Determinants of long-term outcomes and heterogeneity in Gram-negative community-acquired pneumonia

革兰氏阴性社区获得性肺炎长期结局和异质性的决定因素

• 批准号: 10676010
• 负责人: Taylor David Coston
• 金额: $ 8.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676010
• 关键词: Acute Disease; Admission activity; Area; Automobile Driving; Award; Biological; Biological Markers; Burkholderia pseudomallei; COVID-19 pandemic; Categories; Cessation of life; Clinical; Cluster Analysis; Country; Critical Care; Data; Data Set; Development; Enrollment; Environment; Epidemiologic Methods; Ethics; Etiology; Faculty; Funding; Future; Genetic Variation; Goals; Gram-Negative Bacteria; Health; Heterogeneity; Hospital Mortality; Hospitalization; Hospitals; IL8 gene; Immune response; Infection; Inflammation; Inflammatory; Integration Host Factors; Interleukin-6; K-Series Research Career Programs; Laboratories; Longitudinal cohort; Lower Respiratory Tract Infection; Lung; Mechanical ventilation; Mediating; Medicine; Mentorship; Outcome; Patient Admission; Patients; Physicians; Plasma; Pneumonia; Predisposition; Prevention; Prospective cohort; Recovery; Research; Research Personnel; Research Project Summaries; Research Training; Risk; Risk Factors; Sampling; Scientist; Severities; Severity of illness; Shock; Subgroup; Survivors; TNF gene; Techniques; Testing; Thailand; Therapeutic; Training; Universities; Washington; Work; acute infection; adverse outcome; biological heterogeneity; burden of illness; career; clinical heterogeneity; clinical translation; community acquired pneumonia; community burden; comorbidity; cytokine; follow-up; global health; hospital readmission; improved; individualized medicine; insight; longitudinal analysis; low and middle-income countries; lung health; mortality; novel; pathogen; readmission rates; skills; targeted treatment; translational physician

PROJECT SUMMARY Research: Lower respiratory infections such as community-acquired pneumonia (CAP) are the leading cause of infection-related deaths worldwide. Emerging evidence suggests that adverse long-term health outcomes are more common in CAP survivors compared with patients hospitalized for other reasons, challenging the concept of CAP as solely an acute disease. The mechanisms underlying adverse long-term CAP sequelae are unknown, although dysregulation of the host immune response during acute infection has been postulated to be a contributing factor. Moreover, the clinical and biological heterogeneity of CAP serves as a major barrier to identification of individualized and targeted therapies, which may impede prevention of adverse long-term outcomes. In Thailand, the burden of CAP is high and in the northeastern region of the country the Gram- negative bacterium Burkholderia pseudomallei is the most common and deadly etiology. Studying CAP due to this single pathogen (Bp-CAP) may help to disentangle CAP heterogeneity and host-mediated determinants of long-term outcomes. Utilizing a uniquely large multicenter prospective cohort of patients hospitalized with Bp- CAP in Northeast Thailand, Dr. Coston will address the following Aims: (1) Determine if admission CAP severity is associated with adverse outcomes after discharge; (2) Identify pro-inflammatory cytokines associated with adverse outcomes after discharge; (3) Identify novel subgroups of Bp-CAP by applying clustering strategies to routinely collected clinical and laboratory data. The proposed work will yield insight into determinants of long-term outcomes and heterogeneity in Bp-CAP, which could facilitate identification of modifiable factors and host-focused tailored therapeutics in the future. Such findings may be generalizable to other CAP etiologies and are an important area of future study. Candidate/Environment: The candidate, Dr. Coston, is a promising junior investigator who is beginning his career as a clinical-translational physician-scientist focused on the global threats pneumonia and severe infections. He has assembled a team of accomplished faculty to provide him with mentorship and training throughout the award. He will avail of the University of Washington’s rich academic environment, pulmonary and global health expertise, and track record of training successful physician-scientists in pulmonary and critical care medicine. Through the proposed research, he will develop fundamental skills for analysis of longitudinal cohort data, cluster analysis, study of biomarkers in the host response to infection, and ethical conduct of research in global settings. The research and training proposed in this project will further Dr. Coston’s development as a physician-scientist and will prepare him to compete successfully for a K23 career development award.

项目概要 研究：社区获得性肺炎（CAP）等下呼吸道感染是主要原因 世界范围内与感染相关的死亡人数不断增加，这表明长期健康结果不佳。 与因其他原因住院的患者相比，CAP 幸存者中更常见，这对 CAP 的概念仅是一种急性疾病，其长期不良后遗症的机制是： 未知，尽管急性感染期间宿主免疫反应的失调被认为是 此外，CAP 的临床和生物学异质性是一个主要障碍。 确定个体化和靶向治疗，这可能会妨碍预防长期不良反应 在泰国，CAP 的负担很重，在该国的东北部地区，Gram- 阴性菌鼻疽伯克霍尔德氏菌是研究 CAP 的最常见和致命的病原菌。 这种单一病原体 (Bp-CAP) 可能有助于解开 CAP 异质性和宿主介导的决定因素 利用独特的大型多中心前瞻性住院 Bp- 患者队列。 在泰国东北部的 CAP，Coston 博士将解决以下目标： (1) 确定是否录取 CAP 严重程度与出院后的不良后果相关；(2) 识别促炎细胞因子 (3) 通过应用识别 Bp-CAP 的新亚组 拟议的工作将深入了解常规收集的临床和实验室数据。 Bp-CAP 中长期结果和异质性的决定因素，这有助于识别 未来可改变的因素和以宿主为中心的定制疗法可能会推广到。 其他 CAP 病因也是未来研究的重要领域。 候选人/环境：候选人，科斯顿博士，是一位有前途的初级研究员，正在开始他的研究。 作为一名临床转化医师科学家，专注于全球威胁肺炎和重症 他组建了一支经验丰富的教师团队为他提供指导和培训。 在整个获奖过程中，他将利用华盛顿大学丰富的学术环境。 和全球卫生专业知识，以及在肺和疾病领域培训成功的医师科学家的记录 通过拟议的研究，他将培养分析重症监护医学的基本技能。 队列数据、聚类分析、宿主对感染反应的生物标志物研究以及纵向伦理学 该项目中提出的研究和培训将进一步促进博士在全球范围内的研究。 科斯顿作为一名医师科学家的发展将为他成功竞争 K23 职业生涯做好准备 发展奖。