Transmission and the respiratory tract in cryptosporidiosis

描述（由申请人提供）：本R21申请对生物防御和新发传染病研究机会的PA-04-119（取代03-080）作出回应。隐孢子虫病是临床上引起腹泻的重要原因。由于腹泻的严重和慢性，以及缺乏有效的治疗，这种感染对免疫缺陷的个体可能会危及生命。隐孢子虫病通常被认为完全局限于肠道，传播方式完全是粪-口。本提案将探讨隐孢子虫病对呼吸道感染的贡献，如果有的话。基于大量数据（间接信息、人类病例报告和病例系列、动物研究、基于人群的研究和人类志愿者研究），我们假设隐孢子虫呼吸道感染经常发生。然而，据我们所知，还没有对这种可能性进行前瞻性研究。我们设计了一项针对乌干达儿童的严谨研究，要么令人信服地证实，要么反驳这一假设。这项研究的结果将具有重要的临床、生物学和流行病学意义，这可能是重要的，因为缺乏治疗。例如，呼吸道隐孢子虫病的发现可能导致改善临床护理（呼吸支持，如氧气）和阻断传播的新措施（因为肺分泌物[痰]可能是传播源）。呼吸道感染有多普遍，因而又有多严重，目前还不清楚。在修订后的申请中，我们加强并重点关注乌干达的临床研究，并删除了先前旨在探索仔猪呼吸道传播问题的特定目的。如果我们在乌干达的项目表明呼吸道隐孢子虫病发生在儿童身上，那么我们将在下一步的应用中再次解决这个问题。该项目将侧重于尝试从急性或持续性腹泻并伴有咳嗽，伴有或不伴有呼吸急促的儿童的诱导痰中恢复隐孢子虫卵囊。这些研究将在乌干达坎帕拉穆拉戈医院就诊的患有急性或持续性腹泻和咳嗽伴或不伴呼吸急促的儿童中进行。多年来，我们一直在穆拉戈医院开展一项关于3-59个月儿童腹泻和营养不良的项目，并发表了几篇文章。在这次重新提交中，我们通过增加样本量来加强研究，并建议对寄生虫分离物进行更完整的遗传分析。这项研究对公共卫生很重要，因为它可以帮助我们了解寄生虫是否也会导致儿童肺部感染。

DESCRIPTION (provided by applicant): This R21 application responds to PA-04-119, replacing 03-080, on Biodefense and Emerging Infectious Diseases Research Opportunities. Cryptosporidiosis is a clinically significant cause of diarrhea. The infection can be life-threatening in individuals with immunodeficiencies because of the severity and chronicity of the diarrhea, and lack of effective therapy. Cryptosporidiosis is usually considered to be wholly confined to the gut, and the mode of transmission to be exclusively fecal-oral. This proposal will explore the contribution, if any, of Cryptosporidiosis to respiratory tract infections. We hypothesize, based on a wealth of data (circumstantial information, human case reports and case series, animal studies, human population-based studies, and human volunteer studies), that respiratory infections with Cryptosporidium occur frequently. However, to our knowledge, no study has ever been conducted to prospectively study this possibility. We have designed a rigorous study of children in Uganda that should either convincingly confirm, or refute, this hypothesis. The outcome of this study will have significant clinical, biological and epidemiological implications, which could be important, given the lack of therapy. For example, the finding of respiratory Cryptosporidiosis may lead to improved clinical care (respiratory support, such as oxygen), and new measures to interrupt transmission (since pulmonary secretions [sputum] may be a source for transmission). How common - and consequently how significant - are infections of the respiratory tract, is unclear. In this revised application, we have strengthened and focused on the clinical study in Uganda, and dropped a prior specific Aim designed to explore the question of respiratory transmission in piglets. Should our project in Uganda show that respiratory Cryptosporidiosis occurs in children, then we will again address that question in a next-step application. The project will focus on attempts to recover Cryptosporidium oocysts from induced sputum of children with acute or persistent diarrhea concurrently experiencing cough, with or without fast breathing. These studies will be performed in children presenting to Mulago Hospital in Kampala, Uganda with acute or persistent diarrhea and cough with or without fast breathing. Mulago Hospital is a site where we have had an ongoing program on diarrhea and malnutrition in children aged 3-59 months for several years, which resulted in several publications. In this resubmission, we have strengthened the study by increasing the sample size, and by proposing to perform more complete genetic analysis of the parasite isolates. This study is important to public health because it may help us to understand if the parasite also causes a lung infection in children.