Optimizing the diagnosis of pediatric Clostridium difficile infection

优化儿科艰难梭菌感染的诊断

• 批准号: 9220710
• 负责人: LARRY K KOCIOLEK
• 金额: $ 19.01万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220710
• 关键词: Academic achievement; Address; Adult; Adverse event; Antibiotic Resistance; Antibiotics; Biological Assay; Centers for Disease Control and Prevention (U.S.); Chicago; Child; Child Care; Childhood; Clinical; Clostridium difficile; Colitis; Data; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Diarrhea; Doctor of Philosophy; Enzyme Immunoassay; Epidemiology; Etiology; Expenditure; Feces; Foundations; Future; Gene Mutation; Genomic approach; Genomics; Genotype; Goals; Health Care Costs; Healthcare; Hospitalized Child; Hospitals; Incidence; Infection; Intestines; Investigation; K-Series Research Career Programs; Laboratories; Learning; Life; Measures; Mentorship; Methodology; Methods; Microbiology; Morbidity - disease rate; Nucleic Acid Amplification Tests; Pathogenesis; Patient Care; Patients; Pediatric Hospitals; Performance; Phylogenetic Analysis; Population; Prevalence; Prevention; Preventive Clinical Trial; Production; Public Health; Reference Standards; Research; Research Infrastructure; Sensitivity and Specificity; Specificity; Testing; Therapeutic; Toxin; Translational Research; Trees; Universities; Virulence Factors; Wit; base; career; comparative genomics; cost; experience; genome sequencing; genomic biomarker; genomic data; improved; medical schools; methicillin resistant Staphylococcus aureus; mortality; pathogen; patient oriented research; performance tests; predictive marker; preference; public health relevance; whole genome

 DESCRIPTION (provided by applicant): Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections (HAI). Despite rising CDI incidence in children, studies of pediatric CDI are relatively limited. Diagnosing CDI in children is very challenging, particularly because children are commonly asymptomatic carriers of C. difficile. Nucleic acid amplification tests (NAATs) are most commonly used to diagnose CDI at US children's hospitals, primarily because of adult studies suggesting suboptimal sensitivity of toxin enzyme immunoassays (EIAs). NAATs are highly sensitive and also detect C. difficile in children who are asymptomatic carriers. Thus, NAAT positivity does not necessarily indicate that C. difficile is the cause of a child's diarrhea, and CDI misdiagnosis among carriers is a common consequence of using NAATs. To overcome the limitations of both NAATs and EIAs, a recently developed ultrasensitive toxin assay is under investigation in adult patients. CDI misdiagnosis leads to unnecessary antibiotic utilization for CDI among carriers, increasing healthcare costs, antibiotic resistance, and adverse events. CDI misdiagnosis also biases investigation of pediatric CDI. Therefore, improved CDI diagnostic strategies are necessary to improve patient care for this common HAI and reduce misclassification bias in future CDI investigation in children. To address these challenges, the proposed study aims to comprehensively evaluate various laboratory methodologies to better differentiate CDI and carriage, resulting in improved CDI diagnosis in children. In addition, using whole genome sequencing (WGS), we aim to identify genomic differences between strains causing CDI and carriage that may reveal genomic targets unique to strains causing carriage or CDI that can be adapted for CDI diagnostic testing. Specifically, we aim to: (1) Define the optimal testing strategy for diagnosing CDI in children wit diarrhea; (2) Determine the relative propensity of various NAATs to identify C. difficile carriage in children without diarrhea; and (3) Using WGS, (a) Identify C. difficile genotypes isolated from children; and (b) Identify genomic biomarkers of CDI and carriage. With co-mentorship from Alan Hauser, MD, PhD and Dale Gerding, MD, Larry Kociolek, MD seeks to build upon his previous CDI translational research experience. Dr. Kociolek will learn genomic methods of C. difficile characterization and methods for applying pathogen genomic data to patient-oriented research. Dr. Kociolek's overarching career goal is to become a leader in the investigation of pediatric CDI and coordinate collaborative efforts to reduce CDI burden in children. The excellent integrated research infrastructure at the Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine will facilitate achievement of his academic goals. Future research directions include coordinating a multi-center pediatric study to validate optimal CDI diagnostic strategies and subsequently identifying both host and pathogen factors that contribute to CDI and its complications in children. These data are essential for guiding future clinical trials of preventive and therapeutic strategies for CDI in children.

 描述（由适用提供）：艰难梭菌感染（CDI）是最常见的医疗保健相关感染之一（HAI）。尽管儿童的CDI增加了，但小儿CDI的研究相对有限。诊断儿童的CDI非常挑战，特别是因为儿童通常是艰难梭菌的不对称载体。核酸扩增测试（NAAT）最常用于诊断美国儿童医院的CDI，主要是由于成人研究表明毒素酶免疫测定（EIAS）的次优敏感性。 NAAT是高度敏感的，并且在不对称载体的儿童中也检测到艰难梭菌。那就是NAAT积极性并不一定表明艰难梭菌是 儿童腹泻的原因和携带者之间的CDI诊断是使用NAAT的常见结果。为了克服NAAT和EIA的局限性，成年患者正在研究最近开发的超敏感毒素测定法。 CDI诊断导致携带者中CDI的不必要的抗生素利用，增加医疗保健成本，抗生素耐药性和不良事件。 CDI诊断还偏向小儿CDI的研究。因此，需要改进的CDI诊断策略来改善这种常见的HAI的患者护理，并减少未来CDI对儿童投资的错误分类偏见。为了应对这些挑战，拟议的研究旨在全面评估各种实验室方法，以更好地区分CDI和载体，从而改善儿童的CDI诊断。此外，使用整个基因组测序（WGS），我们旨在确定引起CDI和载体的菌株之间的基因组差异，这些菌株可能揭示了菌株独有的基因组靶标，从而导致载体或CDI可用于CDI诊断测试。具体而言，我们的目标是：（1）定义腹泻儿童诊断CDI的最佳测试策略； （2）确定各种NAAT的相对承诺，即识别出没有腹泻儿童的艰难梭菌载体； （3）使用WGS，（a）识别从儿童中分离出的艰难梭菌基因型； （b）确定CDI和载体的基因组生物标志物。在医学博士Alan Hauser和医学博士Dale Gerding的艾伦·豪瑟（Alan Hauser）的同时，马里兰州的拉里·科科莱克（Larry Kociolek）试图以他以前的CDI转化研究经验为基础。 Kociolek博士将学习艰难梭菌表征的基因组方法和将病原体基因组数据应用于患者研究的方法。 Kociolek博士的总体职业目标是成为小儿CDI投资的领导者，并协调减少儿童CDI Burnen的合作努力。 Ann＆Robert H. Lurie儿童医院和西北大学Feinberg医学院的优秀综合研究基础设施将有助于实现其学术目标。未来的研究方向包括协调一项多中心的儿科研究，旨在验证最佳的CDI诊断策略，并随后识别有助于CDI及其并发症的宿主和病原体因素。这些数据对于指导儿童CDI的预防和治疗策略的未来临床试验至关重要。