Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure

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死亡的主要原因， 世界各地。目前的管理包括抗生素来杀死细菌和使用器官支持机器来治疗器官衰竭，而没有任何标准的基于炎症的治疗。在接受这种标准护理方法的儿童中，许多人活了下来，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由风湿性疾病引起的炎症诱导的多系统器官衰竭中使用的非常不同的方法来获得见解。儿科风湿病的标准治疗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，旨在减少由生物标志物（如C反应蛋白（CRP）和铁蛋白）反映的炎症。在脓毒症中检查这种范例，我们进行了单中心研究，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死亡相关。此外，这些表型中CRP和铁蛋白反应的演变与结局相关。我们建议通过在NICHD协作儿科重症监护研究网络（CPCCRN）内招募的400名脓毒症患者中进行观察性队列研究，评估这些观察结果与全国儿童的临床相关性，解决三个具体目标：1）确定三种独特脓毒症MOF表型的发生率和结局：血小板减少症相关的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反应< 200 pg/mL;严重脓毒症患儿中sFasL水平> 200 ng/mL的序贯性MOF定义为呼吸窘迫伴肝功能障碍; 2）确定遗传和环境危险因素对这三种脓毒症诱导的MOF表型中的每一种的发展的相对贡献;和3）证明由CRP和/或铁蛋白水平反映的全身炎症在具有这些脓毒症诱导的MOF表型的儿童中增加，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生物学谱和全身炎症生物标志物反应相关，则需要进一步研究使用表型特异性治疗来使患有严重脓毒症诱导的MOF的儿童的CRP和铁蛋白水平正常化。

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.