Multiple Organ Dysfunction Trajectory Phenotypes After Severe Trauma Are Associated With Distinct Immune Profiles and Outcomes
- 1University of Washington
Abstract
BACKGROUNDTraditional organ dysfunction classifications after severe trauma rely on binary categories (e.g., chronic critical illness [CCI] versus rapid recovery), which likely oversimplify the true heterogeneity of postinjury organ dysfunction trajectories and their underlying immune-biologic drivers. We hypothesized that severely injured trauma patients demonstrate multiple, distinct organ dysfunction phenotypes distinguished by unique immune signatures.
METHODSWe performed a prospective, longitudinal, observational cohort study of severely injured trauma patients at high risk for multiple organ dysfunction at a single Level 1 trauma center. Organ dysfunction was quantified daily through 28 days, death, or discharge using a trauma-specific modified Sequential Organ Failure Assessment (mSOFA) score excluding the neurologic subdomain to isolate systemic organ dysfunction from traumatic brain injury. We utilized group-based trajectory modeling to identify longitudinal mSOFA phenotypes. Plasma immune protein trajectories were compared across phenotypes using mixed-effects models with time interaction.
RESULTSSixty-nine patients were enrolled. Trajectory modeling identified five mSOFA phenotypes (c1-c5) with differences in resuscitation requirements, shock severity, and 28-day mortality, but not baseline demographics, injury severity, or early physiologic parameters. The phenotypes revealed organ dysfunction heterogeneity not fully captured by CCI/rapid recovery classification. Forty of 92 measured immune markers showed phenotype-differentiated trajectories (FDR<0.1). The most fulminant phenotype (c5) was distinguished by IL-17C, CXCL5, and CXCL6, implicating epithelial-barrier and neutrophil-trafficking mechanisms. The phenotype with highest CCI incidence (c3) was distinguished by rising CXCL9, ARTN, and TWEAK, implicating Th1 polarization and tissue-inflammation/repair signaling. The clinically distinct, older-age phenotype (c4) carried the largest differentiating signature (29 proteins), spanning renal injury/repair, endothelial activation, and adaptive lymphocyte modulation.
CONCLUSIONSOrgan dysfunction after severe trauma is more biologically heterogeneous than traditional clinical classifications suggest. Distinct mSOFA trajectory phenotypes correspond to distinct immune signatures, supporting separable pathobiology rather than a single axis of injury severity, with implications for phenotype-targeted precision immunomodulatory approaches in critical illness.
LEVEL OF EVIDENCELevel III, Prognostic/Epidemiological.
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BibTeX
@misc{ding2026multiple,
title = {{Multiple Organ Dysfunction Trajectory Phenotypes After Severe Trauma Are Associated With Distinct Immune Profiles and Outcomes}},
author = {H. Ding and M. Cox and Q. Qiu and N. Mirabadi and D. Bobrovnikov and K. Gerbino and K. Scherler and K. Walters and G. O'Keefe and S. Brakenridge},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.26365695},
url = {https://www.medrxiv.org/content/10.64898/2026.10.15.26365695v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Multiple Organ Dysfunction Trajectory Phenotypes After Severe Trauma Are Associated With Distinct Immune Profiles and Outcomes
AU - H. Ding
AU - M. Cox
AU - Q. Qiu
AU - N. Mirabadi
AU - D. Bobrovnikov
AU - K. Gerbino
AU - K. Scherler
AU - K. Walters
AU - G. O'Keefe
AU - S. Brakenridge
PY - 2026
DA - 2026/10/15
PB - medRxiv
DO - 10.64898/2026.10.15.26365695
UR - https://www.medrxiv.org/content/10.64898/2026.10.15.26365695v1
AB - BACKGROUNDTraditional organ dysfunction classifications after severe trauma rely on binary categories (e.g., chronic critical illness [CCI] versus rapid recovery), which likely oversimplify the true heterogeneity of postinjury organ dysfunction trajectories and their underlying immune-biologic drivers. We hypothesized that severely injured trauma patients demonstrate multiple, distinct organ dysfunction phenotypes distinguished by unique immune signatures. METHODSWe performed a prospective, longitudinal, observational cohort study of severely injured trauma patients at high risk for multiple organ dysfunction at a single Level 1 trauma center. Organ dysfunction was quantified daily through 28 days, death, or discharge using a trauma-specific modified Sequential Organ Failure Assessment (mSOFA) score excluding the neurologic subdomain to isolate systemic organ dysfunction from traumatic brain injury. We utilized group-based trajectory modeling to identify longitudinal mSOFA phenotypes. Plasma immune protein trajectories were compared across phenotypes using mixed-effects models with time interaction. RESULTSSixty-nine patients were enrolled. Trajectory modeling identified five mSOFA phenotypes (c1-c5) with differences in resuscitation requirements, shock severity, and 28-day mortality, but not baseline demographics, injury severity, or early physiologic parameters. The phenotypes revealed organ dysfunction heterogeneity not fully captured by CCI/rapid recovery classification. Forty of 92 measured immune markers showed phenotype-differentiated trajectories (FDR<0.1). The most fulminant phenotype (c5) was distinguished by IL-17C, CXCL5, and CXCL6, implicating epithelial-barrier and neutrophil-trafficking mechanisms. The phenotype with highest CCI incidence (c3) was distinguished by rising CXCL9, ARTN, and TWEAK, implicating Th1 polarization and tissue-inflammation/repair signaling. The clinically distinct, older-age phenotype (c4) carried the largest differentiating signature (29 proteins), spanning renal injury/repair, endothelial activation, and adaptive lymphocyte modulation. CONCLUSIONSOrgan dysfunction after severe trauma is more biologically heterogeneous than traditional clinical classifications suggest. Distinct mSOFA trajectory phenotypes correspond to distinct immune signatures, supporting separable pathobiology rather than a single axis of injury severity, with implications for phenotype-targeted precision immunomodulatory approaches in critical illness. LEVEL OF EVIDENCELevel III, Prognostic/Epidemiological.
ER -