MICRONUTRIENTS AND ENTERIC INFECTION IN AFRICAN CHILDREN

肠道感染仍然是发展中国家儿童死亡的主要原因。 在艾滋病毒感染流行的地区，肠道感染和持续性腹泻对公共卫生的重要性更大。 然而，我们对HIV感染常见地区儿童肠道感染的模式知之甚少，也不知道感染与HIV活性（通过血浆HIV RNA测定）或宿主免疫活性（通过CD 4计数测定）的关系。 虽然正在推广补充微量营养素，包括提供维生素A和锌，作为减少感染性腹泻发病率和流行率的有效手段，但人们对它们在非洲儿童或感染艾滋病毒的儿童中实现这些目标的功效知之甚少。 本研究有以下具体目标：1）确定病原体特异性模式的肠道感染艾滋病毒感染和未感染的儿童生活在南非农村，特别关注隐孢子虫和其他原生动物病原体的感染。2)确定特定病原体感染是否与持续腹泻超过14天的发展相关; 3）确定两种微量营养素补充剂的疗效：a）含有维生素A、C、E和硒的混合物;和B）在HIV感染和未感染HIV的儿童腹泻流行日添加锌的相同微量营养素补充剂。4)通过甘露醇-乳果糖渗透性试验测定微量营养素补充剂是否改善肠道完整性。5)根据这些发现，为非洲和其他艾滋病毒血清阳性率高的地区提供微量营养素补充剂的使用建议。 为了回答这些问题，我们建议招募和研究三个队列的儿童生活在南非农村地区超过三年的时间：1）78名艾滋病毒感染的儿童; 2）120名艾滋病毒感染的母亲所生的未感染艾滋病毒的儿童; 3）120名未感染艾滋病毒的母亲所生的未感染艾滋病毒的儿童。 儿童将在三个月大时被确定，并被跟踪到2岁。 从入组到12个月大，将给予补充营养素。现场工作人员将每周访问儿童，并记录腹泻和其他发病率。 粪便用于检测肠道病原体，包括沙门氏菌、志贺氏菌、弯曲杆菌、大肠杆菌。大肠杆菌（使用毒力基因探针测定）、轮状病毒、肠道腺病毒40/41、星状病毒和诺瓦克病毒，以及原生动物病原体C.小孢子虫（包括菌株的基因分型）、环孢子虫和比氏肠细胞虫将从患有腹泻的儿童和健康儿童的子集中获得。 将定期测量人体测量学，并进行生物阻抗以确定身体成分。 在所有儿童接受微量营养素补充时，将对他们进行肠道渗透性的非侵入性测试（乳果糖-甘露醇测试）。 计算研究样本量，以确定安慰剂治疗组和两个微量营养素补充组之间腹泻流行天数的20%差异。 这项研究还将使我们能够确定持续性腹泻的风险因素，并在艾滋病毒感染常见的地区开发感染性腹泻的管理算法。

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.