Distinct immunologic endotypes are associated with clinical trajectory after severe blunt trauma and hemorrhagic shock

Abstract

Background: The genomic/cytokine "storm" after severe trauma is well described. However, the differing composition, magnitude and resolution of this response, and its relationship to clinical outcomes remain unclear.

Methods: This is a secondary analysis of a prospective longitudinal cohort study of severely injured trauma patients in hemorrhagic shock. Peripheral blood sampling was performed at 0.5, 1, 4, 7, 14, and 28 days after injury for measurement of circulating immune biomarkers. K-means clustering using overall mean and trajectory slope of selected immunologic biomarkers were used to identify distinct temporal immunologic endotypes. Endotypes were compared with known clinical trajectories defined as early death (<14 days), chronic critical illness (CCI) (ICU length of stay of ≥14 days with persistent organ dysfunction), and rapid recovery (RAP) (ICU length of stay of <14 days with organ recovery).

Results: The cohort included 102 subjects enrolled across 2 level 1 trauma centers. We identified three distinct immunologic endotypes (iA, iB, and iC), each with unique associations to clinical trajectory. Endotype iA (n = 47) exhibited a moderate initial proinflammatory response followed by a return to immunologic homeostasis, with a primary clinical trajectory of RAP (n = 44, 93.6%). Endotype iB (n = 44) exhibited an early hyperinflammatory response with persistent inflammation and immunosuppression, with the highest incidence of CCI (n = 10, 22.7%). Endotype iC (n = 11) exhibited a similar hyperinflammatory response, but with rapid return to immunologic homeostasis and a predominant trajectory of RAP (n = 9, 81.8%). Patients with endotype iB had the highest severity/duration of organ dysfunction and highest incidence of nosocomial infections (50%, p = 0.001), and endotype iB was the predominant endotype of patients who developed CCI (10 of 13 patients, 76.9%; p = 0.002).

Conclusion: We identified three distinct immunologic endotypes after severe injury differing the magnitude and duration of the early response. The clinical trajectory of CCI is characterized by an endotype (iB) defined by persistent alteration in inflammation/immunosuppression and is associated with poor clinical outcomes.

Level of evidence: Prognostic, level III.

Trial registration: ClinicalTrials.gov NCT01810328.

Copyright © 2020 American Association for the Surgery of Trauma.

Figures

Figure 1.. Principle component analysis of cluster endotypes.

Results of 3-group cluster analysis defining endotypes iA (n=47), iB (n=44) and iC (n=11). The first two principle components (PC1, PC2) are defined as X and Y-axes of the two-dimension space respectively. The fraction of the variance explained by a principal component to the total variance is shown for PC1 (27.3%) and PC2 (17.4%). Clustering results and endotype assignment of each data point are labeled and shown in the figure key. K-means clustering centroids are also visualized for each cluster.

Figure 2.. Contribution of individual biomarkers to cluster endotypes.

Similar to Figure 1, the first two principle components (PC1, PC2) are defined as X and Y-axes of the two-dimension space respectively. The fraction of the variance explained by a principal component to the total variance is shown for PC1 (27.3%) and PC2 (17.4%). Variable contributions to PC1 and PC2 are plotted, with increasing distance representing increased magnitude of variable contribution.

Figure 3.. Immune endotype biomarker heatmap.

Heatmap of biomarker temporal mean and trajectory slope, grouped by endotype (iA, iB, iC). Individual subjects are represented by column and biomarkers by row. Temporal mean and trajectory slope values are calculated based on the log-transformed biomarker measurements and then standardized as Z-scores, with white cell color representing the cohort mean, red spectrum above cohort mean and blue spectrum below cohort mean.

Figure 4.. Select inflammatory and immunosuppressive biomarker trajectories by endotype.

Log-transformed circulating (A) IL-6, (B) IL-8, (C) IL-10 and (D) soluble programmed death ligand 1 (sPD-L1) levels measured from peripheral blood at 0.5, 1, 4, 7 and 14 days after injury and classified by endotype (iA, iB, iC).