TY - JOUR
T1 - Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation
AU - Lindell, Robert B.
AU - Zhang, Donglan
AU - Bush, Jenny
AU - Wallace, Douglas C.
AU - Rabinowitz, Joshua D.
AU - Lu, Wenyun
AU - Wherry, E. John
AU - Weiss, Scott L.
AU - Henrickson, Sarah E.
N1 - Funding Information:
Financial support was provided by NIGMS K23GM110496, the Endowed Chair, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, and the University of Pennsylvania Perelman School of Medicine. Dr. Lindell is also supported by the Thrasher Research Fund #15351. Dr. Wallace is also supported by NIH grants NS021328, MH108592, and OD010944, U.S. Department of Defense grants W81XWH-16-1-0401 and W81XWH-21-1-0128, (PR202887.e002). Dr. Wherry is also supported by the Parker Institute for Cancer Immunotherapy which supports the cancer immunology program at UPenn, and by NIAID AI155577, AI115712, AI117950, AI108545, AI082630. Dr. Weiss is also supported by NICHD R01HD102396. Dr. Henrickson is also supported by NIAID K08AI135091, the Burroughs Wellcome Fund CAMS, the Clinical Immunology Society, and the American Academy of Allergy, Asthma, and Immunology.
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Background:Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use.Objective:To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis.Methods:Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type.Results:Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106cells vs. 8.4 pmol/s/106cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen.Conclusion:Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.
AB - Background:Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use.Objective:To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis.Methods:Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type.Results:Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106cells vs. 8.4 pmol/s/106cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen.Conclusion:Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.
KW - Cytokine
KW - Immunoparalysis
KW - T cell
KW - flow cytometry
KW - immunometabolism
KW - metabolomics
KW - pediatric
KW - sepsis
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U2 - 10.1097/SHK.0000000000001943
DO - 10.1097/SHK.0000000000001943
M3 - Article
C2 - 35759301
AN - SCOPUS:85132961627
SN - 1073-2322
VL - 57
SP - 191
EP - 199
JO - Shock
JF - Shock
IS - 6
ER -