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

doi:10.1186/s13054-023-04628-x

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis

Crit Care. 2023 Sep 6;27(1):347. doi: 10.1186/s13054-023-04628-x.

Authors

Zhenziang Fan¹, Kate F Kernan², Yidi Qin³, Scott Canna⁴, Robert A Berg⁵, David Wessel⁶, Murray M Pollack⁶, Kathleen Meert^{7

8}, Mark Hall⁹, Christopher Newth¹⁰, John C Lin¹¹, Allan Doctor¹¹, Tom Shanley¹², Tim Cornell¹², Rick E Harrison¹³, Athena F Zuppa⁵, Katherine Sward¹⁴, J Michael Dean¹⁴, H J Park³, Joseph A Carcillo¹⁵

Affiliations

¹ Department of Computer Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
² 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, Suite 2000, 4400 Penn Avenue, Pittsburgh, PA, 15421, USA.
³ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Anesthesiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶ Division of Critical Care Medicine, Department of Pediatrics, Children's National Hospital, Washington, DC, USA.
⁷ Division of Critical Care Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA.
⁸ Central Michigan University, Mt Pleasant, MI, USA.
⁹ Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital Immune Surveillance Laboratory, and Nationwide Children's Hospital, Columbus, OH, USA.
¹⁰ Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹¹ Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO, USA.
¹² Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, Ann Arbor, MI, USA.
¹³ Division of Critical Care Medicine, Department of Pediatrics, Mattel Children's Hospital at University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
¹⁵ 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, Suite 2000, 4400 Penn Avenue, Pittsburgh, PA, 15421, USA. carcilloja@ccm.upmc.edu.

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.

Keywords: Hyperferritinemic sepsis; Immunoparalysis; Macrophage activation syndrome; Multiple organ failure; Severe sepsis; Thrombocytopenia-associated multiple organ failure.

MeSH terms

Child
Cytokines
Ferritins
Humans
Hyperferritinemia*
Macrophage Activation Syndrome* / complications
Sepsis* / complications

Substances

Cytokines
Ferritins

Abstract

MeSH terms

Substances

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