Predictive Approaches and Technology Development for Identification of Susceptibility to Multiple Independent Infections in Trauma Patients

识别创伤患者多重独立感染易感性的预测方法和技术开发

• 批准号: 10455798
• 负责人: LAURENCE G RAHME
• 金额: $ 84.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455798
• 关键词: Adult; Aftercare; Antibiotics; Bacterial Antibiotic Resistance; Biological Assay; Blood; Blunt Trauma; Characteristics; Clinic; Clinical; Clinical Data; Clinical assessments; Companions; Data; Detection; Development; Early Diagnosis; Early treatment; Ensure; Genomics; Glues; Goals; Grant; Health Care Costs; Hospitalization; Human; Immune; Immune response; Immunity; Incidence; Individual; Infection; Infection Control; Inflammation; Injury; Injury Severity Score; Lead; Length of Stay; Leukocytes; Measures; Mechanical ventilation; Methods; Modeling; Molecular Biology; Monitor; Morbidity - disease rate; Multi-Drug Resistance; Organ; Outcome; Pathogen detection; Patient Care; Patient-Focused Outcomes; Patients; Performance; Population; Predisposition; Prevalence; Prognosis; Prognostic Marker; Prophylactic treatment; Prospective Studies; Protocols documentation; Publications; Quality of Care; RNA; Recovery; Reporting; Resistance; Resistance profile; Risk; Secondary to; Sepsis; Statistical Models; Symptoms; Technology; Testing; Therapeutic Intervention; Translating; Trauma; Trauma patient; Trauma recovery; Validation; antibiotic resistant infections; base; biomarker panel; care costs; clinical database; clinically relevant; cohort; combat; combinatorial; design; gene panel; genetic signature; genomic biomarker; high risk; improved; innovation; mortality; nano-string; novel; novel strategies; outcome prediction; pathogen; patient population; precision medicine; predictive modeling; predictive panel; prevent; prophylactic; prospective; response to injury; severe burns; severe injury; side effect; skin barrier; success; technology development; tool; transcriptome; transcriptomics; trauma care; wound

Despite significant advances in trauma care, infections remain the primary cause of morbidity and mortality in severe trauma patients primarily due to their increased risk for multiple independent infection episodes (MIIE), secondary to dysregulated immunity, compromised skin barrier, and prolonged hospitalization. Current methods to combat infections mainly focus on early diagnosis and treatment after they establish. Analyzing retrospectively, a unique, comprehensive multi-center transcriptome and clinical database of adult blunt trauma patients from the “Inflammation and the Host Response to Injury Study” (Glue Grant), we developed a first-in-class multi-biomarker panel that predicts the risk of increased susceptibility to MIIE days before infections occur. The predictive pipeline we developed is a method that is fundamentally different from existing approaches/technologies that focus on rapid pathogen or sepsis detection after establishment. Our predictive model using blood RNA gene signatures of patients with severe trauma provides a more accurate prediction of MIIE outcome compared to using only clinical assessment. This proposal's overall objectives are to test the clinical utility of our method prospectively and develop a simplified, sensitive assay that will be clinically expedient for the assessment of the infection susceptibility risk prognostic biomarkers (ISRPB) expression levels. This will meet our long-term goal of a translational precision medicine strategy aspiring to be FDA qualified. Our success in modeling retrospectively the risk of increased susceptibility to MIIE in an adult severe trauma cohort let us hypothesize that the identified gene panel of multiple ISRPB can be validated in a blunt and penetrating severe adult trauma patient population and that a model combining ISRPB genomic measures with clinical data will be an effective and easy-to-use tool for clinicians to predict which trauma patients are at increased risk for MIIE. Thus, Aim 1 is designed to conduct a prospective study to externally validate the identified ISRPB multi-gene panel in predicting increased risk for MIIE in a new adult trauma patient population; Aim 2 will identify clinical variables and differences in pathogen prevalence associated with MIIE and construct combined models for MIIE outcome prediction that include transcriptomic and clinical measures; and Aim 3 will employ cutting edge technology to develop a clinically expedient and sensitive assay to predict MIIE. The proposed strategy is expected to lead to a paradigm shift in infection control, which currently heavily depends on the routine monitoring of vital signs and clinical symptoms of overt infection. Our approach will collectively create an innovative combinatorial strategy for early MIIE prediction and provide means for infection prophylaxis that will reduce patient morbidity and mortality, shorten hospital stays, reduce care costs, improve antibiotic stewardship and limit adverse side effects in patients associated with antibiotic use. Our approach could also be applied to other conditions that render patients vulnerable to infections.

尽管创伤护理取得了重大进展，但感染仍然是发病的主要原因， 严重创伤患者的死亡率主要是由于其多重独立感染的风险增加 MIE发作，继发于免疫失调，皮肤屏障受损和住院时间延长。 目前防治感染的方法主要集中在感染后的早期诊断和治疗。 回顾性分析，一个独特的，全面的多中心转录组和成人临床数据库 钝伤患者从“炎症和宿主对损伤的反应研究”（胶格兰特），我们开发了 一个一流的多生物标志物面板，预测前几天MIE易感性增加的风险 发生感染。我们开发的预测管道是一种从根本上不同于 现有的方法/技术集中在建立后的快速病原体或脓毒症检测。我们 使用严重创伤患者血液RNA基因特征的预测模型提供了更准确的 与仅使用临床评估相比，MIIE结果的预测。 该提案的总体目标是前瞻性地测试我们方法的临床实用性， 一种简化的、灵敏的检测方法，将在临床上方便地评估感染易感性 风险预后生物标志物（ISRPB）表达水平。这将实现我们的长期目标， 精准医疗战略渴望获得FDA资格。 我们成功地回顾性地模拟了成年重度MIE患者对MIE易感性增加的风险， 创伤队列让我们假设，多个ISRPB的鉴定基因组可以在钝性 和穿透性严重成人创伤患者群体，并且结合ISRPB基因组测量的模型 将是一个有效的和易于使用的工具，为临床医生预测创伤患者在 MIE的风险增加。因此，目标1旨在进行前瞻性研究，以外部验证 鉴定的ISRPB多基因组在预测新的成人创伤患者群体中MIE风险增加中的作用; 目的2将确定与MIE相关的病原体患病率的临床变量和差异， 用于MIIE结局预测的组合模型，包括转录组学和临床指标; Aim 3将 采用最先进的技术开发一种临床上方便和敏感的检测方法来预测MIE。 拟议的战略预计将导致感染控制的模式转变，目前严重的 取决于对生命体征和明显感染的临床症状的常规监测。我们的方法将 共同创造了一种创新的组合策略，用于早期MIE预测，并为感染提供了手段。 预防将降低患者发病率和死亡率，缩短住院时间，降低护理成本，改善 抗生素管理并限制患者与抗生素使用相关的不良副作用。我们的方法 也可以应用于使患者容易感染的其他情况。

项目成果

A PREVENTIVE TOOL FOR PREDICTING BLOODSTREAM INFECTIONS IN CHILDREN WITH BURNS.

预测烧伤儿童血流感染的预防工具。

• DOI: 10.1097/shk.0000000000002075
• 发表时间: 2023
• 期刊: Shock (Augusta, Ga.)
• 作者: Tsurumi,Amy;Flaherty,PatrickJ;Que,Yok-Ai;Ryan,ColleenM;Banerjee,Ankita;Chakraborty,Arijit;Almpani,Marianna;Shankar,Malavika;Goverman,Jeremy;Schulz3rd,JohnT;Sheridan,RobertL;Friedstat,Jonathan;Hickey,SeanA;Tompkins,RonaldG
• 通讯作者: Tompkins,RonaldG