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.

侵入性曲霉病（IA）是免疫功能低下患者发病和死亡的主要原因，超过30例 每年在全球范围内发展有IA和至少有200,000个IA案件的百万个人。尽管有 发育有效的三唑抗真菌药物用于治疗IA，与IA相关的死亡率仍然为22-40％。 及时，准确地诊断IA，结合迅速开始适当的抗真菌治疗 改善患者的预后，但由于现有诊断的缺点而具有挑战性。由于 IA诊断的局限性以及不立即治疗IA的潜在严重临床后果，临床医生 通常向怀疑IA的患者开出经验性抗真菌治疗，暴露许多最终的患者 没有IA具有不必要的抗真菌药物，其毒性和成本。照顾的主要需求 免疫功能低下的患者是一种诊断，可以快速，准确地识别IA，而无需侵入性 程序。为了满足这种未满足的需求，我们提出了一种新型微流体气体的进一步发展 色谱分化的迁移率光谱法（GC-DMS）呼吸分析设备，用于快速， 基于科学前提，IA患者具有独特的曲霉，对IA的无创诊断 在呼吸中，挥发性倍半萜二级代谢物签名。我们已经在 概念证明的研究和随后的验证研究对可疑侵入性真菌疾病的患者进行了验证研究。 结合了我们在工程，诊断产品开发和呼吸分析方面的专业知识，我们已经开发了 一个集成的，功能齐全的GC-DMS微分析仪原型用于快速床边呼吸分析， 成功地检测使用该设备的IA患者中的倍半萜烯代谢产物。目标 这个快速的SBIR提案是GC-DMS微分析仪呼吸的进一步优化和开发 快速诊断IA的分析平台。第一阶段的目的是优化 微分析仪设备中的倍苯二酚代谢物，降低了这些分析物的检测极限 评估一组可疑侵入性真菌疾病的患者的敏感性。在第二阶段，目的是：（1） 完整的微分析仪在设计控制下的IA诊断设备开发，并纳入一般和 特殊控制措施，（2）自动化的GC-DMS峰峰算法 识别IA呼吸签名，（3）为此进行全面的分析验证研究 GC-DMS微分析仪的呼气测试。成功完成这些目标后，微分析仪 IA的呼气测试将在FDA 510（k）清除的多中心临床验证研究中进行评估 和CE Mark认证。这种诊断设备将改变对免疫功能低下的患者的护理 IA的风险，减少诊断延迟，促进早期，适当的抗真菌治疗以及改善 这些患者的临床结果。