Elsevier

Endocrine Practice

Volume 15, Issue 5, July–August 2009, Pages 438-449
Endocrine Practice

Original Article
Vitamin D for Treatment and Prevention of Infectious Diseases; A Systematic Review of Randomized Controlled Trials

https://doi.org/10.4158/EP09101.ORRGet rights and content

ABSTRACT

Objective

To review the existing human controlled intervention studies of vitamin D as adjunctive therapy in settings of infection and provide recommendations for design and implementation of future studies in this field on the basis of the evidence reviewed.

Methods

We conducted a systematic review of randomized controlled clinical trials that studied vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948 through 2009 were identified through search terms in PubMed and Ovid MEDLINE.

Results

Thirteen published controlled trials were identified by our search criteria. Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient demographics, sample size, and vitamin D intervention strategies. Serious adverse events attributable to vitamin D supplementation were rare across all studies. On the basis of studies reviewed to date, the strongest evidence supports further research into adjunctive vitamin D therapy for tuberculosis, influenza, and viral upper respiratory tract illnesses. In the selected studies, certain aspects of study design are highlighted to help guide future clinical research in the field.

Conclusion

More rigorously designed clinical trials are needed for further evaluation of the relationship between vitamin D status and the immune response to infection as well as for delineation of necessary changes in clinical practice and medical care of patients with vitamin D deficiency in infectious disease settings. (Endocr Pract. 2009;15:438-449)

Section snippets

INTRODUCTION

The link between vitamin D deficiency and susceptibility to infection has been suggested for longer than a century, with the early observation that children with nutritional rickets were more likely to experience infections of the respiratory system, leading to the coining of the phrase “rachitic lung” (1). The isolation of vitamin D3 from cod liver oil, which was used to treat tuberculosis (TB) in the 1930s, led to its widespread use in TB treatment and prevention, until the introduction of

Vitamin D and Bacterial Infections

The pioneering work by Rook et al (12) and Crowle et al (13) in the 1980s demonstrated that vitamin D enhanced bactericidal activity of human macrophages against Mycobacterium tuberculosis, the causative agent of TB. This discovery led to a new era of interest regarding the role of vitamin D in determining pathogenesis and the immune response to bacterial pathogens. Liu et al (11) provided a key mechanism to how vitamin D may enhance innate immunity. This group demonstrated that stimulation of

METHODS

We conducted a systematic review of randomized controlled clinical trials that investigated the relationship between vitamin D therapy and clinical outcomes related to infectious diseases in humans. We reviewed the medical literature in PubMed and Ovid MEDLINE from 1948 through 2009, using combinations of search terms including the following: “vitamin D2, ergocalciferol, vitamin D3, cholecalciferol, vitamin D analogue, vitamin D, rickets, infection, immunity, treatment, tuberculosis, upper

RESULTS

We found 13 controlled trials that met our search criteria 35., 36., 37., 38., 39., 40., 41., 42., 43., 44., 45., 46., 47. (Table 1). Ten trials were placebo controlled 35., 36., 37., 40., 42., 43., 44., 45., 46., 47., and 9 of the 10 were conducted in a double-blind design. Five of the 13 trials 35., 36., 37., 38., 39. addressed vitamin D supplementation in patients with bacterial infection, with 4 of the 5 trials evaluating vitamin D as adjunctive therapy in patients with various forms of TB

CONCLUSION

Recent studies have described a high prevalence of vitamin D insufficiency and overt vitamin D deficiency in human populations worldwide (48). As our knowledge of the extraskeletal functions of vitamin D continues to grow, the clinical significance of maintaining vitamin D sufficiency becomes more apparent. Several of the studies reviewed in this report build on existing preclinical research in vitamin D immunology, which demonstrates a likely connection among vitamin D repletion,

DISCLOSURE

The authors have no conflicts of interest to disclose.

ACKNOWLEDGMENT

This work was supported by National Institutes of Health grants T32DK007298 (to A.V.Y.), K24 RR023356 (to T.R.Z.), and K23 AR054334 (to V.T.).

We thank Dr. Roberto Pacifici, principal investigator of National Institutes of Health grant T32DK007298, for his generous support of work related to this publication.

REFERENCES (54)

  • P.A. Danai et al.

    Seasonal variation in the epidemiology of sepsis

    Crit Care Med.

    (2007)
  • W.B. Grant

    Variations in vitamin D production could possibly explain the seasonality of childhood respiratory infections in Hawaii

    Pediatr Infect Dis J.

    (2008)
  • J.J. Cannell et al.

    Epidemic influenza and vitamin D

    Epidemiol Infect.

    (2006)
  • A.K. Bhalla 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

    J Clin Endocrinol Metab.

    (1983)
  • W.E. Stumpf et al.

    Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid

    Science.

    (1979)
  • M.T. Cantorna et al.

    Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence

    Exp Biol Med (Maywood).

    (2004)
  • J. Wactawski-Wende et al.

    Calcium plus vitamin D supplementation and the risk of colorectal cancer [published correction appears in N Engl J Med. 2006;354:1102]

    N Engl J Med.

    (2006)
  • J.N. Flanagan et al.

    Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D

    Anticancer Res

    (2006)
  • P.T. Liu et al.

    Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response

    Science.

    (2006)
  • G.A. Rook et al.

    Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes

    Immunology.

    (1986)
  • A.J. Crowle et al.

    Inhibition by 1,25(OH)2- vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages

    Infect Immun

    (1981)
  • T.T. Wang et al.

    Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression [published correction appears in J Immunol. 2004;173:following 6489]

    J Immun.

    (2004)
  • J. Wehkamp et al.

    Defensins and cathelicidins in gastrointestinal infections

    Curr Opin Gastroenterol.

    (2007)
  • M.H. Malik et al.

    Genetic susceptibility to total hip arthroplasty failure: a preliminary study on the influence of matrix metalloproteinase 1, interleukin 6 polymorphisms and vitamin D receptor

    Ann Rheum Dis.

    (2007)
  • J. Horgan

    Space invaders: Extra! Extra! Flu linked to sunspots

    Sci Am

    (1990)
  • T.A. Reichert et al.

    Influenza and the winter increase in mortality in the United States, 1959-1999

    Am J Epidemiol.

    (2004)
  • D. Kobasa et al.

    Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus

    Nature.

    (2004)
  • Cited by (0)

    Published as a Rapid Electronic Article in Press at http://www.endocrinepractice.org on June 2, 2009. DOI: 10.4158/EP09101.ORR.

    View full text