Multivitamins Appear to Decrease the Frequency of Minor Infections
March 31, 2003
(American College of Physicians-American Society of Internal Medicine) -- A daily multivitamin and mineral supplement reduced the incidence of infection and related work absenteeism among healthy people aged 45 or older, according to a new randomized, controlled trial.
Of 130 people over age 45 who took either a multivitamin or a placebo (dummy pill) daily for one year, 43 percent who took the multivitamin reported getting a cold or other minor infections compared to 73 percent who took the placebo.
The results were most significant in people with type 2 diabetes. In this group, only 17 percent of those who took the multivitamin reported getting an infection compared to 93 percent of those who took the placebo.
An editorial notes that although millions of Americans take multivitamin and mineral supplements, few studies have documented the benefits.
Effect of a Multivitamin and Mineral Supplement on Infection and Quality of Life
A Randomized, Double-Blind, Placebo-Controlled Trial
Thomas A. Barringer, MD; Julienne K. Kirk, PharmD; Amy C. Santaniello, PharmD; Kristie Long Foley, PhD; and Robert Michielutte, PhD
We conducted a randomized, double-blind, placebo-controlled trial in two academic primary care clinics. Study participants were recruited by announcements made in the primary care clinics, at senior group meetings in the community, and to employees in the medical facilities where the study was conducted. Participants had to be 45 years of age or older and willing to be randomly assigned to the treatment or placebo group. Persons were excluded if they were currently using immunosuppressive drugs or anticoagulants; had used vitamin or mineral supplements (except calcium) in the past month; had a history of kidney stones; had malignant disease, renal insufficiency, hepatic impairment, dementia, or uncontrolled hypertension; abused alcohol or drugs; or were pregnant or lactating.
A total of 158 persons were enrolled and provided written informed consent. The institutional review boards of Carolinas Medical Center, Charlotte, and Wake Forest Medical Center, Winston-Salem, North Carolina, approved the study. After stratification by age (45 to 64 years or 65 years) and diabetes status (type 2 diabetes mellitus only), a computer-generated list was used to randomly assigned participants to the treatment group (n = 78) or the placebo group (n = 80). Participants were stratified by age and diabetes because increasing age and presence of diabetes may decrease immune function and increase the likelihood of subclinical micronutrient deficiencies and susceptibility to infection.
Participants in the treatment group received a daily oral tablet that contained amounts of vitamins and minerals very similar to those found in most commercially available multivitamin and mineral supplements. Participants in the placebo group received a daily oral tablet containing calcium, 120 mg; magnesium, 100 mg; and vitamin B2 (riboflavin), 3.4 mg. These ingredients were chosen so that the tablet would look and smell as similar as possible to the complete multivitamin and mineral supplement and would cause similar changes in the color of participants' urine. Tishcon Corp. (Westbury, New York) prepared the supplement and placebo pills specifically for this study. All participants were required to take the tablets daily for 1 year.
Baseline measurements included sociodemographic characteristics, clinical data, nutritional status, level of stress, health behaviors, and quality of life. All sociodemographic data were dichotomized and included age (45 to 64 years or 65 years), sex, ethnicity (black or white), and years of education (less than high school or high school graduate and beyond). Clinical data included body mass index (normal, <25 kg/m2; overweight, 25 to 29.9 kg/m2; obese, 30 kg/m2). Hemoglobin A1c level was measured among participants with diabetes. We also assessed history of vitamin use in the year before the study, previous influenza immunization, and whether the participant had had at least one infection in the previous year.
Nutritional status was assessed with a 3-day food diary that participants kept at baseline and at 6 months. At randomization, participants were given detailed written and verbal instructions on how to fill out the food diary, and the study nutritionist reviewed each completed diary with the participant. Analysis was performed by using Nutritionist V, version 2.0 (First DataBank, Inc., San Bruno, California). Nutrient deficiency, for the purpose of this study, was defined as intake below the 33rd percentile of the recommended daily allowance (RDA) for zinc; selenium; iron; folic acid; or vitamins A, C, E, or B6.
Selection was based on research indicating that even moderate deficiencies of these individual nutrients can impair markers of immune function (3-6, 15-17). Our choice of the 33rd percentile was somewhat arbitrary. There is no standard cut-point for micronutrient deficiency as it relates to impairment of immune function because the role of each micronutrient depends on many other factors, such as age, chronic disease, other nutrient deficiencies, and bioavailability. Because many variables are unique to each individual and sample, previous studies demonstrating an immune function benefit from supplementation have defined deficiency post hoc (11, 16).
Stress, which has been shown to influence susceptibility to minor infection (18, 19), was measured by using a 10-item scale that assessed perceived stress during the previous month (20). Each question was measured on a scale of 0 to 4 points, yielding a possible range of 0 to 40 points. For health behaviors, we included smoking status (current, past, or never) and measures of routine physical and recreational exercise (very or moderately active vs. inactive), using items from the National Health and Nutrition Examination Survey II.
The primary end point of our study was incidence of participant-reported infection. Infection data were obtained from symptom checklist diaries recorded daily by the study participants. Detailed instructions on keeping the diaries were given to each participant at the start of the study, and participants were encouraged to call with any questions if they became uncertain. Each participant brought his or her diary to every quarterly study visit, and all aspects of the recorded data were reviewed with participants for clarity, accuracy, and completeness. Using this record of illness, the study physician then assigned a specific diagnosis and duration. Standard criteria were used to diagnose common adult infectious illnesses (upper respiratory tract infection, lower respiratory tract infection, influenza-like syndrome, gastrointestinal infection, and urinary tract infection).
Symptom checklist records that fit into the above categories prompted further detailed interview by the physician to confirm or exclude other infectious and noninfectious entities (for example, allergic rhinitis and medication-induced diarrhea).
Infection incidence was determined by using both continuous and categorical variables. First, we calculated the mean number of total "symptomatic days" due to infection per year. Because many study participants (n = 54) reported no infection and the data were therefore considerably skewed, the dichotomous variable of infection versus no infection proved more meaningful. We also assessed the significance of infections by ascertaining "absentee" days, that is, days of infection-related illness that resulted in missed work or inability to perform planned activities.
The secondary end point, quality of life, was assessed at baseline and at 12 months. Proxy measures of physical and mental health were obtained by using the Medical Outcomes Study 12-Item Short Form (SF-12) (21). We computed total scores using weighted-item response categories similar to those used to score the 36-Item Short-Form Health Survey (22). Adverse effects, adherence, and any substantial change in medical status were assessed at the quarterly visits.
The treatment group was more physically active and better nourished than the placebo group but was similar with respect to baseline covariates. The overall sample was predominately female, white, and between the ages of 45 and 64 years. Approximately 10% of participants had not finished high school. Two thirds of the sample were overweight or obese, and approximately 30% had type 2 diabetes mellitus. Approximately 18% of the total sample were classified as nutritionally deficient. Slightly more than half of the participants in both the placebo and treatment groups remembered having had at least one infection in the previous year.
Twenty-eight persons did not complete the trial (15 in the treatment group vs. 13 in the placebo group). Participants who withdrew were more likely to be 45 to 64 years of age and nondiabetic at baseline, but no other differences were noted. The most commonly reported reason for withdrawal was the inconvenience of keeping a daily diary or attending quarterly physician visits. One serious adverse event, a cardiac arrest, occurred during the trial; the affected participant was successfully resuscitated and continued in the study.
No infections requiring hospitalization occurred during the study period. Forty-two percent of participants had upper respiratory tract infections, 19% had influenza-like syndromes, 12% had gastrointestinal infections, 7% had lower respiratory tract infections, and fewer than 2% had urinary tract infections or miscellaneous infections. Twenty percent of persons experienced more than one type of infection over the study year.
Seventy-three percent of the placebo group experienced one or more infection-related illnesses versus 43% of the treatment group (P < 0.001). Similarly, 57% of the placebo group reported illness-related absenteeism versus 21% of the treatment group. Analysis within the age and diabetes subgroups showed that the differential effect of vitamin supplementation on infection was found primarily among participants with diabetes. Ninety-three percent of diabetic participants in the placebo group experienced an infectious illness versus only 17% of diabetic participants in the treatment group (relative risk, 0.18 [95% CI, 0.07 to 0.44]). Similarly, 89% of diabetic participants in the placebo group reported one or more absentee days compared with 0% of diabetic participants in the treatment group. Participants without diabetes did not differ by study group.
We did not find an effect of age on infection. However, the lack of a statistically significant effect among participants older than 65 years of age does not allow us to draw any meaningful conclusions because only 33 participants were in this age group. Participants younger than 65 years of age experienced an apparent reduction in infection because of vitamin supplementation (78% in the placebo group vs. 43% in the treatment group); however, the difference in outcome between the two age groups was not statistically significant (P > 0.2). At baseline, diabetic participants were more likely than nondiabetic participants to be deficient in one or more micronutrients (33% vs. 19%; P = 0.06).
Treatment Effects on Quality of Life
The quality-of-life scores in our study were similar to those in persons who reported minor medical problems in a validation study of the SF-12 (21). In multivariate analyses, vitamin supplementation had no effect on physical or mental health scores (difference, 1.02 [CI, 2.22 to 4.2] and 0.98 [CI, 1.97 to 3.94], respectively). No additional analyses of quality of life were conducted within the age and diabetes subgroups because treatment had no main effect on outcome.
Our trial, which was performed in a sample of middle-aged persons, demonstrated a benefit in incidence of infection. However, this benefit was almost entirely observed in participants with diabetes, for whom the magnitude was dramatic. Correction of micronutrient deficiencies would be the most biologically plausible explanation for our results. When we defined nutritional deficiency as intake below the 33rd percentile of the RDA, participants who were diabetic at baseline were more likely than nondiabetic participants to be deficient in one or more micronutrients. It remains uncertain, however, whether these small differences in nutritional status were enough to account for the dramatic difference in outcome. This uncertainty is due not only to the limitations of our study but also to inherent difficulties in defining micronutrient deficiency.
Most of the previous research on vitamin and mineral supplementation has evaluated its effect on various markers of immune function (3-10, 15, 16). A few studies have evaluated clinical outcomes, although mostly in severely compromised or malnourished persons. Research in samples of relatively healthy elderly persons, however, has shown that even mild nutrient deficiencies can impair immune response (3-6, 12, 13, 16). Such subclinical deficiencies are common in community-dwelling elderly persons and probably account for some of the impaired immunity in this population (11-13, 15-17).
Whether these data can be extrapolated to other minimally compromised groups, such as middle-aged participants with stable chronic disease processes, is unknown.
Our findings suggest that in certain diabetic samples, perhaps those with a high prevalence of micronutrient deficiency, daily use of a multivitamin and mineral supplement can decrease infection frequency. These dramatic results warrant testing in a larger clinical trial, both for confirmation and to disentangle the effects of chronic disease status from those of other important factors, such as ethnicity and obesity, that serve as proxies for socioeconomic status and poorer nutrition. Multivitamin and mineral supplements are convenient and relatively inexpensive. If our results are confirmed in a larger trial, the widespread implementation of this preventive measure could have a substantial economic impact and could ease the burden of suffering in our society.
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Source: Annals of Internal Medicine, 4 March 2003 Volume 138 Number 5.
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