Point-of-Care Microfluidic Biochip for Biomarkers Monitoring for Contributing in Early Sepsis Diagnosis

主要研究者/项目负责人（最后一名、第一名、中间名）：Bashir、Rashid 脓毒症，一种由宿主对感染的反应失调引起的危及生命的器官功能障碍（脓毒症- 3定义），是死亡的主要原因和医院最昂贵的条件。每年有超过3000万人受到影响 在全球范围内，至少有170万成年人患败血症（近27万人死亡），在美国每年花费240亿美元。 被诊断为败血症且没有持续器官衰竭迹象的患者有约15-30%的死亡机会。但 严重脓毒症或脓毒性休克患者的死亡率可增加至40-60%。三分之一死于医院的病人 得了败血症这些死亡率上升的一个主要因素是无法准确和快速地诊断潜在的 败血症患者同样，脓毒症是再次入院的主要原因（比心脏病住院的比例更高）。 在美国，心脏病发作、心力衰竭、COPD和肺炎）。急诊科和重症监护室依赖于监测极不特异性的 参数（例如发热、低血压、心率增加），以启动临床诊断并开始治疗。这些 粗糙的指标使医生将早期败血症与其他几种疾病相混淆。早期发病的阳性诊断 脓毒症是关键的，因为死亡率随着治疗的延迟而增加。据报道存活率下降了7.6% 每隔一个小时，没有给予适当的抗生素，这些延误加剧了不必要的医院费用。来 在过去的30年里，诊所使用不同的标准，如SIRS，LODS和SOFA或qSOFA作为筛查工具来评估 潜在脓毒症患者器官功能障碍的严重程度。这些标准中的共同因素是非特异性， 非常高的假阳性率。对于阳性标准的患者，最终的诊断测试是血培养， 5天为阴性结果。同样，血培养具有非常高的假阴性率（> 60%），并且对 苛养病原体如肺炎衣原体。更重要的是，血培养不能成为金标准方法 用于脓毒症诊断。这种技术只能检测血液中细菌的存在（菌血症），而不能检测血液中细菌的存在。 这必然意味着疾病。许多非菌血症感染也可导致危及生命的败血症。为了提高 脓毒症诊断的准确性和敏感性，脓毒症-3定义强调了两种病原体的要求 检测和关于患者的免疫系统的个性化状态的信息。因此，我们建议将重点 我们致力于监测这种免疫反应的选择性生物标志物。然而，没有一个单一的，甚至是一个组合， 生物标志物已被验证用于脓毒症的诊断。因为没有单一的生物标志物能够特异性地预测脓毒症， 我们建议开发一种用于测量细胞表面和血浆蛋白质生物标志物的即时微流控生物芯片， 将有助于脓毒症的早期诊断。微流控生物芯片将提供完整的白色血细胞 计数（WBC）以及中性粒细胞（nCD 64）、降钙素原（PCT）、C反应蛋白表达的定量 (CRP)和白细胞介素6（IL-6）。多项研究已经证明这些生物标志物对脓毒症的高敏感性。的 所提出的设备将联合收割机首次结合细胞表面蛋白和血浆蛋白生物标志物的分析， 同样的血液样本这样的设备，结合在医院进行的常规测试， 加快脓毒症的诊断，从而加快临床决策，为患者提供正确的治疗。

Principal Investigator/Program Director (Last, first, middle): Bashir, Rashid Project Summary: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis- 3 definition), is the leading cause of death and most expensive condition in hospitals. Annually, > 30 million people affected worldwide, with at least 1.7 million adults developing sepsis (nearly 270K die) at a cost of $24 billion per year in the U.S. Patients diagnosed with sepsis and no ongoing sign of organ failure have about a 15-30% chance of death. However, the mortality rate can increase up to 40-60% for severe sepsis or septic shock patients. One in three patients who die in a hospital have sepsis. One major factor in these rising mortality rates is the inability to accurately and quickly diagnose potentially septic patients. Likewise, sepsis is a leading cause of hospital readmission (higher proportion than hospitalizations for heart attack, heart failure, COPD, and pneumonia in the U.S.). EDs and ICUs rely on monitoring extremely non-specific parameters (e.g. fever, low blood pressure, increased heart rate) to initiate a clinical diagnosis and begin treatment. These crude indicators cause doctors to mistake early stage sepsis with several other diseases. A positive diagnose of early onset sepsis is critical because mortality increases with delays in treatment. Survival rates have been reported to drop by 7.6% every hour that the proper antibiotics are not administered, and these delays compound unnecessary hospital costs. Over the last 30 years, clinics have used different criteria such as SIRS, LODS and SOFA or qSOFA as screening tools to assess the severity of organ dysfunction in a potentially septic patient. Common factors among these criteria are non-specificity and very high false positive rates. For patients with positive criteria, the final diagnostic test is a blood culture that may take up to 5 day for a negative result. Likewise, blood culture has a very high false negative rate (> 60%) and does not work for fastidious pathogens such as Chlamydia pneumoniae. More importantly, blood culture cannot be a gold standard method for sepsis diagnosis. This technique only detects the presence of bacteria in the bloodstream (bacteremia), which does not necessarily indicate illness. Many non-bacteremic infections can also cause life-threatening sepsis. In order to improve the accuracy and sensitivity of sepsis diagnosis, the Sepsis-3 definition underscores the requirements for both pathogen detection and information about the personalized state of the immune system of the patient. Therefore, we propose to focus our efforts on monitoring selective biomarkers of this immune response. However, no single, or even a combination of biomarkers has been validated for the diagnosis of sepsis. Because no single biomarker is specific enough to predict sepsis, we propose to develop a point-of-care microfluidic biochip for measuring cell-surface and plasma-proteins biomarkers that will be used for contributing in early sepsis diagnosis. The microfluidic biochip will provide a complete white blood cell count (WBC), as well as quantification of CD64 expression on neutrophil (nCD64), procalcitonin (PCT), C-Reactive Protein (CRP) and Interleukin 6 (IL-6). Multiple studies have demonstrated the high sensitivity of these biomarkers to sepsis. The proposed device will combine for the first time the analysis of cell-surface proteins and plasma proteins biomarkers from the same sample of blood. Such a device, combined with the routinely test performed in the hospitals, could significantly accelerate the diagnosis of sepsis and as consequence the clinical decision, to provide the correct treatment to the patients.