Resubmission: Elucidating Pediatric Sepsis by Defining Comprehensive Signatures for Diagnosis and Outcome

重新提交：通过定义诊断和结果的综合特征来阐明儿童败血症

• 批准号: 10364419
• 负责人: Prashant Mahajan
• 金额: $ 59.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364419
• 关键词: 18 year old; Accident and Emergency department; Address; Age; Antibiotics; Antimicrobial Resistance; Area; Bacteria; Bioinformatics; Biological Markers; Blood; Blood specimen; Cessation of life; Child; Childhood; Clinical; Clinical Data; Consent; Custom; Data; Data Set; Diagnosis; Diagnostic; Disease; Electronic Health Record; Emergency Department patient; Emergency department visit; Enrollment; Etiology; Functional disorder; Future; Goals; Guidelines; Heart Rate; Hour; Immune; Immune response; Immunoassay; Immunologics; Infection; Inpatients; Intervention; Knowledge; Laboratories; Life; Liquid substance; Measures; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Multicenter Studies; Nucleic Acids; Observational Study; Organ; Organ failure; Outcome; Patient Monitoring; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Physiological; Process; Provider; Recommendation; Research Personnel; Resources; Resuscitation; Ribosomes; Risk; Sampling; Science; Sepsis; Septic Shock; Shock; Speed; Subgroup; Syndrome; Technology; Temperature; Testing; Time; Viral; Viremia; Virus; Work; accurate diagnosis; clinical decision-making; detection assay; evidence base; experience; improved; mortality; multidisciplinary; nanorod; nucleic acid detection; outcome prediction; pathogen; patient response; pediatric emergency; pediatric patients; pediatric sepsis; precision medicine; prospective; rapid diagnosis; risk stratification; septic patients; tertiary care; tissue culture; tool; transcriptomics; working group

PROJECT SUMMARY: Sepsis, defined as life-threatening organ dysfunction resulting from a dysregulated immune response of the patient to infection, is a major cause of pediatric morbidity and mortality. Annually, sepsis accounts for ~100,000 emergency department (ED) and ~25-50% of children with sepsis will die due to complications that include shock and multiple organ dysfunction. These unacceptably high bad outcomes are mostly because of our limited understanding of the fundamental underlying immune response processes at the cellular level that are involved in pediatric sepsis. There is an urgent need for generating high quality evidence using multidisciplinary teams to rapidly and accurately diagnoses sepsis so that appropriate therapies can be initiated in the ED to reduce morbidity and mortality in children. We believe that the patient has a unique “sepsis” signature when they first present to the ED and we can define this signature by studying the changes in the vital signs (such as temperature, heart rate) and initial laboratory tests, i.e. physiologic profile along with tests that measure the immune response i.e. the immunologic profile and their changes in the ribosomal nucleic acids (RNA) at the cellular level i.e. transcriptomic profile. We will also be able to better identify the cause of sepsis i.e. bacteria or non-bacteria (for e.g. viruses) using a more sensitive and faster turnaround test called nanorod PCR, which will help the ED provider in initiating appropriate treatments. We also believe that the changes in the sepsis signature over time will allow us to reliably predict which child is more at risk for developing complications and death very early in the disease course to help reduce sepsis related mortality. In order to achieve our aims, we will conduct a prospective, observational study in children (3 months ≤ 18 years of age) with suspected sepsis in the ED at a tertiary care Children’s Hospital and monitor patients through their inpatient stay (ICU, general unit). We have assembled a team of experienced investigators and have the necessary resources and expertise to achieve the goals of our project that are directly aligned with the NOSI to Advance Understanding and Management of MODS in Children. Our project is the first step towards precision medicine to improve diagnosis, guide appropriate therapies, and reliably prognosticate patient outcomes in children with sepsis.

项目摘要： 败血症，被定义为威胁生命的器官功能障碍，导致的免疫反应失调 患者感染，是小儿发病率和死亡率的主要原因。每年，败血症 〜100,000急诊室（ED）和约25-50％的败血症儿童将因并发症而死 包括冲击和多重组织功能障碍。这些不可接受的高不良结果主要是由于 我们对在细胞水平上基本的基本免疫反应过程的有限理解 参与儿科败血症。迫切需要使用 多学科团队快速准确地诊断败血症，以便可以进行适当的疗法 在急诊室启动，以降低儿童的发病率和死亡率。 我们认为，当患者首次向ED展示时，患者具有独特的“败血症”签名，我们可以 通过研究生命体征的变化（例如温度，心率）和初始 实验室测试，即生理概况以及测量免疫反应的测试，即 免疫学特征及其在细胞水平的核糖体核酸（RNA）中的变化，即 转录组轮廓。我们还将能够更好地识别败血症的原因，即细菌或非细菌（对于 例如病毒）使用称为Nanorod PCR的更灵敏，更快的周转测试，这将有助于ED 提供者开始适当的治疗。我们还认为，随着时间的流逝，败血症签名的变化 将使我们能够可靠地预测哪个孩子在很早的早期就面临着并发症和死亡的风险 疾病的病程有助于降低败血症相关的死亡率。 为了实现我们的目标，我们将对儿童进行一项前瞻性的观察性研究（3个月≤18 年龄）在第三级护理儿童医院的急诊室中怀疑败血症并监测患者 通过他们的住院住宿（ICU，一般单位）。我们组建了一个经验丰富的调查员团队， 拥有必要的资源和专业知识，以实现我们项目的目标直接与之保持一致的目标 NOSI提高对儿童Mod的理解和管理。我们的项目是第一步 迈向精确医学，以改善诊断，指导适当的疗法并可靠地探测 败血症儿童的患者结局。