A Rapid Breath Test for Invasive Aspergillosis

侵袭性曲霉病的快速呼吸测试

• 批准号: 10215505
• 负责人: Donald E Pogorzelski
• 金额: $ 100万
• 依托单位: VOLATYLIX, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215505
• 关键词: Address; Antifungal Agents; Antifungal Therapy; Aspergillosis; Aspergillus; Biological Assay; Biopsy; Breath Tests; Calibration; Caring; Certification; Cessation of life; Clinical; Complex; Culture Techniques; Dangerousness; Data; Development; Device or Instrument Development; Devices; Diagnostic; Diagnostic tests; Disease; Engineering; Evaluation; Fungal Drug Resistance; Gas Chromatography; Goals; Hospitals; Human; Immunocompromised Host; Individual; Infection; Lung; Mass Fragmentography; Measures; Microfluidics; Molds; Morbidity - disease rate; Mycoses; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Performance; Pharmacotherapy; Phase; Procedures; Quality Control; Reagent; Recording of previous events; Reproducibility; Respiratory System; Risk; Sampling; Sensitivity and Specificity; Sesquiterpenes; Signs and Symptoms; Small Business Innovation Research Grant; Software Validation; Specificity; Spectrometry; Spottings; System; Testing; Time; Toxic effect; Triazoles; Vendor; Woman; Yeasts; accurate diagnosis; automated algorithm; base; cost; design; detection limit; improved; meetings; mortality; mouse model; noninvasive diagnosis; novel; operation; portability; product development; prognostic value; prospective; prototype; rapid diagnosis; response; validation studies

Invasive aspergillosis (IA) is a leading cause of morbidity and death in immunocompromised patients, with over 30 million individuals at risk for IA and at least 200,000 IA cases developing worldwide each year. Despite the development of potent triazole antifungal drugs for the treatment of IA, IA-associated mortality is still 22-40%. Timely and accurate diagnosis of IA, in conjunction with prompt initiation of appropriate antifungal therapy, improves patient outcomes, but is challenging due to the shortcomings of existing diagnostics. Due to the limitations of IA diagnostics and the potentially severe clinical consequences of not treating IA promptly, clinicians routinely prescribe empiric antifungal therapy to patients with suspected IA, exposing many patients who ultimately do not have IA to unnecessary antifungal drugs, with their toxicities and costs. A major unmet need in the care of immunocompromised patients is a diagnostic that can identify IA rapidly and accurately, without requiring invasive procedures. To address this unmet need, we propose further development of a novel microfluidic gas chromatography-differential mobility spectrometry (GC-DMS) breath analysis device for the rapid, noninvasive diagnosis of IA, based on the scientific premise that patients with IA have a unique Aspergillus volatile sesquiterpene secondary metabolite signature in their breath. We have demonstrated this premise in an initial proof-of-concept study and subsequent validation study in patients with suspected invasive fungal disease. Combining our expertise in engineering, diagnostic product development, and breath analysis, we have developed an integrated, fully functioning GC-DMS Microanalyzer prototype for rapid bedside breath analysis, successfully detecting these breath sesquiterpene metabolites in patients with IA using this device. The goal of this Fast Track SBIR proposal is further optimization and development of the GC-DMS Microanalyzer breath analysis platform for the rapid diagnosis of IA. The objective of phase I is to optimize the preconcentration of sesquiterpene metabolites in the Microanalyzer device, lowering its limit of detection for these analytes and evaluating its sensitivity in a set of patients with suspected invasive fungal disease. In phase II, aims are to: (1) complete Microanalyzer diagnostic device development for IA under design control, incorporating general and special control measures, (2) develop and validate GC-DMS peak-finding algorithms for the automated identification of the IA breath signature, and (3) perform comprehensive analytical validation studies for this GC-DMS Microanalyzer breath test for IA. Upon successful completion of these objectives, the Microanalyzer breath test for IA will be ready for evaluation in a multicenter clinical validation study for FDA 510(k) clearance and CE mark certification. This diagnostic device will transform the care of immunocompromised patients at risk for IA, reducing diagnostic delays, facilitating early, appropriate antifungal treatment, and improving clinical outcomes in these patients.

侵袭性曲霉病（IA）是免疫功能低下患者发病和死亡的主要原因， 全球每年至少有200，000例IA病例。尽管 尽管开发了强效的三唑类抗真菌药物用于治疗IA，但IA相关死亡率仍为22- 40%。 及时准确诊断IA，并及时开始适当的抗真菌治疗， 改善了患者的治疗效果，但由于现有诊断方法的缺点而具有挑战性。由于 IA诊断的局限性和不及时治疗IA的潜在严重临床后果，临床医生 对疑似IA的患者常规开具经验性抗真菌治疗，暴露了许多最终 不要IA到不必要的抗真菌药物，其毒性和成本。在照顾儿童方面的一个主要未得到满足的需要 免疫功能低下的患者是一种诊断，可以快速，准确地识别IA，而不需要侵入性 程序.为了解决这一未满足的需求，我们建议进一步开发一种新的微流体气体 色谱-差示迁移率光谱（GC-DMS）呼吸分析装置， IA的非侵入性诊断，基于IA患者具有独特的曲霉菌 挥发性倍半萜次级代谢物的特征。我们已经证明了这一前提， 在疑似侵袭性真菌病患者中进行初步概念验证研究和后续验证研究。 结合我们在工程、诊断产品开发和呼吸分析方面的专业知识，我们开发了 一个集成的，功能齐全的GC-DMS微量分析仪原型，用于快速床边呼吸分析， 使用该装置成功检测IA患者的这些呼吸倍半萜代谢物。的目标 快速跟踪SBIR建议是GC-DMS微量分析仪呼吸的进一步优化和发展 分析平台，快速诊断IA。第一阶段的目标是优化 微量分析仪装置中的倍半萜代谢物，降低了这些分析物的检测限， 评估其在一组疑似侵袭性真菌病患者中的敏感性。第二阶段的目标是：（1） 在设计控制下完成IA的微量分析仪诊断设备开发， 特殊的控制措施，（2）开发和验证GC-DMS的自动寻峰算法， 识别IA呼吸特征，以及（3）对此进行全面的分析验证研究 IA的GC-DMS微量分析仪呼吸试验。成功完成这些目标后， IA的呼吸测试将准备好在FDA 510（k）批准的多中心临床验证研究中进行评价 CE标志认证。这种诊断设备将改变免疫功能低下患者的护理， 降低IA的风险，减少诊断延迟，促进早期，适当的抗真菌治疗， 这些患者的临床结果。