Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure Renewal

小儿脓毒症引起的多器官衰竭更新的炎症表型

• 批准号: 10017690
• 负责人: JOSEPH A CARCILLO
• 金额: $ 50.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017690
• 关键词: Accident and Emergency department; Address; Adenoviruses; Adult; American; Anti-Inflammatory Agents; Antibiotics; Big Data; Bioinformatics; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Coagulation Process; Complement; Computers; Cytomegalovirus; DNA; DNA Viruses; Data; Depressed mood; Development; Excision; Funding; Future; Genes; Germ; Hemorrhage; Herpesvirus 1; Home environment; Human Genetics; Human Herpesvirus 4; Human Herpesvirus 6; IV Fluid; Immune; Immunity; Incidence; Individual; Infection; Inflammation; Intensive Care Units; Interleukin-1; Interleukin-18; Interleukin-6; Kidney Failure; Knowledge; Liver Failure; Machine Learning; Macrophage activation syndrome; Mendelian disorder; Methods; Modeling; Molecular Biology; Monoclonal Antibodies; Multiple Organ Failure; National Institute of General Medical Sciences; Natural Immunity; Organ; Pathogenicity; Patients; Pediatric Intensive Care Units; Phenotype; Plasma; Plasma Exchange; Precision medicine trial; Proteins; Research Personnel; Risk; Sampling; Sepsis; Septic Shock; Specific qualifier value; Syndrome; Technology; Testing; Thrombocytopenia; Time; United States National Institutes of Health; Variant; Viremia; Virus; Virus Diseases; adaptive immunity; base; clinical biomarkers; co-infection; cohort; cytokine; design; exome; fighting; gene interaction; genetic analysis; individual patient; individualized medicine; mortality; mortality risk; novel; precision medicine; recruit; science education; septic patients; targeted treatment; trial design; virus genetics

Carcillo R01 Project Abstract Every year over 1 million American adults and children develop overwhelming infection leading to a rotting of their body we call ‘sepsis’, and death in up to 1 of 3 afflicted (www.nigms.nih.gov>NIGMS Home>Science Education). National efforts emphasizing early recognition, intravenous fluids to help organs, and antibiotics to kill infection, have reduced mortality so that now 1 of 4 die. We and others have asked the question “why do patients continue to die despite these national efforts?’ In the previous funding period we showed in 401 children with sepsis that those who developed organ shut down despite these efforts, did so because they were a) unable to fight germs causing unending infection, b) unable to stop clotting off their body causing kidney failure, and/or c) unable to kill viruses causing liver failure; all of which led to death from uncontrolled inflammation with clotting, bleeding and liver failure. Fortunately, each of these organ shutdown groups has hopeful treatments. With the new information we collected in the previous funding period we have already designed and started clinical trials testing these treatments including immune boosters for children unable to kill germs, plasma removal and replacement using plasma exchange for children unable to stop clotting, monoclonal antibodies to kill viruses and their homes to reverse liver failure in children unable to do so on their own, and anti-inflammatory proteins to reverse uncontrollable inflammation, in hopes of helping save many of the 1 of 4 children still dying from sepsis related organ shutdown. In this next funding period, we propose to use the clinical information and samples already obtained in our previous study to take advantage of the wonderful advances made this millenia in computer technology, big data, bioinformatics, and the study of human and virus genetics to perform Specific Aim 1) use a ‘Watson’ like approach to ask the computer to help us figure out if the children with sepsis have any other causes of organ shutdown that we can help, Specific Aim 2) use an ‘Ancestry.com’-like or ‘23 and me’-like approach to identify ‘precision medicine’ therapies for causes of organ shutdown that we can treat on a patient by patient basis, and Specific Aim 3) use a bedside molecular biology test approach to identify individualized therapies to kill DNA viruses and reduce cytokine inflammation. We think that DNA viruses are the unappreciated co-infection which causes uncontrolled cytokine inflammation and leads to organ shutdown. Our long term objective is to plan ‘precision’ medicine and ‘individualized’ medicine clinical trials testing therapies on an individual patient basis in order to further reduce death from sepsis organ shutdown in children.

Carcillo R 01项目摘要 每年有超过100万的美国成年人和儿童发展成压倒性的感染， 我们称之为“败血症”的身体腐烂， （www.nigms.nih.gov>NIGMS Home>Science Education）.国家努力强调尽早 认识，静脉输液，以帮助器官，抗生素杀死感染，已经减少了 所以现在四分之一的人会死我们和其他人问过这样一个问题：“为什么病人 尽管有这些国家的努力，他们仍然死亡？”在上一个融资期， 401名患有败血症的儿童，尽管做出了这些努力， 因为它们a）无法对抗细菌，导致无休止的感染，B）无法阻止 使其身体凝血，引起肾衰竭，和/或c）不能杀死引起肝衰竭的病毒; 所有这些都导致了不受控制的炎症，凝血，出血和肝功能衰竭的死亡。 幸运的是，这些器官关闭小组中的每一个都有希望的治疗方法。与新 我们在上一个资助期收集的信息，我们已经设计并开始 临床试验测试这些治疗方法，包括免疫增强剂，为儿童不能杀死 细菌，血浆清除和更换使用血浆置换的儿童无法停止 凝血，单克隆抗体杀死病毒和他们的家园，以扭转肝功能衰竭的儿童 无法做到这一点，对自己和抗炎蛋白逆转不可控 炎症，希望帮助拯救仍死于败血症相关疾病的四分之一儿童中的许多人 器官衰竭在下一个资助期内，我们建议使用临床信息， 在我们之前的研究中已经获得的样本，以利用这些惊人的进步， 在计算机技术、大数据、生物信息学以及人类和 病毒遗传学执行特定目标1）使用“沃森”式方法要求计算机 帮助我们弄清楚败血症患儿是否有其他原因导致器官衰竭， 可以帮助，具体目标2）使用类似于“23和我”的方法来识别 针对器官关闭原因的“精准医学”疗法，我们可以通过以下方式治疗患者 患者基础和特定目标3）使用床边分子生物学测试方法来识别 个体化治疗，以杀死DNA病毒和减少细胞因子炎症。我们认为 DNA病毒是一种不受重视的合并感染，它导致细胞因子失控 炎症并导致器官关闭。我们的长期目标是“精准规划” 医学和“个体化”医学临床试验，在个体患者身上测试治疗方法 在此基础上，进一步减少儿童脓毒症器官关闭的死亡。