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Impact of Vitamin D on Infectious Disease

      Abstract

      Background

      Observational studies have linked vitamin D status and infectious disease. This association is supported by the presence of the vitamin D receptor and CYP27B1 in immune cells. This review aims to consolidate data from clinical trials that used vitamin D for the treatment or prevention of infectious disease.

      Methods

      The authors searched the term "(vitamin D OR ergocalciferol OR cholecalciferol OR vitamin D2 OR vitamin D3 OR calcitriol) AND (infection OR tuberculosis OR sepsis OR pneumonia)" with limits preset to manuscripts published in English and with human subjects. They identified controlled trials that measured infectious outcomes (eg, incidence and severity of disease, time to disease resolution or recurrence, measures of clinical improvement, mortality). Studies that used analog, topical or micronutrient formulations of vitamin D, assessed only vitamin D status or lacked a comparison group were excluded. The references from eligible manuscripts and from 2 recent reviews were scanned for additional manuscripts.

      Results

      One thousand two hundred eighty-four manuscripts were identified with our search terms, with 60 papers still eligible after review of the title and abstract. Full review of these papers, their references and 2 related reviews yielded 38 manuscripts.

      Conclusions

      Although some prospective studies show positive results regarding vitamin D on infectious disease, several robust studies are negative. Factors such as high variability between studies, the difference in individual responsiveness to vitamin D and study designs that do not primarily investigate infectious outcomes may mask the effects of vitamin D on infections.

      Key Indexing Terms

      Although best studied in bone disease,
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      respiratory tract infections [RTIs] and influenza,
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      An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men.
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      Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh.
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      Epidemic influenza and vitamin D.
      chronic obstructive pulmonary disease [COPD] exacerbations,
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      Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
      • Janssens W.
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      Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene.
      cystic fibrosis [CF],
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      • Judd S.E.
      • Shah R.
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      Vitamin D and bone health in adults with cystic fibrosis.
      • Pincikova T.
      • Nilsson K.
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      Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study.
      sepsis
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      Seasonal variation in the epidemiology of sepsis.
      and human immunodeficiency virus [HIV]
      • Rodriguez M.
      • Daniels B.
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      High frequency of vitamin D deficiency in ambulatory HIV-positive patients.
      ). Furthermore, vitamin D deficiency is associated with an increased risk for all-cause and infection-related mortality in the general population.
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      Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults.
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      25-hydroxyvitamin D levels and the risk of mortality in the general population.
      Although mechanistic evidence linking vitamin D with immunity is strong, randomized controlled trials have yielded inconsistent results.
      The active form of vitamin D is 1,25-dihydroxycholecalciferol (1,25(OH)2D3, or calcitriol), which is formed by 2 sequential hydroxylation reactions. The 1st reaction occurs in the liver and forms 25-hydroxyvitamin D (25(OH)D), the levels of which indicate vitamin D status.
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      The 2nd reaction forms calcitriol through CYP27B1, an enzyme located in the kidneys and target organs.
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      The photoproduction of 1 alpha,25-dihydroxyvitamin D3 in skin: an approach to the therapy of vitamin-D-resistant syndromes.
      Calcitriol acts through the vitamin D receptor (VDR), a polymorphic nuclear receptor that modulates the expression of genes involved in immune function and cytokine production.
      • Srviastava M.D.
      • DeLuca H.
      • Ambrus J.L.
      Inhibition of IL-6 and IL-8 production in human fibroblast cell lines by 1,25 (OH)2 vitamin D3 and two of its analogs with lower calcemic activity.
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      Vitamin D and the hema-tolymphopoietic tissue: a 1994 update.
      • Lemire J.M.
      Immunomodulatory role of 1,25-dihydroxyvitamin D3.
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      1 alpha,25-dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes.
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      Mechanisms of gene regulation by vitamin D(3) receptor: a network of coactivator interactions.
      The VDR and CYP27B1 are present in immune cells
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      • et al.
      Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation.
      • Stumpf W.E.
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      • et al.
      Target cells for 1,25- dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid.
      and bronchial and pulmonary epithelial cells,
      • Yim S.
      • Dhawan P.
      • Ragunath C.
      • et al.
      Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D (3).
      • Hansdottir S.
      • Monick M.M.
      • Hinde S.L.
      • et al.
      Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense.
      among others, and are upregulated after the ligation of specific toll-like receptors by extracellular pathogens,
      • Liu P.T.
      • Stenger S.
      • Li H.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      implicating vitamin D in innate immunity.
      • White J.H.
      Vitamin D, signaling, infectious diseases, and regulation of innate immunity.
      By binding the VDR, calcitriol induces several endogenous antimicrobial peptides (AMPs) in human monocytes, neutrophils and epithelial cells (eg, cathelicidin LL-37,
      • Liu P.T.
      • Stenger S.
      • Li H.
      • et al.
      Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
      • Wang T.T.
      • Nestel F.P.
      • Bourdeau V.
      • et al.
      Cutting edge: 1,25- dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
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      • Schmidtchen A.
      • et al.
      Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL- 37.
      • Thijssen H.H.
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      • Drittij-Reijnders M.J.
      The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat.
      α-defensin,
      • Thijssen H.H.
      • Janssen C.A.
      • Drittij-Reijnders M.J.
      The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat.
      β-defensin
      • Wang T.T.
      • Nestel F.P.
      • Bourdeau V.
      • et al.
      Cutting edge: 1,25- dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
      and neutrophil gelatinase-associated lipocalin
      • Wang T.T.
      • Nestel F.P.
      • Bourdeau V.
      • et al.
      Cutting edge: 1,25- dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
      ) and upregulates nitric oxide synthase.
      • Rockett K.A.
      • Brookes R.
      • Udalova I.
      • et al.
      1,25-dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of mycobacterium tuberculosis in a human macrophage-like cell line.
      AMPs inhibit infection by bacteria, viruses and fungi,
      • Ramanathan B.
      • Davis E.G.
      • Ross C.R.
      • et al.
      Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity.
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      • et al.
      Epithelial defensins impair adenoviral infection: implication for adenovirus-mediated gene therapy.
      • Klotman M.E.
      • Chang T.L.
      Defensins in innate antiviral immunity.
      whereas nitric oxide synthase augments bacterial killing by upregulating the oxidative burst in activated macrophages.
      • Sly L.M.
      • Lopez M.
      • Nauseef W.M.
      • et al.
      1alpha,25-dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phos-phatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase.
      Vitamin D may also induce a T-helper-2 (Th2)-based response,
      • Rook G.A.
      • Hernandez-Pando R.
      • Lightman S.L.
      Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance.
      characterized by high immunoglobulin IgE and eosinophilia,
      • Cox F.E.
      • Liew F.Y.
      T-cell subsets and cytokines in parasitic infections.
      • Thorne K.J.
      • Mazza G.
      Eosinophilia, activated eosinophils and human schistosomiasis.
      to combat extracellular infections by parasites, protozoa and fungi.
      • Diaz A.
      • Allen J.E.
      Mapping immune response profiles: the emerging scenario from helminth immunology.
      • Romani L.
      Cell mediated immunity to fungi: a reassessment.
      In addition to its role in innate immunity, calcitriol suppresses pro-inflammatory cytokines in vitro
      • Martineau A.R.
      • Wilkinson K.A.
      • Newton S.M.
      • et al.
      IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37.
      and in vivo
      • Schleithoff S.S.
      • Zittermann A.
      • Tenderich G.
      • et al.
      Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
      • Zittermann A.
      • Frisch S.
      • Berthold H.K.
      • et al.
      Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers.
      and upregulates anti-inflammatory cytokines, such as interleukin-10.
      • Schleithoff S.S.
      • Zittermann A.
      • Tenderich G.
      • et al.
      Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
      • Coussens A.
      • Timms P.M.
      • Boucher B.J.
      • et al.
      1alpha,25- dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by mycobacterium tuberculosis infection.
      Because the inflammatory response associated with infections such as influenza, pneumonia and sepsis increases both clinical severity and mortality,
      • Kobasa D.
      • Takada A.
      • Shinya K.
      • et al.
      Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.
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      Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?.
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      • et al.
      Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study.
      • Yende S.
      • D'Angelo G.
      • Kellum J.A.
      • et al.
      Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis.
      the ability to reduce inflammation may allow vitamin D to decrease mortality and disease burden in certain infections.
      This review focuses on controlled intervention studies that use vitamin D in the treatment and prevention of infectious disease. we aimed to identify existing trials, assess comparisons between dosing strategies and populations previously tested and identify sources of variability that may contribute to the inconsistencies between trials.

      MATERIALS AND METHODS

      We performed a systematic review of controlled intervention trials in which vitamin D was used for the treatment or prevention of infectious disease. we evaluated the following outcomes related to infection: incidence and severity of infection, time to infection resolution or recurrence, mortality and measures of clinical improvement, such as weight gain and improvements on imaging studies. we searched PubMed through the date (May 21, 2014) using the search term "(vitamin D OR ergocalciferol OR cholecalciferol OR vitamin D2 OR vitamin D3 OR calcitriol) AND (infection OR sepsis OR pneumonia OR tuberculosis)." Limits were present to manuscripts published in the English language and involving human subjects. The titles and abstracts of search results were reviewed for prospective, controlled, intervention trials using vitamin D2, D3 or calcitriol. Exclusion criteria were (1) review articles, (2) retrospective studies, (3) studies lacking a comparison group, (4) studies that used vitamin D analogs, (5) studies that used vitamin D as part of micronutrient or topical formulas or (6) studies that evaluated vitamin D status as the only end point. Manuscripts not excluded by information in the abstract and title were examined in their entirety and their references reviewed for additional eligible manuscripts. The references of relevant review articles identified in our search were also scanned for eligible manuscripts. Two independent reviewers (J.A.A. and M.D.K.) identified manuscripts using these criteria and a 3rd reviewer (V.T.) settled disagreements. Data were collected, and paper quality was assessed in duplicate by 2 independent reviewers (M.D.K. and N.S.). The quality of each paper was scored on 2 rating scales (the 5-point Maryland Scientific Methods Scale
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      and the 17-point Methodological Quality Rating Scale
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      ), and a final quality score agreed upon by both reviewers. In both scales, higher numbers represent a more rigorous study design.
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.

      PubMed Search Results

      After evaluating the titles and abstracts of 1,284 manuscripts identified by our search terms (Figure 1), 60 manuscripts were examined in their entirety and 29 manuscripts remained eligible. Six additional manuscripts were added after reviewing the references of these papers. The references of 2 recent reviews identified by our search terms
      • Jolliffe D.A.
      • Griffiths C.J.
      • Martineau A.R.
      Vitamin D in the prevention of acute respiratory infection: systematic review of clinical studies.
      • Yamshchikov A.V.
      • Desai N.S.
      • Blumberg H.M.
      • et al.
      Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials.
      were also evaluated, yielding 3 additional manuscripts. A total of 38 papers were included in this review.
      Figure thumbnail gr1
      Figure 1Flow diagram of studies identified for review.

      RESULTS

      Study Design

      The 38 prospective controlled trials included in this paper were published after 1994 and evaluated populations receiving vitamin D for treatment, an adjunct to treatment, or prevention of infectious disease. A majority of these trials studied respiratory disease,
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      • Murdoch D.R.
      • Slow S.
      • Chambers S.T.
      • et al.
      Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      • Kriesel J.D.
      • Spruance J.
      Calcitriol (1,25-dihydroxy-vitamin D3) co-administered with influenza vaccine does not enhance humoral immunity in human volunteers.
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      such as RTI (Table 1), pneumonia and exacerbations linked to RTI (Table 2) and TB (Table 3). Of the remaining trials (Table 4), 3 evaluated infection rates and antibiotic use in adults
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      and single trials studied populations with hepatitis C virus,
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      heart transplants,
      • Briffa N.K.
      • Keogh A.M.
      • Sambrook P.N.
      • et al.
      Reduction of immuno-suppressant therapy requirement in heart transplantation by calcitriol.
      HIV,
      • Arpadi S.M.
      • McMahon D.
      • Abrams E.J.
      • et al.
      Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents.
      schistosomiasis
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.
      and infection in pregnancy.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      Of these manuscripts, 2 combined multiple, randomized, controlled data sets
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      and 8 provided a secondary analysis of previously published data.
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      All studies were double blinded except for 2 that used a single-blind model
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.
      and 6 that were nonblinded.58,61,65,71,8793 Two trials did not randomize participants.
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      All studies contained placebo groups except for 3 that used an alternative vitamin D dose for comparison
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      and 4 that used no treatment for comparison.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      Paper quality scores ranged from 5 to 16 on the Methodological Quality Rating Scale, with 36% of included studies having "excellent methodology" indicated by a score ≥14.
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      Table 1Vitamin D supplementation in RTIs
      Author, country, latitude
      Latitudes approximated using cities identified as locations of study recruitment.
      Study designSubjects: number, age,
      Age listed as mean (SD).
      baseline VitD sufficiency → VitD status after supplementation
      Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20-30 ng/mL and deficient <20 ng/mL.
      Intervention: dose,
      All doses are listed as IUs.
      formulation, intervals of administration, total study length
      Total VitD dose,
      All doses are listed as IUs.
      IU
      Infectious outcomeStudy-related AEScore
      Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)54 and Methodological Quality Rating Scale (scored 1-17).55 In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      Positive studies
       Aloia and Li-Ng,
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      Long Island, NY, 40.8°
      Placebo, randomized, double-blind, single-center, 2° analysis280 postmenopausal women800 D3 PO daily for 2 yr and 2,000 D3 PO for 1 yr, followed to 3 yr1,314,000↓ Cold and influenza symptoms, ↓self-reported RTINone5,14
      VitD: n = 104, 59.9 (6.2) yr Placebo: n = 104, 61.2 (6.3) yr VitD deficient →(NP)
       Laaksi et al,
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      Pori, Finland, 61.5°
      Placebo, randomized, double-blind, single-center164 healthy adults400 D3 PO daily for 6 mo73,200Number of days absent from duty due to RTI, ↓ RTI reported over 6 mo, ↔ 25D over winter in intervention group, ↑25D compared with placebo after winterNausea (n = 1), diarrhea (n = 1)5, 11
      VitD: n = 80 Placebo: n = 84 Age: 18–28 yr VitD sufficient → sufficient
       Urashima et al,
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      Tokyo, Japan, 35.7°
      Placebo, randomized, double-blind, multicenter430 healthy children1,200 D3 PO daily for 3 mo108,000↓ Influenza A incidence, Yasthma attacks in children with asthmaNone5,13
      VitD: n = 217, 10.0 (2.2) yr Placebo: n = 213, 10.4 (2.4) yr VitD sufficiency (NP)
       Majak et al,
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      Łódź, Poland, 51.8°
      Placebo, randomized, double-blind, single-center48 children with new asthma500 D3 PO daily for 6 mo152,500

      ↓ Symptom score, number of asthma exacerbations due to RTI, ↑lung function, ↔25D
      None5,14
      VitD: n = 24, 10.8 (3.2) yr Placebo: n = 24, 11.1 (3.3) yr VitD sufficient → sufficient
       Bergman et al,
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      Huddinge, Sweden, 59.2°
      Placebo, randomized, double-blind, single-center140 with antibody deficiency or >4 RTI/yr4,000 D3 PO daily for 12 mo1,460,000↓ Rate of infection, ↓ antibiotic use, ↓number of days on antibiotics, ↑25DNone5,15
      VitD: n = 70, 55.4 yr Placebo: n = 70, 50.8 yr VitD deficient/insufficient → sufficient
       Camargo et al,
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      Ulaanbaatar, Mongolia, 48.0°
      Placebo, randomized, double-blind, multicenter, 2° analysis247 children300 D3 PO daily for 3 mo27,000↓RTI, ↑25DNone5,12
      VitD: n = 144, 10.1 (0.9) yr Placebo: n = 103, 9.8 (1) yr VitD deficient → insufficient
       Kalra et al,
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      Lucknow, India, 26.8°
      Comparison, randomized, single-blind, single center97 pregnant women randomized to group 1 or 2. 43 controls, received usual careGroup 1: 600,000 D3 PO in 2nd trimester, group 2: 120,000 D3 PO in both 2nd and 3rd, followed to 9 mo in infants60,000 or 240,000↑Growth characteristics continuing past 9 mo, ↔ RTI, ↑25D in group 2 compared with group 1 and placeboNone4, 11
      VitD group 1: n = 48, 26.3 (4.2) yr

      VitD group 2: n = 49, 27.0 (3.8) yr

      Placebo: n = 43, 26.2 (3.7) yr

      VitD deficient → insufficient
      Negative studies
       Rehman,
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      Kerala, India, 8.5°
      Comparison, nonrandomized, single center27 children prone to RTI, 20 age/sex-matched controls60,000 PO weekly for 6 wk, followed to 24 wk, formulation (NP)360,000↔ observed infectionsNone4, 5
      VitD: n = 27

      Comparison: n = 20

      Age: 3–12 yr

      VitD sufficiency (NP)
       Kriesel and Spruance,
      • Kriesel J.D.
      • Spruance J.
      Calcitriol (1,25-dihydroxy-vitamin D3) co-administered with influenza vaccine does not enhance humoral immunity in human volunteers.
      UT, 30.5°
      Placebo, randomized, double-blind, single-center175 healthy adults40 calcitriol IM with flu shot, followed to 3 mo40↔ HAI titers against H1N1, H3N2, influenza B↑Pain at injection site5, 13
      VitD: n = 87, 32 (8) yr

      Placebo: n = 88, 32 (8) yr

      VitD sufficiency (NP)
       Li-Ng et al,
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      Long Island, NY, 40.8°
      Placebo, randomized, double-blind, single-center148 healthy adults2,000 D3 PO daily for 4 mo168,000↔ incidence or severity of RTI during winter, t 25DNone5, 10
      VitD: n = 84, 59.3 (13) yr Placebo: n = 78, 58.1 (13.4) yr VitD insufficient → sufficient
       Jorde et al,
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      6 centers, varying countries
      Combined analysis of 10 placebo, randomized, double-blind, multicenter, 2° analysis of 10 trials (NP)569 healthy adults1,111-6,800 PO daily, followed to at least 12 wk between September and April, formulation (NP)Varied↔ Length or incidence of influenza-like illnessNone5, 6
      VitD: n = 289

      Placebo: n = 280

      Age: 63 (32–84)
      Age listed as median (range).
      yr

      VitD sufficiency (NP)
       Murdoch et al,
      • Murdoch D.R.
      • Slow S.
      • Chambers S.T.
      • et al.
      Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
      Christchurch, New Zealand, 43.0°
      Placebo, randomized, double-blind, multicenter322 healthy adults200,000 D3 PO baseline and 1 mo both groups, 100,000 D3 PO monthly for 18 mo2,000,000 or 400,000↔ Incidence or severity of RTI, ↑25DNone5, 16
      VitD: n = 161, 47 (10) yr

      Placebo: n = 161, 48 (10) yr

      VitD insufficient → sufficient
       Goldring et al,
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      London, England, 51.5°
      Comparison, randomized, double-blind, single-center180 pregnant women at 27-wk gestationDaily 800 D2 PO until birth or 200,000 D3 PO at baseline, followed to 3 yr200,000 or 800 per day (number of days varied between the subjects)↔ Wheezing, 2° OC ↔ RTI, atopy, eczema risk, lung function, exhaled NO during 1st 3 yrNone5, 16
      Daily VitD2: n = 60, 37.1 (36.5–38.8)
      Age listed as median (IQR).
      yr

      Bolus VitD3: n = 60, 37.9 (36.9–39.9)
      Age listed as median (range).
      yr

      No VitD: n = 60, 37.4 (36.5– 39.5)
      Age listed as median (range).
      yr

      VitD sufficiency (NP)
      2° OC, infectious disease was a secondary outcome in the study; 25D, 25-hydroxyvitamin D; AE, study-related adverse events; HAI, hemagglutination inhibition; IM, intramuscular; IQR, interquartile range; IU, international unit; NO, nitric oxide; (NP), information not published; PO, per os; RTI, respiratory tract infection; SD, standard deviation; VitD, vitamin D.
      a Latitudes approximated using cities identified as locations of study recruitment.
      b Age listed as mean (SD).
      c Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20-30 ng/mL and deficient <20 ng/mL.
      d All doses are listed as IUs.
      e Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      and Methodological Quality Rating Scale (scored 1-17).
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      f Age listed as median (range).
      g Age listed as median (IQR).
      Table 2Vitamin D supplementation in pneumonia and conditions related to RTIs
      Author, country, latitude
      Latitudes approximated using cities identified as locations of study recruitment.
      Study designSubjects: number, age,
      Age listed as mean (SD).
      baseline VitD sufficiency → VitD status after supplementation
      Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      Intervention: dose,
      AH doses are listed as IUs.
      formulation, intervals of administration, total study length
      Total VitD dose,
      AH doses are listed as IUs.
      IU
      Infectious outcomeStudy-related AEScore
      Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)54 and Methodological Quality Rating Scale (scored 1-17).55 in both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      Positive studies
      CF
       Grossmann et al,
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      Atlanta, GA, 33.9°
      Placebo, randomized, double-blind, single-center30 hospitalized for CF exacerbations250,000 D3 PO baseline, followed to 12 mo250,000↑1-yr survival and hospital-free days, ↑(NS) IV antibiotic-free days, ↑(NS) >95% pre-admission FEV1, ↑25DNone5, 15
      VitD: n = 15, 24.9 (16.01) yr

      Placebo: n = 15, 28.2 (30.89) yr

      VitD sufficient → sufficient
       Grossmann et al,
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      Atlanta, GA, 33.9°
      2° analysis
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      As in Ref.
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      As in Ref.
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      250,000↓TNF-α at 12 wk, ↓(NS) IL-6, ↔IL-1β, IL-8, IL-10, IL-18BP, NGALNone5, 13
      COPD exacerbations
       Lehouck et al,
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      Leuven, Belgium, 50.9°
      Placebo, randomized, double-blind, single-center182 severe COPD and history of recent infections100,000 D3 PO monthly, followed to 12 mo1,200,000Time to first exacerbation, rate of exacerbation, FEV1, QOL, or mortality, Y exacerbations in subset with 25D <10 ng/mL, ↑25DMild hyperCa2+ (n = 4)5, 15
      VitD: n = 91, 68 (9) yr

      Placebo: n = 91, 68 (8) yr

      VitD insufficient → sufficient
      Pneumonia prevention
       Manaseki-Holland et al,
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      Kabul, Afghanistan, 33.5°
      Placebo, randomized, double-blind, single-center453 children with severe pneumonia100,000 IU PO D3 at once, followed to 3 mo100,000↔ Time to recovery of pneumonia, ↓repeat episode of pneumonia in 90 d after admissionNone5, 12
      VitD: n = 224, 13.18 (9.1) mo

      Placebo: n = 229, 13.19 (9.2) mo

      VitD sufficiency (NP)
      Negative studies
       Pneumonia treatment Choudhary and Gupta,
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      India, 21.0°
      Placebo, randomized, double-blind, single-center200 children with severe pneumonia1,000–2,000 IU PO, given up to = 5d, formulation (NP)5,000–10,000↔ Duration of pneumonia, hospitalization or symptomsVomiting (n = 1), diarrhea (n = 1)5, 10
      VitD: n = 100, 14.1 (12.2) mo

      Placebo: n = 100, 13.8 (14.1) mo

      VitD sufficiency (NP)
      Pneumonia prevention
       Manaseki-Holland et al,
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      Kabul, Afghanistan, 33.5°
      Placebo, randomized, single center3,046 children with pneumonia100,000 D3 PO every 3 mo, followed to 18 mo600,000↔ Incidence or severity of pneumoniaToxic 25D level (150 ng/mL, n= 1)5, 14
      VitD: n - 1,524

      Placebo: n = 1,522

      Age: 1-11 mo

      VitD sufficiency (NP)
      25D, 25-hydroxyvitamin D; AE, study-related adverse events; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FEVİ, forced expiratory volume; hyperCa2+, hypercalcemia (mild hypercalcemia, 10.8-11.6 mg/dL); İL, interleukin; IQR, interquartile range; IU, international unit; IV, intravenous; NGAL, neutrophil gelatinase-associated lipocalin; NP, information not published; NS, not significant; PO, per os; QOL, quality of life; RTI, respiratory tract infection; SD, Standard deviation; TNF-α, tumor necrosis factor-α; VitD, vitamin D.
      a Latitudes approximated using cities identified as locations of study recruitment.
      b Age listed as mean (SD).
      c Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      d AH doses are listed as IUs.
      e Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      and Methodological Quality Rating Scale (scored 1-17).
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      in both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      Table 3Vitamin D supplementation in TB
      Author, country, latitude
      Latitudes approximated using cities identified as locations of study recruitment.
      Study designSubjects: number, age,
      Age listed as mean (SD).
      baseline VitD sufficiency → VitD status after supplementation
      Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      Intervention: dose,
      All doses are listed as IUs.
      formulation, intervals of administration, total study length
      Total VitD dose,
      All doses are listed as IUs.
      IU
      Infectious outcomeStudy-related AEScore
      Paper quality measures listed as Maryland Scientific Methods Scale (scored 1–5)54 and Methodological Quality Rating Scale (scored 1–17).55 In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      Positive studies
       TB treatment
       Morcos et al,
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      Cairo, Egypt, 30.1°
      Placebo, randomized, single center24 children with TB1,000 PO daily for 8 wk, formulation (NP)56,000↑ Clinical improvement on sonography, ↔ x-ray, ↑weight, ↔25DNone5, 10
      VitD: n = 12

      Placebo: n = 12

      Age: 1.5–13 yr

      VitD insufficient → insufficient
       Nursyam et al,
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      Jakarta, Indonesia, 6.2°
      Placebo, randomized, double-blind, single-center67 adults with TB10,000 PO daily, for 6 wk, followed to 12 wk, formulation (NP)420,000Sputum smear conversion, ↑(NS) radiological improvementNone5, 9
      VitD: n = 34, 29.85 (11.08) yr Placebo: n = 33, 32.55 (11.6) yr VitD sufficiency (NP)
       Martineau et al,
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      London, England, 51.5°
      Placebo, randomized, double-blind, multicenter126 adults with TB100,000 D3 PO every 2 wk for 6 wk, followed to 8 wk400,000Sputum culture conversion overall, ↑in tt genotype of Taq1 VDR, ↑25DEnlarging abscess (n = 2), mild hyperCa2+ (n = 2)5, 14
      VitD: n = 62, 30.7 (24.5–41.5)
      Age listed as median (IQR).
      yr

      Placebo: n = 64, 30.5 (24.8– 38.4)
      Age listed as median (IQR).
      yr

      VitD insufficient → sufficient
       Coussens et al,
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      London, England, 51.5°
      2° analysis
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      Selected subsets from
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      As reported in
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      400,000Sputum smear conversion, ↑treatment-induced resolution of lymphopenia and monocytosis, ↓IL-4, CCl5, IFN-γ, AMP, MMP-9As reported in
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      5, 11
       Mily et al,
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      Bangladesh, 23.7°
      Placebo, multicenter15 healthy adults5,000 D3 PO daily for 4 d20,000500 mg PB with VitD ↑LL-37 peptide and transcript expression, ↔MTB killing by macrophages, 4MTB killing by lymphocytes, ↔25DNone4, 7
      VitD + PB: n = 12

      Placebo: n = 3

      Age: 18–55 yr

      VitD deficient → deficient
       Salahuddin et al,
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      Nairobi, Kenya, 1.3°
      Placebo, randomized, double-blind, multicenter259 adults with TB600,000 D3 IM baseline and 1 mo, followed to 3 mo1,200,000↑Weight gain, ↓ disease on chest x-ray (decreased cavity size and fewer lobes involved), ↑IFN-γ secretion in deficient subgroup, ↔TB scoreNone5, 14
      VitD: n = 132, 27.8 (13.2) yr

      Placebo: n = 127, 28.3 (14.1) yr

      VitD insufficient → (NP)
       TB prevention
       Martineau et al,
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      London, England, 51.5°
      Placebo, randomized, double-blind, multicenter192 healthy adults with TB contacts100,000 PO D2 baseline, followed to 6 wk100,000↑ Whole blood restriction BCG-lux luminescence in vitro,IFN-γ response, ↑25DNone5, 13
      VitD: n = 96, 30.1 (25.1–44.1)
      Age listed as median (IQR).


      Placebo: n = 96, 37.5 (29.8– 45.2)
      Age listed as median (IQR).


      VitD deficient → insufficient
       Ganmaa et al,
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      Ulaanbaatar, Mongolia, 47.9°
      Placebo, randomized, double-blind, single-center120 healthy children800 PO D3 daily for 6 mo146,400↑Growth, ↓ (59%, NS) reduction in TST conversion rate, ↑25DNone5, 13
      VitD: n = 61, 13.1 (1.5) yr

      Placebo: n = 59, 13.0 (1.1) yr

      VitD deficient → insufficient
       Negative studies
       TB treatment Wejse et al,
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      Guinea-Bissau, West Africa, 12.0°
      Placebo, randomized, double-blind, multicenter365 adults with TB100,000 D3 PO at baseline, 5, 8 mo, followed to 12 mo300,000TB clinical severity score, sputum smear conversion rate, mortality, weight gain, 25DNone5, 15
      VitD: n = 187, 37 (13) yr

      Placebo: n = 180, 38 (14) yr

      VitD sufficient → sufficient
       Kota et al,
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      Hyderabad, India, 17.4°
      Comparison, randomized, controlled, single center35 adults with type 2 DM and TB60,000 D3 PO weekly for 12 wk720,000Sputum smear conversion, ↑25DNone5, 12
      VitD: n = 15, 38.4 (19.6) yr

      No VitD: n = 15, 40.2 (17.7) yr

      VitD deficient → insufficient
      Ralph et al,
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      Timika, Indonesia, 4.5°
      Placebo, randomized, double-blind, factorial, single center200 adults with smear positive TB

      -
      50,000 PO D3 baseline and 4 wk, followed to 24 wk100,000↔ Sputum culture conversion rate or chest x-ray findingsNone5, 12
      VitD (some with arginine): n 5 101

      Placebo: n = 99

      Age: 28 (15–73)
      Age listed as median (range).
      yr VitD sufficiency (NP)
      25D, 25-hydroxyvitamin D; AE, study-related adverse events; AMP, antimicrobial peptide; CCl5, chemokine ligand 5; DM, diabetes mellitus; hyperCa
      • Fraser D.R.
      • Vitamin D.
      +, hypercalcemia (mild hypercalcemia, 10.8-11.6 mg/ dL); IFN-g, interferon g; IQR, interquartile range; IL, interleukin; IM, intramuscular; IU, international unit; LL-37, cathelicidin; MMP-9, matrix metalloproteinase 9; MTB, Mycobacterium tuberculosis; NP, information not published; NS, not significant; PB, phenylbutyrate; PO, per os; SD, standard deviation; TB, tuberculosis; TST, tuberculin skin test; VDR, vitamin D receptor; VitD, vitamin D.
      a Latitudes approximated using cities identified as locations of study recruitment.
      b Age listed as mean (SD).
      c Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      d All doses are listed as IUs.
      e Paper quality measures listed as Maryland Scientific Methods Scale (scored 1–5)
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      and Methodological Quality Rating Scale (scored 1–17).
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      f Age listed as median (IQR).
      g Age listed as median (range).
      Table 4Vitamin D supplementation in miscellaneous conditions
      Author, country, latitude
      Latitudes approximated using cities identified as locations of study recruitment.
      Study designSubjects: number, age,
      Age listed as mean (SD).
      baseline VitD sufficiency → VitD status after supplementation
      Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      Intervention: dose,
      All doses are listed as IUs.
      formulation, intervals of administration, total study length
      Total VitD dose,
      All doses are listed as IUs.
      IU
      Infectious outcomeStudy-related AEScore
      Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)54 and Methodological Quality Rating Scale (scored 1-17).55 In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      Positive studies
       Infection and antibiotic use
       Bischoff-Ferrari et al,
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      Zurich, Switzerland, 47.4°
      Comparison, randomized, double-blind, single-center173 elderly with acute hip fracture800 or 1,200 D3 PO D3 daily for 12 mo292,000 or 730,000↓Hospital readmission in 1,200 group, ↓infection rate, ↑25DMild hyperCa2+ (n = 3) at 7– 10 d and 6 mo5, 15
      2,000 VitD: n = 86, 84.1

      (7.0) yr

      800 VitD: n = 87, 84.4

      (6.8) yr

      VitD deficient →sufficient in both groups
       Tran et al,
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      Australia and Tasmania, 23.0– 48.4°
      Placebo, randomized, double-blind, multicenter, 2° analysis644 elderly adults30,000 or 60,000 D3 PO monthly for 12 mo360,000 or 720,000↓(28%, NS) antibiotic prescription overall, ↓antibiotic use in subjects >70 yr, ↑25DHyperCa2+ (n = 1)5, 16
      60,000 VitD: n = 205

      30,000 VitD: n = 210

      Placebo: n = 205

      Age: 60–84 yr

      VitD deficient →

      insufficient 30,000 group, sufficient in 60,000 group
       Pregnancy outcomes
       Wagner et al,
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      SC and NC, 34.0, 35.5°
      Combined analysis of 2 randomized, comparison, double-blind, 2° analysis758 pregnant women in 2nd trimester400, 2,000 or 4,000 D3 PO daily from 2nd trimester to birth, followed to 12 moVaried↑25D in mothers and cord blood in 2,000 and 4,000 IU groups. 2° OC ↓odds infection, preterm birth, preeclampsia and gestational DM combined with every 10 ng/mL ↑in 25D.None5, 13
      4,000 VitD: n = 295, 27 (18–41)
      Age listed as median (range).
      yr

      2,000 VitD: n = 297, 26 (16–41)
      Age listed as median (range).
      yr

      400 VitD: n = 166, 27 (18–41)
      Age listed as median (range).
      yr

      VitD insufficient → sufficient in mothers, insufficient in neonate
       Schistosomiasis
       Snyman et al,
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.
      Eastern S. Africa, 25.0°
      Placebo, randomized, single-blind, number of centers (NP)59 males with schistosomiasis40 IU calcitriol daily for = d, followed to 3 wk200↑Circulating lymphocytes, percent of eosinophil vacuolization, specific antibody formation, ↓ECP levelsNone5, 9
      VitD: n = 30

      Placebo: n = 29

      Ages: 14–18 yr

      VitD sufficiency (NP)
       HCV treatment
       Abu-Mouch et al,
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      Hadera, Israel, 32.5°
      Comparison, randomized, multicenter72 with chronic HCV2,000 D3 PO daily for 48 wk672,000↑Virologic response at 4, 12 and 24 wk, ↓nonresponse rate in VitD group, ↑25DNone5, 13
      VitD: n = 36, 47 (11) yr

      Placebo: n = 36, 49 (7)yr

      VitD deficient/

      insufficient →sufficient
       Negative studies Infection and antibiotic use
       Avenell et al,
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      England and Scotland, 51.5, 56.0°
      Placebo, randomized, double-blind, factorial, multicenter, 2° analysis5,292 adults800 D3 PO daily for 24– 64 mo134,400– 358,400↓(10%–15%, NS) self-reported infectionsNone5, 12
      VitD: n = 2,643, 77 (6) yr

      Placebo: n = 2,649, 77 (6) yr

      VitD sufficiency (NP)
       HIV
       Arpadi et al,
      • Arpadi S.M.
      • McMahon D.
      • Abrams E.J.
      • et al.
      Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents.
      NY, 40.7°
      Placebo, randomized, double-blind, multicenter56 children with HIV100,000 D3 PO every 2 mo for 12 mo600,000↑25D, 2° OC: ↔CD4 count, CD4%, viral load at 12 moNone5, 15
      VitD: n = 29, 10.2 (2.9) yr

      Placebo: n = 27, 10.6 (2.4) yr

      VitD insufficient → sufficient
       Post-transplantation
       Briffa et al,
      • Briffa N.K.
      • Keogh A.M.
      • Sambrook P.N.
      • et al.
      Reduction of immuno-suppressant therapy requirement in heart transplantation by calcitriol.
      Sydney, Australia, 33.9°
      Placebo, randomized, double-blind, single-center, some control from other cohort study99 heart transplant recipients20 daily for 6 mo, 20– 40 daily for 12 mo or 20–40 daily for 24 mo3,660–29,280↓Oral cyclosporine requirement 2° OC: ↔ in infection, rejection or mortality ratesNone5, 10
      VitD: n = 52

      Placebo: n = 29

      Control (cohort): n = 18

      Age: (NP)

      VitD sufficiency (NP)
      2° OC, infectious disease was a secondary outcome in the study; 25D, 25-hydroxyvitamin D; AE, study-related adverse events; CD4, cluster of differentiation 4; DM, diabetes mellitus; ECP, eosinophil cationic protein; HCV, hepatitis C virus; HIV, human immunodeficiency virus; hyperCa2+, hypercalcemia (mild hypercalcemia, 10.8-11.6 mg/dL); IQR, interquartile range; IU, international unit; NP, information not published; NS, not significant; PO, per os; SD, standard deviation; VitD, vitamin D.
      a Latitudes approximated using cities identified as locations of study recruitment.
      b Age listed as mean (SD).
      c Vitamin D deficiency is described by 25(OH)D concentration: sufficient >30 ng/mL, insufficient 20 to 30 ng/mL and deficient <20 ng/mL.
      d All doses are listed as IUs.
      e Paper quality measures listed as Maryland Scientific Methods Scale (scored 1-5)
      • Sherman L.W.
      • National Institute of Justice (U.S.)
      • University of Maryland at College Park
      • Department of Criminology and Criminal Justice
      Preventing crime: what works, what doesn't, what's promising: a report to the United States Congress.
      and Methodological Quality Rating Scale (scored 1-17).
      • Miller W.R.
      • Wilbourne P.L.
      Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders.
      In both scales, a higher number indicates better-quality methods. Scores were determined independently by 2 reviewers, with differences reconciled to decide on a quality score for each paper.
      f Age listed as median (range).

      Respiratory Tract Infections

      Thirteen papers assessed vitamin D in the prevention of RTI,
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      • Murdoch D.R.
      • Slow S.
      • Chambers S.T.
      • et al.
      Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      • Kriesel J.D.
      • Spruance J.
      Calcitriol (1,25-dihydroxy-vitamin D3) co-administered with influenza vaccine does not enhance humoral immunity in human volunteers.
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      whereas others studied conditions associated with RTI, including exacerbations of COPD
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      and CF.
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      RTI prevention with vitamin D yielded mixed results in healthy adults. Two positive studies found fewer RTI
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      and decreased cold and influenza incidences
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      with daily vitamin D3 doses between 400 and 2,000 IU given for 6 and 36 months, respectively. However, the remaining trials found no change in the incidence or severity of RTI or influenza symptoms after doses of vitamin D3 given daily (2,000 IU doses for 4 months
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      or 1,111–6,800 IU doses for 3 months during influenza season
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      ) or monthly (100,000 IU doses for 18 months).
      • Murdoch D.R.
      • Slow S.
      • Chambers S.T.
      • et al.
      Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
      Positive studies in healthy school-aged children found daily doses between 300 and 1,200 IU of vitamin D3 given over periods between 3 and 6 months to significantly decrease the risk of RTI,
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      influenza A
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      and asthma exacerbations.
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      However, no change in wheezing, RTI or other atopic illness was seen in the offspring of pregnant women who received either 800 IU of vitamin D2 daily until delivery or 200,000 IU of vitamin D3 given once.
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      There was also no change in RTI incidence in the offspring of women who received between 60,000 and 240,000 IU of vitamin D3 during the 2nd and 3rd trimesters of pregnancy.
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      Several papers evaluated RTI-prone populations. In children with a high incidence of RTI,
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      60,000 IU of vitamin D3 given weekly for 6 weeks showed no significant change in observed RTI. However, 4,000 IU of vitamin D3 given daily for a year in RTI-prone adults reduced overall rates of infections and the number of days on antibiotics by 50%.
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      Similarly, a population of CF patients who received a single 250,000 IU dose of vitamin D3 while hospitalized experienced a significant increase in hospital-free days during the year after the dose
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      and 50.4% decrease in tumor necrosis factor-a concentrations up to 12 weeks after the dose.
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      In this population, however, there were no differences between the vitamin D and placebo groups in the number of antibiotic-free days, recovery of lung function
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      or change in interleukin-6.
      • Grossmann R.E.
      • Zughaier S.M.
      • Liu S.
      • et al.
      Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
      In patients with moderate to very severe COPD, 100,000 IU of vitamin D3 at monthly intervals resulted in improvement in lung function, rates of exacerbation and morbidity and mortality,
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      although positive results were limited to participants who were vitamin D deficient at baseline.
      In summary, some studies suggest that vitamin D may have some benefit in reducing the risk of RTI in young healthy adults and adolescents, whereas the efficacy of vitamin D in adults with chronic lung disease is less clear. Vitamin D intervention during pregnancy did not seem to reduce the risk of RTI or asthmatic symptoms in the offspring.

      PNEUMONIA

      Three studies evaluated the impact of vitamin D on pneumonia,
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      yielding largely negative results. Hospitalized children received no benefit on the duration of illness, hospitalization or symptoms with 1,000 to 2,000 IU doses of vitamin D3 given for up to 5 days.
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      Two studies by Manaseki-Holland et al
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      found that 100,000 IU doses of vitamin D3 given once
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      and at 3-month intervals for 18 months
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      showed no change in the incidence, severity or time to recovery from pneumonia. Although the initial trial showed a 13% decreased risk of repeat pneumonia compared with placebo in the 90 days after the dose,
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      this result was not reproduced in the second trial, which had a large sample size.
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.

      TUBERCULOSIS

      Vitamin D has been extensively studied in the prevention
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      and treatment
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      of TB. Studies that assessed TB prevention showed a single dose of 100,000 IU of vitamin D2 to significantly increase whole blood restriction of Bacillus Calmette-Guerin (BCG)-lux luminescence (an in vitro indicator of TB growth restriction) in adults
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      and for daily doses of 800 IU of vitamin D3 to cause a significant increase in anthropometric measurements and a 59% (nonsignificant) reduction in tuberculin skin test conversion rates when given to children for 6 weeks.
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      The remaining studies assessed vitamin D both as an adjunct to antibiotic treatment for TB
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      and in its ability to kill Mycobacterium tuberculosis (MTB).
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      Vitamin D supplementation led to clinical improvements in 4 studies, including weight gains (in adults receiving two 600,000 IU doses of vitamin D3
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      and children receiving 1,000 IU doses daily for 8 weeks
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      ), less tissue involvement on sonography (after 1,000 IU daily for 2 months
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      ) and chest x-ray (after 5,000 IU of vitamin D3 daily for 3 months
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      ). Conversely, no improvement on x-ray was seen in children receiving daily doses of vitamin D (1,000 IU over 2 months
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      ) or adults receiving daily (10,000 IU for 6 weeks
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      ) or monthly (50,000 IU given twice
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      ) doses of vitamin D3. In Wejse et al,
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      100,000 IU doses of vitamin D3 given to adults with TB at baseline, 5 and 8 months also did not impact clinical severity scores or weight gain, among other outcomes.
      Conversion of sputum smear or sputum culture was used to measure response to treatment in several studies, although only sputum culture conversion is independently linked to long-term risk of treatment failure and relapse.
      • Benator D.
      • Bhattacharya M.
      • Bozeman L.
      • et al.
      Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.
      Nursyam et al
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      found 10,000 IU of vitamin D3 given daily for 6 weeks to significantly increase sputum smear conversion (100% in the treatment group versus 76.7% in the placebo group, P = 0.002). However, 2 studies showed no acceleration of sputum smear conversion with 3 doses of 100,000 IU of vitamin D3 given over 8 months
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      or 6 weekly doses of 60,000 IU of vitamin D3.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      Two studies
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      also showed negative results when testing the time to sputum culture conversion using vitamin D3 given as two 50,000 IU doses 1 month apart
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      and four 100,000 IU doses of at 2-week intervals.
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      Despite negative results in the study overall, Martineau et al,
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      however, did find in subgroup analysis based on the genotype of the Taq1 VDR polymorphism that those with a tt genotype experienced a significantly accelerated conversion compared with those with the Tt or TT genotype.
      Several studies tracked the impact of vitamin D on cytokines that promote anti-MTB activity and the resolution of infection. Suppression of antigen-stimulated pro-inflammatory cytokines, attenuation of anti-inflammatory cytokines and a more rapid treatment-induced resolution of lymphopenia and monocytosis associated with TB infection occurred after 100,000 IU doses of vitamin D3 given monthly for 4 months.
      • Coussens A.K.
      • Wilkinson R.J.
      • Hanifa Y.
      • et al.
      Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.
      Interferon-γ (IFN-γ) levels were impacted variably; 2 doses of 600,000 IU of vitamin D3 increased IFN-γ expression,
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      whereas a single 100,000 IU dose of vitamin D2 showed no change.
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      Two studies evaluated vitamin D in combination with another chemical thought to modulate activity against MTB; 5,000 IU of vitamin D3 given for 4 days alone or in combination with phenylbutyrate induced both circulating levels and transcript expression of the AMP LL-37,
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      whereas 50,000 IU doses with or without L-arginine showed no significant change in sputum culture conversion rate or x-ray involvement.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      In summary, vitamin D given largely as an adjunctive therapy with traditional anti-TB regimens has little impact on clearance of MTB from sputum in larger randomized controlled trials of patients with active TB infection. However, certain subpopulations may demonstrate benefit, such as patients with different polymorphisms of the VDR, severely low vitamin D status or infection with different strains of TB. There may be other benefits of vitamin D besides on the clearance of MTB from sputum, such as dampening the inflammatory response or anthropometric changes that may help TB patients recover in the long term.

      Miscellaneous

      Eight papers evaluated nonrespiratory illness, with variable results. Negative findings were present for HIV patients, who experienced no improvements in viral load and CD4 count,
      • Arpadi S.M.
      • McMahon D.
      • Abrams E.J.
      • et al.
      Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents.
      heart transplant recipients, who experienced no change in infection rates
      • Briffa N.K.
      • Keogh A.M.
      • Sambrook P.N.
      • et al.
      Reduction of immuno-suppressant therapy requirement in heart transplantation by calcitriol.
      and for a population of elderly adults who experienced no decrease in self-reported infections.
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      However, several studies yielded positive results. In elderly adults, 1,200 IU of vitamin D3 given daily reduced infection rates,
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      whereas monthly 60,000 IU doses of vitamin D3 caused a significant reduction in the amount of antibiotics used.
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      A population of pregnant women experienced a significant decrease in the combined odds of infection, preterm birth, preeclampsia and gestational diabetes associated with each 10 ng/mL increase in 25 (OH)D concentration after supplementation, although the impact of vitamin D on rates of infection alone was not significant.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      A 2,000 IU daily dose of vitamin D3 given in addition to standard hepatitis C virus treatment increased the response to treatment at 4, 12 and 24 weeks (P < 0.01 at all points),
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      and calcitriol augmented the Th2 response necessary for eradication of protozoan infections in patients with schistosomiasis.
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.

      Adverse Effects

      A majority of studies reported no difference in adverse events between intervention and control groups nor observed events deemed related to vitamin D.
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      • Ralph A.P.
      • Waramori G.
      • Pontororing G.J.
      • et al.
      L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      • Martineau A.R.
      • Wilkinson R.J.
      • Wilkinson K.A.
      • et al.
      A single dose of vitamin D enhances immunity to mycobacteria.
      • Manaseki-Holland S.
      • Qader G.
      • Isaq Masher M.
      • et al.
      Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.
      • Grossmann R.E.
      • Zughaier S.M.
      • Kumari M.
      • et al.
      Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial.
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      • Murdoch D.R.
      • Slow S.
      • Chambers S.T.
      • et al.
      Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      • Kalra P.
      • Das V.
      • Agarwal A.
      • et al.
      Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant.
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      • Arpadi S.M.
      • McMahon D.
      • Abrams E.J.
      • et al.
      Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents.
      • Briffa N.K.
      • Keogh A.M.
      • Sambrook P.N.
      • et al.
      Reduction of immuno-suppressant therapy requirement in heart transplantation by calcitriol.
      Mild hypercalcemia in the intervention group was reported in 4 studies
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      and a toxic level of 25(OH)D was reported in 1 study,
      • Manaseki-Holland S.
      • Maroof Z.
      • Bruce J.
      • 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.
      though no subsequent complications were reported. Two participants developed enlarging abscesses thought to be potentially because of the intervention in 1 study,
      • Martineau A.R.
      • Timms P.M.
      • Bothamley G.H.
      • et al.
      High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.
      and symptoms such as vomiting and diarrhea were identified in a small number of participants (n = 4).
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      Calcitriol administered with the influenza vaccination caused increased pain at the injection site.
      • Kriesel J.D.
      • Spruance J.
      Calcitriol (1,25-dihydroxy-vitamin D3) co-administered with influenza vaccine does not enhance humoral immunity in human volunteers.

      DISCUSSION

      Although studies have consistently demonstrated an epidemiologic association between vitamin D deficiency and infectious processes,
      • Holick M.F.
      High prevalence of vitamin D inadequacy and implications for health.
      • Ferrari M.
      • Schenk K.
      • Papadopoulou C.
      • et al.
      Serum 25-hydroxy vitamin D and exercise capacity in COPD.
      • Wilkinson R.J.
      • 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.
      • Laaksi I.
      • Ruohola J.P.
      • Tuohimaa P.
      • et al.
      An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men.
      • Roth D.E.
      • Shah R.
      • Black R.E.
      • et al.
      Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh.
      • Karatekin G.
      • Kaya A.
      • Salihoglu O.
      • et al.
      Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers.
      • Ginde A.A.
      • Mansbach J.M.
      • Camargo Jr., C.A.
      Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection Impacts of Vitamin D on Infectious Disease in the third National Health and Nutrition examination survey.
      • Grant W.B.
      Variations in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii.
      • Cannell J.J.
      • Vieth R.
      • Umhau J.C.
      • et al.
      Epidemic influenza and vitamin D.
      • Donaldson G.C.
      • Seemungal T.A.
      • Bhowmik A.
      • et al.
      Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
      • Janssens W.
      • Bouillon R.
      • Claes B.
      • et al.
      Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene.
      • Wolfenden L.L.
      • Judd S.E.
      • Shah R.
      • et al.
      Vitamin D and bone health in adults with cystic fibrosis.
      • Pincikova T.
      • Nilsson K.
      • Moen I.E.
      • et al.
      Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study.
      • Danai P.A.
      • Sinha S.
      • Moss M.
      • et al.
      Seasonal variation in the epidemiology of sepsis.
      • Rodriguez M.
      • Daniels B.
      • Gunawardene S.
      • et al.
      High frequency of vitamin D deficiency in ambulatory HIV-positive patients.
      the evidence from controlled interventional trials has been inconsistent. Vitamin D administration yielded at least 1 positive end point in 10 of 16 trials evaluating RTI and RTI-associated clinical conditions, 1 of 3 trials evaluating pneumonia, 9 of 11 trials measuring TB treatment and prevention and 1 of 3 trials evaluating infections and antibiotic use. However, these positive end points were not necessarily the primary end points of their respective trials and were, at times, restricted to particular subgroups within the cohort. Ultimately, there was a high degree of variability between the results of the studies, making it difficult to draw a unifying conclusion on the impact of vitamin D on infectious outcomes. Although the association between vitamin D deficiency and infection does not necessarily imply causation, it is possible that a causal relationship may be masked by several variables inherent to the current trials that contribute to the inconsistencies of results between studies.
      Unlike vitamin D as treatment for bone health, the dose and duration of treatment necessary to optimize infectious outcomes is currently unknown. This lack of standardization has led to a variety of dosing strategies in the studies included in this review. For one, vitamin D was administered at intervals ranging from days to months. Although vitamin D administered daily, weekly or monthly can sustain the same circulating concentrations of 25(OH)D over an equivalent period of time,
      • Ish-Shalom S.
      • Segal E.
      • Salganik T.
      • et al.
      Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients.
      the high number of trials with daily dosing (more than 50% of studies)
      • Morcos M.M.
      • Gabr A.A.
      • Samuel S.
      • et al.
      Vitamin D administration to tuberculous children and its value.
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      • Mily A.
      • Rekha R.S.
      • Kamal S.M.
      • et al.
      Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis.
      • Ganmaa D.
      • Giovannucci E.
      • Bloom B.R.
      • et al.
      Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
      • Choudhary N.
      • Gupta P.
      Vitamin D supplementation for severe pneumonia—a randomized controlled trial.
      • Goldring S.T.
      • Griffiths C.J.
      • Martineau A.R.
      • et al.
      Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial.
      • Majak P.
      • Olszowiec-Chlebna M.
      • Smejda K.
      • et al.
      Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection.
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      • Laaksi I.
      • Ruohola J.P.
      • Mattila V.
      • et al.
      Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men.
      • Li-Ng M.
      • Aloia J.F.
      • Pollack S.
      • et al.
      A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.
      • Bergman P.
      • Norlin A.C.
      • Hansen S.
      • et al.
      Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.
      • Urashima M.
      • Segawa T.
      • Okazaki M.
      • et al.
      Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children.
      • Aloia J.F.
      • Li-Ng M.
      Re: epidemic influenza and vitamin D.
      • Jorde R.
      • Witham M.
      • Janssens W.
      • et al.
      Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Platz A.
      • et al.
      Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial.
      • Wagner C.L.
      • McNeil R.B.
      • Johnson D.D.
      • et al.
      Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.
      • Snyman J.R.
      • de Sommers K.
      • Steinmann M.A.
      • et al.
      Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.
      • Abu-Mouch S.
      • Fireman Z.
      • Jarchovsky J.
      • et al.
      Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naive patients.
      • Avenell A.
      • Cook J.A.
      • Maclennan G.S.
      • et al.
      Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438).
      • Briffa N.K.
      • Keogh A.M.
      • Sambrook P.N.
      • et al.
      Reduction of immuno-suppressant therapy requirement in heart transplantation by calcitriol.
      raises concerns over compliance; several large clinical trials have reported low adherence to daily doses of vitamin D.
      • Unson C.G.
      • Litt M.
      • Reisine S.
      • et al.
      Adherence to calcium/vitamin D and estrogen protocols among diverse older participants enrolled in a clinical trial.
      • Sanfelix-Genoves J.
      • Gil-Guillen V.F.
      • Orozco-Beltran D.
      • et al.
      Determinant factors of osteoporosis patients' reported therapeutic adherence to calcium and/or vitamin D supplements: a cross-sectional, observational study of postmenopausal women.
      The doses of vitamin D3 also varied (300
      • Camargo Jr., C.A.
      • Ganmaa D.
      • Frazier A.L.
      • et al.
      Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia.
      to 10,000 IU
      • Nursyam E.W.
      • Amin Z.
      • Rumende C.M.
      The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.
      for daily doses, 1,400
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      to 60,000 IU
      • Kota S.K.
      • Jammula S.
      • Kota S.K.
      • et al.
      Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis.
      • Rehman P.K.M.
      Subclinical rickets and recurrent infection.
      for weekly doses and 30,000
      • Tran B.
      • Armstrong B.K.
      • Ebeling P.R.
      • et al.
      Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.
      to 600,000 IU
      • Salahuddin N.
      • Ali F.
      • Hasan Z.
      • et al.
      Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study (supplementary cholecalciferol in recovery from tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'.
      for single or monthly doses), as did the formulation. Although most trials used oral vitamin D3, 2 trials used vitamin D2,