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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM108618-01
Application #
8610429
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (82))
Program Officer
Dunsmore, Sarah
Project Start
2014-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$549,374
Indirect Cost
$188,116
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Davila, Sam; Halstead, E Scott; Hall, Mark W et al. (2018) Viral DNAemia and Immune Suppression in Pediatric Sepsis. Pediatr Crit Care Med 19:e14-e22
Carcillo, Joseph A; Shakoory, Bita; Simon, Dennis et al. (2018) Understanding Disseminated Intravascular Coagulation and Hepatobiliary Dysfunction Multiple Organ Failure in Hyperferritinemic Critical Illness. Pediatr Crit Care Med 19:1006-1009
Kernan, Kate F; Ghaloul-Gonzalez, Lina; Shakoory, Bita et al. (2018) Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. Genes Immun :
Carcillo, Joseph A; Podd, Bradley; Simon, Dennis W (2017) From febrile pancytopenia to hemophagocytic lymphohistiocytosis-associated organ dysfunction. Intensive Care Med 43:1853-1855
Kernan, Kate F; Carcillo, Joseph A (2017) Hyperferritinemia and inflammation. Int Immunol 29:401-409
Carcillo, Joseph A; Podd, Bradley; Aneja, Rajesh et al. (2017) Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome. Pediatr Crit Care Med 18:S32-S45
Podd, Bradley S; Simon, Dennis W; Lopez, Santiago et al. (2017) Rationale for Adjunctive Therapies for Pediatric Sepsis Induced Multiple Organ Failure. Pediatr Clin North Am 64:1071-1088
Carcillo, Joseph A; Halstead, E Scott; Hall, Mark W et al. (2017) Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome. Pediatr Crit Care Med 18:513-523
Carcillo, Joseph A; Sward, Katherine; Halstead, E Scott et al. (2017) A Systemic Inflammation Mortality Risk Assessment Contingency Table for Severe Sepsis. Pediatr Crit Care Med 18:143-150
Carcillo, Joseph A; Dean, J Michael; Holubkov, Richard et al. (2017) Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial. JPEN J Parenter Enteral Nutr 41:1325-1335

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