Zinc supplementation for the prevention of acute lower respiratory infection in children in developing countries: meta-analysis and meta-regression

of randomized trials. Int J Epidemiol. 2010; 39(3):795-808 (ISSN: 1464-3685) Roth DE; Richard SA; Black RE Department of International Health, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. BACKGROUND: Routine zinc supplementation is a potential intervention for the prevention of acute lower respiratory infection (ALRI) in developing countries. However, discrepant findings from recent randomized trials remain unexplained. METHODS: Randomized trials of zinc supplementation in young children in developing countries were identified by a systematic literature review. Trials included in the metaanalysis met specific criteria, including participants <5 years of age, daily/weekly zinc and control supplementation for greater than 3 months, active household surveillance for respiratory morbidity and use of a case definition that included at least one sign of lower respiratory tract illness. ALRI case definitions were classified on the basis of specificity/severity. Incidence rate ratios (IRRs) were pooled by random-effects models. Meta-regression and sub-group analysis were performed to assess potential sources of between-study heterogeneity. RESULTS: Ten trials were eligible for inclusion (n = 49 450 children randomized). Zinc reduced the incidence of ALRI defined by specific clinical criteria [IRR 0.65, 95% confidence interval (CI) 0.52-0.82], but had no effect on lower-specificity ALRI case definitions based on caregiver report (IRR 1.01, 95% CI 0.91-1.12) or World Health Organization 'non-severe pneumonia' (0.96, 95% CI 0.86-1.08). By meta-regression, the effect of zinc was associated with ALRI case definition, but not with mean baseline age, geographic location, nutritional status or zinc dose. CONCLUSIONS: Routine zinc supplementation reduced the incidence of childhood ALRI defined by relatively specific clinical criteria, but the effect was null if lower specificity case definitions were applied. The choice of ALRI case definition may substantially influence inferences from community trials regarding the efficacy of preventive interventions.
2006 American Society for Clinical Nutrition Zinc and pneumonia1,2 K Michael Hambidge

1. 1From the University of Colorado Health Sciences Center, Denver, CO Recent experience with lower mortality and morbidity due to infectious disease in welldesigned, randomized, controlled trials of zinc supplements in young children has highlighted zinc deficiency as a public health problem of global proportions (1). This experience applies especially to diarrhea and pneumonia, the most prevalent causes worldwide of infectious disease mortality in young children. The most extensive and

impressive data relate to the use of zinc as a preventive measure. A pooled analysis of the results of trials in 9 countries and on 4 continents showed odds ratios (ORs) in zincsupplemented groups of 0.82 (95% CI: 0.72, 0.93) and 0.75 (0.63, 0.88) for diarrheal incidence and prevalence, respectively (2). The data for pneumonia prevention were even more impressive: the OR was 0.59 (0.41, 0.83). Moreover, the use of zinc supplements as a preventive modality has been associated with lower mortality, notably that due to pneumonia (3). Zinc administered as a therapeutic agent to young children with acute or persistent diarrhea also reduces the duration of the diarrhea and is associated with a lower rate of treatment failure or death (4). However, results of studies of zinc administered as adjuvant therapy for pneumonia have been more limited. In a recent study in Bangladesh, zinc given together with antimicrobial therapy to young children with pneumonia was associated with a significant reduction in the duration of pneumonia compared with that in the control group, who received the same antimicrobial therapy but no zinc (5). Comparable benefits of zinc supplementation, although not identical in the affected variables, were reported from a study in Kolkarta, India, but in male children only (6). In this issue of the Journal, Bose et al (7) report no benefits of a zinc supplement in the management of pneumonia in young children in Tamilnadu, India. Although they were quite thorough in reviewing factors that may have accounted for their negative result, no apparent explanation was forthcoming. A pharmacologic effect of zinc is plausible (5), but, as in the report by Bose et al, it is widely accepted that the beneficial effects of zinc supplements in the prevention and treatment of diarrhea and pneumonia are most likely to be due to the prevention or correction of zinc deficiency. Hence, beneficial effects of zinc supplements in the acute management of pneumonia are not to be expected unless the infant or child is zinc deficient. As has been typical for the reported studies of zinc administration used to prevent or treat diarrhea or pneumonia, Bose et al do not include data on habitual dietary zinc intake or, indeed, dietary zinc during hospitalization. The mean baseline serum zinc concentration in their study was higher than that in the 2 studies they discussed that had positive results (5, 6), but a wide range of mean baseline serum or plasma zinc concentrations has been reported in studies in which zinc supplements have had a positive effect in preventing diarrhea and pneumonia (2) or in treating diarrhea (4). In the placebo groups, serum zinc was significantly higher at discharge than at baseline in all 3 studies, which was attributed to a cessation of the effects of the acute phase response. The differential between the study of Bose et al (7) and the 2 positive studies (5, 6) was maintained, however, and the mean for the former was well within a normal range. The adequacy of dietary zinc varies with age in young children in developing countries, who typically depend on long-term breastfeeding as well as on the consumption of plant-based complementary foods. Breastfed infants delivered at term with birth weights appropriate for gestational age are likely to have adequate zinc intakes for at least the first 4 mo of life. In contrast, it is almost certain that dietary zinc intakes in infants >6 mo old in developing countries will fail to meet requirements. The quantity of zinc derived from breast milk by 6 mo is very limited, and zinc-unfortified, plant-based complementary foods do not, at least currently, provide adequate zinc, which has been categorized as a problem nutrient. The typically low dietary zinc intake of older infants

suggests that zinc supplements for the treatment of pneumonia are more likely to be effective in infants aged >6 mo. From a nutritional perspective, therefore, an argument can be made for a different subdivision by age than that selected by Bose at al and other investigators. Although the information on the lack of a treatment effect with age in the study of Bose et al indicates that additional insights are unlikely to be gained from a different agebased subdivision in their study, the young age of all participants in a recent trial by Brooks et al (8) provides a plausible explanation for the negative results with zinc supplementation. This was a well-documented negative study on the value of short-term zinc therapy during the management of acute diarrhea in infants <6 mo old. One important piece of information missing from the report by Brooks et al, however, was the birth weight of the participants. Low-birth-weight infants, especially those identified as small-for-gestational age, benefit from zinc supplements commencing early in infancy (9). Zinc requirements in all low-birth-weight infants are higher than those in normalweight infants, and the infants' ability to absorb the needed quantities of zinc appears to be limited (10). Hence, if the report by Brooks et al (8) discouraged the use of zinc supplements in infants aged <6 mo with diarrhea, it would be unfortunate if this discouragement extended to the low-birth-weight infant. The significant treatment effect in subgroup analysis of the hot season that favors the placebo group should be considered when balancing the potential benefits and risks of zinc supplementation. Although there are extensive reassuring data about the safety of zinc supplements in typical doses of 1020 mg Zn/d, this is not the first instance in which zinc supplements have been associated with undesirable negative results. Finally, the study of Bose et al leaves doubt about the more general benefits to be derived from the routine administration of zinc as an adjuvant therapy for pneumonia in young children in the developing world and, as the authors conclude, indicates the priority of the need for additional studies in representative populations. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: Pooled analysis of randomized controlled trials Z.A. Bhutta, MBBS, PhD, R.E. Black, MD, MPH, K.H. Brown, MD, J.Meeks Gardner, PhD, Zinc Investigators Collaborative Group* Aga Khan University Medical Centre, Karachi, Pakistan; Johns Hopkins School of Public Health, Baltimore, Maryland; University of California, Davis, California; University of the West Indies, Mona, Jamaica; Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; Trisakti University, Jakarta, Indonesia; Dhaka Medical College, Dhaka, Bangladesh; Emory University, Atlanta, Georgia; National Institute of Nutrition, Hanoi, Vietnam; Nutrition Research Institute, Lima, Peru; National Institute of Nutrition, Mexico City, Mexico; International Centre for Diarrhoeal Disease Research, Bangladesh,

Dhaka, Bangladesh; Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala; and All India Institute of Medical Sciences, New Delhi, India Abstract Objectives: This study assessed the effects of zinc supplementation in the prevention of diarrhea and pneumonia with the use of a pooled analysis of randomized controlled trials in children in developing countries. Study design: Trials included were those that provided oral supplements containing at least one half of the United States Recommended Daily Allowance (RDA) of zinc in children <5 years old and evaluated the prevention of serious infectious morbidity through household visits. Analysis included 7 continuous trials providing 1 to 2 RDA of elemental zinc 5 to 7 times per week throughout the period of morbidity surveillance and 3 short-course trials providing 2 to 4 RDA daily for 2 weeks followed by 2 to 3 months of morbidity surveillance. The effects on diarrhea and pneumonia were analyzed overall and in subgroups defined by age, baseline plasma zinc concentration, nutritional status, and sex. The analysis used random effects hierarchical models to calculate odds ratios (OR) and 95% CIs. Results: For the zinc-supplemented children compared with the control group in the continuous trials, the pooled ORs for diarrheal incidence and prevalence were 0.82 (95% CI 0.72 to 0.93) and 0.75 (95% CI 0.63 to 0.88), respectively. Zincsupplemented children had an OR of 0.59 (95% CI 0.41 to 0.83) for pneumonia. No significant differences were seen in the effects of the zinc supplement between the subgroups examined for either diarrhea or pneumonia. In the short-course trials the OR for the effects of zinc on diarrheal incidence (OR 0.89, 95% CI 0.62 to 1.28) and prevalence (OR 0.66, 95% CI 0.52 to 0.83) and pneumonia incidence (OR 0.74, 95% CI 0.40 to 1.37) were similar to those in the continuous trials. Conclusions: Zinc supplementation in children in developing countries is associated with substantial reductions in the rates of diarrhea and pneumonia, the 2 leading causes of death in these settings. (J Pediatr 1999;135:689-97)