Can Vitamin D Protect Against Colds and Flus?
By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationships to this field of study.
Synopsis: Laboratory science has delineated convincing connections between vitamin D and immune system function, some of which have been borne out in clinical trials on the prevention and treatment of respiratory infections.
The connection between vitamin d and bone health, and the associations with vitamin D deficiency or insufficiency and fractures or falls, has been well investigated in the medical literature. More recent findings, including the presence of a vitamin D receptor (VDR) in many human tissues,1,2 are pointing to other roles for this vitamin-hormone. With respect to immune system function, there are physiological, observational, and clinical underpinnings for an effect of vitamin D on upper respiratory infection (URI) prevention and, possibly, treatment.
As early as the 1800s, a possible connection between vitamin D deficiency and infections was proposed, though the physicians at first had the cause-effect reversed. In 19th and 20th century Europe, the incidence of tuberculosis and pneumonia was found to be significantly higher in people suffering from rickets, or severe vitamin D deficiency; hence, the thought that it was actually the infection that caused the rickets.1-3 By the 1920s, researchers finally realized that vitamin D in cod liver oil cured rickets, and correctly surmised that it was the deficiency of vitamin D that led to infections. It took many more years to elucidate the mechanism behind that effect.
More recently, researchers have posited that increased incidence and severity of upper respiratory infections with viruses such as influenza, rhinovirus, and respiratory syncytial virus, and pneumococcal infection in the fall and winter may, in fact, be due to dropping serum 25-hydroxyvitamin-D (25(OH)D) levels as the amount and intensity of sunlight falls, as much as from the indoor crowding that occurs during those seasons.3-6 One study found a correlation between serum 25(OH)D and incidence of such infections.7 In a double-blind fashion, these researchers checked 25(OH)D levels monthly from September to January in 198 adults, asking them to report any symptoms consistent with a viral URI. Complicated statistical analyses done on the clinical symptoms and serum 25(OH)D levels found that a level of 38 ng/mL best differentiated the groups that did or did not develop a viral URI; serum 25(OH)D above 38 ng/mL cut the risk approximately in half (P < 0.0001). The researchers were unable to comment on whether the duration of URIs varied with differing serum 25(OH)D.
A review of data collected during the National Health and Nutrition Examination Survey between 1988-1994 found that the medium serum 25(OH)D was 29 ng/mL and that there was an inverse relationship between serum 25(OH)D and recent URI (P < 0.001).8 People with serum 25(OH)D < 10 ng/mL had the highest rate of URI, but so did people in the 10-30 ng/mL group when compared to > 30 ng/mL. The authors saw some indication of a plateau effect at 30 ng/mL beyond which there would be minimal additional protective effect against URIs, but they said follow-up trials are warranted to further elucidate this.
Some hints from vitamin D research done for other purposes expand on the idea that there might be benefits with respect to viral URI infections; although there can be methodological flaws with this type of retrospective analysis, it is interesting for hypothesis generation. For example, a secondary analysis was done on data collected from a randomized trial of vitamin D for bone mineral density improvements in African American women, showing that the women in the vitamin D group had fewer colds and flus and that these infections, when they did occur, lacked a seasonality.9 However, other researchers sent questionnaires to women who had completed a trial of vitamin D and/or calcium for the secondary prevention of osteoporotic fractures; the authors did not find a protective effect of vitamin D on URI incidence nor antibiotic use, though they comment on the fact that noncompliance and the nonspecificity of the questions could have accounted for the lack of an association.10
Further research found no difference in serum 25(OH)D in Canadian children younger than age 2 admitted for lower respiratory infection when compared to a control group without a history of infection.11 The authors assert that vitamin D may be more effective against bacterial than viral infections, possibly due to vitamin D's preferential shift toward increasing (Th)-2 rather than (Th)-1; higher levels of T helper cells (Th)-1 seem to correlate with decreased severity of some respiratory virus infections,11 explaining why a vitamin D and (Th)-2 connection may not translate to efficacy with viral infections. In addition, vitamin D may be a major factor only in cases of severe deficiency; many of the Canadian children in this study were ingesting some vitamin D in formula or as supplements and had mid-range serum 25(OH)D levels.
A different Canadian study in children younger than 5 years old measured 25(OH)D in those admitted to the hospital with lower respiratory infection (n = 105) vs. those presenting with non-respiratory complaints (n = 92), and found similar vitamin D levels: 33 ng/mL vs. 32.5 ng/mL, respectively.12 However, the subset of children admitted to the intensive care unit (ICU) had 25(OH)D of 19.6 ng/mL, significantly lower than the control group (P = 0.001) or children admitted just to the general pediatric floor (P = 0.001). The researchers conclude that vitamin D deficiency is a risk factor for more severe respiratory disease and ICU admission.
Other observations are that the role of vitamin D in the innate immune system response may explain the higher incidence and increased severity of tuberculosis in African Americans in the United States, a demographic shown to generally have a lower serum 25(OH)D.13
Mechanisms of Action
Past reviews in Alternative Medicine Alert have detailed the different forms of vitamin D, its metabolites, and relationship to calcium absorption and bone formation. Its immune system effects may, in fact, be as significant and widespread throughout the body. As mentioned above, many tissue types have VDRs, including thymic and bone marrow B and T cells. After the most active form of vitamin D 1,25-dihydroxyvitamin D binds to VDR, transcriptional regulation of numerous proteins occurs, affecting calcium and phosphate metabolism, cell proliferation and differentiation, and immune system function.1
There are complicated effects of vitamin D on both the innate and acquired, or adaptive, immune systems (see diagrams in references 1 and 2); overall, most experts consider 1,25-dihydroxyvitamin-D to be a potent "immunomodulator," acting via numerous mechanisms.13 The specific immune system effects of vitamin D derivatives are numerous and varied (see Table at right, Specific Immune System Effects of Vitamin D and Associated Mechanisms).
Human Clinical Trials
The medical literature is rife with attempts to prevent or treat various infections with vitamin D supplementation. Some trials used cod liver oil,3 known to be a source of vitamin D, vitamin A, and omega-3 fatty acids, but it is difficult to tease out the vitamin D effect from the other nutrients. Research focusing on vitamin D has had a mixture of results, from convincing efficacy or borderline benefit, to no effect, some of which is related to the study population (demographic, baseline vitamin D, etc.) and specific intervention (dose and dosing regimen). Although some research has revisited the tuberculosis-vitamin D connection,17 this section will focus on those trials specific to URIs.
One review collected the results from 13 trials, 10 of which were placebo-controlled, that addressed vitamin D therapy and clinical outcomes relevant to infectious diseases.18 The trials varied widely in patient population, age, medical conditions (URIs to schistosomiasis), vitamin D dose, and whether ergocalciferol (D2) or cholecalciferol (D3) was used. The authors were convinced of a role for vitamin D in the prevention and treatment of tuberculosis, influenza, and other viral URIs, though they deferred to future research to refine the details. Furthermore, all future research, they argue, needs to include baseline and follow-up serum 25(OH)D testing, to acknowledge the 30-32 ng/mL threshold level for clinical effect, and to improve on basic methodology.
Other themes surface from a review of individual research trials. For example, in the pediatric realm, a randomized, double-blind, placebo-controlled trial in Japan with intention-to-treat analysis in 430 school children (334 completed the study) used 1,200 IU of vitamin D3 daily from December to March and found that there was a modest decrease in the incidence of seasonal influenza A in the treatment group (RR = 0.36, P = 0.04).16 It could be argued that this intervention started late, given that it can take up to 3 months to reach a steady state of vitamin D after beginning supplementation, and that is what accounted for the results showing only modest effects.
Another trial, this time in 162 adults, showed that 2,000 IU vitamin D3 administered from December to June did not decrease the incidence of URIs when compared to placebo, nor was there any difference in severity or duration of URI symptoms.15 Baseline serum 25(OH)D was 25 ng/mL (63.7 nmol/L) and increased to 34.7 ng/mL (86.7 nmol/L) after 3 months; these values are close to what is thought to be a "threshold effect" below which minimal, if any, physiological effect is seen. Also, sub-group analyses in this trial show that vitamin D supplementation may have a greater benefit in people with lower baseline values, explaining, perhaps, why some people respond to vitamin D supplementation and others don't. However, researchers have noted that some people have genetic VDR polymorphisms that may lead to decreased expression of VDRs and therefore less vitamin D effect in combating infections.12 In addition, there is some concern about the research methodology in the above trial, as it is unclear whether an intention-to-treat analysis was undertaken on the 148 people who actually completed the trial.
The negative trials give us some indication about the proper possible use of vitamin D, but efficacy trials are still necessary to definitively establish benefit.
In 164 Finnish military recruits, those who received 400 IU vitamin D daily from October to March were not absent less often from work (P = 0.096) but they did have fewer self-reported URIs (P = 0.045) than the placebo group.19 The number-needed-to-treat for this intervention was 6.4, calculated from men without any absences from work. Although there were 60 dropouts over the course of the study, the researchers used intention-to-treat analyses, making the results more accurate and, therefore, believable. The treatment group achieved a serum 25(OH)D of 28.7 ng/mL after 6 months of supplementation, probably not an adequate level for most physiological effects of vitamin, while the placebo group dropped to 20.4 ng/mL. In Afghanistan, 415 children with pneumonia were randomized to receive either one dose of 100,000 IU vitamin D3 orally or placebo.20 The intervention did not affect the duration of illness but it decreased the number of children with repeat pneumonia in the ensuing 90 days (P = 0.01) and lengthened the number of days from 59 to 72 until the next pneumonia (P = 0.02). No adverse effects were noted.
The specifics of dosing was discussed in detail in the July 2010 issue of Alternative Medicine Alert. The research described above seems to indicate the importance of a serum 25(OH)D threshold effect and the fact that it may require approximately 2-3 months of supplementation to reach a steady state.21 There is some individual variation in what dose is required to reach a particular serum 25(OH)D, possibly due to a nonlinear serum response to dosing; vitamin D is metabolized more quickly at increased serum levels.7 That said, most people eventually will raise their serum 25(OH)D by 10 ng/mL with supplementation of 1,000 IU,22 and this amount of vitamin D supplementation is thought to bring 50% of people above a serum 25(OH)D level of 30 ng/mL.23 None of the clinical trials in this review provide sufficiently convincing results relevant to dosing to expand upon the past recommendations focused more upon serum 25(OH)D.
The above-mentioned review of 13 trials reported adverse effects as "rare" and only two instances of hypercalcemia necessitating a reduction or discontinuation of vitamin D.18 Other trials reported no adverse effects,16 or no difference in the rate of adverse effects between vitamin D and placebo arms.15 One oft-quoted editorial mentions the safety of vitamin D for people of all ages, except for those with granulomatous diseases who would need a lower dose.22
From the times of rampant rickets and tuberculosis to the present day, observational data have shown a close connection between low serum 25(OH)D and the incidence of URIs, which could partly explain the seasonality of many URI etiologic agents. Human clinical trials have illustrated a few themes. People with lower serum 25(OH)D are at risk for more severe respiratory disease, but also may be the people who respond better to vitamin D supplementation. It seems that a minimum serum 25(OH)D level of 30-35 ng/mL is necessary to provide a protective effect against URIs, depending on the study. Published clinical trials have used vitamin D doses between 400-2,000 IU daily, though in some cases supplementation began in the winter, apparently too late to provide benefit if steady state 25(OH)D requires 2-3 months of treatment.
Vitamin D is a therapy of minimal risk, but possibly significant benefit with respect to URIs; therefore, until proven otherwise and for a growing number of health effects, all clinicians should be recommending vitamin D supplementation unless specifically contraindicated. Conforming to the research results reviewed here, supplementation should begin during the fall season, well in advance of the winter URI "season." The exact dose to be used is still a matter of speculation, and researchers instead have focused on the serum 25(OH)D thought to be protective; practitioners should aim for levels of at least 30-35 ng/mL for their patients.
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