Fungal biomarkers for diagnosis and response to therapy for pediatric candidemia

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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.