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

• 批准号: 8610429
• 负责人: JOSEPH A CARCILLO
• 金额: $ 54.94万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610429
• 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; 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 Operator 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; public health relevance; respiratory; response; standard of care; treatment strategy; von Willebrand Factor

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 were 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.

导致许多重要器官衰竭的压倒性感染和败血症仍然是 美国儿童和全世界儿童的死亡率。目前的管理包括抗生素致死 细菌和使用器官支持机治疗衰竭器官，而不是任何标准的炎症使用 以治疗为基础。在接受这种标准护理方法的儿童中，许多人活着，但太多了 其他人会死。造成这些不同结果的原因仍然是一个重要的知识鸿沟。我们想知道 是否可以通过考虑在引起炎症时使用的非常不同的方法来获得洞察力 风湿病引起的多系统器官衰竭。儿科风湿病的护理标准 确定风湿性疾病特有的炎症病理生物学表型，然后使用表型 针对C-反应蛋白(CRP)等生物标志物反映的炎症的特定治疗 还有铁蛋白。在脓毒症患者中，我们进行了一项单中心研究，发现有三个 脓毒症特有的炎症病理生物学表型与多器官衰竭死亡有关。 此外，这些表型中的CRP和铁蛋白反应的演变与预后相关。 我们建议通过执行一项调查来评估这些观察结果对全国儿童的临床相关性 NICHD儿科协作中心招募的400例脓毒症患者的观察性队列研究 重症监护研究网络(CPCCRN)针对三个具体目标： 1)确定脓毒症多器官功能衰竭的三种独特表型：血小板减少症的发生率和结局 相关多器官功能衰竭由三个器官衰竭定义，包括新发的血小板减少症、肾功能不全、 和ADAMTS 13活性&lt；57%；免疫麻痹/淋巴衰竭相关的MOF，定义如下 体外全血内毒素刺激的肿瘤坏死因子反应3天后为200pg/mL； 多器官功能衰竭的定义是呼吸窘迫，随后是肝功能障碍，sFasL水平&gt；200 ng/mL，in 严重脓毒症患儿； 2)确定遗传和环境风险因素对发展的相对贡献 这三种败血症均可诱导多器官功能衰竭表型； 3)证明由C反应蛋白和/或铁蛋白水平反映的全身炎症在 这些脓毒症的儿童诱导多器官功能衰竭表型，并随时间改变CRP和铁蛋白水平 与结果相关。 如果国家的结果被发现与这种炎症、病理生物学和全身性疾病的范围有关 炎症生物标记物的反应，然后进一步研究表型特异性治疗的使用 严重脓毒症所致多器官功能衰竭患儿的C反应蛋白和铁蛋白水平正常化是必要的。