RNA Biosignatures in the Emergency Evaluation of Febrile Infants

描述(申请人提供)：发烧婴儿的诊断评估和管理，尤其是那些60天及以下的发烧婴儿，仍然是临床医生面临的挑战，尤其是在急诊科(ED)；虽然大多数发烧婴儿会有非细菌感染，但近10%会有严重的细菌感染(SBI)，然而有或没有SBI的发烧婴儿在临床上通常是无法区分的。目前推荐的评估发烧婴儿的方法是不充分和有争议的，因为许多常规的SBI筛查测试是不准确的。然而，在当今时代，有一些新的方法，包括基因组测序的进展，以及进行高通量脱氧核酸(DNA)和核糖核酸(RNA)分析的技术，这些方法有助于更好地了解宿主-病原体对感染的反应。因此，一个新的方法来区分感染了细菌病原体的发热婴儿和那些感染了非细菌病原体的婴儿，就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中诱导出不同的转录生物特征，这可以通过微阵列分析可靠地测量到。我们假设，诊断生物特征的应用将允许在急诊室评估为细菌感染的发热婴儿和感染非细菌病原体的婴儿之间进行准确的区分。我们评估发烧婴儿的最终模式转变将导致对发烧婴儿的诊断评估得到改进，侵入性更小，并将通过减少(1)不必要的侵入性测试(包括腰椎穿刺术)、(2)经验抗生素的使用、(3)住院和相关医源性并发症以及(4)家庭的情感和经济负担的数量，产生重大和有益的影响。在这项前瞻性研究中，在获得知情同意后，向儿科急救应用研究网络(PECARN)的22名参与急救的合格发烧婴儿60天或以下的婴儿进行登记。我们将定义和验证在常规临床评估中获得的少量血液中的细菌和非细菌诊断生物特征。此外，我们将评估较新的筛查试验(降钙素原)，并比较其与传统筛查试验、参考标准(相关标本的微生物培养，如血液、脑脊液和尿液的微生物培养)和诊断生物学特征在评估发热儿SBI方面的特点。 公共卫生相关性：发烧是急诊科就诊的一个非常常见的原因，60天以下发烧的婴儿患严重细菌感染的风险很高。由于常规使用的筛查测试和临床评估不足以确定这些严重感染，我们建议使用一种新型的诊断血液测试，以观察婴儿对感染的反应。这将使我们能够可靠地区分患有和没有严重细菌感染的人，这反过来将减少：(A)大量不必要的侵入性检查，(B)不必要的抗生素的使用，以及(C)幼儿住院，从而减少家庭的情感负担和美国医疗保健系统的成本。

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.