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.

摘要 重症监护病房（ICU）住院的主要驱动因素是肺炎。免疫功能低下的病人 占ICU肺炎入院人数20%的人群， 呼吸道微生物以及机会致病菌，这些病原体不能容易地培养或用标准 经验性抗生素虽然用于临床鉴定感染的标准实践包括广泛的培养， 非培养技术，这些测试往往需要许多天才能产生结果， 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， 鉴定特定病原体以指导治疗。确定致病病原体的困难， 指导适当的治疗会增加这些患者的成本和死亡率;死亡率高达30%-50%。 目前的感染诊断黄金标准依赖于数十年前的技术，可能需要数周才能完成， 具有有限的灵敏度，并且在可以通过单一筛选的微生物的类型和数量方面受到限制。 test.因此，由于目前的诊断无法全面筛查和诊断， 准确检测微生物病原体，这是改善这些患者临床结局的重要障碍。 患者我们已经开发了一种全面的下一代测序（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。 我们以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对微生物和分子方法的优越性， 诊断.我们的NGS诊断（Dx）面板是对当前方法的重大技术创新; Dx试剂盒直接使用患者样本（而不是依赖于培养物），提供更高的灵敏度 比qPCR或元基因组测序方法和屏幕的存在数以万计的其他 微生物在一个单一的分析。这些功能是可能的，由于我们的创新设计，除了专有的 实验室和分析工作流程。该项目的长期目标是提供一种新的临床工具， 检测和表征具有感染性肺部并发症的免疫功能低下患者的感染。 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， 首次使用我们的AMR和宿主免疫筛查，为诊断提供支持性信息， 治疗指导。具体来说，我们将1）估计我们的面板提供明确检测的速度， 当临床试验失败时，一种或多种病原体，2）建立使用我们的AMR谱来替代 临床培养分离物测试3）确定在该群体中免疫谱的可行性和4）确定 低侵入性鼻咽拭子是否有潜力在更大的队列中进行进一步研究。总 这一诊断的市场是肺炎住院患者的集合。我们的竞争优势包括 提高灵敏度，全面的微生物检测和治疗效果的见解在一个单一的测定。