TY - JOUR
T1 - Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network
T2 - a causal inference analysis
AU - Fan, Zhenziang
AU - Kernan, Kate F.
AU - Qin, Yidi
AU - Canna, Scott
AU - Berg, Robert A.
AU - Wessel, David
AU - Pollack, Murray M.
AU - Meert, Kathleen
AU - Hall, Mark
AU - Newth, Christopher
AU - Lin, John C.
AU - Doctor, Allan
AU - Shanley, Tom
AU - Cornell, Tim
AU - Harrison, Rick E.
AU - Zuppa, Athena F.
AU - Sward, Katherine
AU - Dean, J. Michael
AU - Park, H. J.
AU - Carcillo, Joseph A.
N1 - Funding Information:
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.
Funding Information:
Clinical Research Investigation and Systems Modeling of Acute illness center: Ali Smith, BS; Octavia Palmer, MD; Vanessa Jackson, AA; Renee Anderko, BS, MS. Children’s Hospital of Pittsburgh: Jennifer Jones, RN; Luther Springs. Children’s Hospital of Philadelphia: Carolanne Twelves, RN, BSN, CCRC; Mary Ann Diliberto, BS, RN, CCRC; Martha Sisko, BSN, RN, CCRC, MS; Pamela Diehl, BSN, RN; Janice Prodell, RN, BSN, CCRC; Jenny Bush, RNC, BSN; Kathryn Graham, BA; Kerry Costlow, BS; Sara Sanchez. Children’s National Hospital: Elyse Tomanio, BSN, RN; Diane Hession, MSN, RN; Katherine Burke, BS. Children’s Hospital of Michigan, Central Michigan University: Ann Pawluszka, RN, BSN; Melanie Lulic, BS. Nationwide Children’s Hospital: Lisa Steele, RN, CCRC; Andrew R. Yates, MD; Josey Hensley, RN; Janet Cihla, RN; Jill Popelka, RN; Lisa Hanson-Huber, BS. Children’s Hospital Los Angeles and Mattel Children’s Hospital: Jeni Kwok, JD; Amy Yamakawa, BS. Children’s Hospital of Washington University of Saint Louis: Michelle Eaton, RN. Mott Children’s Hospital: Frank Moler, MD; Chaandini Jayachandran, MS, CCRP. University of Utah Data Coordinating Center: Teresa Liu, MPH, CCRP; Jeri Burr, MS, RN-BC, CCRC, FACRP; Missy Ringwood, BS, CMC; Nael Abdelsamad, MD, CCRC; Whit Coleman, MSRA, BSN, RN, CCRC. For information regarding this article, E-mail: carcilloja@ccm.upmc.edu and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
Funding Information:
Supported, in part, by grant R01GM108618 (to Dr. Carcillo and Dr Park) and 1K23GM148827-01 (to Dr Kernan) from the National Institute of General Medical Sciences, and by 5U01HD049934-10S1 (to Dr Carcillo), from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Hyperferritinemic sepsis
KW - Immunoparalysis
KW - Macrophage activation syndrome
KW - Multiple organ failure
KW - Severe sepsis
KW - Thrombocytopenia-associated multiple organ failure
UR - http://www.scopus.com/inward/record.url?scp=85169813353&partnerID=8YFLogxK
U2 - 10.1186/s13054-023-04628-x
DO - 10.1186/s13054-023-04628-x
M3 - Article
AN - SCOPUS:85169813353
SN - 1364-8535
VL - 27
JO - Critical Care
JF - Critical Care
IS - 1
M1 - 347
ER -