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区域，肠道感染和持续性腹泻具有更大的公共卫生重要性。然而，在艾滋病毒感染常见的地区，关于儿童肠道感染的模式知之甚少，以及感染如何与通过血浆HIV RNA测量的艾滋病毒活性或通过CD4计数确定的宿主免疫能力相关。虽然正在宣传补充微量营养素，包括提供维生素A和锌，作为减少传染性腹泻发病率和流行率的有效手段，但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效力知之甚少。本研究有以下具体目的：1)确定南非农村hiv感染和未感染儿童肠道感染的病原体特异性模式，特别关注小隐孢子虫和其他原生动物病原体的感染。2)确定特定病原体的感染是否与持续腹泻的发展有关，持续时间超过14天；3)确定两种微量营养素补充剂的功效；a)含有维生素a、C、E和硒的混合物；b)在感染艾滋病毒和未感染艾滋病毒的儿童腹泻流行的日子，补充相同的微量营养素，并添加锌；4)通过甘露醇-乳果糖渗透性试验确定微量营养素补充剂是否能改善肠道完整性。5)根据这些发现，制定在非洲和其他艾滋病病毒血清高流行地区使用微量营养素补充剂的建议。为了回答这些问题，我们建议招募和研究三组生活在南非农村地区的儿童，为期三年；1) 78名感染艾滋病毒的儿童；2)感染艾滋病毒的母亲所生的120名未感染艾滋病毒的儿童；3)未感染艾滋病毒的母亲所生的120名未感染艾滋病毒的儿童。儿童将在3个月大时被确定，并一直跟踪到2岁。微量营养素的补充将从登记到12个月。外地工作人员将每周访问儿童，并记录腹泻和其他发病率。用于检测肠道病原体的粪便，包括沙门氏菌、志贺氏菌、弯曲杆菌、致泻性大肠杆菌（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小梭菌（包括菌株的基因分型）、卡耶坦环孢子虫和bienezoi肠细胞虫，将从腹泻儿童和一部分健康儿童中获得。将定期测量人体测量，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，将对他们进行无创的肠道渗透性测试（乳果糖-甘露醇测试）。研究样本量的计算是为了确定安慰剂治疗组和两种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危险因素，并开发在艾滋病毒感染普遍的地区管理感染性腹泻的算法。

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.