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Graat JM, Schouten EG, Kok FJ. Effect of Daily Vitamin E and Multivitamin-Mineral Supplementation on Acute Respiratory Tract Infections in Elderly Persons: A Randomized Controlled Trial. JAMA. 2002;288(6):715–721. doi:10.1001/jama.288.6.715
Author Affiliations: Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, the Netherlands.
Context Immune response in elderly individuals has been reported to improve
after micronutrient supplementation. However, efficacy trials evaluating infectious
diseases as outcomes are scarce and inconclusive.
Objective To investigate the effect of daily multivitamin-mineral and vitamin
E supplementation on incidence and severity of acute respiratory tract infections
in elderly individuals.
Design A randomized, double blind, placebo-controlled, 2 × 2 factorial
Setting and Participants A total of 652 noninstitutionalized individuals aged 60 years or older
enrolled from 2 community-based sampling strategies in the Wageningen area
of the Netherlands, conducted from 1998 to 2000. At baseline, 6% of participants
had suboptimal ascorbic acid and 1.3% had suboptimal α-tocopherol plasma
Intervention Physiological doses of multivitamin-minerals, 200 mg of vitamin E, both,
Main Outcome Measures Incidence and severity of self-reported acute respiratory tract infections
at 15 months, as assessed by a nurse (telephone contact), home visits, and
microbiological and serological testing in subsets of patients.
Results During a median observation period of 441 days, 443 (68%) of 652 participants
recorded 1024 respiratory tract infection episodes. The incidence rate ratio
of acute respiratory tract infection for multivitamin-mineral supplementation
was 0.95 (95% confidence interval, 0.75-1.15; P =
.58) and for vitamin E supplementation, 1.12 (95% confidence interval, 0.88-1.25; P = .21). Severity of infections was not influenced by
multivitamin-mineral supplementation. For vitamin E vs no vitamin E, severity
was worse: median (interquartile range) for illness-duration was 19 (9-37)
vs 14 (6-29) days, P = .02; number of symptoms, 6
(3-8) vs 4 (3-8), P = .03; presence of fever, 36.7%
vs 25.2%, P = .009; and restriction of activity,
52.3% vs 41.1%, P = .02.
Conclusions Neither daily multivitamin-mineral supplementation at physiological
dose nor 200 mg of vitamin E showed a favorable effect on incidence and severity
of acute respiratory tract infections in well-nourished noninstitutionalized
elderly individuals. Instead we observed adverse effects of vitamin E on illness
An age-related decline in immune response may increase the risk of infectious
diseases and their complications.1 Beneficial
effects of micronutrient supplementation on immune response have been observed
not only in institutionalized older persons but also in healthy noninstitutionalized
elderly individuals.2 Supplementation with
multivitamins and minerals at the recommended dietary allowance (RDA) level
mainly improved cellular immune parameters.2,3
For vitamin E, a higher dose, such as 200 mg/d, has been required to demonstrate
For infectious disease occurrence, however, evidence demonstrating the
efficacy of multivitamin-mineral supplementation at the RDA level3,5 or at a high level4
is limited and studies have shown contradictory results. More specifically,
the effect of multivitamin-mineral supplementation at physiological doses
or of 200 mg of vitamin E on respiratory tract infections has not been investigated
in noninstitutionalized elderly persons. Results in institutionalized elderly
individuals have been inconsistent.6-8
The aim of our randomized intervention trial was to determine whether
long-term daily supplementation with multivitamins and minerals at the RDA
level or with 200 mg of vitamin E reduced incidence and severity of acute
respiratory tract infections in noninstitutionalized elderly persons.
A total of 652 men and women (≥60 years) were enrolled in the randomized,
double-blind, placebo-controlled trial. All together 11 417 individuals
were invited to participate through 2 community-based sampling strategies:
via the population registry of the town of Doetinchem, the Netherlands, and
via direct mail to senior citizens' apartments in several other towns. Figure 1 shows the flow diagram of participants.
Individuals were excluded if they used immunosuppressive treatment, anticoagulants
interfering with vitamin K metabolism,9 or
dietary supplements in the previous 2 months or if they had a history of cancer,
liver disease, or fat malabsorption during the 5 years before randomization.
Participants were enrolled between September 1, 1998, and March 23, 1999,
and were followed up for a maximum of 15 months. Eleven participants in the
multivitamin-mineral, 10 in the vitamin E, 11 in the multivitamin-mineral
plus vitamin E, and 6 in the placebo groups did not meet the compliance criteria
of taking at least 80% of their capsules but were included in both analyses;
26, 28, 26, and 25, respectively, were excluded from the per-protocol analysis
for discontinuing the intervention. None of the reasons for discontinuing
intervention were considered a result of the treatment.
Written informed consent was obtained prior to study participation.
The medical ethics committee of Wageningen University, the Netherlands, approved
the research protocol.
The following treatments were applied in a 2 × 2 factorial design:
multivitamins and minerals, vitamin E, multivitamins and minerals plus vitamin
E, and placebo. The multivitamin-mineral capsule contained: retinol (600 µg),
beta-carotene (1.2 mg), ascorbic acid (60 mg), vitamin E (10 mg), cholecalciferol
(5 µg), vitamin K (30 µg), thiamin mononitrate (1.4 mg), riboflavin
(1.6 mg), niacin (18 mg), pantothenic acid (6 mg), pyridoxine (2.0 mg), biotin
(150 µg), folic acid (200 µg), cyanocobalamin (1 µg), zinc
(10 mg), selenium (25 µg), iron (4.0 mg), magnesium (30 mg), copper
(1.0 mg), iodine (100 µg), calcium (74 mg), phosphor (49 mg), manganese
(1.0 mg), chromium (25 µg), molybdenum (25 µg), and silicium (2
µg). We chose dosages at RDA levels for vitamins and 25% to 50% of RDA
levels for minerals because multivitamin-mineral supplementation near RDA
levels previously was shown to decrease duration of infections in noninstitutionalized
elderly persons.3 The vitamin E capsule contained
200 mg/dL of α-tocopheryl acetate because this dose was suggested to
be optimal for improving immune response.4
Placebo capsules contained soybean oil. Quality control of the capsules after
treatment showed no decrease in the original contents.
Each participant received 2 capsules per day to be ingested with dinner
for a maximum of 15 months. A computer-generated, 4-per-block, randomization
list was created by the pharmacy (Roche Vitamins, Europe, Basel, Switzerland),
allocating treatment to participant number. Block-randomization was used to
obtain balanced groups over seasons. Numbered boxes containing identical-looking
capsules were transported from the pharmacy to the Wageningen University.
At enrollment, boxes were assigned consecutively to participants. Treatment
allocation was kept at the pharmacy exclusively in sealed opaque envelopes
while participant identity was known exclusively at the Wageningen University.
None of the treatment codes was broken during the study period. After the
investigator performed all analyses, the pharmacy disclosed the treatment
list to the Wageningen University. Roche Vitamins, provided the randomization
code and the supplements and performed the vitamin concentration analyses
in this trial. The company was not involved in the design and conduct of the
study, the collection, analyses, and interpretation of the data, or the preparation,
review, approval, or control of the manuscript.
Participants completed a questionnaire about relevant population characteristics
and supplement use at baseline, and yearly influenza vaccination after treatment.
Body mass index was calculated by dividing weight in kilograms by the square
of height in meters. Baseline plasma samples were collected for determination
of α-tocopherol, ascorbic acid, retinol, and carotenoids. To monitor
compliance, these assessments were repeated in a postintervention sample of
a subset (n = 300). Returned capsules were counted for all participants.
The before and after intervention blood samples were collected between
8:30 and 11 AM. A light breakfast, without fruit or fruit juices, was allowed
before sampling. Plasma was stored at − 80°C within 6 hours of blood
draw. The reversed-phase high-pressure liquid chromatography method10 was used to analyze fat-soluble vitamin concentrations.11 Ascorbic acid concentration was obtained via standard
procedures and assessed by fluorometric assay.12
Total cholesterol levels were analyzed using the enzymatic Chod-Pap method
with Cobas-Bio centrifugal analyzer.13 Detection
levels and intraday and interday repeatability were within normal ranges and
were sufficient for all analyses.10,11
Suboptimal plasma vitamin levels were based on other studies in elderly persons.14,15
Main outcomes were incidence and severity of acute respiratory tract
infections assessed using a diary in which participants, who received thorough
instruction, recorded all acute symptoms. Acute symptoms were defined as follows
(1) sudden onset, (2) a pattern that differed from any usual symptoms, and
(3) 1 or more of the respiratory tract symptoms like rhinitis, sore throat,
or cough persisted for at least 2 days.16 Presence
of accompanying signs was also recorded in the diary: fever, phlegm production,
wheezing, pain during breathing, headache, shivering, perspiration, muscular
pain, malaise, tearful eyes, pain in facial sinuses, ear pain, staying in
bed, restriction of daily activities, staying at home, and use of medication
or other treatment. Indicators of severity were defined beforehand as (1)
total duration of respiratory episodes, (2) number of symptoms, (3) percentage
of participants with fever, (4) restriction of activity, or (5) episode-related
Participants were requested to report symptoms of a possible acute respiratory
tract infection by telephone to the study nurse who checked whether the symptoms
met the definition. Rectal temperature was self-assessed with a study-supplied
thermometer on all symptomatic days.
As a more specific diagnostic test, microbiology by polymerase chain
reaction and serology tests were performed in a random subsample of 97 symptomatic
patients during 107 illness episodes from October 1, 1998, until October 1,
1999. A nose-throat swab and acute-phase blood sample was taken within 3 days
and a convalescent blood sample between 2 and 4 weeks after onset of symptoms.
The nose-throat swab and paired blood sample were tested for the 9 most common
respiratory pathogens: rhinovirus, enterovirus, coronavirus, respiratory syncytial
virus, influenza virus A and B, parainfluenza virus, adenovirus, and Mycoplasma pneumoniae.17-19
Assuming an infection rate of 0.9 episodes per person per year and a
25% reduction in incidence, sample size calculations showed that with a power
of 80% and an α of .05 (1 sided), 220 participants in the vitamin E
and 220 individuals in the multivitamin and mineral group should be included.
Power was regarded sufficient by including more than 300 participants in both
groups, and infection rate was 1.59 per person per year. Although the initial
sample size was based on a 1-sided test on the assumption that effects would
only be seen in 1 direction, after the study was completed the need for 2-sided
tests became evident. P values are therefore based
on 2-sided tests.
An asymptomatic period of at least 7 days was required before a subsequent
episode was recognized as a new infection. Participants were considered at
risk of a new infection during the entire follow-up minus the duration of
each illness episode, and minus 7 days following each episode. Data analysis
was performed according to intention-to-treat (ie, based on all participants
as randomized). A per-protocol analysis was also performed but did not substantively
change the study results.
First, data were analyzed by 4 treatment groups separately. Second,
after evaluating possible interactions, data were analyzed according to the
2 × 2 factorial design.
Continuous data are expressed as mean (SD) and compared using analysis
of variance (ANOVA). Total carotenoid concentrations, total illness-duration,
and the number of symptoms were log-transformed to account for nonnormality
before ANOVA was performed and P values were obtained
from ANOVA with log-transformed values. Frequencies, including percentages,
were calculated for categorical data and these variables were compared by χ2 tests. We used a Poisson regression model with number of episodes
as the dependent variable, treatment group as the independent variable, and
log-person time as the offset included in the model. P
values less than .05 were regarded as statistically significant. Analyses
were preformed using SAS statistical software version 6.12 (SAS Institute
Inc, Cary, NC).
Baseline characteristics and plasma antioxidant-vitamin concentrations
of the 652 participants were similar across groups (Table 1). Only 2% of the participants lived in homes for the aged.
We therefore consider our study population to be noninstitutionalized. In
total, 105 (16%) of 652 participants discontinued the intervention (Figure 1).
At baseline 40 (6%) and 1 (0.2%) of 652 individuals had suboptimal ascorbic
acid and α-tocopherol concentrations, respectively. After intervention,
ascorbic acid was suboptimal in 4 (1.3%) of 300 participants.
After treatment, ascorbic acid, total carotenoids, α-tocopherol,
and cholesterol-adjusted α-tocopherol levels increased significantly
in the multivitamin-mineral and multivitamin-mineral plus vitamin E group,
while γ-tocopherol decreased significantly. In the vitamin E group, α-tocopherol
and cholesterol-adjusted α-tocopherol levels increased significantly,
while γ-tocopherol levels decreased significantly. In the placebo group,
none of the measured vitamins changed significantly.
The median follow-up duration was 441 days in each group, representing
complete follow-up for 15 months in 84% and including at least 3 winter months
(October-February) for 92% of the participants. Of the 652 participants, 443
(68%) recorded a total of 1024 acute respiratory tract infection episodes.
The study nurse received by telephone 763 (74.4%) of 1024 reports from 381
(86.0%) of 443 participants. Nearly all (99.2%; 757/763) reports were evaluated
as acute respiratory tract infection, the symptoms being distinguishable from
allergies. Infection was microbiologically confirmed in 62 (58%) of 107 of
the symptomatic periods. In only 4 (4%) of 91 matched asymptomatic participants
was a pathogen identified. The relatively high percentage of microbiological
substantiation during the symptomatic periods supports the quality of the
A mean of 1.59 episodes was recorded per person per year. The multivitamin-mineral
group had 240 episodes with 71% of the participants experiencing at least
1 episode, the vitamin E group had 280 episodes among 68%, the multivitamin-mineral
plus vitamin E group had 274 episodes among 66%; and the placebo group had
230 episodes among 67%.
To assess treatment effect, we first analyzed incidence and severity
of the 4 treatment groups separately (Table
2). The only significant difference among the treatment groups was
the percentage of participants who experienced restriction of activity, which
was significantly lower in the multivitamin-mineral group compared with placebo.
Second, the 2 × 2 factorial design was used to obtain a more stable
estimate of incidence and severity. Neither incidence nor severity was significantly
different between the multivitamin-mineral and the no multivitamin-mineral
groups (Table 3). Incidence was
not significantly different between the vitamin E and the no-vitamin E groups.
However, severity tended to be greater in the vitamin E group. Among participants
receiving vitamin E and experiencing an infection, total illness-duration
and total number of symptoms were significantly higher, and fever and restriction
of activity occurred more frequently, than those in the no-vitamin E groups
(Table 4). Furthermore, when 1-sided
tests were used as originally planned, no P values
were significant for any of the tests except for the effect of vitamin E on
For all microorganisms demonstrated, frequency was not different among
the 4 treatment groups (Table 5).
After study completion, participants completed a questionnaire asking what
they thought the supplemental vitamins contained. Of the 652 participants,
437 (67%) had no idea what the capsule contained, 169 (26%) had the wrong
idea, and 46 (7%) were correct.
This randomized placebo-controlled trial demonstrates that long-term
daily supplementation with a physiological dose of multivitamins and minerals
or with 200 mg of vitamin E did not lower incidence and severity of acute
respiratory tract infections in noninstitutionalized elderly persons. However,
among persons experiencing an infection, those individuals who received vitamin
E instead had longer total illness duration, more symptoms, and a higher frequency
of fever and restriction of activity.
In our trial, 94% of the participants met the compliance criteria of
80% capsule intake. Accordingly, the multivitamin-mineral and vitamin E group
showed a large increase in plasma vitamin concentrations, whereas this was
not the case in the placebo group. Baseline characteristics were well balanced
across groups. Assessment of infectious disease was based on self-report,
which may have led to misclassification. However, such misclassification would
have been nondifferential (ie, similar for all groups), resulting in possible
underestimation of the treatment effect. We tried to assess the outcome as
accurately as possible: a prospective diary, telephone calls, home visits,
measuring rectal temperature, plus microbiological and serological testing
in a sample. This method of assessing infection has been used before and follows
widely accepted criteria.3,4,7,8
An infection was confirmed in 58% of the symptomatic periods. This percentage
is high compared with other studies in which a general practitioner or study
nurse evaluated symptoms.20,21
Therefore, the outcome assessment in our study seems to have been reasonably
accurate. Finally, one may argue that an asymptomatic period of 7 days is
inadequate to discriminate between exacerbation of previous infections and
new episodes. Although arbitrarily chosen, this period is considerably longer
than asymptomatic periods of previous studies.22,23
Past studies of multivitamin and mineral supplementation in noninstitutionalized
elderly persons addressed incidence and duration of infectious diseases in
general.3,5 Supplementation trials
that specifically focused on incidence of acute respiratory tract infections
have been performed only in institutionalized elderly patients.8
In the latter intervention studies, incidence was not reduced, consistent
with our findings. On the contrary, Chandra3
reported a decreased duration of infectious diseases in noninstitutionalized
elderly individuals. However, in that study the proportion of individuals
with suboptimal blood vitamin concentrations was much higher. Since Girodon
et al8 did not observe a lower incidence in
institutionalized elderly individuals, it may not be surprising that multivitamin
and mineral supplementation in our population did not decrease incidence of
acute respiratory tract infections. The low percentage of participants having
suboptimal micronutrient status may reflect a relatively well nourished population
and may explain the lack of a treatment effect. The rationale for the selection
of noninstitutionalized elderly persons was based on an improved immune response
after multivitamin and mineral supplementation in such populations3 although this may not necessarily translate to a hard
end point such as respiratory tract infections. It is conceivable that particular
subgroups of elderly persons who have suboptimal micronutrient concentrations
might benefit from additional dietary supplementation.
The only previous studies of vitamin E supplementation in noninstitutionalized
elderly persons were intended to measure immune response and assessed infectious
diseases only as a secondary outcome. A lower incidence of all infections
was reported in noninstitutionalized elderly individuals4
while Harman et al6 observed no effect on incidence
of respiratory tract infections in institutionalized elderly patients. Although
not statistically significant, a higher incidence of upper respiratory tract
infection in those supplemented with 50 or 100 mg of vitamin E was observed
by Pallast et al.24 We could find no published
data on vitamin E supplementation and the severity of respiratory tract infections.
Many investigators have reported that supplementation with vitamin E
improves immune response by enhancing lymphocyte proliferation and IL-2 production
and by decreasing prostaglandin E2 (PGE2) production
by affecting cyclooxygenase 2 activity.4,9
Others have shown no positive relation between vitamin E and immune indices.25,26 It should be realized that our observed
effect of vitamin E on severity of illness might even reflect a more effective
Vitamin E may improve immunity by being converted into an α-tocopheroxyl
radical. This radical can act as a prooxidant unless it is reduced by ascorbic
acid or glutathione.27,28 The
prooxidant mechanism of vitamin E has not yet been thoroughly assessed.28 Possibly, a balance between antioxidants is important
in the prooxidant role of vitamin E. An imbalance may be more pronounced after
long-term supplementation with one nutrient administered in amounts much higher
than the RDA level. Azzi and Stocker27 suggest
that the antioxidant effect of vitamin E is not the primary action of this
vitamin. Recently, inhibitory effects of vitamin E on protein kinase C and
glutathione S-transferase π have been reported.27,29
Most previous studies suggest a beneficial effect of multivitamin, mineral,
and vitamin E supplementation on immune response. From a public health point
of view, studying incidence of infections, especially the frequent respiratory
tract infections, has much greater relevance. Studies have reported that 50%
of elderly people use dietary supplements,30
with multivitamin, mineral, and vitamin E supplements being the most common.30,31 It would be worthwhile to study the
effect of multivitamins and minerals in elderly people with suboptimal plasma
concentration of vitamins. If our results are confirmed and vitamin E exacerbates
respiratory tract infections, elderly people, especially those who are already
well-nourished, should be cautious about taking vitamin E supplements.
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