Biomarker Profiles for Early Diagnosis of Sepsis in Neonates

新生儿败血症早期诊断的生物标志物谱

• 批准号: 7690324
• 负责人: James P Mapes
• 金额: $ 38.79万
• 依托单位: RULES-BASED MEDICINE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690324
• 关键词: Age; Algorithms; Antibiotics; Antigens; Biological Markers; Birth Weight; Blood; Blood Proteins; Blood specimen; C-reactive protein; Clinical; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Early Diagnosis; Enrollment; Ensure; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Future; Gestational Age; Glucose; Goals; Hand; Health Sciences; Heel; Hour; Immunoassay; Individual; Infant; Infant Care; Infection; Intervention; Laboratories; Life; Measures; Medicine; Methods; Modeling; Neonatal Intensive Care Units; Neonatal Screening; New Mexico; Organism; Paper; Pattern; Phase; Physiological; Plasma; Population; Population Study; Predictive Value; Proteomics; Recurrence; Research; Research Personnel; Resistance development; Risk; Sampling; Screening procedure; Sensitivity and Specificity; Sepsis; Serum; Source; Spottings; Staging; Symptoms; Technology; Testing; Therapeutic; Time; Treatment Effectiveness; Universities; Validation; Variant; Very Low Birth Weight Infant; Weight; antimicrobial drug; base; chemokine; clinical Diagnosis; cost; cytokine; experience; high risk; improved; molecular marker; neonate; novel; numb protein; outcome forecast; postnatal; prospective; protein profiling; response; septic; time use; validation studies

DESCRIPTION (provided by applicant): Sepsis is a frequent and serious problem in neonatal intensive care units, particularly in very low birth weight (VLBW) infants. Over 20% of all VLBW infants experience one or more episodes of late-onset sepsis. Unfortunately, diagnosis by blood culture is difficult, time consuming, and lacks sensitivity. Delaying treatment until symptoms arise can be life threatening. On the other hand, recurrent treatment with antibiotics in non- infants holds potential risks to these infants by furthering the development of resistant organisms. A number of research groups are performing detailed studies of individual biomarkers that have shown altered expression in septic infants and may be relevant to the development of the condition. However, the standard method for measuring plasma or serum levels of cytokines, chemokines or other biomarkers is to measure them one at a time using Enzyme-Linked Immunosorbent Assay (ELISA). Clearly, no single molecular marker, or small group of markers, will be able to accurately classify individuals at highest risk. In addition, one-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. The recent development of bead-based multiplex immunoassays provides an efficient approach for performing a rapid assessment of large numbers of protein antigens. Rules- Based Medicine (RBM) has extended this approach to perform Multi-Analyte Profiles (MAP) of blood proteins using very small sample volumes (10-20 ¿L) with a dynamic range of fg/mL to mg/mL. This technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with late-onset sepsis. During Phase I, RBM, and the University of New Mexico Health Sciences Center (UNMHSC), propose to characterize the progression of protein profiles in the blood of VLBW infants with late-onset sepsis vs. normal VLBW infants over a seven day period, and identify biomarker patterns associated with late-onset sepsis that will significantly improve clinical diagnosis. In addition, a new source for obtaining a diagnostic [blood] sample will be evaluated. During Phase II, a prospective validation of the MAP identified for late-onset sepsis in VLBW infants during Phase I efforts will be performed. The sensitivity, specificity, and positive and negative predictive values for each analyte, as well as, the MAP of biomarkers for predicting late-onset sepsis will be determined. In addition, a proposed normal physiological range of MAP analytes for VLBW infants based on gestational age, birth weight and postnatal age will be developed. The identification of novel biomarker patterns of infants in the early stages of late-onset sepsis, as well as infants at high risk for developing late-onset sepsis, will allow for improved management of the condition by shortening the time course of antibiotic administration, aiding the determination of treatment effectiveness, and will provide a framework for developing and evaluating new treatments.

描述（由申请人提供）：败血症是新生儿重症监护室常见且严重的问题，特别是极低出生体重（VLBW）婴儿。所有VLBW婴儿中超过20%经历一次或多次迟发性脓毒症发作。不幸的是，通过血培养诊断是困难的，耗时的，并且缺乏灵敏度。延迟治疗直到出现症状可能会危及生命。另一方面，在非婴儿中反复使用抗生素治疗，通过促进耐药生物体的发展，对这些婴儿具有潜在风险。一些研究小组正在对个别生物标志物进行详细研究，这些生物标志物在脓毒症婴儿中的表达发生了变化，可能与病情的发展有关。然而，用于测量细胞因子、趋化因子或其他生物标志物的血浆或血清水平的标准方法是使用酶联免疫吸附测定（ELISA）一次测量一种。显然，没有一个单一的分子标记，或一小群标记，将能够准确地分类个人在最高风险。此外，对每种推定的生物标志物进行一次一个的评估会导致相当长的时间、成本和样本量。因此，系统鉴定蛋白质谱、预测临床事件风险、评价治疗反应和确定潜在机制的能力受到严重限制。基于微珠的多重免疫测定的最新发展为进行大量蛋白质抗原的快速评估提供了有效的方法。基于规则的医学（RBM）已经扩展了这种方法，使用非常小的样品体积（10-20 μ L）进行血液蛋白的多分析物谱（MAP），动态范围为fg/mL至mg/mL。该技术非常适合于平行筛选大量标志物以鉴定与晚发型脓毒症相关的蛋白质谱。在I期期间，RBM和新墨西哥州大学健康科学中心（UNMHSC）建议在7天内表征患有晚发型脓毒症的VLBW婴儿与正常VLBW婴儿血液中蛋白质谱的进展，并鉴定与晚发型脓毒症相关的生物标志物模式，这将显著改善临床诊断。此外，还将评价获得诊断[血液]样本的新来源。在II期研究中，将对在I期研究中发现的极低出生体重婴儿迟发性脓毒症的MAP进行前瞻性验证。将确定每种分析物的灵敏度、特异性、阳性和阴性预测值，以及用于预测迟发性脓毒症的生物标志物的MAP。此外，还将根据胎龄、出生体重和出生后年龄制定VLBW婴儿MAP分析物的拟定正常生理范围。在晚发性脓毒症早期阶段的婴儿以及发展为晚发性脓毒症的高风险婴儿中鉴定新的生物标志物模式，将允许通过缩短抗生素施用的时间过程来改善病情的管理，帮助确定治疗有效性，并将提供用于开发和评估新治疗的框架。