Salivary Diagnostics for Sepsis Screening in the Neonate

用于新生儿败血症筛查的唾液诊断

• 批准号: 10624543
• 负责人: Jill Lamanna Maron
• 金额: $ 68.99万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624543
• 关键词: Accounting; Age; Antibiotic Therapy; Antibiotics; Apnea; Biological Markers; Blood; Blood Volume; Boston; Bronchopulmonary Dysplasia; C-reactive protein; Clinical; Clinical Data; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Drug Prescriptions; Enrollment; Evaluation; Florida; Gestational Age; Goals; Hospitals; Hour; Immune response; Infant; Infant Care; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; International; Investigation; Laboratories; Life; Measurement; Medical center; Monitor; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Neonatology; Newborn Infant; Nosocomial Infections; Organism; Periventricular Leukomalacia; Population; Prospective cohort; Proteins; Reference Values; Research; Research Personnel; Resistance; Role; Saliva; Salivary; Salivary Proteins; Sampling; Sensitivity and Specificity; Sepsis; Serum; Source; Survivors; Symptoms; TNF gene; Technology; Testing; Time; Training; Translating; Universities; Validation; Weight; Woman; accurate diagnostics; adverse outcome; base; biomarker signature; care outcomes; cohort; common symptom; design; diagnostic accuracy; diagnostic assay; improved; innovation; medical schools; microbiome; mortality; neonatal care; neonatal infection; neonatal morbidity; neonatal outcome; neonatal sepsis; neonate; potential biomarker; predictive modeling; preterm newborn; procalcitonin; prospective; protein expression; recruit; saliva diagnostic; saliva sample; salivary assay; screening; sex; single molecule

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.

项目概要 新生儿感染及其最严重的败血症是新生儿发病和死亡的主要原因 新生儿人口，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个重大的诊断挑战。早期临床症状 脓毒症是早产儿中常见的微妙或更常见的反映症状（即呼吸暂停）。 数十年对炎症生物标志物的研究确定了理想的感染筛查平台 必须设计为连续且同时监测多个生物标志物。然而连续血清取样 对新生儿来说是不切实际的、有害的和侵入性的。重复抽血的安全替代方法是 通过无创获取唾液样本来量化生物标志物水平。本研究的总体目标 应用程序的目的是配对 MPI 博士的专业知识。吉尔·马龙和大卫·沃尔特翻译第一个无创测试 从连续时间点同时量化新生儿唾液中的六种炎症生物标志物，以改善 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) 的实验室在过去十年中一直致力于推进新生儿唾液领域的发展 诊断，包括第一个证明新生儿唾液 C 反应蛋白的临床用途 （CRP）定量。与此同时，哈佛医学院的沃尔特实验室发明了多重检测 单分子阵列 (SiMoA) 技术能够定量唾液中的多种蛋白质 飞秒级的样本源。我们共同优化并调整了 SiMoA 平台，以 成功定量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，经过培训 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合作， 联合研究人员 James Wynn 博士（佛罗里达大学盖恩斯维尔分校 [UF]）和 Joseph Bliss 博士（妇女和 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 临床和人口统计数据将与 2,250 名婴儿的唾液生物标志物特征相结合 在 TMC 或 W&I NICU 进行“排除败血症”评估，以开发新生儿的预测模型 感染。在目标 2 中，预测模型将在由 1,750 名婴儿组成的独立队列中得到验证 UF 排除败血症。最后，在目标 3 中，采集了目标 1 和 2 中所有未感染新生儿的唾液样本 将用于生成整个新生儿年龄（24 至 42 周）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生物标志物的潜力 与炎症相关的新生儿发病率。我们的目标是提高败血症筛查的准确性， 减少不必要的抗生素治疗，并显着改善新生儿护理和结果。