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护理点测试，以评估 婴儿新生儿败血症(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。该测试预计将是简单的，用户友好的，便携式的，适合用于 新生儿重症监护室。NS和NEC与高死亡率和发病率有关，包括不良神经功能障碍。 发展成果。此外，这两种情况都与全身炎症反应有关。 他们最初的临床表现相似，非特异性和微妙的，导致更大的可能性 误诊。对于临床医生来说，辨别哪些患者有发展为NEC或NS AS的风险是很重要的 这两种疾病的临床恶化都会以暴发性的方式发展，导致休克和死亡 几个小时的临床报告。目前还没有敏感和特异的检测方法来早期检测NS和 NEC。IAIP在血浆中浓度相对较高，在先天免疫中发挥重要作用 调节宿主对病理性侮辱的炎症反应的蛋白质。在急性全身炎症期间 在严重感染、创伤和损伤后，这些蛋白质迅速耗尽，导致体内 血浆水平。我们先前曾报道成人败血症和婴儿的IAIP水平显著降低。 使用NS和NEC。在我们最近完成的研究中，我们证实IAIP水平是一种敏感和特异的 对NS和NEC的预测标志，更值得注意的是，IAIP测试具有极好的高负性预测 NS值(98%)和NEC值(100%)都表明这项测试对影响判断是潜在有用的 在常规检测不能提供信息的情况下，是否停止抗菌治疗。 此外，我们的结果表明，开发一种基于横向流动的定量测试是可行的 能够在15分钟内测量IAIP。这与我们6小时所获得的结果是相当的。化验室 基于竞争性酶联免疫吸附试验(R2&gt；0.8)。在这项建议中，我们将扩展这些研究以改进快速检测 通过设计验证和设计验证，针对完全开发的产品设计并进一步优化原型测试 在多个临床上收集疑似NS和NEC的婴儿的临床样本的设计验证 网站。快速通道SBIR项目的具体目标是：1)可行性研究，将竞争激烈的 横向流动分析到更强健和改进的“三明治”快速IAIP分析形式；2)设计验证 横向流动IAIP快速检测的研究：2)IAIP快速检测试纸与读数系统的集成；4) IAIP快速检测性能的交叉验证研究及其预测价值的验证研究 使用收集的临床样本。这些研究的目的是获得一个健壮和完全开发的原型 准备好进行需要FDA监管批准的未来研究的测试。这件事的影响 该项目是巨大的，因为快速检测将有助于降低与 对NS和NEC的破坏性疾病以及支持对婴儿的抗生素管理。

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.