Optimizing the diagnosis of pediatric Clostridium difficile infection

 描述（由申请方提供）：艰难梭菌感染（CDI）是最常见的医疗保健相关感染（HAI）之一。尽管儿童CDI发病率上升，但儿科CDI的研究相对有限。诊断儿童CDI非常具有挑战性，特别是因为儿童通常是无症状的C。很难在美国儿童医院，核酸扩增试验（NAAT）最常用于诊断CDI，主要是因为成人研究表明毒素酶免疫测定（EIA）的敏感性不佳。NAAT是高度敏感的，也可以检测C。无症状携带者中的艰难梭菌。因此，NAAT阳性并不一定表明C。艰难梭菌是 儿童腹泻的原因，以及携带者中的CDI误诊是使用NAAT的常见后果。为了克服NAAT和EIA的局限性，最近开发的一种超灵敏毒素测定法正在研究中。CDI误诊导致携带者对CDI使用不必要的抗生素，增加医疗保健成本，抗生素耐药性和不良事件。CDI误诊也会使儿科CDI的研究产生偏差。因此，有必要改进CDI诊断策略，以改善这种常见HAI的患者护理，并减少未来儿童CDI调查中的错误分类偏倚。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和携带，从而改善儿童的CDI诊断。此外，使用全基因组测序（WGS），我们的目标是确定引起CDI和携带的菌株之间的基因组差异，这些差异可能揭示引起携带或CDI的菌株所特有的基因组靶标，这些靶标可适用于CDI诊断检测。具体而言，我们的目标是：（1）确定诊断腹泻儿童CDI的最佳检测策略;（2）确定各种NAAT识别C的相对倾向。无腹泻儿童中艰难梭菌携带情况;（3）使用WGS，（a）鉴定C.从儿童分离的艰难梭菌基因型;和（B）鉴定CDI和携带的基因组生物标志物。与艾伦豪瑟，医学博士，博士和戴尔格尔丁，医学博士，拉里Kociolek，医学博士共同导师寻求建立在他以前的CDI翻译研究经验。Kociolek博士将学习C.艰难的表征和应用病原体基因组数据以患者为导向的研究的方法。Kociolek博士的首要职业目标是成为儿科CDI研究的领导者，并协调合作努力，以减少儿童的CDI负担。Ann & Robert H.芝加哥卢里儿童医院和西北大学范伯格医学院将促进他的学术目标的实现。未来的研究方向包括协调多中心儿科研究，以验证最佳的CDI诊断策略，并随后确定导致儿童CDI及其并发症的宿主和病原体因素。这些数据对于指导未来儿童CDI预防和治疗策略的临床试验至关重要。

 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.