Immunological Phenotyping of Febrile and Afebrile Critically Ill Septic Patients

项目总结/摘要 博士Anne Drewry是一名重症监护医生，其长期目标是成为一名独立资助的临床试验医生， 重症监护领域，重点关注体温在脓毒症中的作用。无热性脓毒症患者 即使在考虑了潜在的混杂因素（如年龄、疾病）后， 严重性）。鉴于炎症和免疫在发热生理学中的作用，免疫功能障碍 是发烧失败和临床结果恶化之间的潜在联系。本提案的目的是 以确定发热和非发热患者之间的免疫表型是否不同。中央hypoth- 脓毒症患者如果没有发烧，将表现出更严重的脓毒症诱导的免疫抑制， 比发烧的病人。这一假设得到了候选人初步数据的支持， 无发热与单核细胞功能受损和持续性淋巴细胞减少相关， 脓毒症引起的免疫抑制它将通过进行前瞻性队列研究进行测试，其中包括： 研究的具体目的：（1）确定发热和无热脓毒症患者是否表现出生物标志物的差异 脓毒症引起的免疫抑制;（2）比较发热患者免疫抑制的临床体征 和无发热患者。入组后，严重脓毒症的危重患者将被分为发热组和 基于脓毒症24小时内是否存在体温≥ 38.0°C的无发热组 诊断.脓毒症诱导的免疫抑制将通过单核细胞HLA-DR的系列测量来评估。 表达、LPS诱导的TNF-α产生、抗CD 3/抗CD 28诱导的IFN-γ产生和绝对lym-1。 吞噬细胞计数。临床结果将包括继发感染的获得和潜伏性病毒的重新激活。 诡计这项工作意义重大，因为它是一系列研究的第一步，预计将导致 无热脓毒症患者免疫功能障碍的靶向治疗。申请人将实施本项目 在她的导师（Richard霍奇基斯博士和Marin Kollef博士）和多学科顾问团队的支持下， 具有脓毒症免疫学、临床研究设计/执行和统计学专业知识的导师。申请人，在con- 她与导师进行了磋商，并设计了一个全面的职业发展计划， 在（1）转化实验室技术，（2）适应性试验设计，（3）先进的统计学，和（4） 计划和执行多中心试验，目标是在K23奖励结束前提交R 01 期鉴于其大量的危重病人和充足的机会，研究培训和多学科， 华盛顿大学是支持这项研究项目的理想环境， 候选人的整体职业发展。

PROJECT SUMMARY/ABSTRACT Dr. Anne Drewry is an intensivist with the long-term goal of becoming an independently funded clinical trialist in the field of critical care, with a focus on the role of body temperature in sepsis. Afebrile septic patients are twice as likely to die than febrile patients, even after accounting for potentially confounding factors (e.g. age, illness severity). Given the role of inflammation and immunity in the physiology of fever generation, immune dysfunction is a potential link between failure to mount a fever and worse clinical outcomes. The objective of this proposal is to determine whether immunological phenotypes differ between febrile and afebrile patients. The central hypoth- esis is that septic patients who fail to mount a fever will demonstrate more severe sepsis-induced immune im- pairment than febrile patients. This hypothesis is supported by the candidate’s preliminary data suggesting that absence of fever is associated with impaired monocyte function and persistent lymphopenia, key mechanisms of sepsis-induced immunosuppression. It will be tested by performing a prospective cohort study with the follow- ing specific aims: (1) to determine whether febrile and afebrile septic patients exhibit differences in biomarkers of sepsis-induced immunosuppression; and (2) to compare clinical signs of immunosuppression among febrile and afebrile patients. Following enrollment, critically ill patients with severe sepsis will be divided into febrile and afebrile groups based on the presence or absence of body temperature ≥ 38.0°C within 24 hours of sepsis diagnosis. Sepsis-induced immunosuppression will be assessed via serial measurements of monocyte HLA-DR expression, LPS-induced TNF-α production, anti-CD3/anti-CD28-induced IFN-γ production, and absolute lym- phocyte counts. Clinical outcomes will include acquisition of secondary infections and reactivation of latent vi- ruses. This work is significant because it is the first step in a continuum of research that is expected to lead to targeted treatment of immune dysfunction in afebrile septic patients. The applicant will implement this project with support from of her mentors (Drs. Richard Hotchkiss and Marin Kollef) and a multidisciplinary team of advi- sors with expertise in sepsis immunology, clinical study design/execution, and statistics. The applicant, in con- sultation with her mentors, has also designed a comprehensive career development plan emphasizing training in the areas of (1) translational laboratory techniques, (2) adaptive trial design, (3) advanced statistics, and (4) planning and execution of multicenter trials, with the goal of R01 submission prior the end of the K23 award period. Given its high volume of critically ill patients and ample opportunities for research training and multidis- ciplinary collaboration, Washington University is an ideal environment to support this research project and the candidate’s overall career development.