nutr 104: 1487–1491.
- Henry HL (2011) Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 25: 531–541.
- Hollis BW, Conrad HR, Hibbs JW (1977) Changes in plasma 25-hydroxycholecalciferol and selected blood parameters after injection of massive doses of cholecalciferol or 25-hydroxycholecalciferol in non-lactating dairy cows. J Nutr 107: 606–613.
- Vieth R (2009) How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology. Anticancer Res 29: 3675–3684.
- Trivedi DP, Doll R, Khaw KT (2003) Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 326: 469.
- Moreira-Pfrimer LD, Pedrosa MA, Teixeira L, Lazaretti-Castro M (2009) Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial. Ann Nutr Metab 54: 291–300.
- Hagenau T, Vest R, Gissel TN, Poulsen CS, Erlandsen M, et al. (2009) Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int 20: 133–140.
Source: PubMed