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主要原因