Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis
IntroductionRecent studies of adult sepsis patients demonstrate the existence of two subphenotypes that differ in risk of mortality: a hyper-inflammatory subphenotype with a high risk of mortality, and a hypo-inflammatory or “not hyper-inflamed” subphenotype with a relatively lower risk of mortality...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-05-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1520848/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850136515844243456 |
|---|---|
| author | E. Scott Halstead E. Scott Halstead E. Scott Halstead Daniel J. McKeone Daniel J. McKeone Abigail M. Samuelsen Shouhao Zhou Anthony S. Bonavia Anthony S. Bonavia Anthony S. Bonavia |
| author_facet | E. Scott Halstead E. Scott Halstead E. Scott Halstead Daniel J. McKeone Daniel J. McKeone Abigail M. Samuelsen Shouhao Zhou Anthony S. Bonavia Anthony S. Bonavia Anthony S. Bonavia |
| author_sort | E. Scott Halstead |
| collection | DOAJ |
| description | IntroductionRecent studies of adult sepsis patients demonstrate the existence of two subphenotypes that differ in risk of mortality: a hyper-inflammatory subphenotype with a high risk of mortality, and a hypo-inflammatory or “not hyper-inflamed” subphenotype with a relatively lower risk of mortality. We recently investigated the association of organ dysfunction with ex vivo immune profiling in sixty (60) critically ill adult patients with sepsis. In this secondary analysis we measured cytokine biomarkers with an automated, microfluidic immunoassay device (Ella™) and sought to investigate the functional immune profiles of patients in the hyper/hypo-inflammatory subphenotype groups.MethodsSubjects were consecutively identified adults, older than 18 years, and enrolled within 48 hours of sepsis onset. Whole blood cytokine analysis was performed in all patients. Additionally, ex vivo cytokine production was measured following 4h of stimulation. Cytokine concentrations were measured using the Ella™ automated immunoassay system.ResultsSubjects were divided into hypo-inflammatory (42 patients) and hyper-inflammatory (18 patients) subtypes using a previously validated parsimonious model based on concentrations of IL-6, TNFR1 and bicarbonate. The hyper- and hypo-inflammatory clusters demonstrated a near four-fold difference in 30-day mortality (44.4% vs 11.9%, p=0.0046). Following 4h of ex vivo stimulation with LPS, TNF production was lower in the hyper-inflammatory group as compared with the hypo-inflammatory group (p=0.0159). Ex vivo phorbol 12-myristate 13-acetate (PMA)-stimulated IFN-γ production (4h) by whole blood did not differ between groups.ConclusionsThese data further validate the use of IL-6, TNFR1 and bicarbonate to discern inflammatory sub-groups of patients with critical illness. They also confirm the observation that the presence of the hyper-inflammatory subphenotype is often accompanied by a compensatory anti-inflammatory response syndrome. Future investigations should focus on prospective validation of this panel for prognostic enrichment of clinical research studies. |
| format | Article |
| id | doaj-art-9d2230cef7e84636a3f51a73be4f706f |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-9d2230cef7e84636a3f51a73be4f706f2025-08-20T02:31:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15208481520848Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysisE. Scott Halstead0E. Scott Halstead1E. Scott Halstead2Daniel J. McKeone3Daniel J. McKeone4Abigail M. Samuelsen5Shouhao Zhou6Anthony S. Bonavia7Anthony S. Bonavia8Anthony S. Bonavia9Division of Critical Care Medicine, Department of Pediatrics, Penn State University College of Medicine, Hershey, PA, United StatesDepartment of Molecular and Precision Medicine, Penn State University College of Medicine, Hershey, PA, United StatesCritical Illness and Sepsis Research Center, Penn State College of Medicine, Hershey, PA, United StatesCritical Illness and Sepsis Research Center, Penn State College of Medicine, Hershey, PA, United StatesDivision of Pediatric Hematology/Oncology, Department of Pediatrics, Penn State University College of Medicine, Hershey, PA, United StatesDivision of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, United StatesDivision of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, PA, United StatesDepartment of Molecular and Precision Medicine, Penn State University College of Medicine, Hershey, PA, United StatesCritical Illness and Sepsis Research Center, Penn State College of Medicine, Hershey, PA, United StatesDivision of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Penn State University College of Medicine, Hershey, PA, United StatesIntroductionRecent studies of adult sepsis patients demonstrate the existence of two subphenotypes that differ in risk of mortality: a hyper-inflammatory subphenotype with a high risk of mortality, and a hypo-inflammatory or “not hyper-inflamed” subphenotype with a relatively lower risk of mortality. We recently investigated the association of organ dysfunction with ex vivo immune profiling in sixty (60) critically ill adult patients with sepsis. In this secondary analysis we measured cytokine biomarkers with an automated, microfluidic immunoassay device (Ella™) and sought to investigate the functional immune profiles of patients in the hyper/hypo-inflammatory subphenotype groups.MethodsSubjects were consecutively identified adults, older than 18 years, and enrolled within 48 hours of sepsis onset. Whole blood cytokine analysis was performed in all patients. Additionally, ex vivo cytokine production was measured following 4h of stimulation. Cytokine concentrations were measured using the Ella™ automated immunoassay system.ResultsSubjects were divided into hypo-inflammatory (42 patients) and hyper-inflammatory (18 patients) subtypes using a previously validated parsimonious model based on concentrations of IL-6, TNFR1 and bicarbonate. The hyper- and hypo-inflammatory clusters demonstrated a near four-fold difference in 30-day mortality (44.4% vs 11.9%, p=0.0046). Following 4h of ex vivo stimulation with LPS, TNF production was lower in the hyper-inflammatory group as compared with the hypo-inflammatory group (p=0.0159). Ex vivo phorbol 12-myristate 13-acetate (PMA)-stimulated IFN-γ production (4h) by whole blood did not differ between groups.ConclusionsThese data further validate the use of IL-6, TNFR1 and bicarbonate to discern inflammatory sub-groups of patients with critical illness. They also confirm the observation that the presence of the hyper-inflammatory subphenotype is often accompanied by a compensatory anti-inflammatory response syndrome. Future investigations should focus on prospective validation of this panel for prognostic enrichment of clinical research studies.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1520848/fullsepsisbiomarkerphenotypecytokinescritical illnesshumans |
| spellingShingle | E. Scott Halstead E. Scott Halstead E. Scott Halstead Daniel J. McKeone Daniel J. McKeone Abigail M. Samuelsen Shouhao Zhou Anthony S. Bonavia Anthony S. Bonavia Anthony S. Bonavia Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis Frontiers in Immunology sepsis biomarker phenotype cytokines critical illness humans |
| title | Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis |
| title_full | Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis |
| title_fullStr | Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis |
| title_full_unstemmed | Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis |
| title_short | Functional immune profiling of hyper- and hypo-inflammatory subphenotypes of critical illness: a secondary analysis |
| title_sort | functional immune profiling of hyper and hypo inflammatory subphenotypes of critical illness a secondary analysis |
| topic | sepsis biomarker phenotype cytokines critical illness humans |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1520848/full |
| work_keys_str_mv | AT escotthalstead functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT escotthalstead functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT escotthalstead functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT danieljmckeone functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT danieljmckeone functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT abigailmsamuelsen functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT shouhaozhou functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT anthonysbonavia functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT anthonysbonavia functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis AT anthonysbonavia functionalimmuneprofilingofhyperandhypoinflammatorysubphenotypesofcriticalillnessasecondaryanalysis |