RNA Biosignatures: A Paradigm Change for the Management of Young Febrile Infants

 描述(由申请人提供)：每年约500,000名发烧婴儿=60天大到美国急诊科(ED)就诊。这些发烧的婴儿中有6%-10%会有侵袭性细菌感染(菌血症、尿路感染或脑膜炎)。目前评估幼年发烧婴儿的方法并不理想，因为它们包括频繁的侵入性手术、过度使用经验性抗生素和不必要的住院，这可能会导致医源性并发症，并具有重大的成本影响。这些问题的主要原因是缺乏高精度和短时间的周转测试，以可靠地区分患有和不患有细菌感染的发烧婴儿。我们研究的长期目标是调查全基因组RNA表达谱，以定义RNA生物特征，从而能够准确诊断发烧婴儿=60天时的隔离细菌感染、隔离病毒感染和细菌-病毒c-感染。我们的具体目标是(1)确定60天龄发烧婴儿中分离的细菌感染、分离的病毒感染和病毒-细菌混合感染的RNA生物签名；(2)证明上述定义的RNA生物签名在24-72小时时间段内的稳定性；以及(3)在一个基于PCR的新型平台上验证RNA生物签名，该平台具有快速(2-4小时)的周转时间。我们将对60天大的发热婴儿进行前瞻性、多中心、横断面研究，这些婴儿正在接受细菌感染的评估。在获得监护人的知情同意后，我们将采集2毫升全血(1毫升用于RNA表达分析；1毫升用于全面病毒研究)和1毫升鼻咽拭子用于全面的呼吸道病毒诊断。此外，在选定的一组从急诊室住院或返回急诊室的发烧婴儿中，我们将在首次样本采集后24-72小时采集第二份1毫升血液样本进行顺序RNA生物签名分析。使用同一样本的等量血液，我们将在基于聚合酶链式反应的平台上验证RNA生物签名。解决发烧婴儿的最佳评估和管理问题，将确保这一弱势儿童群体有机会充分发挥其健康和富有成效的生活潜力，不受疾病或残疾的影响，这符合NICHD的使命。

 DESCRIPTION (provided by applicant): Every year ~ 500,000 febrile infants = 60 days of age present to US emergency departments (ED). 6-10% of these febrile infants will have invasive bacterial infections (bacteremia, urinary tract infections or meningitis). Current approaches for the evaluation of young febrile infants are suboptimal because they include frequent invasive procedures, overuse of empirical antibiotics and unnecessary hospitalizations, which can lead to iatrogenic complications and have substantial cost implications. The primary cause of these problems is lack of highly accurate and short turn-around testing to reliably distinguish young febrile infants with and without bacterial infections. The long-term objective of our research is t investigate whole genome RNA expression profiles to define RNA biosignatures that allow precise diagnosis of isolated bacterial infections, isolated viral infections and bacterial-viral c-infections in febrile infants = 60 days of age. Our specific aims are to (1) define the RNA biosignatures in febrile infants = 60 days of age with isolated bacterial infections, isolated vira infections and viral-bacterial co-infections; (2) demonstrate the stability of the above defined RNA biosignatures over a 24-72 hour time period; and (3) validate the RNA biosignatures on a novel, PCR-based platform that has a rapid (2 - 4 hour) turnaround time. We will conduct a prospective, multi-center, cross-sectional study of febrile infants = 60 days of age who are being evaluated for bacterial infections. After obtaining informed consent from the guardian we will collect 2 ml of whole blood (1 ml for RNA expression analysis; 1 ml for comprehensive viral studies) and 1 nasopharyngeal (NP) swab for a comprehensive respiratory viral diagnosis. Additionally, in a selected group of febrile infants who are either hospitalized from the ED or those who return to the ED, we will obtain a second 1 ml blood sample for sequential RNA biosignature analysis at 24 - 72 hours after the initial sample collection. Using an aliquot of blood from the same sample we will validate RNA biosignatures on the PCR-based platform. Addressing the optimal evaluation and management of the febrile infant will assure that this vulnerable population of children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability and is consistent with the mission of NICHD.