EV Sepsis Natural History

EV脓毒症自然史

• 批准号: 10248358
• 负责人: DAVID W KIMBERLIN
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248358
• 关键词: Activated Partial Thromboplastin Time measurement; Adenoviruses; Alanine Transaminase; Antiviral Agents; Aspartate Transaminase; Bilirubin; Biological Markers; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Urea Nitrogen; Blood specimen; California; Case Series; Child; Clinical; Clinical Research; Coagulation Process; Creatinine; Cytomegalovirus; Data; Development; EFRAC; Echocardiography; Enrollment; Ensure; Enterovirus; Etiology; Fibrin fragment D; Funding; Future; Hematocrit procedure; Hemoglobin; Hepatitis; Human; Infant; Infection; Knowledge; Laboratories; Life; Literature; Meningoencephalitis; Methodology; Molecular Diagnostic Testing; Morbidity - disease rate; Myocarditis; Natural History; Neonatal; Neonatal Mortality; Organ; Outcome; Parechovirus; Pattern; Performance; Perinatal Infection; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Platelet Count measurement; Polymerase Chain Reaction; Population; Prothrombin time assay; Publishing; Pulmonary Inflammation; Rare Diseases; Recording of previous events; Sample Size; San Francisco; Sepsis; Severity of illness; Shortening Fraction; Simplexvirus; Specimen; Survivors; Syndrome; Technology; Therapeutic Trials; Thrombocytopenia; Time; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Viral Load result; Viremia; Virus; White Blood Cell Count procedure; adverse outcome; clinical trial readiness; congenital infection; design; efficacy study; experience; follow-up; improved; improved outcome; inclusion criteria; interest; mortality; neonatal human; neonate; next generation sequencing; novel; pathogen; population based; prospective; rare condition; tool; trial readiness

This study, Neonatal Enterovirus and Human Parechovirus Viral Sepsis: Natural History and Predictors of Morbidity and Mortality, is scientifically led by Mark Abzug, MD. Neonatal viral sepsis is a clinical syndrome characterized by a constellation of organ involvement that includes hepatitis, coagulopathy (thrombocytopenia with or without derangement of clotting times), and/or myocarditis, sometimes occurring in concert with meningoencephalitis or pneumonitis. Although a number of viruses can cause neonatal viral sepsis, including herpes simplex virus (HSV), cytomegalovirus (CMV), and adenovirus, two of the most frequent causes are enteroviruses (EVs) and human parechoviruses (HPeVs). Antiviral treatment for neonatal EV or HPeV sepsis is needed, but not yet commercially available. The design of future antiviral trials for neonatal viral sepsis would greatly benefit from a better understanding of the natural history of this serious, but rare, condition. More precise definition of rates of long-term morbidity and mortality associated with neonatal EV and HPeV sepsis, and better delineation of clinical and laboratory parameters that are predictive of adverse outcomes, are important to inform the optimal design of therapeutic trials, including issues such as appropriate endpoints, sample size, and inclusion criteria. The potential utility of quantitative PCR (qPCR) or other laboratory biomarkers to predict severity of illness, long-term sequelae, or mortality in these illnesses is currently unknown. If qPCR was shown to be a useful predictor of or surrogate for clinical outcomes, this could greatly facilitate the performance of therapeutic trials. Finally, studies to date suggest that a portion of children presenting clinically with neonatal viral sepsis do not have EVs, HPeVs, or other known viruses. It is important to better understand the full spectrum of etiologic agents using state-of-the-art tools for pathogen discovery. The proposed study is designed to fill in these gaps in our knowledge about neonatal viral sepsis to advance trial readiness for the anticipated development of antiviral treatment therapy for this condition. This will be accomplished by evaluating the following specific aims: 1) to estimate the morbidity and mortality rates of neonatal EV sepsis and neonatal HPeV sepsis; 2) to identify clinical and laboratory parameters, including quantitative polymerase chain reaction (qPCR), predictive of morbidity and mortality from neonatal EV and neonatal HPeV sepsis; and 3) to determine the etiologies of neonatal viral sepsis not due to EV, HPeV, HSV, CMV, and adenovirus using next-gen sequencing for pathogen discovery. The systematic prospective multicenter assessment of neonatal viral sepsis, including EV and HPeV sepsis, will produce data that can be used in the design of future Phase I, II, and III treatment studies with antiviral drugs currently in development by pharmaceutical companies, such as KYORIN Pharmaceutical Co., Ltd., and Vaxart, Inc.

这项研究，新生儿肠道病毒和人类副肠孤病毒病毒性脓毒症：自然史和预测因素 发病率和死亡率由医学博士 Mark Abzug 科学领导。新生儿病毒性败血症是一种临床综合征 其特点是一系列器官受累，包括肝炎、凝血病（血小板减少症） 有或没有凝血时间紊乱）和/或心肌炎，有时与 脑膜脑炎或肺炎。尽管许多病毒可引起新生儿病毒性败血症，包括 单纯疱疹病毒 (HSV)、巨细胞病毒 (CMV) 和腺病毒，其中两个最常见的原因是 肠道病毒（EV）和人类副肠病毒（HPeV）。新生儿 EV 或 HPeV 败血症的抗病毒治疗 需要，但尚未商业化。新生儿病毒性败血症的未来抗病毒试验的设计 更好地了解这种严重但罕见的疾病的自然史将大大受益。 更精确地定义与新生儿 EV 和 HPeV 相关的长期发病率和死亡率 败血症，以及更好地描述可预测不良结果的临床和实验室参数， 对于指导治疗试验的最佳设计非常重要，包括适当的终点等问题， 样本量和纳入标准。定量 PCR (qPCR) 或其他实验室的潜在用途 目前正在开发用于预测这些疾病的疾病严重程度、长期后遗症或死亡率的生物标志物 未知。如果 qPCR 被证明是临床结果的有用预测指标或替代指标，这可能会极大地促进临床结果的发展。 促进治疗试验的进行。最后，迄今为止的研究表明，部分儿童 临床上表现为新生儿病毒性败血症的患者不存在 EV、HPeV 或其他已知病毒。这很重要 使用最先进的病原体发现工具更好地了解全部病原体。 拟议的研究旨在填补我们关于新生儿病毒性败血症的知识空白，以推进 为针对这种情况的抗病毒治疗的预期发展做好试验准备。这将是 通过评估以下具体目标来实现：1）估计发病率和死亡率 新生儿 EV 败血症和新生儿 HPeV 败血症； 2) 确定临床和实验室参数，包括 定量聚合酶链反应 (qPCR)，预测新生儿 EV 的发病率和死亡率 新生儿 HPeV 败血症； 3) 确定并非由 EV、HPeV、HSV 引起的新生儿病毒性败血症的病因， CMV 和腺病毒使用下一代测序来发现病原体。系统化前瞻性 对新生儿病毒性败血症（包括 EV 和 HPeV 败血症）的多中心评估将产生可用于 用于设计当前正在开发的抗病毒药物的未来 I、II 和 III 期治疗研究 由 KYORIN Pharmaceutical Co., Ltd. 和 Vaxart, Inc. 等制药公司开发。