Biomarkers and Risk Stratification in Pediatric Community-Acquired Pneumonia

 描述（由申请人提供）：社区获得性肺炎（CAP）是儿童中最常见的严重细菌感染，也是儿科住院的主要原因。尽管其意义重大，但目前决定住院治疗患有CAP的儿童是使用临床因素，成像和测试，不能准确或可靠地评估疾病风险。其结果是住院率和临床管理的巨大差异。三种新的生物标志物-降钙素原、肾上腺髓质素原和肺炎球菌细菌负荷-已被证明有可能提高CAP严重程度的预测。然而，目前还没有循证临床预测规则来衡量疾病的严重程度或预测CAP儿童的临床结局。除了缺乏循证决策辅助工具外，护理的广泛变化突出了对疾病严重程度的进一步了解和指导儿科CAP管理的工具的迫切需要。拟议的研究将通过追求以下具体目标来解决这一重要的知识和实践差距：（1）确定CAP儿童中宿主和病原体生物标志物与临床结果（包括住院需求）之间的关联;和（2）开发并内部验证CAP儿童住院需求的临床预测规则。为了实现这些目标，候选人，托德弗洛林，医学博士，MSCE，将利用现有的研究基础设施开发与他的导师在他的KL 2奖，并已与CAP招收儿童自2013年7月。强大的基础设施是K23的主要数据来源，包括辛辛那提儿童医院医学中心（CCHMC）艾德的积极招募机制和CAP儿童标本生物储存库的开发。作为一名儿科急诊医生，Florin博士在完成拟议的K23研究和培训目标方面具有独特的优势。Florin博士的长期目标是成为临床和转化研究方法的专家，以改善儿科CAP和其他常见的严重儿科感染在急性护理环境中的诊断和结果。为了扩大他的研究培训，包括预测建模，分子流行病学，生物标志物发现和多中心儿科急诊医学研究的先进统计方法，Florin博士制定了详细的职业发展计划，包括指导，教学课程，动手实验室经验和完成拟议的研究。他组建了一支由经验丰富的导师组成的多学科团队，他们在儿科肺炎，传染病研究，生物标志物发现，预测建模和多中心急诊医学研究方面具有专业知识。Florin博士将定期与他的导师单独会面，并作为一个完整的委员会每季度一次，以确保完成所有的研究和培训基准。美国最大的儿科研究机构之一CCHMC对年轻研究人员的机构承诺，通过提供强大的指导，正式的指导，统计数据库支持，专业实验室和发展成为独立临床研究者所需的实践经验，提供了理想的合作培训环境。该提案将使Florin博士作为独立的医生-科学家为艾德儿科传染病研究做出重大贡献，并为未来R 01资助的项目做好准备，这些项目的重点是使用生物标志物来改善儿童肺炎的诊断和管理。

 DESCRIPTION (provided by applicant): Community-acquired pneumonia (CAP) is the most common serious bacterial infection in children and a leading cause of pediatric hospitalization. Despite its significance, the decision to hospitalize a child with CAP is currently made using clinical factors, imaging and tests that do not accurately or reliably assess disease risk. The result is substantial variation in hospitalization rates and clinical management. Three newer biomarkers - procalcitonin, proadrenomedullin, and pneumococcal bacterial load - have demonstrated potential to improve severity prediction in CAP. Yet, there are currently no evidence-based clinical prediction rules to gauge disease severity or predict clinical outcomes among children with CAP. The extensive variation in care, in addition to the lack of evidence-based decision aids, highlights the critical need for an improved understanding of disease severity and tools to guide management for pediatric CAP. The proposed research will address this important knowledge and practice gap by pursuing the following specific aims: (1) to determine the association between host and pathogen biomarkers and clinical outcomes, including need for hospitalization, in children with CAP; and (2) to develop and internally validate a clinical prediction rule for need for hospitalization of children with CAP. To achieve these aims, the candidate, Todd Florin, MD, MSCE, will leverage an existing study infrastructure developed in conjunction with his mentors during his KL2 award and that has been enrolling children with CAP since July 2013. The robust infrastructure, the primary data source for this K23, includes an active enrollment mechanism in the Cincinnati Children's Hospital Medical Center (CCHMC) ED and the development of a biorepository of specimens from children with CAP. As a pediatric emergency medicine physician, Dr. Florin is uniquely positioned to accomplish the proposed K23 research and training aims. Dr. Florin's long-term goal is to become an expert in clinical and translational research methods to improve the diagnosis and outcomes of pediatric CAP and other common, serious pediatric infections in the acute care setting. In order to expand his research training to include advanced statistical methods in predictive modeling, molecular epidemiology, biomarker discovery, and multicenter pediatric emergency medicine research, Dr. Florin has developed a detailed career development plan consisting of mentorship, didactic coursework, hands-on laboratory experience and completion of the proposed research. He has assembled a multidisciplinary team of experienced mentors with expertise in pediatric pneumonia, infectious diseases research, biomarker discovery, predictive modeling and multicenter emergency medicine research. Dr. Florin will meet regularly with his mentors individually, and quarterly as a full committee, to ensure completion of all research and training benchmarks. The institutional commitment to young researchers at CCHMC, one of the largest pediatric research institutions in the United States, provides an ideal collaborative training environment by providing the strong mentorship, formal instruction, statistical database support, specialized laboratories, and practical experiences necessary to develop into an independent clinical investigator. This proposal will allow Dr. Florin to make significant contributions to pediatric infectious diseases research in the ED as an independent physician-scientist and prepare him for future R01-funded projects focused on use of biomarkers to improve pneumonia diagnosis and management in children.