Salivary Diagnostics for Sepsis Screening in the Neonate

项目总结 新生儿感染，及其最严重的形式，败血症，是导致发病率和死亡率的主要原因。 新生儿人口，占全世界新生儿死亡的24%。尽管新生儿护理方面取得了进展， 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： 败血症是在早产儿中常见的轻微或更常见的镜像症状(即呼吸暂停)。 几十年来对炎症生物标志物的研究已经确定了一个理想的感染筛查平台 必须设计成能够连续和同时监测多个生物标志物。然而，连续的血清采样 对新生儿来说是不切实际的、有害的和侵入性的。反复抽血的一个安全的替代方案是 通过非侵入性获取的唾液样本来量化生物标记物水平。这项研究的总体目标 应用程序是将MPI的专业知识Jill Maron博士和David Walt博士结合起来，以翻译第一个非侵入性测试 同时定量新生儿唾液中六种炎症标志物的连续时间点以改善 感染筛查的准确性，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动新生儿唾液领域的发展 诊断学，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传输 单分子阵列(SiMoA)技术能够从单个唾液中定量检测多个蛋白质 飞秒量级的样本源。我们共同优化和调整了SiMoA平台，以 成功定量新生儿唾液中的六种炎性生物标志物(CRP、降钙素原、肿瘤坏死因子) α[肿瘤坏死因子-α]和白介素1β、6和8)。在我们提议的前瞻性、观察性试验中，经过培训 和验证队列，我们已经与新生儿感染和免疫反应方面的国际专家配对， 共同调查人员，詹姆斯·韦恩博士(佛罗里达大学，盖恩斯维尔[UF])和约瑟夫·布利斯博士(女性和 婴儿医院[W&I])开发并验证新生儿败血症的预测模型。在目标1中，相关 临床和人口学数据将与2250名接受手术的婴儿的唾液生物标志物签名相结合 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名婴儿的独立队列上进行验证 密歇根大学的一项排除败血症。最后，在目标3中，所有未感染的新生儿的唾液样本都登记在目标1和目标2中 将用于生成新生儿年龄(24至42周)内每个生物标志物的标准唾液值 和体重(500至4500克)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预后。

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.