Fungal biomarkers for diagnosis and response to therapy for pediatric candidemia

描述（由申请人提供）：念珠菌是危重儿童常见的致命感染。商业生产的专门用于诊断念珠菌病的生物标志物目前已被批准用于成人。这些生物标志物包括Fungitell(R)检测，该检测可检测(1？3)-b- d -葡聚糖，以及用于检测甘露聚糖抗原和抗甘露聚糖抗体的血小板假丝酵母抗原/抗体Plus测定。然而，这些生物标志物在儿童中的数据有限。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病的预后。我们的首要目标是为儿科念珠菌病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念珠菌病并监测儿科患者的治疗反应。我们将前瞻性地收集500名重症监护病房（ICU）儿童的多中心队列，这些儿童有新发，非特异性感染体征和措施(1?3)-?？- d -葡聚糖，甘露聚糖抗原，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到念珠菌诊断的时间。此外，我们将跟踪正在接受念珠菌治疗的儿科患者的生物标志物动力学，以确定这些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，无论是独立的还是联合的，都是确保儿科念珠菌病快速诊断和监测抗真菌治疗反应的工具。该提案将集中在两个具体目标上：1)在念珠菌病高危儿科患者队列中单独和联合定义每种生物标志物的操作特征。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的生物标志物的测试后概率。我们假设当三种生物标志物中至少有两种呈阳性时，检测后念珠菌的概率将超过30%。当一项或没有一项检测阳性时，检测后念珠菌的概率将降低到< 1%。2)在入组后5、7和14天确定念珠菌病患儿各生物标志物的特征，以监测治疗反应和预后。我们假设，随着时间的推移，每种生物标志物水平的百分比下降将与部分或完全临床反应的可能性相关。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NIAID资助的38个站点联盟，即国际儿科真菌网络。这项研究的影响将是建立被批准用于成人的生物标志物的效用，用于诊断儿童念珠菌病和监测对治疗的反应。这将产生针对念珠菌病的新的循证儿科诊断策略，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.