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: 10207661
• 负责人: JOSEPH A CARCILLO
• 金额: $ 41.62万
• 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/10207661
• 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; 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; systemic inflammatory response; targeted treatment; thrombotic; 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 R01项目摘要 每年有100多万美国成年人和儿童患上压倒性的感染 来腐烂他们的身体，我们称之为‘败血症’，死亡在高达三分之一的痛苦 (www.nigms.nih.gov&gt；NIGMS Home&gt；科学教育)。强调及早的国家努力 认知、静脉输液帮助器官，以及抗生素杀死感染，都减少了 死亡率，所以现在每4人中就有1人死亡。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，还是会继续死亡吗？在上一个资助期中，我们在 401名患有败血症的儿童，尽管做出了这些努力，但那些发展出器官的人还是这样做了 因为他们a)无法对抗引起无休止感染的细菌，b)无法阻止 身体凝结导致肾衰竭，和/或c)无法杀死导致肝功能衰竭的病毒； 所有这些都导致了不受控制的炎症和凝血、出血和肝功能衰竭而死亡。 幸运的是，这些器官关闭组中的每一个都有很有希望的治疗方法。带着新的 我们在前一个资助期收集的信息我们已经设计并开始 测试这些治疗方法的临床试验，包括为无法杀死的儿童提供免疫增强剂 使用血浆置换对无法停止的儿童进行细菌、血浆清除和置换 凝血、单抗杀死病毒及其家园以逆转儿童肝功能衰竭 无法自行做到这一点，抗炎蛋白逆转无法控制 炎症，希望帮助挽救仍因脓毒症而死亡的四分之一儿童中的许多人 器官关闭。在下一个资助期，我们建议使用临床资料和 在我们之前的研究中已经获得的样本，以利用这一奇妙的进展 在计算机技术、大数据、生物信息学以及对人类和 病毒遗传学以实现特定目的1)使用类似华生的方法来要求计算机 帮助我们找出脓毒症儿童是否有任何其他导致器官衰竭的原因 可以提供帮助，明确目标2)使用类似Ancestry.com或23 and Me的方法来确定 我们可以用来治疗病人的器官衰竭原因的精准医学疗法 以患者为基础和特定目标3)使用床边分子生物学测试方法来确定 个体化治疗可杀死DNA病毒并减少细胞因子炎症。我们认为 DNA病毒是一种未被认识的混合感染，可导致不受控制的细胞因子 发炎并导致器官衰竭。我们的长期目标是计划“精准” 药物和“个体化”药物临床试验在个别患者身上测试疗法 为进一步减少儿童败血症器官衰竭死亡提供依据。