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: 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
• 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

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(申请人提供)：压倒性感染和败血症导致许多重要器官衰竭，仍然是美国儿童和儿童死亡的主要原因。 在世界各地。目前的管理包括使用抗生素杀灭细菌，以及在没有任何基于炎症的治疗的标准使用的情况下，对衰竭的器官使用器官支持机。在接受这种标准护理方法的儿童中，许多人活着，但太多的人死亡。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从风湿病引起的炎症引起的多系统器官衰竭中使用非常不同的方法来获得洞察力。儿科风湿病的护理标准是确定风湿病特有的炎症病理生物学表型，然后使用针对表型的治疗，以减少C-反应蛋白(CRP)和铁蛋白等生物标记物反映的炎症。在脓毒症中检查这一范式，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死亡有关。此外，这些表型中的C反应蛋白和铁蛋白反应的演变与预后有关。我们建议通过对NICHD合作儿科重症监护研究网络(CPCCRN)内招募的400名脓毒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，该研究涉及三个具体目标：1)确定三种独特的败血症MOF表型的发生率和结果：由三个器官衰竭定义的血小板减少相关性多器官衰竭伴新发的血小板减少、肾功能障碍和ADAMTS 13活动；57%；免疫麻痹/淋巴耗竭相关的多器官功能衰竭，定义为体外全血内毒素刺激的肿瘤坏死因子反应；三天后为200pg/毫升；以及连续性多器官功能衰竭，定义为呼吸窘迫，随后是sFasL水平和GT；在严重脓毒症的儿童中，C反应蛋白浓度为200 ng/mL；2)确定遗传和环境风险因素在这三种败血症诱导的多器官功能衰竭表型中的相对作用；3)证明由CRP和/或铁蛋白水平反映的全身炎症在这些脓毒症诱导的多器官功能衰竭表型中增加，随着时间的推移，C反应蛋白和铁蛋白水平的变化与预后相关。如果国家结果被发现与这种炎症病理生物学和全身炎症生物标记物反应谱有关，那么将有必要进一步研究针对严重脓毒症引起的多器官功能衰竭的儿童使用表型特异性治疗以使CRP和铁蛋白水平正常化。