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.

压倒性的感染和败血症导致许多重要器官衰竭仍然是导致糖尿病的主要原因。 美国儿童和全世界儿童的死亡率。目前的管理包括抗生素杀死 细菌和使用器官支持机器来支持衰竭的器官，而没有任何标准的炎症使用 基础疗法。在接受这种标准护理方法的儿童中， 其他人会死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炎症诱导中使用的非常不同的方法来获得见解， 风湿性疾病引起的多系统器官衰竭。儿科风湿病标准治疗 确定风湿性疾病特有的炎症病理生物学表型， 针对减少由生物标志物如C-反应蛋白（CRP）反映的炎症的特定疗法 和铁蛋白。在脓毒症中检查这种范式，我们进行了一项单中心研究，发现三个 脓毒症特有的炎症病理生物学表型与多器官衰竭的死亡有关。 此外，这些表型中CRP和铁蛋白反应的演变与结局相关。 我们建议通过执行一项研究来评估这些观察结果对全国儿童的临床相关性。 在NICHD协作儿科招募的400例脓毒症患者中进行的观察性队列研究 重症监护研究网络（CPCCRN）致力于三个具体目标： 1)确定三种独特的脓毒症MOF表型的发生率和结局：血小板减少症 相关MOF定义为三个器官衰竭伴新发血小板减少症、肾功能不全， 和ADAMTS 13活性< 57%;免疫麻痹/类磷脂消耗相关的MOF定义为 3天后离体全血内毒素刺激的TNF应答< 200 pg/mL;和 MOF定义为呼吸窘迫伴肝功能障碍，sFasL水平> 200 ng/mL， 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， 这三种脓毒症中的每一种都诱导了MOF表型;以及 3)证明CRP和/或铁蛋白水平反映的全身性炎症在以下情况下增加： 这些脓毒症患儿可诱导MOF表型，CRP和铁蛋白水平随时间发生变化 与结果相关。 如果发现国家结果与炎症病理生物学和全身性疾病谱相关， 炎症生物标志物反应，然后进一步研究针对以下的表型特异性疗法的使用： 在患有严重脓毒症诱导的MOF的儿童中使CRP和铁蛋白水平正常化将是必要的。