Upper Respiratory Infections Clinical Trial
Official title:
Effect of Supplementation With Multivitamins and Minerals on the Incidence of Respiratory Infections in Older People in Ecuador: a Randomised Controlled Trial.
Poor Ecuadorian older people suffer from chronic dietary deficiencies of zinc, iron, copper, vitamins C, B6, B12, D, and folic acid. The investigators have previously shown that these deficiencies are associated with impaired immune function and increased incidence of respiratory infections (RI). The hypothesis is that correction of these specific nutrient deficiencies will improve immune response and thereby enhance resistance to respiratory infections. To test this hypothesis this study will evaluate the effect of supplementation with specific vitamins and minerals found to be deficient in poor elderly Ecuadorians on markers of immune function and the incidence of RI. A randomized, double-blind, placebo-controlled trial in 320 older people (≥65 y)will be carried out in Quito, Ecuador. Participants will receive multivitamin and mineral supplements or placebo tablets daily for 12 months. Nutrients will be provided at US Recommended Daily Allowance (RDA) levels, except for vitamin C and zinc doses, which will be 5 times and 1.25 times higher than the RDA, respectively. Incidence of respiratory infections (the primary outcome) will be assessed weekly by field nurses and physicians from the study team. Secondary outcomes include delayed-type hypersensitivity (DTH) skin test, cathelicidin production by mucosa respiratory cells, and serum C-reactive protein (CRP) as measures of immune function. Blood micronutrient levels and haemoglobin status will be collected as measures of adherence to the trial regimen. Incidence rate of RI and rate ratio (RR) will be calculated to quantify the effect of the intervention on the incidence of respiratory infection. This will be the first trial of its kind conducted specifically in a population of older people known to have poor micronutrient status. The findings of the study may be important for similar populations in other low- and middle-income countries.
Even "subtle subclinical deficiencies of micronutrients and inadequate macronutrient intake
contribute to a decline in immune function in the elderly" [1]. "The impaired regulation of
the immune system in aging contributes to a higher morbidity and mortality from infections,
autoimmune, and neoplastic diseases"[1]. Some studies show that either vitamins or minerals
supplements may improve the immune function in older subjects [2-5 ]. Therefore, it is
plausible to assume that improvement of their nutritional status through MVM supplements may
benefit their ability to fight infections. The hormonal and physiological deregulation in
aging might also benefit from MVM adding to the body effectiveness to deal with common
pathogens in aging.
A previous systematic review and meta-analysis of randomised controlled trials (RCT), which
included papers published before January 2004, found no evidence of an effect of MVM
supplementation on infection rate [6] or duration [7] in older people. However, considerable
clinical and methodological heterogeneity was present in the studies included in this
earlier review. The investigators have updated this earlier systematically review of the
evidence that MVM supplementation is effective in reducing the incidence of infection in
older people. Sub-group analysis explored the effect site of residence (nursing homes or
dwellings) of study participants, primary outcome measure (self report or clinical
evaluation), and baseline micronutrients status of enrolled subjects [8].
The investigators found no evidence of benefits from multivitamin and minerals
supplementation on the rate of infection or the odds ratio of infection in aging subjects.
The investigators also found no benefit of intervention in the subgroups analysed.
Sensitivity analysis of those studies evaluated as free of bias did not substantially alter
this conclusion.
The included trials were heterogeneous in sample size (range 33 to 2799), duration (range 4
to 24 months), and outcome measures. The lack of benefit of the intervention in studies
which found variable percent of subjects with some micronutrient deficiencies at enrolment
could be related to some characteristics of the included trials: All studies but that of
Avenell [9] had not determined the micronutrients status of the target population before the
enrolment. Therefore, the formulas of multivitamin and mineral supplements used were not
aimed to correct any pre-specified deficiency. Moreover, those studies had different
considerations to define the formula, which explains the large variability of the
supplements across the studies. Finally, the assessment of the micronutrient status was also
variable across the studies: dietary intake evaluation and/or micronutrients blood
concentration, which affects the consistency of this subgroup meta-analysis.
It is noteworthy that all studies except one [10] have been carried out in developed
countries where the nutritional status of aging populations seems to be better than that
reported by studies carried out in developing countries. In fact, although the variability
of the assessment methods do not allow to draw a clear conclusion on the baseline
nutritional status of the subjects included in the analysed studies, the prevalence of
deficiencies and the number of micronutrients found deficient are evidently lower than those
referred in studies from developing countries such as those carried out in Ecuador [11]. The
remaining study was carried out in a middle-income country and although data on baseline
nutritional status of enrolled subjects was not published, presumably their micronutrient
status is somehow similar to that found in developed countries.
Based on these considerations, it would be novel to find evidence to support the hypothesis
on the benefit of improving vitamin and mineral consumption, to enhance immune function and
decrease infectious disease episodes in elderly suffering from extent and multiple
micronutrient deficiencies as those of developing countries.
Our research group has been the first to study the nutritional, immunological, and health
status of Ecuadorian older people, who live in poor peri-urban neighbourhoods of Quito, a
city on the Andean Region. The investigators carried out a preliminary study of 145 older
people (age ≥65 years), which revealed inadequate intake of protein and multiple
micronutrients as well as high prevalence of recalled infectious diseases assessed by
physician or hospital visits [12 ]. To better define these findings, the investigators
performed a larger and adequately powered cross-sectional study in Quito with 352 older
people (225 women), whose results have been published in two articles.[1, 11 ] Substantial
deficiencies (> 30% of subjects) of serum/blood concentrations were found for vitamins C
(47%), folate (32%), and zinc (43%) [1]. More than 20% of subjects were also vitamins B6,
and B12 deficient [1]. Severe vitamin D deficiency was found in <15% of subjects and
moderate deficiency was found in 65% of males, and 87% of females [11]. Moreover, 30% of men
and 40% of women were anaemic based on altitude-adjusted haemoglobin values [1, 13]. When
dietary intake was assessed the percent of deficient subjects was even higher [11].
There was correlation between dietary intake and blood concentration of some of these
micronutrients [11]. Therefore, most of these older Ecuadorians suffer from multiple
micronutrient deficiencies due mainly to dietary restriction. This situation makes them
amenable to MVM interventions aimed to correct their nutritional status.
Blood deficiency of any one or more of the following micronutrients vitamin C, vitamin E,
pyridoxal5-phosphate (PLP), folate, iron, or zinc was strongly associated with history of RI
(OR 4.0; 1.76, 9.06) [1 ].
Delayed-type hypersensitivity (DTH) was considerably lower than that observed in US elderly
especially to Trichophyton and tetanus toxoid [1 ] DTH is an in vivo indicator of cellular
immune response status. Vitamin C and zinc concentrations were significantly associated with
Interferon gamma (IFN-γ) concentrations [1]. Serum iron and zinc were significantly
associated with Interleukin 2 (IL-2) levels [1]. Since IFN-γ and IL-2 are T-dependent
cytokines these correlations suggest that deficiency of those micronutrients may explain the
impaired cellular immune response as assessed by DTH. High plasma CRP (>3 mg/l) was present
in 49% of the participants, which could be a proxy of increased pro-inflammatory cytokines
[11]. There was no correlation between protein, carbohydrate, or lipid intake and immune
response or infection.
Taken together, data from these previous studies in Ecuador suggest that both risk for
infections and impaired immune function is associated with deficiencies of critical vitamins
and minerals in Ecuadorian older people. Although it is important to be cautious to conclude
on these studies due to their cross-sectional design, it seems to be necessary to evaluate a
nutritional intervention intended to provide those micronutrients found to be deficient to
improve the immune and health status of elderly Ecuadorians. This approach is different from
that of the previous trials carried out in developed countries which had not evaluated the
micronutrient status of the target population before the enrolment and, in consequence, had
not defined a MVM formula aimed to correct specific deficiencies. Moreover, the
micronutrients deficiencies found in Ecuadorian older subjects appear to affect largely
higher percent of subjects and include more micronutrients than those found at enrolment in
subjects included in studies carried out in developed countries. Therefore,the hypothesis is
that provision of MVM supplements to poor Ecuadorian subjects aimed to correct their
specific micronutrients deficiencies may prove beneficial to reduce the incidence of
respiratory infections via improvement of their immune response assessed by DTH test, and
decreased CRP concentration as proxy of the down regulation of pro-inflammatory cytokines.
Since cathelicidin, an antimicrobial peptide produced by neutrophils, seems to be increased
by vitamin D status [14], the measure of this peptide in supernatants of cultured cells from
the upper respiratory mucosa will be included. Thus, DTH and cathelicidin would provide an
assessment of both innate and adaptive immunity. This study will be the first to be
undertaken in an aging population of a developing country.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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