Resistin Concentration in Early Sepsis and All-Cause Mortality at a Safety-Net Hospital in Riverside County

Abstract

Background: Sepsis mortality has remained unchanged for greater than a decade, and early recognition continues to be the most important factor in mortality outcome. Plasma resistin concentration is increased in sepsis, but its mechanism and clinical relevance is unclear. As one function, resistin interacts with toll-like receptor 4 in competition with lipopolysaccharide, a main component of the gram-negative bacterial cell wall. It is not known if the type of infection leading to sepsis influences resistin production. The objective of this study was to investigate whether 1) early plasma resistin concentration can predict mortality, 2) elevated plasma resistin concentration is associated with clinical disease severity scores, such as SOFA, mSOFA and APACHE II, and 3) plasma resistin concentrations differ between gram negative versus other etiologies of sepsis.

Methods: This was an exploratory study in the framework of a prospective observational design. Peripheral venous blood samples were obtained from subjects admitted to the intensive care unit at clinical recognition of sepsis (0 hour) and at 6 and 24 hours. Vasopressor utilization was not a requirement for inclusion. Plasma was analyzed for resistin concentration by ELISA. Cytokine concentrations including IL-6, IL-8, and IL-10 were determined by cytokine bead array. Cytokine data were evaluated against publicly available sepsis RNA expression datasets to compare protein versus RNA expression levels in predicting clinical disease state. Clinical data were collected from electronic health records for clinical severity index calculations and context for interpretation of resistin and cytokine concentrations. Subjects were followed up to 60 days, or until death, whichever came first. Statistical analysis was completed with R package and SPSS software.

Results: Resistin levels were elevated in subjects admitted to the intensive care unit with sepsis. Four-hundred subjects were screened with 45 subjects included in the final analysis. Thirteen of 45 patients were non-survivors. Mortality within 60 days correlated with significantly higher resistin concentrations than in survivors. A resistin concentration of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours were associated with mortality within 60 days with an area under the curve of 0.82 and 0.88, respectively. Most subjects with resistin concentration greater than these threshold values were deceased prior to 30 days. Resistin concentrations correlated with SOFA, mSOFA, and APACHE II scores in addition to having association with increases in inflammatory and sepsis biomarkers. These associations were validated with analysis of RNA expression datasets.

Conclusion: Plasma resistin concentrations of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours of clinical sepsis recognition are associated with all-cause mortality. Resistin concentration within this timeframe also has comparable mortality association to well-validated clinical severity indices of SOFA, mSOFA, and APACHE II scores.

Keywords: gram-negative; mortality; resistin; sepsis.

Figure 1

Flow diagram of subject enrollment and outcome. T₀ = clinical recognition of sepsis; T_24-high = highest measured resistin concentration within 24 hours of clinical sepsis recognition. *Two non-survivors within 30 days and 1 non-survivor within 60 days had polymicrobial infections including GN bacteria. One non-survivor within 30 days was transitioned to comfort care.

Figure 2

Correlation analysis of immune and clinical parameters. Circle size and saturation of color indicate the strength of the correlation; the color shows the direction of the relationship, with positive being green, negative being black. Multiple test correction was used the method of false discovery rate (FDR) and only the pair correlation with FDR < 0.05 presented circles.

Figure 3

(A) Expression of genes coding for resistin, IL6, and IL8 in patients with different sepsis outcomes (GSE54514). (B) Protein levels of resistin (0, 6 and 24h), IL6 and IL8 (0h) in our dataset. (C) Correlations of genes coding for IL-6 and resistin in GSE54514 GEO (left panel) and plasma protein levels of IL-6 and resistin as reported in this study (right panel). Also see: http://immunodb.org/sepsis/.

Figure 4

Resistin association with all-cause mortality. (A and B). Circulating resistin concentration (ng/mL) at T₀ and at T_24-high in sepsis survivors (S) and non-survivors (NS). (C) Kaplan-Meier curves for all-cause mortality stratified for resistin concentration threshold of > 126 ng/mL at T₀, and (D) stratified for resistin concentration threshold T_24-high of > 197 ng/mL. ***p<0.001; ****p<0.0001.