The Dawning of the “Zinc Era” in the Treatment of Pediatric Acute Gastroenteritis Worldwide?

Abstract

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 zincsupplemented 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 Received December 14, 2005; accepted December 30, 2005. Address correspondence and reprint requests to Roberto Berni Canani, MD, PhD, Department of Pediatrics, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy. (e-mail: berni@ unina.it).