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.

项目总结 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。新出现的证据表明，不利的长期健康后果 与其他原因住院的患者相比，CAP幸存者更常见，这对 CAP的概念仅仅是一种急性疾病。CAP不良长期后遗症背后的机制是 未知，尽管在急性感染期间宿主免疫反应的失调被认为是 成为一个促成因素。此外，CAP的临床和生物学异质性是导致 确定个体化和针对性治疗，这可能会阻碍长期不良反应的预防 结果。在泰国，履约协助方案的负担很重，在该国东北部地区，革兰氏 假性伯克霍尔德氏阴性杆菌是最常见、最致命的病原菌。学习CAP是因为 这种单一的病原体(BP-CAP)可能有助于解开CAP的异质性和宿主介导的决定因素 长期结果。利用一个独特的大型多中心预期BP住院患者队列- 在泰国东北部的CAP，科斯顿博士将解决以下目标：(1)确定入院CAP 严重程度与出院后的不良结局有关；(2)确定促炎细胞因子 与出院后不良结局相关；(3)通过应用 定期收集临床和实验室数据的群集化策略。拟议的工作将深入了解 BP-CAP的长期结局和异质性的决定因素，有助于识别 可修改的因素和未来以宿主为重点的量身定制疗法。这样的发现可能可以推广到 其他CAP病因，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名有前途的初级研究员，他正在开始他的 作为临床-翻译医生-科学家的职业生涯，专注于肺炎和严重肺炎的全球威胁 感染。他组建了一支有成就的教职员工团队，为他提供指导和培训 在整个奖项中。他将利用华盛顿大学丰富的学术环境，肺 和全球卫生专业知识，以及在肺和肺疾病方面培训成功的内科科学家的记录 重症监护医学。通过拟议的研究，他将发展分析的基本技能 纵向队列数据、聚类分析、宿主对感染反应的生物标记物的研究，以及伦理 在全球环境下进行研究。该项目中提出的研究和培训将进一步促进Dr。 科斯顿作为内科科学家的发展，并将为他成功竞争K23职业生涯做好准备 发展奖。