Biomarker Profiles for Early Diagnosis of Sepsis in Neonates

描述（由申请人提供）：脓毒症是新生儿重症监护室常见且严重的问题，特别是在极低出生体重（VLBW）婴儿中。超过20%的VLBW婴儿经历一次或多次迟发性败血症发作。不幸的是，血液培养诊断困难、耗时且缺乏敏感性。在症状出现之前拖延治疗可能会危及生命。另一方面，在非婴儿中反复使用抗生素治疗对这些婴儿有潜在的风险，因为它们会促进耐药菌的发展。一些研究小组正在对个体生物标志物进行详细的研究，这些生物标志物在脓毒症婴儿中表达改变，可能与疾病的发展有关。然而，测量血浆或血清中细胞因子、趋化因子或其他生物标志物水平的标准方法是使用酶联免疫吸附试验（ELISA）一次测量一个。显然，没有单一的分子标记，或一小群标记，能够准确地对高危人群进行分类。此外，对每个假定的生物标志物进行一次评估需要大量的时间、成本和样本量。因此，系统地识别蛋白质谱、预测临床事件风险、评估治疗反应和确定潜在机制的能力受到严重限制。最近发展的基于珠的多重免疫测定为大量蛋白质抗原的快速评估提供了一种有效的方法。基于规则的医学（RBM）已经扩展了这种方法，使用非常小的样本量（10- 20l），动态范围为fg/mL至mg/mL，执行血液蛋白的多分析物谱（MAP）。该技术非常适合于平行筛选大量标记物，以识别与迟发性败血症相关的蛋白质谱。在I期，RBM和新墨西哥大学健康科学中心（UNMHSC）提议在7天的时间内表征患有晚发性脓毒症的VLBW婴儿与正常VLBW婴儿血液中蛋白质谱的进展，并确定与晚发性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，还将评估一种获取诊断[血液]样本的新来源。在II期研究中，将对在I期研究中发现的用于VLBW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敏感性、特异性、阳性和阴性预测值，以及预测晚发型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为超低体重婴儿制定MAP分析的正常生理范围。对迟发性败血症早期婴儿以及迟发性败血症高风险婴儿的新生物标志物模式的识别，将通过缩短抗生素给药的时间过程来改善病情的管理，有助于确定治疗效果，并将为开发和评估新治疗方法提供框架。

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.