Robert B Lindell1,2,3, Donglan Zhang1,4, Jenny Bush1, Douglas C Wallace4,5, Joshua D Rabinowitz6, Wenyun Lu6, E John Wherry2,7,8, Scott L Weiss1,3,4, Sarah E Henrickson2,9. 1. Division of Critical Care Medicine, Department of Anesthesia and Critical Care Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 2. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 3. Pediatric Sepsis Program, Children's Hospital of Philadelphia, Philadelphia, PA. 4. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA. 5. Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 6. Department of Chemistry, Princeton University; Princeton, NJ. 7. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 8. Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 9. Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Abstract
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/106 cells vs. 8.4 pmol/s/106 cells, 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.
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/106 cells vs. 8.4 pmol/s/106 cells, 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.
Authors: Scott L Weiss; Donglan Zhang; Jenny Bush; Kathryn Graham; Jonathan Starr; Jennifer Murray; Florin Tuluc; Sarah Henrickson; Clifford S Deutschman; Lance Becker; Francis X McGowan; Douglas C Wallace Journal: Shock Date: 2020-09 Impact factor: 3.454
Authors: Hector R Wong; Robert J Freishtat; Marie Monaco; Kelli Odoms; Thomas P Shanley Journal: Pediatr Crit Care Med Date: 2010-05 Impact factor: 3.624
Authors: Robert B Lindell; Akira Nishisaki; Scott L Weiss; Danielle M Traynor; Julie C Fitzgerald Journal: Crit Care Med Date: 2020-07 Impact factor: 7.598
Authors: Kristina E Rudd; Sarah Charlotte Johnson; Kareha M Agesa; Katya Anne Shackelford; Derrick Tsoi; Daniel Rhodes Kievlan; Danny V Colombara; Kevin S Ikuta; Niranjan Kissoon; Simon Finfer; Carolin Fleischmann-Struzek; Flavia R Machado; Konrad K Reinhart; Kathryn Rowan; Christopher W Seymour; R Scott Watson; T Eoin West; Fatima Marinho; Simon I Hay; Rafael Lozano; Alan D Lopez; Derek C Angus; Christopher J L Murray; Mohsen Naghavi Journal: Lancet Date: 2020-01-18 Impact factor: 202.731