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NICU环境中使用的简单，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的威胁非常严重，因此迫切需要尽快得到确认。目前，对于这种威胁生命的疾病，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，但确认结果可能至少要等到48小时后才能得到。在本提案中，我们将尝试开发一种基于inter - α抑制剂蛋白（IAIP）的定量快速检测方法，IAIP最近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，可以防止严重感染、烧伤、创伤和损伤后急性全身性炎症中释放的蛋白酶的破坏性作用。因此，这些蛋白质被迅速消耗并随尿液排出，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呈负相关，因此，可在10- 15分钟内获得结果的快速IAIP测试将有助于诊断和/或治疗新生儿败血症。本研究提出的具体目的是：1)验证和比较IAIP单独和与其他生物标志物在检测婴儿败血症和全身性炎症方面的预测价值；2)IAIP定量侧流免疫分析法（LFIA）的原型开发，可用于诊断新生儿败血症和NEC。由于血浆源性IAIP替代疗法已被证明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

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.