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ORIGINAL RESEARCH COMMUNICATION |
1 From the Instituto de Investigación Nutricional, Lima, Perú (MEP, RMM, AD, and CFL); the Program in International Nutrition and Department of Nutrition, University of California, Davis (JMP, BL, and KHB); and the Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore (REB)
2 Supported primarily by the Thrasher Research Fund and the World Health Organization; additional funds were provided by the University of California Pacific Rim Program.
3 Address reprint requests to ME Penny, Instituto de Investigación Nutricional, Avenue La Universidad 685-La Molina, Apartado 18-0191, Lima 18, Perú. E-mail: mpenny{at}iin.sld.pe.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The objective was to determine whether the administration of other micronutrients with zinc modifies the effect of zinc supplementation on children’s morbidity and physical growth.
Design: Two hundred forty-six children aged 6-35 mo with persistent diarrhea were randomly assigned to 1 of 3 groups to receive a daily supplement of 10 mg Zn alone (Zn; n = 81), zinc plus vitamins and other minerals at 1-2 times recommended daily intakes (Zn+VM; n = 82), or placebo (n = 83) for 
6 mo after the diarrhea episode ended. Morbidity information was collected on weekdays. Weight, length, and other anthropometric indicators were measured monthly, and plasma zinc and other indicators of micronutrient status were measured at baseline and 6 mo.
Results: Supplement consumption was high (90%) in all groups, although slightly more vomiting was reported in the Zn+VM group (P < 0.0001, analysis of variance). The change in plasma zinc from baseline to 6 mo was greater in the 2 zinc groups (6.1, 27.3, and 16.2 µg/dL in the placebo, Zn, and Zn+VM groups, respectively; P < 0.0001, analysis of variance). The Zn group had fewer episodes of diarrhea, dysentery, and respiratory illness and a lower prevalence of fever and cough than did the Zn+VM group and a lower prevalence of cough than did the placebo group (P = 0.05). No significant effects of supplementation on growth were observed.
Conclusion: Morbidity was greater after supplementation with zinc plus multivitamins and minerals than it was after supplementation with zinc alone.
Key Words: Zinc supplementation • zinc deficiency • diarrhea • respiratory infection • growth
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Inadequate zinc nutriture may be associated with deficiencies of other micronutrients, and these coexisting nutritional problems could reduce the potential benefit of zinc supplementation on morbidity or growth (8, 9). On the other hand, it is possible that simultaneous administration of multiple other micronutrients could interfere with zinc absorption or utilization. For example, adverse interactions between iron and zinc supplements have been described (10-12). Thus, it is important to determine whether supplementation with multiple micronutrients would be as effective as with zinc alone.
There are several reasons to suspect that poor children in periurban Lima may be zinc deficient, including their frequent consumption of diets that have inadequate zinc contents (13), a high prevalence of diarrhea (14), and low plasma zinc concentrations (13, 15). The current study was therefore designed to evaluate whether daily zinc supplementation for 6 mo in children who had recovered from a recent episode of persistent diarrhea would reduce the incidence and prevalence of subsequent episodes of diarrhea and respiratory illness. Children with a prior episode of persistent diarrhea were selected for study because we anticipated that they would have an elevated risk of zinc deficiency and therefore would likely respond to zinc supplementation. To determine whether additional micronutrients would enhance or diminish the effects of zinc alone, we studied a third group of children who received zinc in combination with multiple other micronutrients.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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14 d were randomly assigned, after being stratified for breastfeeding status, to receive 2 wk of daily supplementation with 1 of 3 indistinguishable supplements: placebo, 20 mg Zn/d as zinc gluconate (Zn group), or 20 mg Zn/d as zinc gluconate plus a mixture of other micronutrients, ie, vitamins and minerals (Zn+VM group). A subset of children consisting of the first 246 children enrolled who intended to remain in the study area subsequently received the same assigned supplement at one-half the initial daily dose (10 mg Zn/d) and continued under observation for a total of 6 mo. The study protocol was approved by the institutional review boards of the Instituto de Investigación Nutricional and the University of California, Davis. Children were enrolled in the study only after a parent provided written informed consent.
Micronutrient supplements
The supplements were supplied as individual doses of a dry micronutrient mixture with added sugar, coloring, and flavoring agents, which were dissolved in clean water in the subjects’ homes and provided as a liquid beverage under the supervision of study personnel on Monday through Friday and by parents or other caregivers during the weekends. The composition of the supplements is shown in Table 1. Fieldworkers recorded the amount of supplement consumed in their presence each day and any amount reportedly given by caregivers at other times. Eighty-three children (29 in the placebo group, 28 in the Zn group, and 26 in the Zn+VM group; P = 0.82) consumed additional iron, either as prescribed by the study team because of anemia at baseline (hemoglobin < 9.0 g/dL) or for family-determined reasons. Of these 83 children, 56 (22 in the placebo group, 18 in the Zn group, and 16 in the Zn+VM group; P = 0.47) received additional iron for 7 d.
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Additional information on characteristics of the home, occupation and education of the parents, and hygiene practices and feeding pattern of the children at the beginning of and during the study was obtained by questionnaire or by direct observation. Children were followed until they completed 6 mo in the study, had no symptoms of illness, and their final blood test was completed. Criteria for terminating the study early in individual children included death of the child, permanent departure from the area, parental decision to withdraw, and, in one case, inability of the study personnel to obtain reliable information (Figure 1).
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Blood samples and laboratory analyses
Nonfasting venous blood was drawn between 0900 and 1200 with the use of mineral-free, lithium-heparin syringes (Sarstedt Inc, Newton, NC). Samples were obtained at enrollment, on day 15, and after 6 mo for measurement of hemoglobin, hematocrit, and plasma zinc. Hemoglobin was measured in the field with a portable Hemocue device (AB Leo Diagnostics, Helsingborg, Sweden). Plasma was separated in acid-washed glassware, and aliquots were stored in mineral-free, colorless plastic vials at -20 °C until processed. The materials and procedures were checked to rule out possible zinc contamination before sampling started. For the measurement of plasma zinc concentration, 2.2 mL of 1 N Ultrex II ultrapure HNO3 (J T Baker Inc, Phillipsburg, NJ) was added to 200 µL plasma (12:1 dilution) in polypropylene tubes and allowed to stand overnight at 4 °C. The samples were then centrifuged (8 min, 24 °C), and the supernatant fluid was analyzed for trace element concentrations with a Tracescan inductively coupled plasma atomic emission spectrometer (Thermo Jarrell Ash; Spectrocell Inc, Oreland, PA). All samples from the same child were measured in a single analytic run and were compared with appropriate ultrapure acid blanks, pooled plasma samples, and inductively coupled plasma standards (QC-21 Spex; Fisher Scientific, Pittsburgh). Specimens were run in duplicate unless the quantity of available sample was insufficient to allow a second measurement. Plasma ferritin concentrations were measured by (IRI kit; Diagnostics Products Corporation, Los Angeles).
Sample size
A sample size of 70 per group for the principal morbidity outcomes was calculated to be sufficient to detect a 25% difference between the placebo and each of the supplemented groups in subsequent prevalence and incidence of diarrhea and a 50% reduction in new episodes of persistent diarrhea, considering a probability of type I and type II errors of 0.05 and 0.2, respectively, and based on information from previous studies in the same communities (14, 17). The number of children who completed the study exceeded the calculated sample size requirements for all principal outcomes.
Data analysis
Data were recorded in the field on pretested forms, which were checked by the field supervisor before the data were entered in computers with the use of programs that had range and logical checks incorporated. About 10% of the data were double-entered to check keypuncher accuracy; such errors were < 0.5%. Univariate analysis was used to identify outliers and extreme values, which were then double-checked against the original field forms. The plan of analysis, including cutoff values for categorical analyses, was determined before the final analysis and before the codes were broken. Analyses were done by using SPSS-PC (version 9; SPSS Inc, Chicago) and SAS (SAS for WINDOWS version 6.12; SAS Institute Inc, Cary, NC). Groups were compared with analysis of covariance by using treatment group as the main effect and sex, age category, stunting, wasting, initial zinc category, initial ferritin category, breastfeeding status, hygiene score, socioeconomic status variables, and number of liquid stools on the day before enrollment as covariates. Nonsignificant covariates were removed in stepwise fashion; a P value > 0.05 was the criterion for exclusion from the model. Adjusted means were compared among groups with Tukey’s test. Collapsed socioeconomic variables were created by using variable clustering techniques and factor analysis (PROC VARCLUS and PROC FACTOR) to aggregate individual items into logical categories. Scale variables were then created from the 4 categories that were derived representing house quality, household size, possessions, and parental characteristics. Several aspects of home hygiene were observed monthly and used to compute a hygiene score for each household. During each monthly assessment, the fieldworkers rated each of the following items as adequate or inadequate using predefined categories: general tidiness of the house, cleanliness of the floor, appearance of the child, stool disposal methods, handling of diapers, and condition of the child’s play area. The hygiene score for each subject was calculated as the mean of the hygiene scores for all visits. Information was also collected weekly on the children’s breastfeeding status.
Definitions
Diarrhea was defined as 3 liquid or loose stools in 24 h. An episode was considered to have ended on the last day of diarrhea followed by 2 diarrhea-free days. If visible blood was reported or observed in any stool during a diarrheal episode, the illness was considered an episode of dysentery. Persistent diarrhea was defined as diarrhea lasting 14 d. Severe diarrhea was defined as an episode lasting 1 d with any 1 of the following signs or symptoms: 6 liquid stools, reported or documented fever, documented dehydration, use of any health service for treatment of diarrhea, or the presence of visible blood in any stool. The definition of vomiting excluded regurgitation, which was defined as intentional spitting out or return of recently consumed food or supplement within 15 min after it was ingested. Acute lower respiratory infection was defined according to the "fieldworker definition" as cough plus 2 consecutive age-specific elevated respiratory rates (> 50/min for children aged 6-11 mo and > 40/min for children aged > 11 mo) or according to the "physician definition" as an episode of bronchitis, pneumonia, asthma, or bronchiolitis diagnosed by the physician’s clinical examination. The physician’s diagnosis of pneumonia was based on the presence of cough and crepitations on chest auscultation. Fever was defined as either reported fever or a rectal temperature > 38 °C, and children were considered to have a poor appetite when the caregiver stated that the child’s dietary intake was reduced from normal. Incidence rates are given as the number of new episodes of illness per 100 d of observation, and prevalence rates are expressed as the percentage of days of observation when the relevant symptoms or signs were present.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Consumption of supplement
There was a high level of adherence to the supplementation protocol, with mean reported daily intake volumes of 94.1%, 92.3%, and 89.5% in the placebo, Zn, and Zn+VM groups, respectively. Consumption of the supplement was slightly lower in the Zn+VM group than in the placebo group (P = 0.019, Tukey’s test for means weighted by days of observation), but there were no significant differences between Zn and placebo groups or between the Zn and Zn+VM groups. Similar results were found when the analysis was restricted to days when consumption of the supplements was observed by the fieldworkers. Vomiting, excluding regurgitation, occurring within 15 min of taking the supplement was more common in the Zn+VM group (4.8% of doses) than in the placebo group (0.6% of doses) or the Zn group (0.6% of doses) (P < 0.0001, log transformation).
Biochemical measures
Both baseline and final plasma zinc concentrations were measured in 204 children (n = 69, 65, and 70 in the placebo, Zn, and Zn+VM groups). Mean plasma zinc concentrations increased by 6.1 µg/dL in the placebo group, 27.3 µg/dL in the Zn group, and 16.2 µg/dL in the Zn+VM group. Differences between the groups are significant (P < 0.0001, ANOVA). With control for initial plasma zinc concentration, the rise in plasma zinc was greater in the Zn group than in both the placebo (P < 0.0001) and the Zn+VM (P = 0.053) groups and greater in the Zn+VM group than in the placebo group (P = 0. 049) (Table 3). All groups showed a significant increase in hemoglobin from the initial values, and these changes from baseline to 6 mo were significantly different between groups (P < 0.001; Table 3). The Zn+VM group, who received iron in the micronutrient supplement, had an increase in mean hemoglobin of 1.53 g/dL, which was significantly greater than the increase of 0.83 g/dL in the placebo group and the increase of 0.33 g/dL in the Zn group (P < 0.0001). Hematocrit increased in the Zn+VM group by 2.47%, which was significantly greater (P < 0.001) than the increase of 1.52% in the placebo group and the 0% increase in the Zn group. The plasma ferritin concentration increased by 16.4 µg/L in the Zn+VM group and by 8.1 µg/L in the Zn group and decreased by 0.5 µg/L in the placebo group. The differences between the groups were significant (P < 0.001).
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14 d) were recorded in 19 children. Respiratory symptoms were common, with cough reported on 49.4% of days. A total of 537 episodes of acute lower respiratory infections were identified, of which 68 were based only on the fieldworker report, 283 were diagnosed by the doctor in children who had not been referred by the fieldworker, and 186 were diagnosed by the fieldworker and confirmed by the doctor. Fifty episodes of pneumonia, as diagnosed by the physician, occurred in 43 children. Reduced appetite was reported on 9.2% of days, and fever was reported on 6.5% of days. For every illness variable analyzed, the direction of the differences between the Zn group and the placebo group tended toward less illness in the Zn group, whereas the direction of the differences between the Zn+VM group and the placebo group tended toward more illness in the Zn+VM group. The particular differences that were statistically significant are indicated in Figure 2. The results of the analysis of covariance models in which the adjusted means of morbidity outcomes were compared by treatment group are shown in Table 4. Variables included in the models were age, sex, initial length-for-age, initial weight-for-length, severity of the diarrhea at entry, baseline plasma zinc concentration, baseline plasma ferritin concentration, consumption of additional therapeutic iron supplements, and hygiene score. Age, length-for-age, number of liquid stools at entry, and hygiene score predicted diarrhea morbidity. The significance values given in Table 4 refer to the results of the general linear models procedure. There was a consistent trend for reduced morbidity in the children who received zinc alone compared with those who received placebo, and this difference was statistically significant for the prevalence of days with cough (P < 0.05, Tukey’s test). In contrast, children in the Zn+VM group had significantly greater rates of morbidity than did the Zn group for the incidence of severe diarrhea, prevalence of cough, prevalence of fever (all P < 0.05, Tukey’s test) and the proportion of children with at least one episode of dysentery (P = 0.05, chi-square test). Adding initial iron status (plasma ferritin < 12 µg/L) to the model, as an interaction term with treatment group, did not account for the differences in morbidity between the groups; however, therapy with additional ferrous sulfate to treat anemia was a significant predictor of fieldworker-defined acute lower respiratory infection, independent of treatment group. Children receiving iron therapy also had a higher rate of cough (P < 0.01) than did those not receiving iron therapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The strengths of this study included its randomized, double-blind design and the supervised administration of the supplements. Except for differences in the relative proportions of boys and girls and the minor differences in initial anthropometric status, the groups were similar at baseline, and child sex and anthropometric variables were controlled during the statistical analyses. Thus, any differences in study outcomes were likely due to the treatments that were provided. Surveillance was conducted daily, so reporting error was unlikely; < 8% of the children dropped out of the study, and no significant differential loss to follow-up between the groups was observed. Although treatment compliance was slightly lower and the number of vomiting episodes was greater after supplementation in the Zn+VM group than in the ZN and placebo groups, compliance was still high in all 3 groups, and it is unlikely that the minor differences that occurred in consumption of the supplements explained the observed differences in morbidity outcomes. When the compliance variable and a group-by-compliance interaction were included in the model, the results were unchanged. Overall, the study group was likely to have been zinc deficient, as indicated by the high percentage of children with low plasma zinc concentrations, and the prevalence of diarrhea was high, as predicted.
The micronutrients contained in the supplements were reasonably well absorbed, as indicated by the increase in plasma zinc concentrations in both zinc-supplemented groups and the increase in hemoglobin concentration in the Zn+VM group. However, it is apparent that some nutrient-nutrient interactions did occur, in that plasma zinc concentrations increased less in the Zn+VM group than in the Zn group. Although we cannot be certain, it is highly likely that the lower plasma zinc concentration in the Zn+VM group than in the Zn group was due to the iron included in the vitamin-mineral mix. It was clearly shown that iron inhibits zinc absorption in humans when these minerals are given together in aqueous solution (12), and infants in a recent study in Java who received supplements containing both iron and zinc had significantly lower plasma zinc concentrations than did those who received zinc only (19). It is also conceivable that zinc inhibited iron absorption from the Zn+VM supplement, as was observed in previous studies (19, 20), but the design of the current study did not permit detection of that possibility.
The sample size was calculated to allow us to distinguish differences of 25% in changes in morbidity. Combined analysis of similar studies showed 20% reductions in diarrhea morbidity (7), so our sample may have been too small to detect this effect size with statistical confidence. Nevertheless, our results are consistent with the hypothesis that zinc supplements taken alone reduce diarrheal and respiratory illness, which agrees with the results of other studies (7, 9). Contrary to our original hypothesis, we found a consistent increase in rates of diarrhea and respiratory illnesses when a full set of micronutrients was provided along with zinc.
The design of the study did not permit us to attribute the adverse effect on morbidity to individual micronutrients included in the Zn+VM supplement. Some other studies with single micronutrients also reported adverse outcomes, especially when the supplements were provided to children who were replete with respect to the micronutrient. For example, Sempertegui et al (21) reported that Ecuadorian children with a normal weight-for-age had an increase in acute lower respiratory infections after receiving supplemental vitamin A. Increased cough was also reported after vitamin A supplementation in India (22), Indonesia (23), and Haiti (24). Because of reports of an increased incidence of malaria, diarrhea, and tuberculosis after parenteral iron supplementation (25-27), and because of the known enhancement of bacterial virulence provided by iron (28), iron supplements have also come under suspicion. However, some studies have not found increased malarial morbidity with oral iron supplementation (29). Although few studies have provided definitive evidence that oral iron supplementation causes increased infectious morbidity in nonmalarial areas (30), some studies have documented increased rates of diarrhea, particularly in infants aged < 12 mo. In one study, for example, Bangladeshi infants aged 2-11 mo who received 15 mg elemental Fe/d had a higher incidence of diarrhea and an increase in the total number of days of diarrhea during the year (31). In Chile, Brunser et al (32) reported increased diarrhea from shigellae in infants who received iron-enriched milk. In a study of infants in Honduras and Sweden (33), lower growth and increased morbidity were reported in the subgroup of iron-replete children who received iron supplements. Children in the current study were older than those enrolled in these aforementioned trials, and the children in the current study seemed to have an increase in symptoms of respiratory disease as well as diarrhea. One factorial trial of iron, zinc, or iron plus zinc supplements in Mexico (34) reported 7-23% more respiratory illness in the iron-supplemented group than in the placebo group, whereas those who received zinc alone and zinc plus iron had less morbidity than did those who received placebo. Given these sets of results and the absence of reports of adverse events associated with the other micronutrients in our mixture, iron may be the most likely component of the mixture responsible for the increased rates of morbidity that were observed. The dose of iron in the supplement provided in the current study was 10 mg elemental Fe, 1 mg · kg body wt-1 · d-1, which is the standard recommended prophylactic dose for infants (35). The iron was given between meals in an aqueous solution along with vitamin C, which may have enhanced absorption of iron from the supplement. It is also possible that the children in the Zn+VM group were subjected to a higher concentration of unabsorbed iron in the small intestine, which could create a local iron-rich environment that would enhance bacterial proliferation, because it is known that many pathogens require iron (28), or impair mucosal immune function, possibly in response to iron-induced cytokine secretion (36). Although speculative, these 2 mechanisms could possibly explain the adverse gastrointestinal outcomes observed in the Zn+VM group. On the other hand, the fact that respiratory outcomes were also affected by the Zn+VM supplement suggests that a systemic effect may have been operative.
We found no effects of the supplements on physical growth. This is in contrast with other studies and with the findings of a recent meta-analysis of zinc supplementation and child growth (3), in which stunted children who received zinc supplements had increased linear growth and weight gain. Control for initial length-for-age in the analysis of the current study did not alter this conclusion, but only 28% of the study subjects were stunted (< -2 SD), and our study was not powered to show differences in this fairly small number of children.
The results of the current study provide additional support for the efficacy of zinc supplements in reducing childhood morbidity in zinc-deficient populations but also suggest a need for caution regarding possible adverse events when other micronutrients are provided with zinc supplements. More studies are needed to determine which nutrients are responsible for the adverse effects that were observed and to confirm the safety of multiple micronutrient supplementation. Unfortunately, confirmation of the current findings would complicate public health programs because such results would imply a need for prior screening of micronutrient status, differential dosing of micronutrients, or both. Given the large number of children who are possible targets of micronutrient supplementation programs, screening could considerably increase program costs. Thus, more studies are needed in a range of different populations to establish appropriate policy recommendations concerning the optimal use of multiple micronutrient supplements.
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ACKNOWLEDGMENTS |
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The study was designed by KHB, MEP, REB, and CFL with advice from BL. KHB wrote the grant application. MEP directed the field study. AD was the field coordinator. RMM was responsible for the study design and the supervision of the entry and preliminary analysis of the data. BL was responsible for the biochemical analyses. JP was responsible for the data analysis. MEP and KHB wrote the first draft of the manuscript with help from REB and BL. All of the authors reviewed the final manuscript. None of the authors had any conflicts of interest.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  L. L Iannotti, N. Zavaleta, Z. Leon, A. H Shankar, and L. E Caulfield Maternal zinc supplementation and growth in Peruvian infants Am. J. Clinical Nutrition, July 1, 2008; 88(1): 154 - 160. [Abstract] [Full Text] [PDF]
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 R. Aggarwal, J. Sentz, and M. A. Miller Role of Zinc Administration in Prevention of Childhood Diarrhea and Respiratory Illnesses: A Meta-analysis Pediatrics, June 1, 2007; 119(6): 1120 - 1130. [Abstract] [Full Text] [PDF]
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 Z. A Bhutta Iron and zinc deficiency in children in developing countries BMJ, January 20, 2007; 334(7585): 104 - 105. [Full Text] [PDF]
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S. Sazawal, U. Dhingra, P. Dhingra, G. Hiremath, J. Kumar, A. Sarkar, V. P Menon, and R. E Black Effects of fortified milk on morbidity in young children in north India: community based, randomised, double masked placebo controlled trial BMJ, January 20, 2007; 334(7585): 140 - 140. [Abstract] [Full Text] [PDF]
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 R. Shamir, I. R. Makhoul, A. Etzioni, and N. Shehadeh Evaluation of a Diet Containing Probiotics and Zinc for the Treatment of Mild Diarrheal Illness in Children Younger Than One Year of Age J. Am. Coll. Nutr., October 1, 2005; 24(5): 370 - 375. [Abstract] [Full Text] [PDF]
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C. F. Walker, K. Kordas, R. J Stoltzfus, and R. E Black Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials Am. J. Clinical Nutrition, July 1, 2005; 82(1): 5 - 12. [Abstract] [Full Text] [PDF]
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 G. Lopez de Romana, S. Cusirramos, D. Lopez de Romana, and R. Gross Efficacy of Multiple Micronutrient Supplementation for Improving Anemia, Micronutrient Status, Growth, and Morbidity of Peruvian Infants J. Nutr., March 1, 2005; 135(3): 646S - 652S. [Abstract] [Full Text] [PDF]
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R. J Walden Supplementation with zinc and other minerals Am. J. Clinical Nutrition, October 1, 2004; 80(4): 1084 - 1084. [Full Text] [PDF]
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M. E Penny, R. E Black, K. H Brown, and B. Lonnerdal Reply to RJ Walden Am. J. Clinical Nutrition, October 1, 2004; 80(4): 1084 - 1085. [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
± SE) in morbidity outcomes in the group who received 10 mg Zn alone (
, Zn group; n = 80) and in the group who received 10 mg Zn plus vitamins and other minerals at 1-2 times recommended daily intakes (
; n = 81) relative to the placebo group (n = 79). *Significantly different from the Zn group, P < 0.05 (Tukey’s test). ALRI, acute lower respiratory infection. 
Significantly different from the placebo group, P < 0.05 (Tukey’s test).