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EDITORIAL |
1 From the University of Colorado Health Sciences Center, Denver, CO
See corresponding article on page 1089.
Recent experience with lower mortality and morbidity due to infectious disease in well-designed, 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 zinc-supplemented 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 age-based 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 normal-weight 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 10–20 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.
ACKNOWLEDGMENTS
The author had no conflict of interest.
REFERENCES
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W A. Brooks, M. Santosham, and R. E Black Zinc, infectious diseases, and low birth weight. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 667 - 667. [Full Text] [PDF]
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