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Original Research Communication |
1 From the Aga Khan University Medical Centre, Karachi, Pakistan; the Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; the Johns Hopkins School of Public Health, Baltimore; the University of California, Davis; the University of the West Indies, Mona, Jamaica; Trisakti University, Jakarta, Indonesia; Dhaka Medical College, Dhaka, Bangladesh; Emory University, Atlanta; the National Institute of Nutrition, Hanoi, Vietnam; the Nutrition Research Institute, Lima, Peru; the National Institute of Nutrition, Mexico City; the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh; the Institute of Nutrition of Central America and Panama, Guatemala City; and the All India Institute of Medical Sciences, New Delhi.
2 Supported by the Johns Hopkins Family Health and Child Survival Cooperative Agreement with the US Agency for International Development and the World Health Organization, Division of Child Health and Development, which provided support for the pooled analysis. REB drafted the manuscript while in residence at the Rockefeller Foundation Bellagio Study and Conference Center. 3 Address reprint requests to RE Black, Department of International Health, The Johns Hopkins School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: rblack{at}jhsph.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: We sought to measure the effect of supplemental zinc given with oral rehydration therapy during recovery from acute or persistent diarrhea.
Design: We conducted pooled analyses including all available published and unpublished randomized controlled trials of the effects of supplementary oral zinc in children aged <5 y with acute or persistent diarrhea. We used Cox survival regression analysis to evaluate the overall effect of zinc on continuation of diarrhea and possible differential effects in subgroups divided by sex, age, weight-for-height, and initial plasma zinc concentration. Dichotomous outcomes were analyzed by logistic regression. To assess the effects of excluding studies without original data from the pooled analyses, effect-size was estimated for all studies by using random-effects models.
Results: Zinc-supplemented children had a 15% lower probability of continuing diarrhea on a given day (95% CI: 5%, 24%) in the acute-diarrhea trials and a 24% lower probability of continuing diarrhea (95% CI: 9%, 37%) and a 42% lower rate of treatment failure or death (95% CI: 10%, 63%) in the persistent-diarrhea trials. In none of the subgroup analyses were the 2 subgroups of each pair significantly different from each other; however, in persistent diarrhea there tended to be a greater effect in subjects aged <12 mo, who were male, or who had wasting or lower baseline plasma zinc concentrations.
Conclusion: Zinc supplementation reduces the duration and severity of acute and persistent diarrhea.
Key Words: Diarrhea • diarrheal disease • malnutrition • meta-analysis • randomized controlled trial • zinc • children • infants • developing countries • zinc supplementation • nutrition • zinc deficiency
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Two well-documented determinants of diarrheal duration are low weight-for-age and decreased cell-mediated immunity (6, 7). A common determinant of both of these factors is zinc deficiency (8, 9), thought to be prevalent in children in developing countries (10). Furthermore, zinc supplementation was shown to reduce the duration and severity of childhood diarrhea in randomized controlled trials (11–20).
We conducted pooled analyses of available randomized controlled trials that evaluated the effects of supplementary oral zinc given as an adjunct to other therapy in children with acute or persistent diarrhea. We also attempted to identify any differential effects in subgroups of children. Finding these differential effects might allow for targeting of this therapy toward children who would derive the greatest benefit. For the pooled analyses, we formed a group of investigators who had conducted trials of zinc supplementation. To reduce possible publication bias, we attempted to include all investigators of published and unpublished trials. The use of original trial data from individual study children allowed standardization of outcome and subgroup definitions, use of information not included in the publications, and use of proper statistical methods. We present here the pooled analyses of a total of 7 trials of zinc supplementation; there were 3 trials in children with acute diarrhea and 4 trials in children with persistent diarrhea. We also performed a meta-analysis of the effect of zinc on diarrheal duration; we included all known trials to ensure that our results were not biased because we excluded from the pooled analyses 3 trials for which original data were not available.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies eligible for inclusion were randomized, controlled, and masked trials that assessed the adjunctive therapeutic benefit of zinc supplements containing 
50% of the US recommended dietary allowance (RDA) per day in children aged <5 y. The children had acute (<14 d pre-enrollment duration) or persistent (14 d pre-enrollment duration) diarrhea and resided in a developing country. Subgroups for the analyses were defined a priori as follows: sex, age (<12 mo or 12 mo), and weight-for-height z score (<-2 or -2 compared with the National Center for Health Statistics reference) (21). Subgroups for baseline plasma zinc concentration were defined as those subjects below or above the median plasma zinc concentration for that study. The subgroups were selected because some original trial reports suggested differential effects by sex, age, nutritional status, or baseline plasma zinc concentrations.
From the search, 26 zinc supplementation trials were identified and 10 of these were therapeutic trials that met the inclusion criteria (11–20). Of the 5 trials of zinc therapy for acute diarrhea, only 3 were incorporated into the pooled analysis because original, individual case data were no longer available for one trial (11) and the investigator did not provide data for another (16). Of the 5 trials on persistent diarrhea, 1 could not be included because original data were not available (12). The published data from the 3 trials that could not be included in the pooled analysis were incorporated in other analyses of effect size for all known trials. All trials used standard fluid and dietary case management of diarrhea as recommended by the WHO (4).
Principal investigators of the trials included in the pooled analysis agreed to join the Zinc Investigators' Collaborative (ZINC) Group, which also included 2 external advisors (SMB and RM) selected by the WHO Programme on Child Health and Development and 1 advisor selected by the coordinators of the ZINC Group (KHB). An initial meeting with some of the investigators and correspondence with the others resulted in consensus on trial inclusion criteria, subgroup and outcome definitions, and procedures for the pooled analyses. After a preliminary analysis, the ZINC Group met to consider conclusions and implications and to evaluate the need for additional analyses. Final analyses and draft manuscripts were approved by all investigators who had trials included and by the advisors.
For the acute-diarrhea trials, diarrhea was defined as 3 or 4 loose stools (depending on the original trial definition) in a 24-h period. The final day of diarrhea was defined as the last day meeting the above definition followed by 48 h without diarrhea. For the persistent-diarrhea trials, the definitions of diarrhea and recovery used in the original trials were retained, as was the definition of treatment failure (generally an increase in diarrheal severity, occurrence of dehydration, or continued diarrhea for >7 d or >14 d). These trials differed in their withdrawal criteria. In the pooled analysis of recovery after enrollment, data from children who withdrew from the study, who were declared a treatment failure, or who died were included up to the time that they dropped out of the study. Children who had no diarrhea after enrollment in the study or who had an unknown pre-enrollment duration were excluded from the analyses of diarrheal recovery. In the acute-diarrhea analysis of 2446 children, 1 did not have a pre-enrollment duration and 30 had no diarrhea after enrollment. In the persistent-diarrhea analysis of 640 children, 3 did not have a pre-enrollment duration and 84 had no diarrhea after enrollment.
Individual subject data were provided from each trial with outcomes redefined as necessary, along with descriptive information on the trial methods and study populations. For the Indonesian trial that included >1 diarrheal episode per child, only the first episode for each child was used.
A detailed methodologic assessment and scoring system (available on request) for assessment of study quality was used. This system incorporated standard randomized controlled trial quality assessments and items specific to these trials, such as definitions of recovery and degree of co-intervention. Trials were independently evaluated by REB and SS and any disagreements were resolved by further review of the methods and consensus. At a meeting of the ZINC Group, the methodologic scores were reviewed by the principal investigators of the trials and any errors and inconsistencies were corrected.
For the pooled analysis of trials with available individual child data, the therapeutic effect of zinc on the duration of diarrhea was analyzed by using Cox survival regression models stratified by individual trial (22, 23) using the exact method for handling ties (23, 24). In the simplest of these, continuation of the episode after enrollment was modeled as the dependent variable and treatment group and pre-enrollment duration were independent variables. Additional analyses were performed with nutritional status, sex, and age added as covariates. The analyses were performed with SAS (version 8.0; SAS Institute, Cary, NC). These models permitted calculation of the relative hazard (RH) for continuation of the episode and its 95% CI. The control group was coded as 1 and the zinc group as 0, resulting in an RH of <1 for a beneficial effect, consistent with the beneficial effect expressed by the odds ratio (OR). The dichotomous dependent outcomes, which were duration 
7 d compared with >7 d postenrollment in acute-diarrhea trials and treatment failure or death in persistent-diarrhea trials, were analyzed by using logistic regression models. These models were also stratified by trial, with treatment group, subgroup categories, and potential interaction terms as independent variables, to calculate the ORs and 95% CIs (25). To evaluate a possible clustering effect in the survival analysis, we used random-effects extensions of the Cox models (26); the robust correlation matrix and SEs were calculated with use of the PHREG procedure in SAS version 8.0 (27).
To estimate summary effects, including data from the 3 eligible trials for which original data were not available, we performed a meta-analysis of effect size. Means and SDs of diarrheal duration in the zinc and control groups were used to estimate the effect size. By using Bayesian methods, we estimated a joint posterior probability distribution for the variable of interest (28). From these joint distributions, effect size and 95% CI were calculated for each study. By using a random-effects hierarchical model (28), the summary effect size and the 95% CI were estimated. The confidence profile method was also used to estimate the ORs and CIs for effects on episodes lasting >7 d in acute-diarrhea trials and effects on treatment failure or death in the persistent-diarrhea trials; summary estimates were determined by using random-effects hierarchical models (28). Of the 3 trials not included in the pooled analysis, only 1 (16) reported data on these outcomes and so was incorporated into the analysis. Finally, to evaluate heterogeneity across studies, we determined the chi-square for heterogeneity.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The study in Bangladesh enrolled only children who were underweight. In part because of this, the nutritional status of children in the 3 trials differed (Table 2). In the trial for which plasma zinc concentrations before and after treatment were available, the mean plasma zinc concentration increased in the zinc group after treatment but did not increase in the control group; this difference between the zinc and control groups was not statistically significant.
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), zinc-supplemented children had a 15% lower probability of continuing diarrhea on a given day (95% CI: 8%, 22%) than did the children in the control group. The random-effects extension of survival analysis yielded similar estimates (Table 3).
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). The effect size for reduction in the mean duration of the diarrheal episode in individual trials ranged from 10% to 24%. The summary estimate of the effect size for reduction in duration was 16% (95% CI: 7%, 26%). The results of these 5 trials were not significantly heterogenous (chi square = 2.99, P = 0.56). For the analysis of the effect on episodes lasting >7 d, zinc-supplemented children had a 27% lower rate of prolonged episodes than did control children (OR = 0.73; 95% CI: 0.55, 0.98). These results were also not significantly heterogenous (chi square = 1.39, P = 0.71).
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). One of the trials in Bangladesh (20) and the one in Pakistan had nutritional-status criteria for enrollment. The background characteristics of children in these 4 trials differed: the children in the Peru study were substantially better nourished than were children in the other studies in terms of weight, but not height (Table 2). This study also differed in that it enrolled children in the community rather than in a health facility. In 3 of the 4 trials, the plasma zinc concentrations showed a significant response to zinc supplementation but did not change significantly in the control group (Table 2).
In a stratified analysis of the persistent-diarrhea trials (Table 3), zinc-supplemented children had a 24% lower probability of continuation of diarrhea on a given day (95% CI: 8%, 38%) than did control children. The random-effects survival analysis yielded similar results (Table 3). Zinc-supplemented children in these trials had a 42% lower rate of treatment failure or death (OR = 0.58; 95% CI: 0.37, 0.40) than did control children. For this outcome, the trials were significantly heterogeneous (chi-square = 8.6, P = 0.04), which was due mainly to the results of the study conducted in Pakistan. After exclusion of this study, there was no significant heterogeneity (chi-square = 3.2, P = 0.20). Random-effects analysis for this outcome yielded an OR of 0.61 (95% CI: 0.26, 1.46).
In the effect-size analysis, which used data from all 5 persistent-diarrhea trials including 1 trial (12) not included in pooled analysis, the mean duration of diarrhea tended to be lower in the zinc-supplemented group in all 5 studies, although this result was significant in only 1 study. The effect size for reduction in the mean duration of the diarrheal episode in individual trials ranged from 12% to 53%. The summary estimate of the effect size for reduction in duration was 29% (95% CI: 6%, 53%). The results of these 5 trials were not significantly heterogenous (chi-square = 2.26, P = 0.69).
In the subgroup analyses in acute-diarrhea trials, the effect of zinc supplementation in each of the subgroups by age, wasting, and sex was significant (Figure 1). The subgroups did not differ from each other in terms of the magnitude of this effect. In persistent diarrhea, age <12 mo, wasting, and male sex were associated with significant effects of zinc on continuation of diarrhea, but their corresponding alternatives were not (Figure 1). However, comparisons between the 2 categories for each subgroup analysis in acute and persistent diarrhea did not show significant differences.
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). In this analysis in children with persistent diarrhea, there was a significant pooled effect only in the subgroup with lower baseline zinc concentrations. The subgroup with higher baseline zinc concentrations had more variability among the trials and a pooled effect that suggested a benefit of zinc supplementation, although this result was not significant.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Note that one of the trials conducted in Bangladesh used a factorial design with zinc and vitamin A; the zinc effect on recovery from diarrhea was significant but there was no effect of vitamin A (16). It is important to examine the effect of zinc supplementation on other measures of severity, such as diarrheal stool output, occurrence of dehydration, treatment failure, or death. The trials provided some information on these outcomes, but the different types of study data available precluded many pooled analyses. Three acute-diarrhea trials with appropriate outcome measures all found reductions in diarrheal severity in zinc-supplemented children compared with control children. Of the 2 trials conducted in India, one found 18% fewer diarrheal stools/d (P < 0.1) (11) and the other found 39% fewer watery stools/d (P < 0.02) (13). In the only hospital-based trial of acute diarrhea, zinc-supplemented children had a 28% lower measured diarrheal stool output/d (P = 0.06) (14). Of the 4 persistent-diarrhea trials that included severity measures, 2 found no significant difference between the groups (15, 19). The trial conducted in India reported a 21% lower diarrheal stool frequency (P = 0.08) (12) and a hospital-based trial in Bangladesh found a 37% lower measured stool output (P < 0.02) in zinc-supplemented children (20). Although there were too few treatment failures or deaths for a pooled analysis of acute-diarrhea trials, these outcomes were reduced by 42% with zinc supplementation in the pooled analysis of persistent-diarrhea trials.
The results of these pooled analyses and additional information from other published randomized trials indicate that zinc, given during acute or persistent diarrhea, can have substantial clinical benefit and suggest that this adjunctive therapy could reduce the risks of dehydration and death from diarrhea. The findings of these trials, which were performed in several different developing countries, indicate that therapeutic use of zinc may have wide applicability. The similar benefits seen in subgroups divided by age, nutritional status, and sex and the relative safety of oral zinc (29) suggest that there is no need to target specific population groups. This further enhances the feasibility of this therapy.
The reduction in the duration and severity of diarrhea as a result of zinc supplementation may be perceived as desirable by the caregivers of children with diarrhea. Perhaps the use of this effective and inexpensive nutrient supplement would be helpful in efforts to reduce the now common treatment of diarrhea with unnecessary antibiotics and other drugs (5). At the same time, it will be important to continue the promotion of appropriate fluid and dietary therapy as the mainstay of efforts to reduce mortality from diarrhea (4).
Pooled analyses have a number of strengths (30). These include 1) the use of rigorous methodologic assessment, 2) the ability to use the most meaningful clinical outcomes, 3) the standardization of subgroup and outcome definitions, 4) the use of optimal statistical procedures made possible by the availability of original trial data, and 5) the involvement of both trial investigators and outside advisors to ensure the most valid results and conclusions. The trials included in this pooled analysis fully met the standards for this mode of evaluation. Four of the trials involved a difference in taste between the zinc and control supplements, but this did not appear to compromise masking. Additional geographic representation (eg, children from Africa) would have been desirable.
Children who were not given zinc supplements generally had stable or declining plasma zinc concentrations; net loss of zinc during diarrhea has been found (31, 32). Zinc-supplemented children generally had increases in plasma zinc concentrations, indicating an effect of the supplement. The subgroup analyses for initial plasma zinc concentration were done by classifying children in each trial as above or below the median zinc concentration for that trial. Because the different distributions of plasma zinc concentrations in different settings may have reflected methodologic differences among the trials, we thought this approach was more appropriate than selecting a single plasma zinc concentration for use in all the trials. Furthermore, plasma zinc can be reduced by illness; therefore, some of the variability could reflect the severity of diarrhea or concomitant infections (33). In acute diarrhea, both of the subgroups with lower and higher baseline zinc concentrations showed a significant effect of supplemental zinc, but the effect tended to be larger in the group with lower baseline zinc concentrations. In children with persistent diarrhea, the group with lower baseline zinc concentrations showed a significant benefit of zinc supplementation and the group with higher baseline zinc did not, although the pooled effect estimate did suggest benefit. These effects suggest that zinc should be provided to all children with acute and persistent diarrhea in such settings.
The mechanisms of these effects of zinc on diarrhea are unclear. Zinc deficiency is associated with many immunologic deficits, and zinc supplementation was shown to improve immune function in children in developing countries (9, 34) and to reduce the incidence and prevalence of diarrhea (35). Other possible mechanisms include effects of zinc deficiency on intestinal permeability (36, 37), regulation of intestinal water and electrolyte transport (38), brush border enzymatic function (39, 40), and intestinal epithelial tissue repair (41, 42).
The use of zinc as adjunctive therapy has the potential to improve the management of diarrhea and increase survival in children, if it can be incorporated into diarrheal disease control programs in developing countries. Primary prevention of zinc deficiency would be expected to reduce infectious disease morbidity and improve the growth and development of children (8, 35, 43–45) and might also reduce the severity of diarrhea. Attention should now focus on the best means of providing zinc during diarrhea or on other ways to improve the zinc nutriture of children in developing countries.
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ACKNOWLEDGMENTS |
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REFERENCES |
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