Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis
Zhenziang Fan,
Kate F. Kernan,
Yidi Qin,
Scott Canna,
Robert A. Berg,
David Wessel,
Murray M. Pollack,
Kathleen Meert,
Mark Hall,
Christopher Newth,
John C. Lin,
Allan Doctor,
Tom Shanley,
Tim Cornell,
Rick E. Harrison,
Athena F. Zuppa,
Katherine Sward,
J. Michael Dean,
H. J. Park,
Joseph A. Carcillo
Affiliations
Zhenziang Fan
Department of Computer Sciences, University of Pittsburgh
Kate F. Kernan
Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Faculty Pavilion, Children’s Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, University of Pittsburgh
Yidi Qin
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
Scott Canna
Department of Pediatrics, Children’s Hospital of Pittsburgh
Robert A. Berg
Department of Anesthesiology, Children’s Hospital of Philadelphia
David Wessel
Division of Critical Care Medicine, Department of Pediatrics, Children’s National Hospital
Murray M. Pollack
Division of Critical Care Medicine, Department of Pediatrics, Children’s National Hospital
Kathleen Meert
Division of Critical Care Medicine, Department of Pediatrics, Children’s Hospital of Michigan
Mark Hall
Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children’s Hospital Immune Surveillance Laboratory, and Nationwide Children’s Hospital
Christopher Newth
Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children’s Hospital Los Angeles
John C. Lin
Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children’s Hospital
Allan Doctor
Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children’s Hospital
Tom Shanley
Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children’s Hospital
Tim Cornell
Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children’s Hospital
Rick E. Harrison
Division of Critical Care Medicine, Department of Pediatrics, Mattel Children’s Hospital at University of California Los Angeles
Athena F. Zuppa
Department of Anesthesiology, Children’s Hospital of Philadelphia
Katherine Sward
Department of Pediatrics, University of Utah
J. Michael Dean
Department of Pediatrics, University of Utah
H. J. Park
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
Joseph A. Carcillo
Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Faculty Pavilion, Children’s Hospital of Pittsburgh, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, University of Pittsburgh
Abstract Background One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network’s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. Methods We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. Results Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55–9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. Conclusions These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
