Breath Volatile Metabolites for the Diagnosis of Coccidioidomycosis

项目摘要/摘要：由高度传染性的二相性真菌引起的球孢子菌病 Posadasii球虫和Coccidioids immitis造成了沉重和迅速增长的疾病负担，有150,000 美国每年都有新病例。球孢子菌病的临床症状变化很大， 取决于暴露的程度和宿主细胞介导的免疫的稳健性-40%的暴露 个人发展为急性原发肺球菌病综合征，与普通人难以区分 社区获得性肺炎(CAP)。虽然这些患者中的大多数最终治愈了感染，但41%-43% 住院天数中位数为6天，致残症状持续数月。一小部分患者， 尤其是细胞免疫受损的人，进展为其他更严重的球虫 临床症状，包括播散性感染，发病率和死亡率高。虽然 在CAP高发地区，30%的CAP病例由球孢子菌病引起，临床表现具有挑战性。 要与病毒或细菌CAP区分开来，现有的诊断测试有很大的局限性，导致 诊断延误的中位数为23-48天，许多患者的延误持续数月。同时， 患者为他们的症状寻求医疗护理，有不必要的住院，暴露在经验性的广泛的- 光谱抗生素、实验室测试、成像和侵入性程序。提高临床水平的关键障碍 这些患者的结果是缺乏可靠的诊断方法来早期识别球孢子菌病。 了解感染的过程，并与其他临床表现相似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 抗真菌治疗，由于症状缓解缓慢，影像和实验室检查异常。至 针对这一未得到满足的需求，我们提出了一种新的方法来诊断球孢子菌病，基于 检测呼吸中真菌挥发性代谢物。我们将检验以下假设：(A)患者患有 球孢子菌病有独特的呼吸代谢物，这使他们与其他感染的患者区分开来， 以及(B)这些代谢物的动力学可预测对抗真菌治疗的反应。我们将：(1)识别呼吸 球孢子菌病患者与临床相似患者的挥发性代谢物 综合征，包括CAP和其他霉菌病，以及(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其临床意义 结果。这些目标的成功实现将为建立一种新的直接检测方法奠定基础 可与护理点式气体传感器系统相耦合，用于快速、床边 识别球孢子菌病患者，减少诊断延误，指导适当的启动 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.