Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation.

TitleImpaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation.
Publication TypeJournal Article
Year of Publication2022
AuthorsLindell, RB, Zhang, D, Bush, J, Wallace, DC, Rabinowitz, JD, Lu, W, E Wherry, J, Weiss, SL, Henrickson, SE
JournalShock
Volume57
Issue6
Pagination191-199
Date Published2022 06 01
ISSN1540-0514
KeywordsChild, Cytokines, HLA-DR Antigens, Humans, Leukocytes, Mononuclear, Lymphocytes, Male, Prospective Studies, Proteomics, Sepsis, Tumor Necrosis Factor-alpha
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>OBJECTIVE: </b>To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSION: </b>Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.</p>

DOI10.1097/SHK.0000000000001943
Alternate JournalShock
PubMed ID35759301
PubMed Central IDPMC9245144
Grant ListK23 GM110496 / GM / NIGMS NIH HHS / United States
R01 HD102396 / HD / NICHD NIH HHS / United States
R01 MH108592 / MH / NIMH NIH HHS / United States
U19 AI117950 / AI / NIAID NIH HHS / United States
R01 AI155577 / AI / NIAID NIH HHS / United States
U19 AI082630 / AI / NIAID NIH HHS / United States
R01 AI115712 / AI / NIAID NIH HHS / United States
K08 AI135091 / AI / NIAID NIH HHS / United States
R01 OD010944 / OD / NIH HHS / United States
P01 AI108545 / AI / NIAID NIH HHS / United States
R01 NS021328 / NS / NINDS NIH HHS / United States
L40 HD103243 / HD / NICHD NIH HHS / United States