Lower Initial Insulin-like Growth Factor-Binding Protein-3 Concentrations May Reflect Immune Suppression and Predict Increased Risk of Sepsis-Related Mortality

Abstract

Insulin-like growth factor-binding protein-3 (IGFBP-3) plays a vital role in cellular growth, development, and survival. Incorporating IGFBP-3 into baseline prognostic evaluations may enhance the prediction of mortality in patients with sepsis. In this study, serum levels of IGFBP-3, C-reactive protein, procalcitonin, lactate, interleukin-6, and mid-regional pro-adrenomedullin were measured upon admission to the internal medicine unit (IMU) in 139 patients with microbiologically confirmed sepsis. The objectives were as follows: (1) to classify septic patient phenotypes based on optimal thresholds of independent prognostic biomarkers and (2) to evaluate whether these biomarkers improve the predictive accuracy of a clinical model (Model 1), which includes the clinical predictors of 1-year mortality. Age, sequential organ failure assessment (SOFA) score, multiple sources of infection, and IGFBP-3 levels independently predicted 1-year mortality. Patients with IGFBP-3 levels below 10.64 had significantly lower median body temperature (p = 0.008), reduced lymphocyte count (p = 0.001), and higher 1-year mortality (p < 0.001). Model 1 included age, SOFA score, and the presence of multiple sources of sepsis as predictor variables. Model 2 incorporated the same variables as Model 1, with the addition of IGFBP-3 levels. When comparing their prognostic performance, Model 2 demonstrated superior predictive accuracy for mortality at 60, 90, and 365 days following admission to the IMU. Low IGFBP-3 levels at IMU admission are strongly associated with worse outcomes in septic patients, supporting its potential use as a prognostic biomarker.

Keywords: gut dysfunction; immune suppression; insulin-like growth factor; insulin-like growth factor-binding protein-3; interleukin-6; lactate; mid-regional pro-adrenomedullin; procalcitonin; sepsis.

Figure 1

(a) Kaplan–Meier curves of freedom from 1-year mortality for patients grouped according to the best prognostic cut-off of insulin-like growth factor-binding protein-3 levels. Abbreviations: IGFBP-3 = insulin-like growth factor-binding protein-3 (expressed as Log levels), IMU = internal medicine unit. Legend: Log-rank < 0.001. (b) Kaplan–Meier curves of freedom from 30-day mortality for patients grouped according to the best prognostic cut-off of insulin-like growth factor-binding protein-3 levels. Abbreviations: IGFBP-3 insulin-like growth factor-binding protein-3 (expressed as Log levels), IMU = internal medicine unit. Legend: Log-rank = 0.007. (c) Time-dependent receiver operating characteristic curves of Model 1 and Model 2 for predicting mortality up to 1 year from internal medicine unit admission. Abbreviations: AUC = area under the receiver operating characteristic curve. Legend: Model 1 includes age, SOFA score, and multiple sources of sepsis. Model 2 includes age, SOFA score, multiple sources of sepsis, and insulin-like growth factor-binding protein-3 levels expressed as Log levels. Time is expressed in days from internal medicine unit admission.

Figure 1

(a) Kaplan–Meier curves of freedom from 1-year mortality for patients grouped according to the best prognostic cut-off of insulin-like growth factor-binding protein-3 levels. Abbreviations: IGFBP-3 = insulin-like growth factor-binding protein-3 (expressed as Log levels), IMU = internal medicine unit. Legend: Log-rank < 0.001. (b) Kaplan–Meier curves of freedom from 30-day mortality for patients grouped according to the best prognostic cut-off of insulin-like growth factor-binding protein-3 levels. Abbreviations: IGFBP-3 insulin-like growth factor-binding protein-3 (expressed as Log levels), IMU = internal medicine unit. Legend: Log-rank = 0.007. (c) Time-dependent receiver operating characteristic curves of Model 1 and Model 2 for predicting mortality up to 1 year from internal medicine unit admission. Abbreviations: AUC = area under the receiver operating characteristic curve. Legend: Model 1 includes age, SOFA score, and multiple sources of sepsis. Model 2 includes age, SOFA score, multiple sources of sepsis, and insulin-like growth factor-binding protein-3 levels expressed as Log levels. Time is expressed in days from internal medicine unit admission.