Fungal biomarkers for diagnosis and response to therapy for pediatric candidemia

用于儿童念珠菌血症诊断和治疗反应的真菌生物标志物

• 批准号: 8760875
• 负责人: Brian T Fisher
• 金额: $ 69.16万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-07 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760875
• 关键词: Adult; Affect; Antibodies; Antifungal Therapy; Antigens; Aspergillosis; Biological Assay; Biological Markers; Blood; Candida; Candidiasis; Case Series; Cell Wall; Characteristics; Child; Childhood; Clinical; Communicable Diseases; Critical Illness; Critically ill children; Data; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early Intervention; Enrollment; Ensure; FDA approved; Foundations; Funding; Future; Goals; Guidelines; Health Care Costs; Hematology; Infection; Intensive Care Units; International; Kinetics; Left; Length of Stay; Mannans; Measures; Modeling; Molecular; Monitor; Morbidity - disease rate; Mycoses; National Institute of Allergy and Infectious Disease; Outcome; Patients; Pediatric Intensive Care Units; Pediatrics; Pharmaceutical Preparations; Positive Test Result; Probability; Publications; Relative (related person); Research; Research Personnel; Risk; Sensitivity and Specificity; Sepsis; Site; Specialist; Symptoms; Test Result; Testing; Therapeutic; Therapeutic Intervention; Time; Time Study; Transplantation; attributable mortality; candidemia; clinical decision-making; cohort; cost; design; evidence base; experience; high risk; improved; member; mortality; multidisciplinary; oncology; outcome forecast; polyglucosan; prospective; public health relevance; rapid diagnosis; response; tool

DESCRIPTION (provided by applicant): Candidemia is a frequently fatal infection in critically ill children. Commercially manufactured biomarkers specific for diagnosing candidemia are currently approved for adults. These biomarkers include the Fungitell(R) assay, which detects (1?3)-b-D-glucan, and the Platelia" Candida Antigen / Antibody Plus assays, which detect mannan antigen and anti-mannan antibody. However, there are limited data on these biomarkers in children. Defining their utility in children could result in improved outcomes of pediatric candidemia through earlier diagnosis and initiation of appropriate antifungal therapy. Our overarching goal is to develop new evidence-based diagnostic strategies for pediatric candidemia. The objective of this proposal is to use three fungal biomarkers to diagnose candidemia and monitor the therapeutic response in pediatric patients. We will prospectively assemble a multi-center cohort of 500 children in the intensive care unit (ICU) with new onset, non-specific signs of infection and measure (1?3)-??-D-glucan, mannan antigen, and anti-mannan antibody levels. We predict that the use of these biomarkers will reduce the time to candidemia diagnosis relative to the current diagnostic strategy, conventional blood culture. Additionally, we will follow biomarker kinetics in pediatric patients being treated for candidemia to determine if changes correlate with clinical response. These complimentary objectives will establish the utility of these biomarkers, independently and in combination, both as tools to ensure a rapid diagnosis of pediatric candidemia and to monitor antifungal therapy response. This proposal will focus on two specific aims: 1) Define the operating characteristics of each biomarker separately and in combination in a cohort of pediatric patients at high-risk for candidemia. Using these operating characteristics, we will then determine the post-test probabilities of the biomarkers for the presence or absence of pediatric candidemia in symptomatic pediatric ICU patients. We hypothesize that when at least two of the three biomarkers are positive, the post-test probability of candidemia will exceed 30%. When one or none of the assays are positive, the post-test probability of candidemia will be reduced to < 1%. 2) Determine the profile of each biomarker in children with candidemia at 5, 7 and 14 days from enrollment to monitor response to therapy and prognosis. We hypothesize that the percent decrease in each biomarker level over time will be associated with the likelihood of a partial or complete clinical response. This multi-center study will benefit from the oversight of a highly experienced steering committee with investigators that have collaborated for over a decade. To accomplish these aims, we will leverage the NIAID- funded 38 site consortium we have established, known as the International Pediatric Fungal Network. The impact of this research will be to establish the utility of biomarkers, approved for adults, for diagnosing candidemia in children and monitoring response to therapy. This will generate new evidence-based pediatric diagnostic strategies for candidemia, leading to improved outcomes.

描述（由申请人提供）：败血症是危重儿童中常见的致死性感染。目前已批准用于诊断念珠菌血症的商业化生物标志物用于成人。这些生物标志物包括Fungitell（R）检测，它检测（1？3）-b-D-葡聚糖，以及检测甘露聚糖抗原和抗甘露聚糖抗体的Platelia念珠菌抗原/抗体Plus检测试剂盒。然而，关于这些生物标志物在儿童中的数据有限。确定其在儿童中的效用可以通过早期诊断和开始适当的抗真菌治疗来改善儿科念珠菌血症的结局。我们的首要目标是为儿科念珠菌血症开发新的循证诊断策略。本提案的目的是使用三种真菌生物标志物来诊断儿科患者的念珠菌血症并监测治疗反应。我们将前瞻性地在重症监护室（ICU）聚集500名新发、非特异性感染体征的儿童，并测量（1？3）-？？-葡聚糖、甘露聚糖抗原和抗甘露聚糖抗体水平。我们预测，相对于目前的诊断策略，传统的血培养，使用这些生物标志物将减少念珠菌血症诊断的时间。此外，我们将跟踪正在接受念珠菌血症治疗的儿科患者的生物标志物动力学，以确定变化是否与临床反应相关。这些互补的目标将建立这些生物标志物的效用，独立和组合，既作为工具，以确保快速诊断儿科念珠菌血症和监测抗真菌治疗的反应。该提案将重点关注两个具体目标：1）在念珠菌血症高风险的儿科患者队列中单独和组合定义每种生物标志物的操作特征。使用这些操作特征，我们将确定有症状的儿科ICU患者中是否存在儿科念珠菌血症的生物标志物的后检验概率。我们假设，当三种生物标志物中至少有两种呈阳性时，念珠菌血症的检测后概率将超过30%。当一个或没有检测结果为阳性时，念珠菌血症的检测后概率将降低至<1%。2)在入组后第5、7和14天确定念珠菌血症儿童中每种生物标志物的特征，以监测对治疗的反应和预后。我们假设每种生物标志物水平随时间的百分比降低将与部分或完全临床应答的可能性相关。这项多中心研究将受益于一个经验丰富的指导委员会的监督，该委员会的研究人员已经合作了十多年。为了实现这些目标，我们将利用我们建立的由NIAID资助的38个地点的联盟，即国际儿科真菌网络。这项研究的影响将是建立生物标志物的效用，批准用于成人，用于诊断儿童念珠菌血症和监测对治疗的反应。这将为念珠菌血症产生新的循证儿科诊断策略，从而改善预后。