CLINICAL STUDY ON INOS ELISA FOR SEPSIS AND SEPTIC SHOCK

我们最初提出，随后发现在一项初步临床研究中，在严重脓毒症和脓毒性休克发作之前的全身炎症反应综合征（SIRS）或脓毒症发作期间，循环中人诱导型一氧化氮合酶（hiNOS）水平出现可测量的增加。我们的目标是开发用于临床使用的免疫测定法，可以快速检测，定量和监测这种增加在严重脓毒症和脓毒性休克发作之前，从而为未来的有害事件提供早期预警信号。早期诊断将为比目前更早开始治疗提供基础。为了实现我们的目标，我们已经开发了一个高度特异性的夹心ELISA的基础上，我们的面板的20抗hiNOS单克隆抗体的hiNOS。在对10名ICU患者进行的一项初步临床研究中，我们开发了针对hiNOS的ELISA和其他三种确证性免疫测定法，用于检测和测量外周血单核细胞（PBMC）中hiNOS的水平。从该初步研究中获得的结果表明，PBMC中hiNOS水平的增加可以被测量，并且可以是一种良好的生物化学标志物，其可以用于预测严重脓毒症和脓毒性休克的发作。本I期项目的目的是将临床研究扩展至更多患者，以评估在初步临床研究期间对更多患者进行的观察结果，从而评估初步临床研究期间进行的观察结果是否普遍适用。一旦完成，整个项目将为标记带来所需的新临床诊断，这反过来将改善危重患者的医疗保健。拟定商业应用：在美国每年发生超过1，200，000例全身炎症反应综合征和脓毒症;这些导致每年超过500，000例严重脓毒症和脓毒性休克以及每年100，000 - 250，000例死亡。需要一种快速测试来评估患者进入脓毒症途径并沿着脓毒症途径进展为严重脓毒症和脓毒性休克。我们的免疫测定旨在满足这一临床需求，通过减少ICU住院时间来降低患者成本，并改善患者预后。

We initially proposed and then subsequently found during a pilot clinical study that a measurable increase in the circulating level of human inducible nitric oxide synthase (hiNOS) occurs during an episode of systemic inflammatory response syndrome (SIRS) or sepsis prior to the onset of severe sepsis and septic shock. Our goal is to develop immunoassays for clinical use that can rapidly detect, quantitate and monitor this increase in hiNOS prior to the onset of severe sepsis and septic shock, and thus provide an early warning signal for future deleterious events. An early diagnosis will provide a basis for an earlier initiation of therapies than is currently practiced. To achieve our goal, we have developed a highly specific sandwich ELISA for hiNOS based upon our panel of twenty anti-hiNOS monoclonal antibodies. The ELISA and three other confirmatory immunoassays that we developed for hiNOS have been used to detect and measure the level of hiNOS in peripheral blood monocytes (PBMC) during an pilot clinical study on a cohort of 10 ICU patients. The results obtained from this pilot study indicate that an increased level of hiNOS in PBMC can be measured and may be a good biochemical marker that can be used to prognosticate the onset of severe sepsis and septic shock. The aim of this phase I project is to extend the clinical study to a larger number of patients in order to assess if the observations made during the pilot clinical study to a larger number of patients in order to assess if the observations made during the pilot clinical study are generally applicable. Once completed, the overall project will bring a needed new clinical diagnostic onto the marker, and this, in turn, will lead to improved health care for critically ill patients. PROPOSED COMMERCIAL APPLICATION: Over 1,200,000 cases/year of systemic inflammatory response syndrome and sepsis occur in the USA; these lead to over 500,000 cases/year of severe sepsis and septic shock and 100,000-250,000 deaths/year. A rapid test to assess a patient's entry into and progress down the sepsis pathway to severe sepsis and septic shock is needed. Our immunoassays are designed to meet this clinical need, to lower patient cost by reducing the length of ICU stays, and to improve patient outcome.