Rapid detection of neonatal sepsis

描述(由申请人提供)：这项拟议研究的主要目标是开发一种快速的护理点(POC)测试，可用于在适合NICU环境下使用的简单、用户友好和便携式设备中识别高危婴儿中的新生儿败血症。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，还没有可靠的POC标记物来诊断这种危及生命的疾病。血培养结果被认为是细菌性脓毒症的黄金标准，但至少要到48小时才能得到确认性结果。在这项提案中，我们将尝试建立一种基于内-α抑制蛋白(IAIP)的定量快速检测方法，该方法最近被证明是一种有价值的生物标志物，具有较高的敏感性和特异性(分别为89.5%和99%)，以及较高的阳性和阴性预测值(分别为85%和98%)。我们假设，作为先天免疫反应的一部分，内源性IAIP可以保护严重感染、烧伤、创伤和损伤后急性全身炎症过程中释放的蛋白酶的破坏性影响。因此，这些蛋白质在尿液中被迅速消耗和排泄，导致血浆水平迅速下降。此外，IAIP水平似乎与疾病的严重程度和进展呈负相关，因此，在10-15分钟内获得结果的快速IAIP检测将有助于作为新生儿败血症的诊断和/或治疗标志物。这项研究的具体目的是：1)验证和比较IAIP单独和其他生物标志物在检测婴儿败血症和全身炎症中的预测价值；2)建立IAIP定量侧向流动免疫分析(LFIA)的原型，该方法可用于诊断新生儿败血症和NEC。由于血浆来源的IAIP替代疗法已被证实在脓毒症的实验模型中有效，成人脓毒症患者的临床试验目前正在进行中，我们的长期目标是研究伴随IAIP治疗疑似脓毒症或低水平NEC的危重婴儿的疗效。 快速检测显示为IAIP。通过结合血浆来源IAIP的预测试验和治疗替代，这一新方法可能为降低新生儿败血症和新生儿NEC的发病率和死亡率提供一种合理的、有针对性的解决方案。此外，基于IAIP的快速检测将为减少疑似但未经证实的全身感染婴儿过度使用抗生素提供客观手段。当人们考虑到患有新生儿败血症和NEC破坏性影响的婴儿严重未得到满足的医疗需求时，拟议的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方法，可用于检测婴儿全身感染(败血症和坏死性小肠结肠炎)等危及生命的情况，使用一种简单、用户友好和便携的设备，适用于新生儿重症监护病房的床边测试。这项测试是基于疾病期间消耗的名为Inter-Alpha Inhibitors的血液蛋白水平。患者诊断和治疗越快，预后就越好，并发症就越少。拟议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.