Reducing morbidity and mortality from acute febrile illness by improved diagnosis

据估计，低收入国家每年有1000万儿童死亡，其中大多数死于富裕国家容易预防、诊断和治疗的感染。实际的总数和病因学分数是未知的，因为很少有人在生活中被诊断或通过尸检分类。在撒哈拉以南非洲，发烧常常被错误地归因于疟疾，而在南亚，发烧则被错误地归因于伤寒。有限的横截面数据表明，误诊是昂贵的和致命的。斯里兰卡缺乏指导急性未分化发热预防和管理的数据。我们的总体假设是，新诊断工具的开发和合理使用将改善临床结果，并限制斯里兰卡等资源贫乏地区急性发热性疾病的成本。我们认为，确定致病因子将为公共卫生工作提供信息，改善临床诊断，并通过开发包括重点诊断测试在内的循证临床算法来减少不必要的发病率，死亡率和成本。因此，我们有以下具体目标：1）调查斯里兰卡急性发热性疾病的分布和决定因素，2）调查斯里兰卡急性发热性疾病诊断的新策略，3）前瞻性验证预测规则，并评估算法的使用和性能以及相关的临床结果和成本。第二个目标将涉及验证立克次体多重实时PCR检测作为原型，用于快速识别难以培养的新出现的感染，推导出临床预测规则，以评估斯里兰卡急性发热的病因，并使用决策分析来评估管理急性发热性疾病的策略。拟议的5年职业发展期包括为接受者提供额外培训和技能所需的活动，以进行翻译研究并作为独立研究员领导多学科团队。该研究将通过以下方面的综合研究来推进该领域：1）传统方法来定义急性发热性疾病的流行病学，2）用于快速诊断急性发热性疾病的新分子和分析决策工具，以及3）与使用算法管理斯里兰卡急性发热性疾病相关的可行性和结果（健康和成本）。这项工作将为预防和管理斯里兰卡的急性发热性疾病提供必要的数据，为一种具有世界重要性的新出现病原体（立克次体）提供分子诊断方法，并为评估在资源贫乏的环境中改进诊断检测和相关结果的方法提供一般方法。.在全球范围内，许多人死于从未被诊断出的感染发烧。我们将开发和研究新的工具，以改进对以发烧为特征的感染的诊断，目标是减少这些感染引起的疾病和死亡，并降低相关医疗保健的费用。拟议的5年培训期将使申请人获得技能，并建立新的合作，以支持在这个被忽视的领域的职业生涯。

DESCRIPTION (provided by applicant): An estimated 10 million children die yearly in low-income countries, the majority from infections easily prevented, diagnosed, and treated in wealthy countries. The actual sum and etiologic fractions are unknown, since few are diagnosed in life or classified by autopsy thereafter. Fever is often attributed erroneously to malaria in sub-Saharan Africa and to typhoid in South Asia. Limited cross-sectional data suggest that misdiagnosis is costly and deadly. Data to guide prevention and management of acute, undifferentiated fever in Sri Lanka are lacking. Our overarching hypothesis is that the development and rational use of new diagnostic tools will improve clinical outcomes and limit costs from acute febrile illness in resource-poor settings such as Sri Lanka. We posit that determination of the causal agents will inform public health efforts, improve clinical diagnosis, and reduce unnecessary morbidity, mortality, and costs by enabling the development of evidence-based clinical algorithms that include focused diagnostic testing. Therefore, we have the following specific aims: 1) To investigate the distribution and determinants of acute febrile illness in Sri Lanka, 2) To investigate new strategies for the diagnosis of acute febrile illness in Sri Lanka, and 3) To prospectively validate the prediction rules and to assess use and performance of the algorithm and related clinical outcomes and costs. The second aim will involve the validation of a multiplex real-time PCR assay for rickettsiae as a prototype for the rapid identification of difficult-to-culture emerging infections, derivation of a clinical prediction rule to assess etiology of acute fever in Sri Lanka, and use of decision analysis to evaluate strategies for managing acute febrile illness. The proposed 5-year career development period includes activities to provide the recipient with the additional training and skills required for her to conduct translational research and lead a multidisciplinary team as an independent investigator. The research will advance the field through integrated study of 1) traditional methods to define the epidemiology of acute febrile illness, 2) new molecular and analytic decision-making tools for rapid diagnosis of acute febrile illness and 3) feasibility and outcomes (health and costs) related to use of an algorithm to manage acute febrile illness in Sri Lanka. This work will provide data essential for prevention and management of acute febrile illness in Sri Lanka, a molecular diagnostic method for an emerging pathogen of worldwide importance (rickettsiae), and a general methodology for assessing approaches to improved diagnostic testing and related outcomes in resource-poor settings. . Globally many die with fever from infections that are never diagnosed. We will develop and study new tools to improve the diagnosis of infections characterized by fever, with the goal of reducing sickness and death from these infections and the cost of related medical care. The proposed 5-year training period will allow the applicant to gain skills and forge new collaborations to support a career in this neglected area.