Breath Volatile Metabolites for the Diagnosis of Coccidioidomycosis

项目摘要/摘要：球孢子菌病，由高度传染性的二型真菌引起 波氏球孢子菌（Coccidioides posadasii）和球孢子菌C.传染病，造成了沉重和迅速增长的疾病负担， 美国每年新增病例。球孢子菌病的临床症状是高度可变的， 取决于暴露程度和宿主细胞介导的免疫力的稳健性-暴露的40% 个体发展为急性原发性肺球孢子菌病综合征， 社区获得性肺炎（CAP）虽然这些患者中的大多数最终解决了感染，但41-43% 平均住院6天，致残症状持续数月。一部分患者， 尤其是细胞介导的免疫力受损的个体，进展为其他更严重的球虫病 临床综合症，包括传播性感染，发病率和死亡率很高。虽然 球孢子菌病导致30%的CAP病例在高度流行的地区，临床表现是具有挑战性的 区分病毒或细菌CAP和可用的诊断测试有很大的局限性，导致 中位诊断延迟为23-48天，许多患者的延迟持续数月。同时， 患者寻求医疗照顾他们的症状，不必要的住院治疗，暴露于经验广泛， 广谱抗生素、实验室检查、成像和侵入性操作。改善临床的关键障碍 这些患者的结果是缺乏可靠的诊断方法， 感染的过程，并将其与其他具有类似临床表现的常见感染区分开来。 一旦球孢子菌病被诊断出来，确定患者是否对抗生素有反应也是一个挑战。 抗真菌治疗，由于症状缓解缓慢，影像学和实验室检查异常。到 为了解决这一未满足的需求，我们提出了一种新的方法来诊断球孢子菌病的基础上， 检测呼吸中的真菌挥发性代谢物。我们将检验以下假设：（a）患者 球孢子菌病具有独特的呼吸代谢物，使其与其他感染的患者区分开来， 和（B）这些代谢物的动力学预测对抗真菌治疗的反应。我们将：（1）识别呼吸 区分球孢子菌病患者与具有相似临床症状的患者的挥发性代谢物 综合征，包括CAP和其他真菌病，和（2）检查这些早期变化之间的关系， 球孢子菌病患者抗真菌治疗后呼吸代谢产物的变化及临床意义 结果。这些目标的成功完成将为直接检测的新方法奠定基础 可以耦合到床旁气体传感器系统，用于快速，床边 鉴别球孢子菌病患者，减少诊断延误，指导适当的 治疗有严重或播散性疾病风险的患者，避免不必要的抗生素使用，以及 改善这种病态的、危及生命的感染患者的临床结果。

Project Summary/Abstract: Coccidioidomycosis, caused by the highly infectious dimorphic fungi Coccidioides posadasii and C. immitis, inflicts a heavy and rapidly growing burden of disease, with 150,000 new cases annually in the United States. Clinical symptoms of coccidioidomycosis are highly variable, depending on the degree of exposure and robustness of host cell-mediated immunity – 40% of exposed individuals develop an acute primary pulmonary coccidioidomycosis syndrome indistinguishable from regular community-acquired pneumonia (CAP). While most of these patients eventually resolve their infection, 41-43% are hospitalized for a median of 6 days, with disabling symptoms lasting several months. A subset of patients, especially individuals with impaired cell-mediated immunity, progress to other, more severe coccidioidal clinical syndromes, including disseminated infection, with high rates of morbidity and death. Although coccidioidomycosis causes 30% of CAP cases in highly endemic regions, the clinical presentation is challenging to differentiate from viral or bacterial CAP and available diagnostic tests have significant limitations, leading to median diagnostic delays of 23-48 days, with many patients having delays lasting several months. Meanwhile, patients seek medical care for their symptoms, with unnecessary hospitalizations, exposure to empiric broad- spectrum antibiotics, laboratory tests, imaging, and invasive procedures. A critical barrier to improving clinical outcomes in these patients is the lack of reliable diagnostic methods that identify coccidioidomycosis early in the course of infection and distinguish it from other common infections with a similar clinical presentation. Once coccidioidomycosis is diagnosed, it is also challenging to determine whether patients are responding to antifungal therapy, due to slow resolution of symptoms and abnormal imaging and laboratory findings. To address this unmet need, we propose a novel approach to the diagnosis of coccidioidomycosis based on detection of fungal volatile metabolites in the breath. We will test the hypotheses that (a) patients with coccidioidomycosis have unique breath metabolites that differentiate them from patients with other infections, and (b) kinetics of these metabolites predict responses to antifungal therapy. We will: (1) identify breath volatile metabolites that distinguish patients with coccidioidomycosis from those with similar clinical syndromes, including CAP and other mycoses, and (2) examine the relationship between early changes in these breath metabolites in patients with coccidioidomycosis treated with antifungal therapy and their clinical outcome. Successful completion of these aims will lay the groundwork for a novel assay for the direct detection of Coccidioides metabolism that can be coupled to a point-of-care gas sensor system for the rapid, bedside identification of patients with coccidioidomycosis, reducing diagnostic delays, guiding appropriate initiation of treatment in patients at risk for severe or disseminated disease, averting unnecessary antibiotic use, and improving clinical outcomes in patients with this morbid, life-threatening infection.