A comprehensive next generation sequencing diagnostic tool for lung infection among hospitalized patients

住院患者肺部感染的综合下一代测序诊断工具

• 批准号: 10547598
• 负责人: Tasha E. Fingerlin
• 金额: $ 30万
• 依托单位: PEAK DIAGNOSTIC PARTNERS LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547598
• 关键词: Acute; Admission activity; Adult; Algorithms; Antibiotics; Antimicrobial Resistance; Autoimmune Diseases; Biological Assay; Biological Products; Bronchoscopy; Chronic Disease; Clinical; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Drug Interactions; Exclusion; Future; Gene Expression; Genes; Goals; Gold; Hospitalization; Human; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunoglobulins; Immunosuppression; Infection; Infectious Agent; Inflammatory Response; Intensive Care Units; Laboratories; Lead; Lung; Lung infections; Methodology; Microbe; Microbiology; Molecular; Organism; Outcome; Pathogen detection; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Pneumonia; Population; Predisposition; Prevention; Resistance; Resistance profile; Respiratory Tract Infections; Risk; Sampling; Sensitivity and Specificity; Serum; Small Business Innovation Research Grant; Specificity; Sputum; Technology; Testing; Treatment Effectiveness; Treatment Efficacy; United States Food and Drug Administration; Viral; antimicrobial; base; cancer therapy; clinical care; clinical diagnosis; clinical practice; cohort; comparative efficacy; cost; design; diagnostic tool; diagnostic value; high risk; immune function; improved; in-vitro diagnostics; innovation; insight; metagenomic sequencing; mortality; nasopharyngeal swab; next generation sequencing; novel; novel diagnostics; opportunistic pathogen; overtreatment; pathogen; pathogenic microbe; patient population; prospective; prototype; research clinical testing; resistance gene; respiratory; respiratory pathogen; screening; standard of care; targeted sequencing; technological innovation; time use; tool

ABSTRACT A major driver of intensive care unit (ICU) hospital admissions is pneumonia. The immunocompromised patient group, which makes up 20% of ICU pneumonia admissions, is at increased risk for severe infection from common respiratory organisms as well as opportunistic pathogens that cannot be easily cultured or treated with standard empiric antibiotics. While standard practice for clinical identification of infection includes extensive culture and non-culture techniques, these tests often take many days to yield results and a definitive causative agent is identified in only 10%-40% of cases. As a result, patients often receive multiple courses of antibiotics without identification of a specific pathogen to guide therapy. The difficulty in determining the offending pathogens to guide proper treatment increases both costs and mortality for these patients; mortality is as high as 30%-50%. Current gold-standard diagnostics for infection rely on decades-old technology that can take weeks to complete, have limited sensitivity, and are limited in the type and number of microbes that can be screened by a single test. Thus, a critical gap exists due to the inability of current diagnostics to comprehensively screen and accurately detect microbial pathogens, which is a significant barrier to improved clinical outcomes for these patients. We have developed a comprehensive next generation sequencing (NGS) panel for detection and identification of microbes that also detects anti-microbial resistance (AMR) and host immune response features. Our previous studies have demonstrated the feasibility of our diagnostic tool for application to low-level respiratory infections in chronic disease and its superiority to both microbiological and molecular approaches to diagnosis. Our NGS diagnostics (Dx) panel is a significant technological innovation over current methodology; the Dx panel utilizes samples directly from the patient (rather than relying on cultures), provides greater sensitivity than qPCR or meta-genomic sequencing approaches and screens for the presence of tens of thousands of other microbes in a single assay. These features are possible due to our innovative design in addition to proprietary laboratory and analysis workflows. The long-term goal of this project is to provide a novel clinical tool for detection and characterization of infections in immunocompromised patients with infectious lung complications. In this Phase I, we will examine the feasibility of our assay for use in this acute clinical setting, evaluating for the first time the use of our AMR and host immune screening to provide supportive information for diagnosis and treatment guidance. Specifically, we will 1) estimate the rate at which our panel provides a definitive detection of one or more pathogens when clinical tests fail, 2) establish the feasibility of using our AMR profile to replace clinical culture isolate tests 3) determine the feasibility of immune profiling in this population and 4) determine whether less invasive nasopharyngeal swabs have the potential for further study in a larger cohort. The total market for this diagnostic is the set of hospitalized patients with pneumonia. Our competitive advantages include improved sensitivity, comprehensive microbe detection and treatment effectiveness insights in a single assay.

抽象的 重症监护病房 (ICU) 住院的一个主要驱动因素是肺炎。免疫功能低下的患者 占 ICU 肺炎入院人数 20% 的人群，因普通肺炎而严重感染的风险增加。 不易培养或用标准方法处理的呼吸道微生物以及机会性病原体 经验性抗生素。虽然感染临床鉴定的标准做法包括广泛培养和 由于非培养技术，这些测试通常需要很多天才能得出结果，并且确定的病原体是 仅在 10%-40% 的病例中发现。因此，患者经常接受多个疗程的抗生素治疗而无需 识别特定病原体以指导治疗。确定致病病原体的困难 指导正确的治疗会增加这些患者的费用和死亡率；死亡率高达30%-50%。 当前感染的黄金标准诊断依赖于几十年前的技术，可能需要数周时间才能完成， 灵敏度有限，并且单次可筛选的微生物类型和数量有限 测试。因此，由于当前的诊断无法全面筛查和评估，存在着严重的差距。 准确检测微生物病原体，这是改善这些疾病临床结果的重大障碍 患者。我们开发了全面的下一代测序（NGS）面板，用于检测和 鉴定微生物，同时检测抗微生物耐药性 (AMR) 和宿主免疫反应特征。 我们之前的研究已经证明了我们的诊断工具应用于低水平的可行性 慢性疾病中的呼吸道感染及其相对于微生物学和分子学方法的优越性 诊断。我们的 NGS 诊断 (Dx) 组合是对当前方法的重大技术创新； Dx 小组直接利用来自患者的样本（而不是依赖培养物），提供更高的灵敏度 比 qPCR 或宏基因组测序方法更能筛选数以万计的其他基因组的存在 一次测定中的微生物。这些功能的实现得益于我们的创新设计以及专有技术 实验室和分析工作流程。该项目的长期目标是提供一种新颖的临床工具 患有感染性肺部并发症的免疫功能低下患者的感染检测和特征分析。 在第一阶段，我们将检查我们的检测方法在这种急性临床环境中使用的可行性，评估 首次使用我们的 AMR 和宿主免疫筛查为诊断和治疗提供支持信息 治疗指导。具体来说，我们将 1) 估计我们的小组提供明确检测的速度 当临床测试失败时，检测一种或多种病原体，2) 确定使用我们的 AMR 谱来替代的可行性 临床培养分离测试 3) 确定在该人群中进行免疫分析的可行性 4) 确定 侵入性较小的鼻咽拭子是否有可能在更大的队列中进行进一步研究。总计 这种诊断的市场是一组住院的肺炎患者。我们的竞争优势包括 在一次检测中提高灵敏度、全面的微生物检测和治疗效果见解。