Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure

小儿脓毒症引起的多器官衰竭的炎症表型

基本信息

批准号：
8795738
负责人：
JOSEPH A CARCILLO
金额：
$ 52.35万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795738
关键词：
ADAMTS Accounting Address Americas Animal Model Antibiotics Bacterial Infections Biological Markers Blood Platelets C-reactive protein Catheters Cause of Death Cell Death Cessation of life Child Childhood Clinical Coagulation Process Cohort Studies Critical Care Cytotoxic T-Lymphocytes Development Disease Endotoxins Enrollment Environmental Risk Factor Evolution Failure Ferritin Functional disorder Future Gene Mutation Genetic Risk Genotype Germ Health Hemoglobin Histiocytosis haematophagic Human Immune Immunization Incidence Infection Inflammation Interleukin-10 Kidney Knowledge L-ferritin Life Liver Dysfunction Liver Failure Logistic Regressions Lymphocyte Function Lymphoid Malignant Neoplasms Measures Mediating Modeling Morbidity - disease rate Multiple Organ Failure Mycoses National Institute of Child Health and Human Development Organ Organ failure Outcome Patients Phenotype Plasma Exchange Population Receiver Operating Characteristics Recruitment Activity Relative (related person)Research Respiratory distress Rheumatology Risk Risk Factors Sampling Sepsis Syndrome System TNF gene Testing Thrombocytopenia Time United States Venous Virus Virus Diseases Whole Blood base clinically relevant genetic profiling genetic risk factor immunoregulation improved innate immune function insight killings liver injury mortality perforin respiratory response standard of care targeted treatment treatment strategy von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Overwhelming infection and sepsis causing many vital organs to fail remains a leading cause of mortality in America's children and in children the world over. Present management includes antibiotics to kill germs and the use of organ support machines for failing organs without any standard use of inflammation based therapies. Among the children who receive this standard of care approach many live but too many others die. The reasons for these divergent outcomes remain an important knowledge gap. We wondered whether insight might be gained from considering the very different approach used in inflammation induced multi system organ failure caused by rheumatologic disease. Standard of care in pediatric rheumatology identifies inflammation pathobiology phenotypes unique to rheumatologic disease and then uses phenotype specific therapies directed to reducing inflammation reflected by biomarkers such as C-reactive protein (CRP) and ferritin. Examining this paradigm in sepsis, we performed a single center study and found that three inflammation pathobiology phenotypes unique to sepsis were related to death from multiple organ failure. Furthermore, evolution of CRP and ferritin responses within these phenotypes was associated with outcome. We propose to assess the clinical relevance of these observations to the nation's children by performing an observational cohort study in 400 sepsis patients recruited from within the NICHD Collaborative Pediatric Critical Care Research Network (CPCCRN) addressing three specific aims: 1) Determine the incidence and outcomes of three unique sepsis MOF phenotypes: Thrombocytopenia Associated MOF defined by three organ failure with new onset thrombocytopenia, renal dysfunction, and an ADAMTS 13 activity < 57%; Immunoparalysis / Lymphoid Depletion associated MOF defined by an ex vivo whole blood endotoxin stimulated TNF response < 200 pg/mL after 3 days; and Sequential MOF defined by respiratory distress followed by liver dysfunction with sFasL level > 200 ng/mL, in children with severe sepsis; 2) Determine the relative contribution of genetic and environmental risk factors to the development of each of these three sepsis induced MOF phenotypes; and 3) Demonstrate that systemic inflammation reflected by CRP and / or Ferritin levels is increased in children with these sepsis induced MOF phenotypes with changes in CRP and Ferritin levels over time being associated with outcomes. If national outcomes are found to be related to this spectrum of inflammation pathobiology and systemic inflammation biomarker responses then further studies of use of phenotype specific therapies directed to normalizing CRP and Ferritin levels in children with severe sepsis induced MOF will be warranted.

描述（由申请人提供）：导致许多重要器官衰竭的压倒性感染和败血症仍然是美国儿童和儿童死亡的主要原因。世界各地。目前的治疗方法包括使用抗生素来杀死细菌，以及使用器官支持机器来治疗衰竭的器官，而没有任何基于炎症的标准疗法。在接受这种标准护理方法的儿童中，许多人存活下来，但也有太多人死亡。这些不同结果的原因仍然是一个重要的知识差距。我们想知道是否可以通过考虑在风湿病引起的炎症引起的多系统器官衰竭中使用的截然不同的方法来获得见解。儿科风湿病的护理标准确定风湿病特有的炎症病理生物学表型，然后使用表型特异性疗法来减少 C 反应蛋白 (CRP) 和铁蛋白等生物标志物反映的炎症。为了检验脓毒症中的这一范例，我们进行了一项单中心研究，发现脓毒症特有的三种炎症病理生物学表型与多器官衰竭导致的死亡相关。此外，这些表型内 CRP 和铁蛋白反应的演变与结果相关。我们建议通过对从 NICHD 儿科重症监护协作研究网络 (CPCCRN) 招募的 400 名败血症患者进行观察性队列研究来评估这些观察结果与全国儿童的临床相关性，该研究旨在解决三个具体目标：1) 确定发病率和结果三种独特的脓毒症 MOF 表型：血小板减少症相关 MOF 定义为三种器官衰竭，伴有新发血小板减少症、肾功能障碍和 ADAMTS 13 活性 < 57%；免疫麻痹/淋巴耗竭相关的 MOF 定义为离体全血内毒素刺激的 TNF 反应 3 天后 < 200 pg/mL；序贯 MOF 定义为患有严重脓毒症的儿童呼吸窘迫，随后出现 sFasL 水平 > 200 ng/mL 的肝功能障碍； 2) 确定遗传和环境风险因素对这三种败血症诱导的 MOF 表型的发展的相对贡献； 3) 证明患有脓毒症诱导的 MOF 表型的儿童中 CRP 和/或铁蛋白水平反映的全身炎症增加，CRP 和铁蛋白水平随时间的变化与结果相关。如果发现国家结果与炎症病理学和全身炎症生物标志物反应相关，那么有必要进一步研究使用表型特异性疗法来使患有严重败血症诱发的 MOF 的儿童的 CRP 和铁蛋白水平正常化。