Fungal biomarkers for diagnosis and response to therapy for pediatric candidemia

描述(申请人提供)：念珠菌症是危重儿童的一种常见的致命感染。目前，商业生产的用于诊断念珠菌血症的生物标志物已被批准用于成人。这些生物标志物包括检测(1？3)-b-D-葡聚糖的Fungitell(R)试验和检测甘露聚糖抗原和抗甘露聚糖抗体的Platelia“念珠菌抗原/抗体加试验”。然而，关于儿童中这些生物标志物的数据有限。确定它们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童念珠菌血症的结果。我们的首要目标是为儿童念珠菌症开发新的循证诊断策略。这项建议的目的是使用三种真菌生物标志物来诊断念珠菌血症并监测儿科患者的治疗反应。我们将前瞻性地收集重症监护病房(ICU)中500名有新发病、非特异性感染迹象的儿童的多中心队列，并测量(1？3)-D-葡聚糖、甘露聚糖抗原和抗甘露聚糖抗体水平。我们预测，与目前的诊断策略--常规血培养相比，这些生物标志物的使用将缩短念珠菌血症的诊断时间。此外，我们将跟踪接受念珠菌血症治疗的儿科患者的生物标记物动力学，以确定变化是否与临床反应相关。这些相辅相成的目标将建立这些生物标志物的效用，无论是独立的还是组合的，作为确保快速诊断儿童念珠菌血症和监测抗真菌治疗反应的工具。这项提案将集中于两个具体目标：1)在一组有念珠菌血症高风险的儿科患者中，单独和联合定义每个生物标记物的操作特征。利用这些操作特征，我们将确定有症状的儿科ICU患者中存在或不存在儿科念珠菌血症的生物标志物的测试后概率。我们假设，当三个生物标志物中至少有两个呈阳性时，检测后念珠菌血症的概率将超过30%。当其中一项检测呈阳性或无一项呈阳性时，检测后发生念珠菌血症的概率将降至1%。2)检测念珠菌血症患儿入院后5、7、14天各生物标志物的变化情况，监测治疗反应和预后。我们假设，随着时间的推移，每个生物标记物水平下降的百分比将与部分或完全临床反应的可能性有关。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，该委员会的调查人员已经合作了十多年。为了实现这些目标，我们将利用NIAID资助的38个SITE联盟，我们已经建立了国际儿科真菌网络。这项研究的影响将是建立批准用于成人的生物标记物用于诊断儿童念珠菌血症和监测治疗反应的效用。这将产生新的以证据为基础的儿童念珠菌血症诊断策略，从而改善结果。

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.