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.

Public Health Relevance

Despite immunizations, deaths from overwhelming infection leading to failure of many vital organs remains the second leading cause of death in America's children and the leading cause in children globally. Presently, we direct therapy to killing the germ and supporting organ function while ignoring inflammation. Our study will document whether inflammation is related to failing organs. This insight will provide evidence for a paradigm shift to investigate use of inflammation directed therapies to reduce child morbidity and mortality from sepsis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-V (82))
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Dunsmore, Sarah
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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