Despite the widespread use of oral rehydration solution (ORS) preparations, up to 5 million children each year still die of diarrhea, almost all in developing countries (1). The World Health Organization (WHO) estimates that, in children younger than 5 years, diarrhea accounts for 18% of cause-specific mortality and that there are 6 to 7 episodes per child per year in the developing world versus 1 to 2 in the developed world (2).
The effects of diarrhea in developed countries are often measured in financial terms. In the United States, acute diarrhea accounts for a minimum of US$23 billion per year due to loss of productivity and medical costs (3). If we restrict the analysis to rotavirus enteritis (the most frequent infectious diarrhea), there is an estimated cost of approximately US$274 million for medical treatment and more than US$1 billion in costs to the community (4). Oral rehydration solutions are now widely used to treat diarrhea and have greatly reduced mortality from dehydration. However, ORS does not decrease the duration of diarrhea or its severity. Despite the advent of a number of antidiarrheal drugs, none has found a place in the routine management of acute diarrhea.
Several hospital and community-based randomized trials, all performed in developing countries, consistently showed that zinc is an effective treatment for acute or persistent diarrhea in children younger than 5 years. Benefits include the reduction of diarrhea duration and its severity as measured by stool output and frequency, and these effects have been obtained in both mild and severe gastroenteritis associated with severe dehydration requiring hospitalization (5). Furthermore, a number of randomized controlled trials carried out in developing countries explored the efficacy of zinc in preventing intestinal infections. The incidence and duration of acute and persistent diarrhea were significantly lower in zinc-supplemented children versus placebo-treated counterparts (6,7). Moreover, in children younger than 5 years, zinc treatment during acute diarrhea illness resulted in fewer subsequent diarrhea episodes and in a concomitant reduction in the use of antibiotics (8,9). The preventive and therapeutic effects of zinc in reducing diarrhea morbidity have relevant economic implications in terms of hospitalization and antibiotic use (10). The only negative data come from a recent trial in infants aged 1 to 6 months performed in Bangladesh in which different doses of zinc (5 or 20 mg/d given for the duration of the illness) did not affect the duration or severity of diarrhea (11). Given the benefits of zinc supplementation in a large number of studies, in May 2004, the United Nations Children's Fund (UNICEF) and the WHO issued a statement recommending that all children with diarrhea in developing countries be treated with zinc (12).
Although zinc is recommended for the treatment of childhood acute diarrhea, several important questions remain to be answered. These can be divided into questions that can be addressed by basic research and questions that can be addressed by applied research (Table 1). A major research goal is to investigate the effects of zinc against specific pathogens that cause diarrhea, especially rotavirus. Besides rotavirus, other major causal agents of infectious diarrhea are Vibrio cholerae and the enterotoxigenic Escherichia coli.
Using an in vitro model, we recently demonstrated that zinc promotes ion absorption and prevents active secretion induced by V. cholerae heat-labile enterotoxin, thereby exerting a direct effect on intracellular cyclic adenosine monophosphate concentration, but it does not affect E. coli heat-stable, enterotoxin-induced ion secretion (13). This finding suggests that zinc exerts selective effects against intestinal pathogens and highlights the need to investigate whether zinc could be useful against other diarrheal mechanisms elicited by different pathogens (14). Should this prove to be the case, the physician has 2 alternatives: either identify the diarrhea-causing agent before administering zinc to candidate children or, given the lack of adverse effects and its low cost, administer zinc to all candidate children.
Both the pilot study by Bhandari et al. (15) and the trial by the INCLEN Childnet Zinc Effectiveness for Diarrhoea Group (IC-ZED group), which appear in this issue of the Journal of Pediatric of Gastroenterology and Nutrition, examine the question of the use of zinc in diarrhea treatment (16).
In the pilot study, zinc tablets were freely distributed with ORS packets to children with diarrhea. Zinc tablets were well accepted by caregivers and children, and their introduction increased ORS use rates when both were promoted together. Consistent with this finding, the distribution of zinc significantly reduced the prescription of other drugs and the cost of treatment. The weakness of this study is the lack of a control group.
The randomized trial by the IC-ZED group was conducted at 6 sites in 5 developing countries. The caregivers of the children recruited received ORS free of charge and instructions in their use. Subjects randomized to the zinc group also received a clear message to use zinc as a complement and not as a replacement for ORS. This recommendation was a fundamental part of the trial. The results favored the zinc group compared with controls: supplementation with zinc did not affect the use of ORS in 5 of 6 sites, there was no difference in vomiting between the 2 groups on days 3 to 5, and the use of antibiotics and antidiarrheal drugs was substantially reduced. The finding of reduced drug intake in the zinc-treated group coincides with the results of the pilot study by Bhandari et al. (15) and of the community trial by Baqui et al. (17). Unfortunately, data about diarrhea duration and severity were not reported, and a cost analysis was not provided. In the IC-ZED group study, there was adherence of about 83% after 3 to 5 days of treatment compared with 56% reported in Bangladesh (18).
The optimal duration of zinc therapy in acute gastroenteritis remains to be established. The UNICEF/WHO recommendation of a treatment course of 10 to 14 days applies to patients in developing countries and is based on the finding that zinc reduces the risk of noninjury death by 50% in the 3 months subsequent to treatment (9). The dosage of zinc supplementation in the treatment of acute diarrhea is better defined: 10 mg daily for children younger than 6 months and 20 mg daily for children older than 6 months. Several clinical trials and meta-analyses have shown that, at these doses, zinc is safe and effective (5-9). This is an important issue because, in many countries, zinc-fortified ORS formulations are already in the market, and the exact amount of zinc administered by this route depends on the amount of ORS ingested by the child.
The studies by Bhandari et al. and by the IC-ZED group represent an important step forward in our understanding of the use of zinc in the treatment of diarrhea. It is well known that ORS is largely underused because they are not perceived as being effective against diarrhea (19). The addition of zinc would not only enhance ORS efficacy, but also increase its use by introducing an active component capable of reducing water loss, rather than relying on components that merely replace fluid loss, as with standard ORS. This aspect of adding zinc to ORS could be even more important than its ion proabsorbative/antisecretory effects.
We believe that the use of zinc as adjunctive therapy has the potential to improve the management of diarrhea and increase survival in children. It has been estimated that the successful implementation of the UNICEF/WHO recommendations on zinc use in the treatment of diarrhea could save nearly 400,000 lives annually (20). Zinc may also improve child health in the public health setting (ie, growth and development, respiratory infections, and malaria) (21). There are several reasons to establish a unique universal ORS, and the composition of ORS has undergone many changes in the last 30 years (19). Perhaps the time has come to consider adding zinc to a new universal ORS.
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