Rapid Test to Assist Therapy in Neonatal Sepsis and Necrotizing Enterocolitis

这项拟议研究的主要目标是开发一种快速的即时检测方法， 基于Inter-alpha抑制剂的婴儿中新生儿败血症（NS）和/或坏死性小肠结肠炎（NEC）的风险 血液中的蛋白质（IAIP）水平预计该测试将简单、用户友好、便携，并适用于 NICU。NS和NEC与高死亡率和发病率相关，包括不良神经毒性。 发展成果。此外，这两种情况都与全身炎症反应有关 它们的初始临床表现相似，非特异性和微妙，导致更大的可能性， 误诊重要的是，临床医生要辨别哪些患者有进展为NEC或NS的风险， 这两种疾病的临床恶化都可能以爆发性的方式进展，导致休克和死亡 几个小时的临床表现目前没有敏感和特异性的测试用于早期检测NS， NEC。IAIP在血浆中以相对高的浓度存在，并作为先天免疫发挥重要作用 调节宿主对病理损伤的炎症反应的蛋白质。在急性全身性炎症期间 在严重感染、创伤和损伤后，这些蛋白质迅速耗尽，导致 血浆水平我们以前报道，IAIP水平显着下降，在成人败血症和婴儿 NS和NEC。在我们最近完成的研究中，我们证实IAIP水平是一个敏感和特异性的指标， 作为NS和NEC的预测标志物，更值得注意的是，IAIP试验具有极好的高阴性预测 NS（98%）和NEC（100%）中的值，表明该测试可能有助于影响判断 当常规检测无法提供信息时，是否停止抗菌治疗。 此外，我们的研究结果表明，这是可行的，以发展一个定量的横向流为基础的测试， 能够在15分钟内测量IAIP，这与我们6小时实验室获得的结果相当 竞争ELISA法（R2>0.8）。在本建议中，我们将扩展这些研究，以提高快速测定 通过设计验证，设计并进一步优化原型测试，以实现完全开发的产品， 使用从多个临床试验中疑似NS和NEC的婴儿中收集的临床样本进行设计验证 网站.快速通道SBIR项目的具体目标是：1）可行性研究，以转换竞争快速 侧向流测定到更稳健和改进的“夹心”快速IAIP测定形式; 2）设计验证 侧流IAIP快速测试的研究; 2）IAIP快速测试条与读取器系统的集成;以及4） IAIP快速测试性能的交叉验证研究及其预测价值的确认研究 使用收集的临床样本。这些研究旨在获得一个强大的和充分发展的原型 该测试已准备就绪，可用于FDA监管批准所需的未来研究。这样做的影响 该项目是巨大的，因为快速检测将有助于降低与糖尿病相关的高发病率和死亡率。 NS和NEC的毁灭性疾病以及支持婴儿的抗生素管理。

The primary goal of this proposed research is to develop a rapid point-of-care test that assesses the risk of neonatal sepsis (NS) and/or necrotizing enterocolitis (NEC) in infants based on Inter-alpha inhibitor proteins (IAIP) levels in blood. The test is expected to be simple, user-friendly, portable and suitable for use in the NICU. NS and NEC are associated with high mortality and morbidity, including adverse neuro- developmental outcomes. Furthermore, both conditions are associated with systemic inflammatory responses and their initial clinical presentations are similar, non-specific and subtle leading to a greater likelihood for misdiagnosis. It is important for clinicians to discern which patients are at risk for progressing to NEC or NS as clinical deterioration in both diseases can progress in a fulminant manner resulting in shock and death within hours of clinical presentation. There is currently no sensitive and specific test for early detection of NS and NEC. IAIP are found in plasma at a relatively high concentration and play an important role as innate immunity proteins to modulate host inflammatory response to pathological insults. During acute systemic inflammation following severe infection, trauma and injury, these proteins are rapidly depleted leading to a rapid decrease in plasma levels. We previously reported that IAIP levels are significantly decreased in adult sepsis and in infants with NS and NEC. In our recently completed studies, we confirmed that IAIP level is a sensitive and specific predictive marker for NS and NEC and more remarkably, the IAIP test has excellent high negative predictive value in both NS (98%) and NEC (100%) indicating that this test is potentially useful to influence the judgment on whether or not to discontinue antimicrobial treatment when the conventional tests are uninformative. Furthermore, our results demonstrated that it is feasible to develop a quantitative lateral flow-based test that is capable of measuring IAIP within 15 min. which is comparable to the results obtained by our 6 hr. laboratory based competitive ELISA (R2>0.8). In this proposal, we will extend these studies to improve the rapid assay design and further optimize the prototype test toward a fully developed product through design verification and design validation using clinical samples collected from infants suspected with NS and NEC at multiple clinical sites. The specific aims of the Fast track SBIR project are: 1) Feasibility study to convert the competitive rapid lateral flow assay to a more robust and improved “sandwich” rapid IAIP assay format; 2) Design verification study of the lateral flow IAIP rapid test; 2) Integration of the IAIP rapid test strip with the reader system and 4) Cross verification studies of the IAIP rapid test performance and confirmation studies of its predictive value using collected clinical samples. These studies are designed to obtain a robust and fully developed prototype test that is ready to enable future studies required for regulatory approval by the FDA. The impact of this project is immense as the rapid test will help reduce the high morbidity and mortality associated with the devastating diseases of NS and NEC as well as support antibiotic stewardship in infants.