Rapid detection of neonatal sepsis

描述（由申请方提供）：本拟议研究的主要目标是开发一种快速床旁（POC）检测，该检测可用于在适用于NICU环境的简单、用户友好和便携式设备中识别高危婴儿的新生儿败血症。由于败血症对新生儿构成非常严重的威胁，因此迫切需要尽快获得确认。目前，对于这种危及生命的疾病，还没有可靠的POC标记物。血培养结果被认为是细菌性败血症的金标准，但确认结果可能要到至少48小时才能得到。在这项提案中，我们将开发一种基于α间抑制蛋白（IAIP）的定量快速检测，该蛋白最近已被证明是一种有价值的生物标志物，具有高灵敏度和特异性（分别为89.5%和99%）以及高阳性和阴性预测值（分别为85%和98%）。我们假设，内源性IAIP，作为先天免疫反应的一部分，保护免受严重感染，烧伤，创伤和损伤后的急性全身性炎症过程中释放的蛋白酶的破坏作用。因此，这些蛋白质被迅速消耗并通过尿液排出，导致血浆水平迅速下降。此外，IAIP水平似乎与疾病严重程度和进展负相关，因此，可以在10- 15分钟内获得结果的快速IAIP测试将可用作新生儿败血症的诊断和/或治疗诊断标志物。该研究的拟定具体目的是：1）单独IAIP和与其他生物标志物一起检测脓毒症和全身性炎症婴儿的预测价值的验证和比较研究，以及2）IAIP定量侧流免疫测定（LFIA）的原型开发，可用于诊断新生儿脓毒症和NEC。由于血浆来源的IAIP的替代疗法已被证明在脓毒症的实验模型中有效，并且目前正在成人脓毒症患者中进行临床试验，因此我们的长期目标是研究由于疑似脓毒症或低水平的NEC引起的危重婴儿中伴随IAIP治疗的疗效。 快速检测的IAIP。通过结合血浆来源的IAIP的预测性测试和治疗性替代，这种新方法可以提供用于降低与新生儿败血症和婴儿NEC相关的发病率和死亡率的合理的靶向解决方案。此外，基于IAIP的快速检测将为减少疑似但未经证实的全身性感染婴儿的抗生素过度使用提供客观手段。当人们考虑到患有新生儿败血症和NEC的破坏性影响的婴儿的严重未满足的医疗需求时，拟议研究的潜在影响是巨大的。 公共卫生相关性：这项拟议研究的目标是开发一种快速检测，可用于检测危及生命的疾病，如全身感染（败血症和坏死性小肠结肠炎）的婴儿使用简单，用户友好和便携式设备适合在新生儿重症监护病房的床边测试。该测试是基于在疾病期间消耗的称为Inter-alpha抑制剂的血液蛋白质的水平。患者的诊断和治疗越快，预后越好，并发症的机会就越少。这项研究的潜在影响是巨大的，因为它将减少这些疾病的破坏性影响。

DESCRIPTION (provided by applicant): The primary goal of this proposed research is to develop a rapid point-of-care (POC) test that can be used to identify neonatal sepsis in high-risk infants in a simple, user-friendly and portable device suitable for use in the NICU setting. Since sepsis presents a very serious threat to neonates, there is an urgent need to obtain confirmation as soon as possible. Currently, there are no reliable, POC markers for this life threatening disease. Blood culture results are considered the gold standard for bacterial sepsis, but confirmatory results may not be available until at least 48 hours. In this proposal, we will attemp to develop a quantitative rapid test based on Inter-alpha Inhibitor Proteins (IAIP) that has been recently demonstrated as a valuable biomarker with high sensitivity and specificity (89.5% and 99%, respectively) and a high positive and negative predictive value (85% and 98% respectively) for neonatal sepsis. We hypothesize that endogenous IAIP, as part of the innate immune response, protect against the damaging effects of proteases released during acute systemic inflammation following severe infections, burn, trauma and injury. As a consequence, these proteins are rapidly consumed and excreted in the urine, leading to a rapid decrease in plasma levels. Furthermore, the IAIP level seems to inversely correlate with disease severity and progression, thus, a rapid IAIP test with result that can be obtained within 10- 15 min would be useful as a diagnostic and/or theranostic marker in neonatal sepsis. The proposed specific aims of the study are: 1) Validation and comparison studies of the predictive value of IAIP alone and with other biomarkers in detecting infants with sepsis and systemic inflammation and 2) Prototype development of a quantitative lateral flow immunoassay (LFIA) for IAIP that can be used to diagnose neonatal sepsis and NEC. As a replacement therapy with plasma derived IAIP has been demonstrated to be effective in experimental models of sepsis and clinical trials in adult septic patients are currently underway, our long-term objective is to study the efficacy of concomitant IAIP treatment in critically ill infants due to suspected sepsis or NEC with low levels of IAIP as revealed by the rapid test. By combining the predictive test and therapeutic replacement of plasma derived IAIP, this novel approach may offer a rational, targeted solution for reducing the morbidity and mortality associated with neonatal sepsis and NEC in infants. Furthermore, an IAIP-based rapid test will provide an objective means for reducing antibiotic overuse in infants with suspected but unproven systemic infection. The potential impact of the proposed research is immense when one considers the serious unmet medical need for infants who suffer from the devastating effects of neonatal sepsis and NEC. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to develop a rapid test that can be used to detect life-threatening conditions such as whole body infection (sepsis and necrotizing enterocolitis) in infants using a simple, user-friendly and portable device suitable fo a bedside testing in the neonatal intensive care unit. The test is based on the level of blood proteins called Inter-alpha Inhibitors that are consumed during the disease. The faster the patient is diagnosed and treated, the better the prognosis and a chance of fewer complications. The potential impact of the proposed research is immense as it will reduce the devastating effects of these diseases.