Simin Nikbin Meydani, Lynette S. Leka, Basil C. Fine, Gerard E. Dallal, Gerald T. Keusch, Maria Fiatarone Singh, Davidson H. Hamer. Vitamin E and Respiratory Tract Infections in Elderly Nursing Home ResidentsA Randomized Controlled Trial. JAMA. 2004;292(7):828–836. doi:10.1001/jama.292.7.828
Author Affiliations: Nutritional Immunology Laboratory (Dr Meydani and Ms Leka) and Biostatistics Unit (Dr Dallal), Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Mass; Department of Pathology, Sackler Graduate School of Biochemical Sciences, Tufts University, Boston (Dr Meydani); Department of Medicine, Mount Auburn Hospital, Cambridge, Mass (Dr Fine); Department of International Health, Boston University School of Public Health, Boston, Mass (Dr Keusch); University of Sydney, Lidcombe, Australia (Dr Singh); Department of Medicine, Tufts University School of Medicine, Boston (Dr Hamer); and the Center for International Health and Development, Boston University School of Public Health, Boston (Dr Hamer).
Context Respiratory tract infections are prevalent in elderly individuals, resulting
in increased morbidity, mortality, and use of health care services. Vitamin
E supplementation has been shown to improve immune response in elderly persons.
However, the clinical importance of these findings has not been determined.
Objective To determine the effect of 1 year of vitamin E supplementation on respiratory
tract infections in elderly nursing home residents.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled trial was conducted from
April 1998 to August 2001 at 33 long-term care facilities in the Boston, Mass,
area. A total of 617 persons aged at least 65 years and who met the study's
eligibility criteria were enrolled; 451 (73%) completed the study.
Intervention Vitamin E (200 IU) or placebo capsule administered daily; all participants
received a capsule containing half the recommended daily allowance of essential
vitamins and minerals.
Main Outcome Measures Incidence of respiratory tract infections, number of persons and number
of days with respiratory tract infections (upper and lower), and number of
new antibiotic prescriptions for respiratory tract infections among all participants
randomized and those who completed the study.
Results Vitamin E had no significant effect on incidence or number of days with
infection for all, upper, or lower respiratory tract infections. However,
fewer participants receiving vitamin E acquired 1 or more respiratory tract
infections (60% vs 68%; risk ratio [RR], 0.88; 95% confidence interval [CI],
0.76-1.00; P = .048 for all participants; and 65%
vs 74%; RR, 0.88; 95% CI, 0.75-0.99; P = .04 for
completing participants), or upper respiratory tract infections (44% vs 52%;
RR, 0.84; 95% CI, 0.69-1.00; P = .05 for all participants;
and 50% vs 62%; RR, 0.81; 95% CI, 0.66-0.96; P =
.01 for completing participants). When common colds were analyzed in a post
hoc subgroup analysis, the vitamin E group had a lower incidence of common
cold (0.67 vs 0.81 per person-year; RR, 0.83; 95% CI, 0.68-1.01; P = .06 for all participants; and 0.66 vs 0.83 per person-year; RR,
0.80; 95% CI, 0.64-0.98; P = .04 for completing participants)
and fewer participants in the vitamin E group acquired 1 or more colds (40%
vs 48%; RR, 0.83; 95% CI, 0.67-1.00; P = .05 for
all participants; and 46% vs 57%; RR, 0.80; 95% CI, 0.64-0.96; P = .02 for completing participants). Vitamin E had no significant
effect on antibiotic use.
Conclusions Supplementation with 200 IU per day of vitamin E did not have a statistically
significant effect on lower respiratory tract infections in elderly nursing
home residents. However, we observed a protective effect of vitamin E supplementation
on upper respiratory tract infections, particularly the common cold, that
merits further investigation.
Infections, particularly respiratory tract infections, are common in
elderly individuals, resulting in decreased daily activity, prolonged recovery
times, increased health care service use, and more frequent complications,
including death.1- 11 In
the United States, an estimated 43% of elderly persons will be admitted to
a nursing home, with more than 85% of them admitted to long-term (>1 year)
care facilities.12 Infections occur more frequently
in nursing home residents than among independent-living elderly,2- 10,13 and
respiratory tract infections are a major cause of morbidity and mortality.9,14,15 Contributing to the
increased incidence of infection with age is the well-described decline in
immune response.16 For example, those who have
diminished delayed-type hypersensitivity skin test responses have higher morbidity
and mortality from cancer, pneumonia, and postoperative complications.17- 19
Nutritional status is an important determinant of immune function.20,21 Nutritional supplementation has been
shown to enhance the immune response in older persons.22,23 In
our earlier placebo-controlled, double-blind trials in elderly persons, vitamin
E supplementation improved immune response, including delayed-type hypersensitivity
and response to vaccines.24,25 Furthermore,
participants receiving vitamin E in the 6-month trial25 had
a 30% lower incidence of infectious diseases (primarily respiratory tract
infections) compared with those receiving placebo, but this result was not
significant, perhaps because of insufficient power, and infections were self-reported.
To overcome these limitations, the current study determined the effect of
1 year of supplementation with vitamin E on objectively recorded respiratory
tract infections in elderly nursing home residents.
This randomized, double-blind, placebo-controlled trial to investigate
the effect of 1 year of vitamin E supplementation on respiratory tract infections
in a nursing home population was conducted from April 1998 to August 2001.
The Tufts–New England Medical Center institutional review board approved
the study protocol and informed consent form. Participants were recruited
from 33 long-term care facilities in the Boston, Mass, area. A total of 2814
residents were initially identified as potential candidates (Figure 1). According to the nursing home staffs, 874 participants
met the following eligibility criteria: aged 65 years or older; life expectancy
greater than 6 months; no anticipated discharge within 3 months; not room-bound
for the past 3 months; absence of active neoplastic disease; no tube feeding,
no kidney dialysis; no intravenous or urethral catheters for the last 30 days;
no tracheostomy or chronic ventilator; antibiotic-free for more than 2 weeks;
no long-term steroid treatment greater than 10 mg/d, no use of immunosuppressive
drugs, or greater than the recommended daily allowance (RDA) level of supplements
of vitamins E, C, or B6, selenium, zinc, beta-carotene, or fish
oil; body mass index of at least 18; serum albumin at least 3.0 g/dL; able
to swallow pills; willing to receive influenza vaccine; and willing to provide
informed consent (for patients with dementia, family members provided informed
Subsequent rescreening by our study nurses led to exclusion of 173 participants
who had given informed consent. An additional 84 candidates were not enrolled
for various reasons detailed in Figure 1.
Participants were assigned to vitamin E or placebo with equal probability
in blocks of 4 according to lists generated by the study's statistician, who
used a computer program. Six randomization lists were constructed for each
nursing home according to age (65-79, 80-89, and ≥90 years) and smoking
or chronic obstructive pulmonary disease (COPD) status (yes or no). Identification
codes of newly enrolled persons were entered in order by the study statistician
into the next available slots in the appropriate list. Those enrolling the
participants had no access to the randomization lists. Participants were unknown
to the statistician. A total of 617 participants were randomized to the vitamin
E (311 participants) or placebo (306 participants) groups.
Nursing home residents have a heterogeneous intake of micronutrients,26,27 some of which are necessary for proper
immune function. To reduce variability, all participants received a capsule
containing 50% of the RDA28 for essential micronutrients.
Fifty percent RDA was selected because few candidates meeting our eligibility
criteria would have intakes less than 50% of the RDA for micronutrients.29
The vitamin E group received a daily capsule containing 200 IU of vitamin
E (DL-α-tocopherol), and the control group received a placebo capsule
containing 4 IU of vitamin E, both in soybean oil. The vitamin E dose was
based on earlier studies in elderly individuals in which 200 IU per day induced
the most robust improvement in immune function.25
Capsules were manufactured by Tishcon Corporation (Westbury, NY) in
2 equal batches, with all ingredients from the same sources. The vitamin E
and placebo capsules were soft gel and identical in color and taste. The manufacturer's
certified ingredient concentrations were confirmed by the investigators. The
capsules were packed by Pharmasource Healthcare Inc (Marlboro, Mass) in 30-dose
blister packs and administered by the clinical nursing home staff during routine
medication rounds. Nurses and participants were blinded to treatment group.
Adherence to study protocol was verified by nursing home medication records,
returned pill count, and quarterly measurement of plasma vitamin E levels.
Primary outcomes of the study included incidence of, number of persons
with, and number of days with respiratory tract infections (upper and lower),
and number of new antibiotic prescriptions for respiratory tract infection.
Because common colds constituted the majority of respiratory tract infection
among all participants randomized and those who completed the study, a post
hoc subgroup analysis was performed to determine the effect of vitamin E on
common colds. Secondary outcomes included emergency department visits, hospitalization,
Information about participant characteristics, baseline diseases and
medications, and vaccination history was obtained from medical records. Fasting
blood was collected at baseline and at study completion for clinical chemistries,
complete blood cell count with differential, plasma vitamin E, and selected
nutrient analyses, as previously described.30,31 In
addition, blood was collected after 3, 6, and 9 months of supplementation
to measure vitamin E levels.
The study nurses collected information weekly relating to infection,
including respiratory and heart rates and temperature. Symptom and physical
examination checklists, focused on the respiratory system, were used to record
clinical findings. The nurses reviewed each participant's medical record for
documentation of laboratory analyses, radiography, medication, nutrient supplementation,
weight, and nurse or physician descriptions of symptoms and signs relating
to respiratory tract infection.
Study nurses were trained by a study physician to elicit relevant respiratory
symptoms and to perform a focused physical examination of the respiratory
system. Supervised practice evaluations were repeated throughout the study
to reinforce the nurses' clinical skills and ensure consistency of the respiratory
tract infection data collection.
At the end of the study, data collected from the participants in each
treatment group, by nursing home, were randomly assigned to 2 of the study
physicians (B.C.F. and D.H.H.) for diagnosis of infections. Infection data
from any one participant was evaluated by only 1 physician, except for 18
participants whose records were used to determine concurrence between physicians.
The study physicians, who were blinded to the treatment group, evaluated
data collected by the nurses from the participant examinations, interviews,
and record reviews to determine incidence and duration of respiratory tract
infection. Clinical definitions of respiratory tract infection were developed
according to accepted definitions.13,32- 37 To
increase the specificity of the definitions, a diagnosis of respiratory tract
infection had to include at least 1 physical sign and not be made on symptoms
alone. An infection was considered resolved when all symptoms ceased. A new
infection was defined as one occurring after at least 7 symptom-free days.
To assess the ability of the study physicians to apply the diagnostic
criteria concordantly, the records of 18 participants were selected at random
for each physician to evaluate independently. After each record was reviewed
in its entirety, a total of 45 respiratory tract infections were identified.
The probability that a physician would diagnose an infection if the other
physician had diagnosed an infection was estimated to be 0.93.38,39
Common Cold. At least 1 of the following signs
or symptoms had to be present: rhinorrhea or stuffy nose (nasal obstruction)
or sneezing plus 1 or more of the following: sore or scratchy throat, dry
cough, hoarseness, or low-grade fever (temperature ≤1°C above normal
range). Symptoms had to be new and not caused by allergies. Seasonal allergic
rhinitis was defined as clear rhinorrhea or nasal congestion plus itchiness
of the nose or eyes or watery eyes; fever, sore throat, and cough had to be
absent; and symptoms had to manifest between April 1 and September 30 and
include at least 1 objective sign of rhinitis.
Influenzalike Illness. Influenzalike illness
was defined as temperature of at least 38°C plus new or increased dry
cough and 1 or more signs or symptoms (chills, new headache or eye pain, myalgias,
malaise or loss of appetite, or sore throat).
Pharyngitis. Pharyngitis was defined as symptoms
of a sore or scratchy throat and at least 1 of the following abnormalities
on pharyngeal examination: erythema, exudate, ulceration, vesicles, or edema.
Otitis Media. Otitis media was defined as ear
pain plus either erythema or bulging of the tympanic membrane.
Sinusitis. Symptoms of sinusitis could include
facial pain, purulent nasal discharge, and nasal congestion. If radiographs
were available, the finding of mucosal thickening, opacities, or air fluid
levels confirmed the diagnosis.
Acute Bronchitis. At least 2 of the following
signs or symptoms had to be present to meet the criteria for acute bronchitis:
increased frequency and severity of cough, new or increased sputum production,
burning substernal chest discomfort with coughing or deep inspiration, and
fever (temperature ≥38°C). Radiologic evidence of pneumonia excluded
Pneumonia. Symptoms of pneumonia could include
cough with or without sputum production, chest pain, dyspnea, and fever. Signs
of infection included elevated temperature (≥38°C), tachycardia, tachypnea,
abnormal breath sounds, and dullness to percussion of the chest. The diagnosis
required radiologic findings of 1 or more new pulmonary infiltrates.
Sample size was based on an estimated mean number of respiratory tract
infections per person-year of 1.00 in the control group5,7 and
0.70 in the treatment group. The within-group SD was estimated at 1.27 according
to data from a local nursing home. With an expected attrition rate of 25%,
the sample size needed to give an 80% chance of detection of the difference
in infection rates at the .05 level of significance was 320 per treatment
group, for a total of 640 participants.
All randomized persons and all completers were compared at baseline,
as were participants who had final measurements taken, by a t test for independent samples (continuous measures) and Pearson χ2 test of homogeneity of proportions (categorical measures). Among completers,
mean differences between the treatment groups with respect to changes in nutritional
status were compared by using a t test for independent
samples. Differences in changes in the fraction of completers who were judged
nutritionally deficient were assessed by using a weighted least-squares linear
model, with time, treatment, and their interaction as predictors. Data on
race was collected from the nursing home medical record.
Rate ratios (RRs) and their confidence intervals (CIs) were obtained
by using Poisson regression, with the natural logarithm of time as an offset.40 Rate ratios were adjusted for obstructive lung disease,
current smoking, diabetes mellitus, dementia, year of enrollment, baseline
albumin level, and baseline hemoglobin level. The adjusted RR for having 1
or more infections was obtained by using logistic regression according to
the method of Zhang and Yu.41 Two-sided observed
significance levels (P values) less than .05 were
considered to be statistically significant. All calculations were performed
using SAS for Windows, version 8.2 (SAS Institute, Cary, NC).
The mean (SD) follow-up time was 317 (104) days for the vitamin E group
and 321 (97) days for the placebo group. Of the 617 randomized persons, 231
(37%) and 220 (36%) in the vitamin E and placebo groups, respectively, completed
the 1-year study period (Figure 1).
The 2 groups did not differ statistically in the proportion or causes of discontinuation
(Figure 1) or in mortality rates
(12.5% [39/311] and 14.4% [44/306] for the vitamin E and placebo groups, respectively).
Table 1 shows participant
characteristics for all who were enrolled in the study (all) and for those
who completed 1 year (completers). The groups were well balanced with regard
to baseline characteristics. One exception was a lower percentage of completers
with diabetes mellitus in the vitamin E group compared with placebo (P = .04) (Table 1).
All participants received influenza vaccine, and the 2 groups did not
differ statistically in the percentage of participants receiving pneumococcal
vaccine (30/311 [9.6%] vitamin E vs 23/306 [7.5%] placebo, P = .53 for all; 29/231 [12.6%] vitamin E vs 19/220 [8.6%] placebo, P = .18 for completers). The mean number of days during
which completers took immune-related medications during the study period did
not differ significantly (nonsteroidal anti-inflammatory drugs [131 vs 110],
antihistamines [4.5 vs 7.9], steroids [16.3 vs 9.2], or nutrient supplements
[84 vs 92] for vitamin E and placebo groups, respectively).
Biochemical and hematological measurements before and after vitamin
E supplementation indicated no difference between the 2 groups, except as
otherwise specified (complete data available on request).
Ninety-eight percent (442/451) of those completing the study consumed
the capsules for at least 330 days (>90% of the 1-year supplementation period).
The number of missed supplements did not differ statistically between the
vitamin E and placebo groups (data available on request). Adherence was confirmed
by plasma vitamin E measurement every 3 months.
Vitamin E and placebo groups did not differ statistically in body mass
index or serum levels of vitamins and minerals before or after supplementation
(data available on request). The vitamin E group had small but significantly
higher hemoglobin levels than the placebo group before and after supplementation
(mean [SD], 12.4 [1.4] vs 12.2 [1.3] g/dL before and 12.4 [1.3] vs 12.1 [1.5]
g/dL after in the vitamin E and placebo groups, respectively; P = .02). Significantly fewer participants had low serum albumin levels
in the vitamin E group compared with placebo at baseline and after supplementation
(Table 2). The percentage of participants
with low albumin levels increased significantly during the 1-year period for
both groups, but the change over time in serum albumin between the 2 groups
did not differ significantly.
Except for vitamin E, the level of micronutrients did not change significantly
during the study period in either group. Plasma vitamin E levels increased
significantly in the vitamin E group, which doubled after 3 months of supplementation
with no further change (mean [SD], 1141  vs 2119  µg/dL before
and after supplementation, respectively; P<.001).
No significant change in serum vitamin E levels was observed in the placebo
group (1148  vs 1209  µg/dL before and after supplementation,
respectively). The fraction of participants with low serum vitamin A levels
increased slightly but significantly, whereas the fraction of participants
with low vitamin D and B6 levels decreased in both groups (Table 2), with no significant difference
between treatments in change over time.
Significantly fewer participants had low hemoglobin levels in the vitamin
E group before and after supplementation (Table 2). The fraction of participants with low hemoglobin levels
in each group did not change significantly over time. Low serum zinc levels
were equally prevalent in both groups (Table 2).
Results generally were similar whether the data from all participants
(Table 3) or completing participants
(Table 4) were compared. Adjustment
for obstructive lung diseases, current smoking status, diabetes mellitus,
dementia, year of enrollment, and baseline albumin and hemoglobin levels did
not affect the outcomes, with a few exceptions, as noted in the text. Further
adjustment for nursing home gave essentially the same results. Thus, only
the unadjusted data are shown (Table 3 and Table 4), except as noted in the text.
The highest incidence of respiratory tract infection occurred in the
winter and the lowest in the summer (0.41 and 0.24 episodes per placebo participant,
respectively). For all study participants, the rate of respiratory tract infection
for vitamin E and placebo groups was 1.35 and 1.47 per person per year, respectively
(Table 3), and for completers,
1.30 and 1.44 respiratory tract infections per person per year, respectively
(Table 4). Rates of respiratory
tract infections and number of days with respiratory tract infections per
person-year (Table 3 and Table 4), although lower in the vitamin
E group, did not differ significantly in either group. However, significantly
fewer persons in the vitamin E group contracted 1 or more respiratory tract
infections (60% [186/311] vs 68% [207/306] for all participants, 65% [150/231]
vs 74% [163/220] for completing participants in the vitamin E and placebo
The incidence, proportion, or number of sick days of lower respiratory
tract infection (includes acute bronchitis and pneumonia) did not differ significantly
between the 2 treatment groups (Table 3, Table 4).
The number of upper respiratory tract infections (URIs) per person-year
and days with URI, although lower in the vitamin E group, were not significantly
different between groups (Table 3 and Table 4). However, significantly fewer
participants in the vitamin E–treated group contracted 1 or more URIs
compared with the placebo group (44% [137/311] vs 52% [159/306], respectively,
for all participants [Table 3];
50% [116/231] vs 62% [136/220], respectively, for completers [Table 4]). After adjusting for obstructive lung disease, current
smoking status, diabetes mellitus, dementia, year of enrollment, and baseline
albumin and hemoglobin levels, the RR for having at least 1 URI was 0.82 (95%
CI, 0.66-0.98, P = .03) among all persons randomized
to receive vitamin E.
Among the URIs, 84% [397/470] were common colds. Post hoc subgroup analysis
indicated that vitamin E–supplemented participants who completed the
study had a significantly lower incidence of common colds (Table 4). In addition, significantly in the vitamin E group acquired
at least 1 cold (for all participants: 40% [125/311] vs 48% [147/306] in the
placebo group [Table 3]; for completers:
46% [106/231] vs 57% [126/220] in the placebo group [Table 4]). After adjustment for obstructive lung disease, current
smoking status, diabetes mellitus, dementia, year of enrollment, and baseline
albumin and hemoglobin levels, the risk ratio for all persons randomized to
vitamin E having at least 1 cold was 0.81 (95% CI, 0.64-0.98; P = .03). The vitamin E group had fewer days with common cold per person-year,
but the result did not reach statistical significance (20% for all randomized
in the vitamin E group [difference of 1.59 days compared with 7.82 days in
the placebo group; P = .11] and 22% for completers
[difference of 2.05 days compared with 9.42 days in the placebo group; P = .11; Table 3 and Table 4]).
Post hoc analysis found no significant effect of vitamin E on other
URIs (0.035 vs 0.050 for influenzalike infections, 0.082 vs 0.073 for pharyngitis,
0.013 vs 0.009 for otitis media, and 0.030 vs 0.009 for sinusitis per person-year
in the vitamin E and placebo groups, respectively), although incidence was
low and the study was not powered to detect differences.
Vitamin E had no significant effect on antibiotic use for all respiratory
tract infections (Table 3 and Table 4), number of emergency department
visits (0.086 for vitamin E vs 0.058 for placebo per person-year; RR, 1.66;
95% CI, 0.80-3.43; P = .17) or hospitalizations for
respiratory tract infection (0.060 for vitamin E vs 0.067 for placebo per
person-year; RR, 0.91; 95% CI, 0.43-1.95; P = .81).
We found that vitamin E had no statistically demonstrable effect on
the incidence or duration of all respiratory tract infections, as well as
upper and lower (after adjustment for confounding factors). However, fewer
persons in the vitamin E group acquired 1 or more respiratory tract infections
or URIs. Common colds were the most frequent URIs, and in a post hoc subgroup
analysis, participants in the vitamin E group who completed the study had
significantly fewer common colds and a 20% lower risk of acquiring a cold
than those in the placebo group. Further clinical trials of vitamin E supplementation
in elderly persons, with common cold as the primary outcome, are warranted.
Although our data suggest that vitamin E may protect against the common
cold, the most frequently encountered form of URI in this study, vitamin E
had no effect on the incidence or duration of other URIs or of lower respiratory
tract infections, which may have been due to the small number of such episodes
or differences in the types of pathogens responsible. Most URIs, especially
the common cold, are caused by viruses. Animal studies suggest that vitamin
E protects against viral but not bacterial infection in aged mice.42 We have found that although vitamin E supplementation
did not protect old mice against primary pulmonary Staphylococcus
aureus infection, it was protective against secondary S aureus infection after influenza infection.43
The respiratory tract infection definitions applied in our study were
derived by using commonly accepted criteria from the medical literature.13,32- 37 These
criteria do not allow the differentiation of viral from bacterial etiology.
Future studies should include detailed microbiologic methods to determine
whether vitamin E has an effect on respiratory tract infections of viral vs
Vitamin E did not affect antibiotic use. If the effects of vitamin E
were on URIs of viral etiology, this could explain the finding. In addition,
overuse of antimicrobial agents in nursing homes44 may
have impaired our ability to demonstrate an effect of vitamin E on antibiotic
Previous studies of vitamin E and infection in the elderly have demonstrated
mixed results. A retrospective study showed that persons with plasma vitamin
E levels above 1670 µg/dL had significantly fewer infections compared
with those with plasma vitamin E levels below 1200 µg/dL (mean, 1.0
vs 2.3, respectively; 95% CI for difference, 0.12-2.48).45 A
recent double-blind trial of Dutch elderly46 persons
living in the community reported no difference for all respiratory tract infections
among those receiving vs not receiving vitamin E (RR, 1.12; 95% CI, 0.88-1.25).
Our population and diagnostic method differed from those of the Dutch study.
In the Dutch study,46 participants self-reported
their infections by telephone, and then the infections were confirmed by nurse
visits. Lack of infection was not confirmed. In our study, the presence and
type of respiratory tract infection, or absence, was documented by infectious
disease specialists according to review of data gathered by trained research
nurses during weekly participant interviews, review of medical records, and
physical examination focused on respiratory tract infection according to standardized
case definitions.13,32- 35 Our
results indicate that vitamin E may reduce URIs, particularly common colds,
with no effect on lower respiratory tract infections or seasonal allergies.
Graat et al46 did not differentiate between
types of infections or between respiratory tract infections and allergies,
and thus might have overlooked any effect of vitamin E on URI. Furthermore,
in our study adherence was checked by nursing home medication records and
by periodic plasma vitamin E measurements, whereas the study by Graat et al46 measured plasma vitamin E levels only at baseline.
Several potential limitations of our study merit comment. First, of
the originally planned sample size of 640, 617 were enrolled. However, this
limitation should not influence the reported results because the change in
power to detect statistical significance was from 80% to 78.5%. Second, 27%
(166/617) of the enrolled persons did not complete the study because of withdrawal
or death. This level of loss to follow-up was anticipated in our original
study design. It demonstrates the challenges inherent in a 1-year study of
a frail nursing home population. Because there were minimal differences in
the characteristics of those who did and did not complete the study, this
loss to follow-up did not have an impact on our overall results. Results among
completers only were more likely to show an effect of vitamin E because attaining
plasma and tissue saturation levels of vitamin E requires several months.25 However, the analysis of all patients randomized
is the most conservative analysis and showed fewer significant effects.
Third, the use of a half RDA multivitamin28 capsule
for all participants might have lessened the impact of vitamin E on respiratory
tract infection by improving the micronutrient status of the placebo group.
However, we found no statistically significant differences between the vitamin
E and placebo groups with change over time in the status of any nutrients
other than vitamin E. Although our vitamin E group had a lower proportion
of persons with low albumin and hemoglobin levels at baseline and follow-up,
statistical adjustment for these potentially confounding factors did not change
our conclusion. A high percentage of participants had low plasma zinc levels,
but the 2 groups did not differ in the fraction of zinc-deficient participants
before or after treatment and thus did not influence the reported results.
Fourth, the significant reduction in URIs with vitamin E supplementation
was not consistent in all analyses, and the common cold analysis was post
hoc. However, these results suggest that future randomized trials of vitamin
E should concentrate on these end points. The common cold is generally less
severe than influenza. However, its much higher incidence and its recognized
morbidity in the elderly33 make it an important
public health problem in this age group. This is particularly relevant because
no clinically useful vaccine or antiviral therapy is available to combat colds.
In conclusion, we found no effect of vitamin E supplementation on the
incidence or duration of respiratory tract infections. However, significantly
fewer vitamin E participants acquired 1 or more respiratory tract infections,
which was most evident in URIs. Post hoc subgroup analysis among individuals
completing the study revealed a significantly lower incidence of common cold
and fewer participants acquiring a cold. Common colds are frequent36 and associated with increased morbidity33 in this age group,
and if confirmed, these findings suggest important implications for the well-being
of the elderly. Future studies in elderly individuals should assess the effect
of vitamin E supplementation on the common cold and incorporate microbiologic
methods to allow for assessment of the impact of vitamin E on specific types
of respiratory pathogens.