Salivary Diagnostics for Sepsis Screening in the Neonate

项目摘要 新生儿感染及其最常见的形式败血症是新生儿疾病发病率和死亡率的主要原因。 新生儿死亡人数占全球新生儿死亡人数的24%。尽管新生儿护理取得了进步， 及时识别受感染的新生儿仍然是一项重大的诊断挑战。早期临床症状 脓毒症是轻微的，或者更经常是早产新生儿中常见的镜像症状（即呼吸暂停）。 数十年来对炎症生物标志物的研究已经确定，理想的感染筛查平台 必须设计成连续和同时监测多种生物标志物。然而，连续血清采样 是不切实际的，有害的和侵入性的。重复抽血的安全替代方法是 通过非侵入性获得的唾液样本定量生物标志物水平。本研究的总体目标是 应用程序是配对的专业知识的MPI博士吉尔马龙和大卫沃尔特翻译的第一个非侵入性测试 同时定量来自连续时间点的新生儿唾液中的六种炎症生物标志物， 感染筛查的准确性，并减少新生儿不必要的抗生素暴露。马龙 塔夫茨医学中心（TMC）的实验室在过去的十年里一直在推进新生儿唾液领域的研究。 诊断，包括第一个证明新生儿唾液c反应蛋白的临床效用 (CRP)量化与此同时，哈佛医学院的沃尔特实验室发明了多路复用技术， 单分子阵列（SiMoA）技术，能够从单个样品中定量唾液中的多种蛋白质， 样品源在飞秒级。我们共同优化和调整了SiMoA平台， 成功定量了新生儿唾液中的六种炎症生物标志物（CRP、降钙素原、肿瘤坏死因子- α [TNF-α]和白细胞介素[IL] 1β、6和8）。在我们提出的前瞻性观察试验中， 和验证队列，我们与新生儿感染和免疫反应方面的国际专家配对， 共同研究者James Wynn博士（佛罗里达大学，盖恩斯维尔[UF]）和Joseph布利斯博士（妇女和 婴儿医院[W&I]）开发和验证新生儿败血症的预测模型。在目标1中，相关 临床和人口统计学数据将与2，250名婴儿的唾液生物标志物特征结合， 在TMC或W&I NICU进行“排除败血症”评估，以开发新生儿预测模型 感染在目标2中，预测模型将在1，750名婴儿的独立队列中进行验证， 排除了佛罗里达大学的败血症最后，在目标3中，来自目标1和2中登记的所有未感染新生儿的唾液样本 将用于生成新生儿年龄（24至42周）内每种生物标志物的标准唾液值 和体重（500至4500 g）谱，同时评估这些生物标志物预测其他 与炎症相关的新生儿发病率。我们的目标是提高脓毒症筛查的准确性， 减少不必要的抗生素治疗，显著改善新生儿护理和结果。

PROJECT SUMMARY Neonatal infection, and in its severest form, sepsis, are leading causes of morbidity and mortality in the neonatal population, accounting for 24% of newborn deaths worldwide. Despite advances in neonatal care, timely identification of an infected newborn remains a significant diagnostic challenge. Early clinical signs of sepsis are subtle or more often mirror symptoms commonly seen in the premature newborn (i.e. apnea). Decades of research on inflammatory biomarkers has determined that an ideal infection screening platform must be designed to serially and simultaneously monitor multiple biomarkers. However serial serum sampling in the newborn is impractical, noxious and invasive. A safe alternative to repeated blood draws would be to quantify biomarker levels through noninvasively obtained saliva samples. The overall goal of this research application is to pair the expertise of MPIs Drs. Jill Maron and David Walt to translate the first noninvasive test to simultaneously quantify six inflammatory biomarkers in neonatal saliva from serial time points to improve infection-screening accuracy and reduce unwarranted antibiotic exposure in the newborn. The Maron Laboratory at Tufts Medical Center (TMC) has spent the last decade advancing the field of neonatal salivary diagnostics, including being the first to demonstrate the clinical utility of neonatal salivary c-reactive protein (CRP) quantification. In parallel, the Walt Laboratory at Harvard Medical School has invented multiplexed Single Molecule Array (SiMoA) technology capable of quantifying multiple proteins in saliva from a single sample source at a femtoscale level. Together, we have optimized and adapted the SiMoA platform to successfully quantify six inflammatory biomarkers in neonatal saliva (CRP, procalcitonin, tumor necrosis factor- alpha [TNF-α], and interleukins [IL] 1β, 6, and 8). In our proposed prospective, observational trial, with training and validation cohorts, we have paired with international experts in neonatal infection and immune response, Co-Investigators, Dr. James Wynn (University of Florida, Gainesville [UF]) and Dr. Joseph Bliss (Women and Infants’ Hospital [W&I]) to develop and validate a predictive model of neonatal sepsis. In Aim 1, pertinent clinical and demographic data will be combined with salivary biomarker signatures of 2,250 infants undergoing a ‘rule out sepsis’ evaluation at either the TMC or W&I NICUs to develop a predictive model of neonatal infection. In Aim 2, the predictive model will be validated on an independent cohort of 1,750 infants undergoing a rule-out-sepsis at UF. Finally in Aim 3, saliva samples from all uninfected newborns enrolled in Aims 1 and 2 will be used to generate normative salivary values of each biomarker across the neonatal age (24 to 42 weeks) and weight (500 to 4500 g) spectrum, while assessing the potential of these biomarkers to predict other neonatal morbidities associated with inflammation. We aim to enhance the accuracy of sepsis screening, reduce unwarranted antibiotic therapy, and significantly improve neonatal care and outcomes.