Vitamin D for Treatment and Prevention of Infectious Diseases: A Systematic Review of Randomized Controlled Trials

Alexandra V. Yamshchikov, MD; Nirali S. Desai, MD; Henry M. Blumberg, MD; Thomas R. Ziegler, MD; Vin Tangpricha, MD, PhD, FACE


Endocr Pract. 2009;15(5):438-449. 

In This Article

Abstract and Introduction


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.


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 antiinfective chemotherapy in the 1950s.[2] More recently, epidemiologic studies have demonstrated strong associations between seasonal variations in vitamin D levels and the incidence of various infectious diseases, including septic shock,[3] respiratory infection,[4] and influenza.[4,5]

Our understanding of vitamin D metabolism and its extraskeletal functions has improved considerably during the past 3 decades. The discovery that vitamin D receptor (VDR) and 1α-hydroxylase, the enzyme necessary for conversion of vitamin D into its active form, are present in cells of the immune system, including circulating mononuclear cells,[6,7] has revolutionized the field of vitamin D immunology. Moreover, the discovery of nonskeletal functions of vitamin D has reinvigorated interest in vitamin D as a potential modulator in a variety of disease states.[8,9,10] Recent studies have demonstrated that vitamin D regulates the expression of specific endogenous antimicrobial peptides in immune cells[11]; this action leads to a potential role for vitamin D in modulating the immune response to various infectious diseases.

These findings highlight the need to refine our understanding of the nonskeletal functions of vitamin D through future controlled studies of vitamin D supplementation and clinical outcomes in specific disease states. In this report, we focus on reviewing 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.