Novel diagnostic and stratification tools for septic shock

感染性休克的新型诊断和分层工具

• 批准号: 8695557
• 负责人: HECTOR R. WONG
• 金额: $ 50.36万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695557
• 关键词: Accident and Emergency department; Address; Adrenal Cortex Hormones; Adult; Bacterial Infections; Biological Markers; Blood; Cessation of life; Child; Child health care; Childhood; Clinical; Clinical Assessment Tool; Clinical Data; Clinical Management; Clinical Research; Clinical Trials; Complex; Conduct Clinical Trials; Critical Care; Critical Illness; Critically ill children; DNA; Data; Databases; Decision Making; Development; Diagnosis; Diagnostic; Enrollment; Evolution; Failure; Fever; Flow Cytometry; Foundations; Funding; Gene Expression; Genes; Genome; Glucocorticoid Receptor; Glucocorticoids; Goals; Hospitals; Immune response; Individual; Inflammation; Intensive Care Units; Interleukins; Investigational Therapies; Laboratories; Link; Measurement; Measures; Medicine; Messenger RNA; Methods; Metric; Mining; Modeling; Organ failure; Outcome; Patients; Phase; Population; Predictive Value; Proteins; Protocols documentation; Public Health; RNA; Receptor Signaling; Recruitment Activity; Repression; Research; Risk; Role; Sampling; Sepsis Syndrome; Septic Shock; Serum; Serum Proteins; Severity of illness; Signal Pathway; Signaling Pathway Gene; Specificity; Statistical Models; Sterility; Stratification; Testing; Time; Translational Research; United States; United States National Institutes of Health; Whole Blood; base; biobank; clinical phenotype; clinical practice; cohort; digital; gene repression; genome-wide; improved; innovation; insight; mRNA Expression; mortality; novel; novel diagnostics; pre-clinical; procalcitonin; programs; public health relevance; randomized trial; receptor expression; tool; transcriptomics

DESCRIPTION (provided by applicant): Septic shock continues to be a major public health problem in both adults and children. An important and unmet clinical gap in the field is the lack of robust stratification and diagnostic tools specific for septic shock. This proposal seeks to directly address this gap. We have leveraged our extensive, multi-center gene expression databank of children with septic shock to identify gene signatures that provide a strong foundation for the development of novel stratification and diagnostic tools for clinical septic shock. The major innovation of this proposal is the ability to directly leverage transcriptomic dat as a basis for clinical advancements, an often stated, but seldom achieved goal of transcriptomics. We are proposing three independent, but highly complementary Specific Aims, all of which directly address the aforementioned, unmet clinical gap. In Specific Aim 1, we will test the hypothesis that the mRNA expression of 84 genes can enhance the accuracy of an existing, validated model to stratify more reliably the risk of death or survival in children with septic shock. We have identified 84 candidate stratification genes having predictive capacity of mortality/survival. Using a digital mRNA measurement platform, we will incorporate the mRNA expression data from these 84 genes to enhance the predictive capacity of a recently developed, serum protein biomarker-based model. The enhanced model will be derived in an existing cohort of 300 patients, and subsequently validated in a prospectively enrolled cohort of 200 patients. In Specific Aim 2, we will test the hypothesis that interleukin-27 can serve as a diagnostic biomarker for bacterial infection. We have identified IL-27 as a candidate diagnostic biomarker for bacterial infection. In a cohort of critically ill children, we have demonstrated tha IL-27 serum protein concentrations can predict bacterial infection with a specificity and positive predictive value of >90%. We will further test the ability of serum IL-27 protein concentration to serve as a diagnostic biomarker in two separate cohorts of patients recruited from the Emergency Department and the Intensive Care Unit. In Specific Aim 3, we will test the hypothesis that there exists a group of patients with septic shock characterized by decreased expression of the glucocorticoid receptor (GCR). Our gene expression data have identified a group of patients with septic shock who are characterized by widespread repression of genes corresponding to the GCR signaling pathway, and this particular group of patients has higher illness severity and mortality, compare to two other groups without repression of GCR signaling pathway genes. This suggests the existence of an identifiable group of patients with septic shock who are relatively less responsive to adjunctive glucocorticoids. If this holds true, it woul represent a major confounder for studying the role of adjunctive corticosteroids for septic shock, which is currently a major controversy in the field. We have developed a flow cytometry-based protocol to directly measure GCR expression in the blood compartment of patients with septic shock. We will systematically measure GCR expression and correlate GCR expression with clinical phenotypes. Collectively, these three Aims have the potential to substantially advance the stratification and diagnostic armamentarium for clinical septic shock.

描述（由申请人提供）：败血性休克仍然是成人和儿童的主要公共卫生问题。该领域一个重要且未满足的临床差距是缺乏针对感染性休克的可靠分层和诊断工具。该提案旨在直接解决这一差距。我们利用广泛的、多中心的感染性休克儿童基因表达数据库来识别基因特征，为临床感染性休克的新型分层和诊断工具的开发奠定了坚实的基础。该提案的主要创新是能够直接利用转录组数据作为临床进展的基础，这是转录组学经常提到但很少实现的目标。我们提出三个独立但高度互补的具体目标，所有这些目标都直接解决上述未满足的临床差距。在具体目标 1 中，我们将测试以下假设：84 个基因的 mRNA 表达可以提高现有经过验证的模型的准确性，以更可靠地对感染性休克儿童的死亡或生存风险进行分层。我们已经鉴定了 84 个具有预测死亡率/生存能力的候选分层基因。使用数字 mRNA 测量平台，我们将整合这 84 个基因的 mRNA 表达数据，以增强最近开发的基于血清蛋白生物标志物的模型的预测能力。增强模型将在现有的 300 名患者队列中得出，并随后在前瞻性招募的 200 名患者队列中进行验证。在具体目标 2 中，我们将检验白细胞介素 27 可以作为细菌感染的诊断生物标志物的假设。我们已确定 IL-27 作为细菌感染的候选诊断生物标志物。在一组危重儿童中，我们证明 IL-27 血清蛋白浓度可以预测细菌感染，其特异性和阳性预测值 >90%。我们将进一步测试血清 IL-27 蛋白浓度作为从急诊科和重症监护室招募的两个独立患者组的诊断生物标志物的能力。在具体目标 3 中，我们将检验以下假设：存在一组感染性休克患者，其特征是糖皮质激素受体 (GCR) 表达下降。我们的基因表达数据确定了一组感染性休克患者，其特征是与 GCR 信号通路相对应的基因广泛受到抑制，与其他两组未抑制 GCR 的患者相比，这组特定患者的疾病严重程度和死亡率更高信号通路基因。这表明存在一组可识别的感染性休克患者，他们对辅助糖皮质激素的反应相对较弱。如果这是真的，这将成为研究辅助皮质类固醇治疗感染性休克的作用的一个主要混杂因素，而这目前是该领域的一个主要争议。我们开发了一种基于流式细胞术的方案，可直接测量感染性休克患者血室中的 GCR 表达。我们将系统地测量 GCR 表达并将 GCR 表达与临床表型相关联。总的来说，这三个目标有可能大大推进临床感染性休克的分层和诊断装备。