Assessment of S100A8/A9 and resistin as predictive biomarkers for mortality in critically ill patients with sepsis

Abstract

Introduction: Sepsis is associated with high mortality. Early intervention is crucial to reducing sepsis-related mortality. This study aims to assess the clinical potential of S100A8/A9 and resistin as novel biomarkers for predicting mortality risk in sepsis patients.

Method: Serum samples were collected and analyzed from 141 adult sepsis patients (discovery cohort), 43 non-sepsis intensive care units (ICU) patients, 15 healthy volunteers, and 55 sepsis patients along with 17 non-sepsis ICU patients (validation cohort). The 28-day mortality and sequential organ failure assessment (SOFA) scores of the participants were compared. Additionally, the predictive ability of S100A8/A9 and resistin for sepsis mortality was evaluated using the area under the receiver operating characteristic curve at ICU admission.

Results: The concentrations of S100A8/A9 and resistin in sepsis patients were noticeably increased relative to non-sepsis patients and healthy controls. Serum S100A8/A9 concentrations in surviving sepsis patients were significantly higher than in non-surviving patients. On the day of admission, serum resistin concentrations in Gram-negative (G-) sepsis patients were considerably elevated relative to Gram-positive (G+) infected sepsis patients. Among sepsis patients admitted to the ICU, the AUC for S100A8/A9 in predicting 28-day mortality was 0.617 (P = 0.032; 95% confidence bounds 0.513-0.721), and for SOFA was 0.750 (P < 0.0001; 95% confidence bounds 0.660-0.840). Sepsis patients with high serum S100A8/A9 concentrations (≥ 377.53 ng/mL) had a higher survival rate relative to those with low concentrations (<377.53 ng/mL). In the validation cohort, the AUC for S100A8/A9 and 28-day mortality was 0.708 (P = 0.032; 95% confidence bounds 0.563-0.854), and for SOFA was 0.698 (P = 0.025; 95% confidence bounds 0.550-0.845). Additionally, sepsis patients with high serum S100A8/A9 concentrations (≥ 377.53 ng/mL) also had a higher survival rate relative to those with lower concentrations (< 377.53 ng/mL). Furthermore, serum resistin levels in patients with a normal phenotype and mixed phenotype with hyperinflammation were predictive of mortality, with an AUC of 0.810 (P = 0.034; 95% confidence bounds 0.605-1.00) and 0.708 (P = 0.015; 95% confidence bounds 0.571-0.846). In patients with a normal sepsis phenotype, those with high serum resistin levels (≥ 63.695 ng/mL) had a lower survival rate compared to those with low resistin levels (< 63.695 ng/mL). In contrast, in patients with a mixed phenotype with hyperinflammation, those with high serum resistin levels (≥ 107.64 ng/mL) had a higher survival rate compared to those with lower resistin levels (< 107.64 ng/mL).

Discussion: Sepsis, the leading cause of death in intensive care unit patients. Identifying reliable biomarkers is essential for improving both the diagnosis and treatment of sepsis. We found that serum S100A8/A9 concentration at ICU admission is a significant predictor of 28-day mortality risk in sepsis patients. Additionally, resistin levels at ICU admission play an important role in predicting 28-day mortality risk in patients with both normal and mixed phenotypes with hyperinflammation. These findings suggest that S100A8/A9 and resistin could serve as effective biomarkers. Moreover, these findings could guide early clinical decisions in the treatment of sepsis patients.

Keywords: 28-day mortality; S100A8/A9; biomarkers; immunophenotype; resistin; sepsis.

Figure 1

Serum S100A8/A9 and resistin levels at admission in the discovery cohort of adult sepsis patients. (A) S100A8/A9 concentrations in serum samples from healthy individuals, ICU non-sepsis patients, and sepsis patients. (B) Resistin concentrations in serum samples from healthy individuals, ICU non-sepsis patients, and sepsis patients. (C) S100A8/A9 concentrations in serum samples from patients with and without septic shock in the discovery cohort. (D) Resistin concentrations in serum samples from patients with and without septic shock in the discovery cohort. (E) S100A8/A9 concentrations in serum samples from sepsis with shock and sepsis without shock survivors. (F) Resistin concentrations in serum samples from sepsis with shock and sepsis without shock survivors. (G) Resistin concentrations in serum samples from sepsis patients with SOFA scores <6.5 and >6.5. (H) Resistin concentrations in serum samples from sepsis patients with G- and G+ bacterial infections. G+, Gram-positive; G-, Gram-negative; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Kruskal-Wallis and Mann-Whitney U test).

Figure 2

Correlation between S100A8/A9, resistin, and various biomarkers. (A) Correlation between S100A8/A9 levels and resistin in the discovery cohort of adult sepsis patients upon ICU admission. (B) Correlation of S100A8/A9 levels with CRP counts in the discovery cohort of adult patients with sepsis on ICU admission. (C) Correlation between S100A8/A9 levels and IL-6 in the discovery cohort. (D) Correlation between resistin levels and PCT in the discovery cohort. (E) Correlation between resistin levels and WBC in the discovery cohort. (F) Correlation between resistin levels and IL-6 in the discovery cohort. (G) Correlation between resistin levels and IL-10 in the discovery cohort. (H) Correlation between resistin levels and PDL-1 in the discovery cohort. (I) Correlation between resistin levels and TNF-α in the discovery cohort. CRP, C-reactive protein; IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-alpha; IL-10, interleukin-10; PDL-1, programmed death-ligand-1. (Spearman's rank correlation coefficient).

Figure 3

Receiver Operating Characteristic (ROC) curves and Kaplan-Meier survival curves for predicting 28-day mortality in adult sepsis patients based on serum biomarkers at admission. (A) ROC curves of serum biomarkers at admission in the discovery cohort of adult sepsis patients, predicting 28-day mortality. (B) Kaplan-Meier survival curves for 141 adult sepsis patients in the discovery cohort, stratified by S100A8/A9 levels using a cutoff of 377.53 ng/mL at ICU admission. (C) ROC curves of serum biomarkers at admission in the validation cohort of adult sepsis patients, predicting 28-day mortality. (D) Kaplan-Meier survival curves for 55 adult sepsis patients in the validation cohort, stratified by S100A8/A9 levels using a cutoff of 377.53 ng/mL at ICU admission. (E) Kaplan-Meier survival curves for 141 adult sepsis patients in the discovery cohort, stratified by SOFA scores using a cutoff of 6.5 at ICU admission. (F) Kaplan-Meier survival curves for 55 adult sepsis patients in the validation cohort, stratified by SOFA scores using a cutoff of 6.5 at ICU admission. AUC, area under the curve; S100A8/A9, S100 calcium-binding protein A8/A9; SOFA, sequential organ failure assessment; PCT, procalcitonin; CRP, C-reactive protein; IL-6, interleukin-6; WBC, white blood cell.

Figure 4

Serum S100A8/A9 and resistin expression levels in sepsis patients with different immunotypes. (A) S100A8/A9 concentrations in serum samples from sepsis patients with normal phenotype (NP), hyperinflammation only (HO), immunosuppression only (IO), mixed phenotype with hyperinflammation (MH), and mixed phenotype with immunosuppression (MI). (B) Resistin concentrations in serum samples from sepsis patients across the same phenotypes. (C) Receiver operating characteristic (ROC) curves for serum biomarkers at admission in predicting 28-day mortality in sepsis patients with normal phenotype. (D) ROC curves for serum biomarkers at admission in predicting 28-day mortality in sepsis patients with mixed phenotype and hyperinflammation. (E) Kaplan-Meier survival curves for 26 sepsis patients with normal phenotype based on the resistin cut-off (63.695 ng/mL) on ICU admission. (F) Kaplan-Meier survival curves for 64 sepsis patients with mixed phenotype with hyperinflammation based on the resistin cut-off (107.64 ng/mL) on ICU admission. NP, normal phenotype; HO, hyperinflammation only; IO, immunosuppression only; MH, mixed phenotype with hyperinflammation; MI, mixed phenotype with immunosuppression in sepsis patients; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Kruskal-Wallis test).

Figure 5

Serum S100A8/A9 and resisitin levels at admission were detected in the validation cohort of adult patients with sepsis. (A) S100A8/A9 concentrations in serum samples collected from healthy individuals, ICU non-sepsis patients and sepsis patients; (B) S100A8/A9 concentrations in serum samples collected from patients with septic shock and patients without shock in the validation cohort; (C) Resistin concentrations in serum samples collected from healthy individuals, ICU non-sepsis patients and sepsis patients; (D) S100A8/A9 concentrations in serum samples from patients with and without septic shock in the validation cohort. (E) Resistin concentrations in serum samples collected from patients with septic shock and patients without shock in the validation cohort; (F) Resistin concentrations in serum samples collected from patients with sepsis with G- bacteria and patients with sepsis with G+ bacteria; (G) Correlation of resistin levels with PCT counts in the validation cohort of adult patients with sepsis on ICU admission; (H) Correlation of resistin levels with IL-6 counts in the validation cohort of adult patients with sepsis on ICU admission; (I) Correlation of resistin levels with PDL-1 counts in the validation cohort of adult patients with sepsis on ICU admission; See Figure 1 legend for expansion of abbreviation.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Kruskal-Wallis and Mann-Whitney U test, Spearman's rank correlation coefficient.).