RNA Biosignatures in the Emergency Evaluation of Febrile Infants

描述（由申请人提供）：对发热婴儿的诊断评估和管理，特别是那些60天及以下的婴儿，仍然是临床医生的一个挑战，特别是在急诊科（ED）；虽然大多数年幼的发热婴儿会有非细菌性感染，但近10%会有严重的细菌感染（SBI），然而有和没有SBI的发热婴儿通常在临床上难以区分。目前推荐的评估发热婴儿的方法是不充分的和有争议的，因为许多常规的SBI筛查试验是不准确的。然而，在当今时代，有一些新的方法，包括基因组测序和进行高通量脱氧核酸（DNA）和核糖核酸（RNA）分析的技术的进步，使人们更好地了解宿主-病原体对感染的反应。因此，一种新的方法来区分感染细菌性病原体和感染非细菌性病原体的发热婴儿是检查宿主对感染的反应。最近的数据表明，不同的病原体在血液白细胞的RNA中诱导不同的转录“生物特征”，可以通过微阵列分析可靠地测量。我们假设，诊断性生物特征的应用将允许准确区分在急诊科评估的年幼发热婴儿是否感染细菌和感染非细菌病原体。我们如何评估年幼发热婴儿的最终模式转变将导致对发热婴儿的改进和更少的侵入性诊断评估，并将通过减少(1)不必要的侵入性检查（包括腰椎穿刺）的数量，(2)经验性抗生素的使用，(3)住院和相关的医源性并发症，以及(4)家庭的情感和经济负担，产生重大而有益的影响。在这项前瞻性研究中，在获得知情同意后，将纳入儿童急诊护理应用研究网络（PECARN）的22个参与ed的60天或以下符合条件的发热婴儿。我们将定义和验证在SBI常规临床评估中获得的小容量血液的细菌和非细菌诊断生物特征。此外，我们将评估新的筛查试验（降钙素原），并将其测试特征与传统筛查试验（全血细胞计数）与参考标准（相关标本如血液、脑脊液和尿液的微生物培养）和诊断性生物特征进行比较，以评估发热婴儿SBI。

DESCRIPTION (provided by applicant): The diagnostic evaluation and management of febrile infants, especially those 60 days of age and younger, remains a challenge for clinicians, especially in the emergency department (ED); Although most young febrile infants will have a non-bacterial infection, nearly 10% will have a serious bacterial infection (SBI), yet febrile infants with and without SBIs are often clinically indistinguishable. The currently recommended approach for the evaluation of febrile infants is inadequate and controversial as many of the routine screening tests for SBI are inaccurate. In the current era, however, there are novel methods, including advances in genomic sequencing and techniques for conducting high through-put deoxynucleic acid (DNA) and ribonucleic acid (RNA) analysis that have led to a better understanding of the host-pathogen response to infections. Thus, a novel approach to distinguish febrile infants infected with bacterial pathogens from those infected with non- bacterial pathogens is to examine the host response to infection. Recent data indicate that different pathogens induce distinct transcriptional "biosignatures" in the RNA of blood leukocytes that can be reliably measured by microarray analysis. We hypothesize that application of diagnostic biosignatures will allow accurate discrimination between young febrile infants evaluated in the ED with bacterial infections and those infected with non-bacterial pathogens. The eventual paradigm shift of how we evaluate young febrile infants will result in improved and less invasive diagnostic evaluations of febrile infants, and will have a significant and beneficial impact by reducing the number of (1) unnecessary invasive tests (including lumbar punctures), (2) use of empirical antibiotics, (3) hospitalizations and associated iatrogenic complications, and (4) emotional and financial burdens on families. In this prospective study, eligible febrile infants 60 days of age or younger who present to 22 participating EDs of the Pediatric Emergency Care Applied Research Network (PECARN) will be enrolled after informed consent is obtained. We will define and validate bacterial and non-bacterial diagnostic biosignatures from small volumes of blood obtained during routine clinical evaluation for SBI. Additionally, we will evaluate the newer screening test (procalcitonin) and compare its tests characteristics with the traditional screening tests, (complete blood counts) with the reference standard (microbiologic cultures of relevant specimens such as blood, CSF and urine) and the diagnostic biosignatures in the evaluation of febrile infants for SBI. PUBLIC HEALTH RELEVANCE: Fever is a very common reason for visits to the emergency department, and febrile infants younger than 60 days of age are at high risk for serious bacterial infections. Since the routinely used screening tests and clinical evaluations to identify these serious infections are not adequate, we are proposing the use of a novel diagnostic blood test which looks at the infant's response to the infection. This will allows us to reliably distinguish those with and without serious bacterial infections, which in turn will reduce; (a) a substantial number of unnecessary invasive tests, (b) use of unnecessary antibiotics, and (c) hospitalizations in young infants, thus, reducing the emotional burden on the families and costs to the U.S. health care system.