RNA Biosignatures in the Emergency Evaluation of Febrile Infants

RNA 生物特征在发热婴儿紧急评估中的应用

• 批准号: 7936478
• 负责人: NATHAN KUPPERMANN
• 金额: $ 82.68万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936478
• 关键词: Accident and Emergency department; Acids; Address; Age; Antibiotics; Applied Research; Bacterial Infections; Blood; Blood Tests; Blood Volume; Body Fluids; Caring; Cerebrospinal Fluid; Characteristics; Child; Childhood; Clinical; Complete Blood Count; Consent; Data; Diagnosis; Diagnostic; Discrimination; Emergency Care; Emergency Situation; Emergency medical service; Emotional; Enrollment; Evaluation; Family; Fever; Genome; Genomics; Grant; Guidelines; Healthcare Systems; Hospitalization; Hour; Immune response; Infant; Infection; Informed Consent; Leukocytes; Measures; Methods; Microarray Analysis; Microbe; Patients; Prospective Studies; RNA; Reference Standards; Research Infrastructure; Research Personnel; Research Priority; Sampling; Screening procedure; Specimen; Spinal Puncture; Techniques; Testing; Time; Translational Research; Urine; Validation; Virus Diseases; Visit; biosignature; clinical practice; clinically relevant; cost; digital; evaluation/testing; experience; febrile infant; high risk; improved; meetings; multidisciplinary; novel; novel diagnostics; novel strategies; pathogen; procalcitonin; public health relevance; research clinical testing; response

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.

描述（由申请人提供）：发热婴儿（尤其是 60 天及以下的婴儿）的诊断评估和管理对于临床医生来说仍然是一个挑战，特别是在急诊室 (ED)；虽然大多数发热婴儿会出现非细菌感染，但近 10% 的婴儿会出现严重细菌感染 (SBI)，但有和没有 SBI 的发热婴儿在临床上通常无法区分。目前推荐的发热婴儿评估方法不充分且存在争议，因为许多 SBI 常规筛查测试不准确。然而，当今时代出现了一些新方法，包括基因组测序以及进行高通量脱氧核酸 (DNA) 和核糖核酸 (RNA) 分析技术的进步，这些方法可以更好地了解宿主病原体对感染的反应。因此，区分感染细菌病原体和感染非细菌病原体的发热婴儿的一种新方法是检查宿主对感染的反应。最近的数据表明，不同的病原体会在血液白细胞的 RNA 中诱导不同的转录“生物特征”，这些特征可以通过微阵列分析进行可靠测量。我们假设，诊断生物特征的应用将能够准确地区分急诊室评估的细菌感染和非细菌病原体感染的发热婴儿。我们评估年幼发热婴儿的方式的最终范式转变将导致对发热婴儿的诊断评估得到改进和侵入性更小，并将通过减少以下次数产生重大且有益的影响：(1)不必要的侵入性测试（包括腰椎穿刺），(2)经验性抗生素的使用，(3)住院治疗和相关医源性并发症，以及(4)情感和财务 给家庭带来负担。在这项前瞻性研究中，在获得知情同意后，将在儿科紧急护理应用研究网络 (PECARN) 的 22 个参与的 ED 就诊的 60 天或以下的符合资格的发热婴儿入组。我们将通过 SBI 常规临床评估期间获得的少量血液来定义和验证细菌和非细菌诊断生物特征。此外，我们将评估新的筛查测试（降钙素原），并将其测试特征与传统筛查测试（全血细胞计数）、参考标准（相关标本的微生物培养，如血液、脑脊液和尿液）以及诊断性生物特征进行比较，用于评估发热婴儿的 SBI。 公共卫生相关性：发烧是去急诊室就诊的一个非常常见的原因，60 天以下的发热婴儿发生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识别这些严重感染，因此我们建议使用一种新型诊断性血液测试来观察婴儿对感染的反应。这将使我们能够可靠地区分那些患有和没有严重细菌感染的人，从而减少； (a) 大量不必要的侵入性检查，(b) 使用不必要的抗生素，以及 (c) 小婴儿住院治疗，从而减轻了家庭的情感负担和美国医疗保健系统的成本。