MICRONUTRIENTS AND ENTERIC INFECTION IN AFRICAN CHILDREN

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Enteric infections remain a leading cause of childhood mortality in developing countries. In regions where HIV infection is prevalent, enteric infections and persistent diarrhea have even greater public health importance. Little is known, however, about the pattern of enteric infection in children in regions where HIV infection is common, and how infection is related to HIV activity as measured by plasma HIV RNA, or host immunocompetence, as determined by CD4 counts. Although micronutrient supplementation, including provision of vitamin A and zinc, are being promoted as effective means of reducing infectious diarrhea morbidity and prevalence, little is know about their efficacy in achieving these goals in African children, or in children who are HIV infected. This study had the following specific aims: 1) To determine the pathogen-specific pattern of enteric infections in HIV-infected and uninfected children living in rural South Africa, with a particular focus on infection with Cryptosporidium parvum and other protozoan pathogens. 2) To determine if infection with specific pathogens is associated with the development of persistent diarrhea lasting greater than 14 days; 3) To determine the efficacy of two micronutrient supplements; a) a mixture containing Vitamins A, C, E, and selenium; and b) the same micronutrient supplement with the addition of zinc, on the prevalent days of diarrhea in both HIV-infected and HIV- uninfected children.; 4) To determine if micronutrient supplementation improves gut integrity as measured by the mannitol-lactulose permeability test. 5) Based upon these findings to develop recommendations for use of micronutrient supplements in Africa and other regions with a high HIV- seroprevalence. To answer these questions we propose enrolling and studying three cohorts of children living in a rural region of South Africa over a three-year period; 1) 78 HIV-infected children; 2) 120 HIV-uninfected children born to HIV-infected mothers; 3) 120 HIV-uninfected children born to mothers without HIV infection. Children will be ascertained at three months of age and followed until age 2 years. Micronutrient supplementation will be given from enrollment until age 12 months. Children will be visited weekly by field staff, and diarrhea and other morbidity recorded. Stool for detection of enteric pathogens, including Salmonella, Shigella, Campylobacter, diarrheagenic E. coli (determined using probes for virulence genes), rotavirus, enteric adenoviruses 40/41, astroviruses and Norwalk virus, and the protozoan pathogens C. parvum (including genotyping of strains), Cyclospora cayetanensis, and Enterocytozoon bieneusi will be obtained from children when they have diarrhea, and from a subset of well children. Anthropometry will be measured regularly, and bioimpedance will be performed to determine body composition. A non-invasive test of gut permeability (the lactulose-mannitol test) will be performed on all children while they are receiving micronutrient supplementation. The study sample size is calculated to allow a determination of a 20 percent difference in prevalent days of diarrhea between the placebo treated group and the two micronutrient supplemented groups. This study will also allow us to determine risk factors for persistent diarrhea, and to develop algorithms for the management of infectious diarrhea in a region where HIV infection is common.