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具有更大的重要性。然而，关于艾滋病毒感染常见地区儿童肠道感染的模式，以及感染与艾滋病毒活动(通过血浆HIV RNA衡量)或宿主免疫能力(由CD4计数确定)之间的关系，人们知之甚少。虽然补充微量营养素，包括提供维生素A和锌，是减少感染性腹泻发病率和流行率的有效手段，但人们对其在非洲儿童或感染艾滋病毒的儿童中实现这些目标的有效性知之甚少。这项研究有以下具体目的：1)确定南非农村地区感染艾滋病毒和未感染艾滋病毒的儿童肠道感染的病原体特异性模式，特别是感染微小隐孢子虫和其他原生动物病原体。2)确定感染特定病原体是否与持续14天以上的持续性腹泻的发展有关；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；以及b)在感染艾滋病毒的儿童和未感染HIV的儿童中，在腹泻流行的日子添加相同的微量营养素补充剂。4)确定补充微量营养素是否改善了甘露醇-乳果糖通透性试验所测量的肠道完整性。5)根据这些调查结果，为在非洲和其他艾滋病毒血清阳性率较高的地区使用微量营养素补充剂制定建议。为了回答这些问题，我们建议对生活在南非农村地区的三组儿童进行为期三年的招募和研究：1)78名感染艾滋病毒的儿童；2)120名感染艾滋病毒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。儿童将在三个月大的时候被确定，并被跟踪到两岁。微量营养素补充剂将从注册开始直到12个月大。外地工作人员将每周探望儿童，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、致泻性大肠埃希菌(使用毒力基因探针检测)、轮状病毒、肠道腺病毒40/41、星状病毒和诺沃克病毒，以及原生动物病原体微小弧菌(包括菌株的基因分型)、卡氏环孢菌和比埃努斯肠细胞体，将从腹泻儿童和部分健康儿童身上获得。将定期测量人体尺寸，并进行生物阻抗测试以确定身体成分。在补充微量营养素的同时，将对所有儿童进行非侵入性肠道通透性测试(乳果糖-甘露醇测试)。研究样本量的计算允许确定安慰剂治疗组和两个补充微量营养素组之间腹泻流行天数的20%的差异。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.