Breath Volatile Metabolites for the Diagnosis of Coccidioidomycosis

呼吸挥发性代谢物用于球孢子菌病的诊断

• 批准号: 10312113
• 负责人: Sophia Koo
• 金额: $ 21.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312113
• 关键词: Academic Medical Centers; Acute; Address; Americas; Antibiotics; Antibody Response; Antifungal Therapy; Arizona; Aspergillosis; Biological Assay; Boston; Caring; Cellular Immunity; Cessation of life; Clinical; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Coupled; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Exposure to; Gas Chromatography; Gases; Goals; Health Personnel; Histoplasmosis; Hospitalization; Hospitals; Image; Immunocompromised Host; Impairment; Individual; Infection; Kinetics; Laboratories; Laboratory Finding; Life; Lung; Mass Fragmentography; Measures; Medical; Metabolism; Modeling; Monitor; Morbidity - disease rate; Mycoses; Outcome; Paracoccidioidomycosis; Patients; Primary Infection; Procedures; Resolution; Risk; Sampling; Serology; Sesquiterpenes; Symptoms; Syndrome; System; Testing; Time; Treatment outcome; United States; Viral; Visit; Woman; Work; bacterial community; base; burden of illness; clinical decision-making; clinical predictors; community acquired pneumonia; desert fever; disabling symptom; fungus; improved; in vivo; laboratory facility; learning strategy; novel; novel strategies; pathogen; patient subsets; point of care; predicting response; prognostic value; prospective; response; sensor; supervised learning; tandem mass spectrometry; treatment response

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.

项目摘要/摘要：球孢子菌病，由高度传染性的二形性真菌引起 Coccidioides posadasii 和 C. immitis 造成了沉重且迅速增长的疾病负担，导致 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， 取决于暴露程度和宿主细胞介导的免疫的稳健性——暴露的 40% 个体出现急性原发性肺球孢子菌病综合征，与普通肺球孢子菌病综合征没有区别 社区获得性肺炎 (CAP) 患者中的大多数最终治愈了感染，占 41-43%。 住院时间中位数为 6 天，残疾症状持续数月， 特别是细胞介导的免疫力受损的个体，会进展为其他更严重的球孢子菌病 临床综合征，包括播散性感染，发病率和死亡率很高。 高流行地区 30% CAP 病例由球孢子菌引起，临床表现具有挑战性 为了区分病毒或细菌 CAP，现有的诊断测试有很大的局限性，导致 诊断延迟中位数为 23-48 天，许多患者的延迟持续数月。 患者因症状而寻求医疗护理，导致不必要的住院治疗、接触经验性广泛治疗 谱抗生素、实验室测试、成像和侵入性手术是改善临床的关键障碍。 这些患者的结果是缺乏早期识别球孢子菌病的可靠诊断方法 感染过程，并将其与具有相似临床表现的其他常见感染区分开来。 一旦诊断出球孢子菌病，确定患者是否对治疗有反应也具有挑战性 由于症状消退缓慢以及影像学和实验室检查结果异常，需要进行抗真菌治疗。 为了解决这一未满足的需求，我们提出了一种基于球孢子菌病诊断的新方法 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，可将其与其他感染患者区分开来， (b) 这些代谢物的动力学预测抗真菌治疗的反应我们将：(1) 识别呼吸。 挥发性代谢物可将球孢子菌病患者与临床相似的患者区分开来 综合征，包括 CAP 和其他真菌病，以及 (2) 检查这些疾病早期变化之间的关系 球孢子菌病抗真菌治疗患者呼气代谢物及其临床 这些目标的成功完成将为直接检测的新型测定奠定基础。 球孢子菌的代谢，可以与床旁气体传感器系统耦合，以实现快速、床边 识别球孢子菌病患者，减少诊断延误，指导适当开始治疗 对有严重或播散性疾病风险的患者进行治疗，避免不必要的抗生素使用，以及 改善患有这种危及生命的病态感染的患者的临床结果。