Biomarker Profiles for Early Diagnosis of Sepsis in Neonates

描述(由申请人提供)：败血症是新生儿重症监护病房中常见且严重的问题，尤其是极低出生体重(VLBW)婴儿。超过20%的极低出生体重儿经历一次或多次迟发性败血症。不幸的是，血培养诊断困难、耗时，而且缺乏敏感性。推迟治疗，直到出现症状可能会危及生命。另一方面，非婴儿反复使用抗生素治疗会进一步发展耐药微生物，从而对这些婴儿构成潜在风险。一些研究小组正在对单个生物标记物进行详细研究，这些标记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，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)一次一个地进行测量。显然，没有任何单一的分子标记或一小群标记能够准确地对高危个体进行分类。此外，对每个假定的生物标志物进行一次一次的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、预测临床事件的风险、评估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分析技术的最新发展为快速检测大量蛋白质抗原提供了一种有效的方法。基于规则的医学已经将这种方法扩展到使用非常小的样本量(10-20？L)来执行血液蛋白质的多分析轮廓(MAP)，动态范围为Fg/mL到mg/mL。这项技术非常适合同时筛选大量标记物，以识别与迟发性脓毒症相关的蛋白质谱。在第一阶段，RBM和新墨西哥大学健康科学中心(MINHSC)建议表征晚发性脓毒症VLBW婴儿与正常VLBW婴儿在七天时间内血液中蛋白质谱的进展，并识别与迟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。在第二阶段，将对在第一阶段努力中确定的极低出生体重儿迟发性败血症的MAP进行前瞻性验证。将确定每个分析物的敏感度、特异度、阳性和阴性预测值，以及预测迟发性脓毒症的生物标志物图。此外，还将制定基于胎龄、出生体重和出生后年龄的极低出生体重儿MAP分析的建议正常生理范围。识别迟发性败血症早期婴儿以及迟发性败血症高危婴儿的新生物标志物模式，将通过缩短抗生素给药时间，帮助确定治疗效果，从而改善对这种情况的管理，并将为开发和评估新的治疗方法提供一个框架。

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.