. 2023 Sep 6;27(1):347.

doi: 10.1186/s13054-023-04628-x.

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

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.

PMID: 37674218
PMCID: PMC10481565
DOI: 10.1186/s13054-023-04628-x

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

Zhenziang Fan et al. Crit Care. 2023.

. 2023 Sep 6;27(1):347.

doi: 10.1186/s13054-023-04628-x.

Authors

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.

PMID: 37674218
PMCID: PMC10481565
DOI: 10.1186/s13054-023-04628-x

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.

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Conflict of interest statement

The authors had no competing interest but they did have the following. Authors Carcillo, Berg, Wessel, Pollack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, and Dean received support for article research from the NICHD. Dr. Carcillo and Dr Park’s institutions also received funding from the National Institute of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from LaJolla Pharmaceuticals (service as a consultant), unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor’s institution received funding from the Department of Defense and Kalocyte. Dr. Shanley received funding from Springer publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is co-founder of Pre-Dixon Bio. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

**Fig. 1**
Mortality and virus DNAemia count distribution by ferritin level and MAS category A Mortality distribution according to ferritin category; B Mortality distribution by MAS (macrophage activation syndrome) category; C Number of circulating DNA viruses (count) by ferritin categories; D Number of circulating DNA viruses by MAS (macrophage activation syndrome) category

**Fig. 2**
Cytokine heatmap of ferritin categories and MAS—The heatmap shows the log ratio of the median biomarker values for various markers of the host response and their hierarchical cluster relationships. Red represents a greater median biomarker value for that phenotype compared with the median for the entire study cohort, whereas blue represents a lower median biomarker value compared with the median for the entire study cohort

**Fig. 3**
Full causal pathway directed acyclic graph analysis of all causal associations found among cytokines, viral DNAemia, hyperferritinemia, MAS, and death. Causal analysis revealed the associations among all variables/outcomes. Red arrows denote a positive causal association (increased variable/outcome: increased variable/outcome), and blue arrows denote a negative causal association (increased variable/outcome: decreased variable outcome). Arrows denote direction of causality

**Fig. 4**
Abridged causal pathway directed acyclic graph analysis of eight cytokines with MAS, hyperferritinemia, and death. Causal analysis revealed the associations among variables/ outcomes. Red arrows denote a positive causal association (increased variable/outcome: increased variable/outcome), and blue arrows denote a negative causal association (increased variable/outcome: decreased variable outcome). Arrows denote direction of causality

See this image and copyright information in PMC

References

1. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–211. - PMC - PubMed
1. Garcia PC, Longhi F, Branco RG, Piva JP, Lacks D, Tasker RC. Ferritin levels in children with severe sepsis and septic shock. Acta Paediatr. 2007;96:1829–1831. - PubMed
1. Tonial CT, Costa CAD, Andrades GRH, et al. Prediction of poor outcomes for septic children according to ferritin levels in a middle-income setting. Pediatr Crit Care Med. 2020;21:e259–e266. - PubMed
1. Carcillo JA, Sward K, Halstead ES, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative pediatric critical care research network investigators: a systemic inflammation mortality risk assessment contingency table for severe sepsis. Pediatr Crit Care Med. 2017;18:143–150. - PMC - PubMed
1. Horvat CM, Bell J, Kantawala S, et al. C-reactive protein and ferritin are associated with organ dysfunction and mortality in hospitalized children. Clin Pediatr (Phila) 2019;58:752–760. - PMC - PubMed

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

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

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