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

Figure 1. Flowchart for selection of eligible…
Figure 1. Flowchart for selection of eligible studies.
Figure 2. Efficacy of vitamin D for…
Figure 2. Efficacy of vitamin D for prevention of respiratory tract infections.
Error bars indicate 95% confidence intervals.
Figure 3. Subgroup analyses.
Figure 3. Subgroup analyses.
Error bars indicate 95% confidence intervals of OR in subgropus of randomized trials. Subgroups were based on RTI being a primary or secondary endpont, trial participants being patients or healthy individuals, children or adults, and vitamin D-sufficient or insufficient, and vitamin D being adminstered daily or as bolus doses. Numbers indicate number of trials in each subgroup and p-values refer to between-group differences in random effects meta-regressions performed separately for each pair of subgroups.
Figure 4. Random effects meta-regressions.
Figure 4. Random effects meta-regressions.
Dotted lines indicate 95% confidence intervals of regression lines (solid lines). Sizes of dots are proportional to the weight of each trial in the regression model.

References

    1. 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.
    1. Pfeffer PE, Hawrylowicz CM (2012) Vitamin D and lung disease. Thorax 67: 1018–1020.
    1. 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.
    1. 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.
    1. 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
    1. 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.
    1. 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.
    1. Hewison M (2011) Antibacterial effects of vitamin D. Nat Rev Endocrinol 7: 337–345.
    1. 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.
    1. 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.
    1. 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
    1. 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.
    1. 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.
    1. Chinn S (2000) A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 19: 3127–3131.
    1. Lipsey MW, Wilson DB (2001) Practical Meta-analysis: Sage.
    1. 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.
    1. Aloia JF, Li-Ng M (2007) Re: epidemic influenza and vitamin D. Epidemiol Infect 135: 1095–1096 author reply 1097–1098.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Choudhary N, Gupta P (2012) Vitamin D supplementation for severe pneumonia–a randomized controlled trial. Indian Pediatr 49: 449–454.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Heaney RP (2012) Vitamin D–baseline status and effective dose. N Engl J Med 367: 77–78.
    1. Martineau AR (2012) Bolus-dose vitamin D and prevention of childhood pneumonia. Lancet 379: 1373–1375.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Henry HL (2011) Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 25: 531–541.
    1. 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.
    1. Vieth R (2009) How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology. Anticancer Res 29: 3675–3684.
    1. 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.
    1. 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.
    1. 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.

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