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Correspondence: vin Tangpricha, MD, PhD, Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, 101 Woodruff Circle NE, WMRB 1301, Atlanta, GA 30322.
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.
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.
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.
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.
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.
By binding the VDR, calcitriol induces several endogenous antimicrobial peptides (AMPs) in human monocytes, neutrophils and epithelial cells (eg, cathelicidin LL-37,
Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL- 37.
1alpha,25-dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phos-phatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase.
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
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
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,
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'.
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, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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.
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.
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.
↔Number of days absent from duty due to RTI, ↓ RTI reported over 6 mo, ↔ 25D over winter in intervention group, ↑25D compared with placebo after winter
Nausea (n = 1), diarrhea (n = 1)
5, 11
VitD: n = 80 Placebo: n = 84 Age: 18–28 yr VitD sufficient → sufficient
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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)
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.
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.
Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.
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.
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.
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 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'.
Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
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.
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.
Combined analysis of 2 randomized, comparison, double-blind, 2° analysis
758 pregnant women in 2nd trimester
400, 2,000 or 4,000 D3 PO daily from 2nd trimester to birth, followed to 12 mo
Varied
↑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.
Placebo, randomized, double-blind, single-center, some control from other cohort study
99 heart transplant recipients
20 daily for 6 mo, 20– 40 daily for 12 mo or 20–40 daily for 24 mo
3,660–29,280
↓Oral cyclosporine requirement 2° OC: ↔ in infection, rejection or mortality rates
None
5, 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)
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.
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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,
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.
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.
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%.
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
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
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,
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,
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.
Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.
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,
Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.
Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
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'.
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.
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
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.
Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
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'.
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 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'.
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'.
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.
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.
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
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.
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'.
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,
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.
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,
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.
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),
A majority of studies reported no difference in adverse events between intervention and control groups nor observed events deemed related to vitamin D.
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'.
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, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
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,
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.
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,
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, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.
Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.
Determinant factors of osteoporosis patients' reported therapeutic adherence to calcium and/or vitamin D supplements: a cross-sectional, observational study of postmenopausal women.
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'.
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