A Rapid Breath Test for Invasive Aspergillosis

侵袭性曲霉病的快速呼吸测试

• 批准号: 9982769
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982769
• 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; Detection; 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; 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，超过30 每年有100万人面临感染IA的风险，全球每年至少有20万人出现IA病例。尽管 开发有效的三唑类抗真菌药物治疗IA，IA相关死亡率仍为22-40%。 及时和准确地诊断IA，同时迅速开始适当的抗真菌治疗， 改善了患者的预后，但由于现有诊断方法的缺陷，这是具有挑战性的。由于 IA诊断的局限性以及不及时治疗IA的潜在严重临床后果，临床医生 对疑似IA的患者常规开出经验性抗真菌治疗，暴露了许多最终 不要对不必要的抗真菌药物进行IA，因为它们的毒性和成本。未得到满足的主要需求 免疫低下患者是一种诊断方法，可以快速准确地识别IA，而不需要侵入性 程序。为了解决这一未得到满足的需求，我们建议进一步开发一种新型微流控气体 气相色谱-差示迁移率光谱仪(GC-DMS)呼气分析装置用于快速、 IA的非侵入性诊断，基于IA患者有独特的曲霉菌这一科学前提 他们呼吸中挥发性倍半萜次级代谢物的特征。我们已经在一个 疑似侵袭性真菌病患者的初步概念验证研究和后续验证研究。 结合我们在工程、诊断产品开发和呼气分析方面的专业知识，我们开发了 一个集成的，全功能的GC-DMS微型分析仪原型，用于床边快速呼吸分析， 使用该装置成功检测了IA患者体内的这些呼吸倍半萜代谢物。的目标是 这一快速跟踪SBIR方案是对GC-DMS微型呼气分析仪的进一步优化和发展 用于IA快速诊断的分析平台。第一阶段的目标是优化预浓缩 倍半萜代谢物在微分析仪设备中，降低了对这些分析物的检测限和 在一组疑似侵袭性真菌病的患者中评估其敏感性。在第二阶段，目标是：(1) 在设计控制下为IA开发完整的微量分析仪诊断设备，包括通用和 特殊控制措施，(2)开发和验证GC-DMS自动寻峰算法 识别IA呼气信号，以及(3)对此进行全面的分析验证研究 用于IA的GC-DMS微型分析仪呼气试验。在成功完成这些目标后，微量分析仪 IA呼气测试将在FDA 510(K)许可的多中心临床验证研究中进行评估 和CE标志认证。这一诊断设备将改变免疫功能低下患者的护理 IA的风险，减少诊断延迟，促进早期、适当的抗真菌治疗，并改善 这些患者的临床结果。