Biomarker Profiles for Early Diagnosis of Sepsis in Neonates

项目概要/摘要： 败血症是新生儿重症监护病房常见且严重的问题，特别是在极低出生体重的新生儿中 （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。延误治疗 直到症状出现才能危及生命。另一方面，在非感染性疾病中反复使用抗生素治疗， 婴儿通过促进抗药性生物体的发展而对这些婴儿具有潜在的风险。一些 研究小组正在对个体生物标志物进行详细的研究，这些生物标志物显示在 败血症婴儿，并可能与病情的发展有关。然而，标准方法 测量细胞因子、趋化因子或其它生物标志物的血浆或血清水平是一次测量一个， 时间使用酶联免疫吸附测定（ELISA）。显然，没有单一的分子标记，或小群体 的标记，将能够准确地分类个人在最高风险。此外，一次评估 每一个假定的生物标志物的成本和样品量都是相当大的。有系统地 鉴定蛋白质谱，预测临床事件的风险，评估治疗反应，并确定潜在的 因此，机制受到严重限制。微珠多重免疫分析技术的研究进展 提供了一种快速评估大量蛋白质抗原的有效方法。规则- 基于医学（RBM）已经扩展了这种方法，以执行血液蛋白质的多分析物谱（MAP 使用非常小的样品体积（10-20 μ L），动态范围为fg/mL至mg/mL。这项技术很好地 适用于平行筛选大量标记物，以鉴定与晚发型 败血症在第一阶段，RBM和新墨西哥州大学健康科学中心（UNMHSC）建议 描述极低出生体重婴儿迟发性败血症与 正常VLBW婴儿在7天的时间内，并确定与晚发型相关的生物标志物模式 败血症，这将大大提高临床诊断。此外，获得诊断的新来源 将对[血液]样本进行评价。在第二阶段，对MAP进行了前瞻性验证， 将在I期研究中进行VLBW婴儿败血症的研究。灵敏度，特异性，阳性和 每种分析物的阴性预测值，以及预测迟发性脓毒症的生物标志物的MAP 将被确定。此外，还提出了VLBW婴儿MAP分析物的正常生理范围， 根据胎龄、出生体重和出生后年龄。鉴定新 晚发性脓毒症早期婴儿的生物标志物模式，以及高风险婴儿， 发展迟发性脓毒症，将允许通过缩短时间来改善病情的管理 抗生素给药过程，帮助确定治疗有效性，并将提供 开发和评估新疗法的框架。

Project Summary/Abstract: 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.