Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) After Surgical Sepsis

Abstract

Objective: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis.

Background: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear.

Methods: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions.

Results: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88).

Conclusions: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

FIGURE 1.

Comparison of outcomes over 1-year after sepsis for CCI versus RAP sepsis cohorts. (A) One-year survival probability and (B) Twelve-month Zubrod score. Data presented as mean ± standard error with statistical significance set at P < 0.05.

FIGURE 2.

Comparison of inflammation and immunosuppression biomarkers for CCI versus RAP and Zubrod 4/5 versus Zubrod 0–3. Inflammation: (A) interferon gamma-induced protein 10 (IP-10), (B) interleukin-8 (IL-8), (C) monocyte chemoattractant protein 1 (MCP-1), (D) granulocyte-macrophage colony-stimulating factor (GM-CSF) and (E) interleukin-6 (IL-6). Immunosuppression: (F) soluble programmed death ligand 1 (sPDL-1) and (G) interleukin-10 (IL-10). Data presented as median (25%, 75%) with * denoting statistical significance set at P < 0.05. Dotted black line represents median of biomarker levels in matched control subjects.

FIGURE 3.

Comparison of stress metabolism and anabolism biomarkers for CCI versus RAP and Zubrod 4/5 versus Zubrod 0–3. Stress metabolism: (A) glucagon-like peptide 1 (GLP-1) and C-reactive protein (CRP). Anabolism: (C) insulin-like growth factor binding protein (IGFBP3) and (D) insulin-like growth factor (IGF). Dotted line represents biomarker levels in control subjects. Data presented as median (25%, 75%) with * denoting statistical significance set at P < 0.05. Dotted black line represents median biomarker levels in matched control subjects.

FIGURE 4.

Angiogenesis biomarkers for CCI versus RAP and Zubrod 4/5 versus Zubrod 0–3. Angiogenesis: (A) angiopoietin 2 (ANG-2) (B) stromal cell derived factor 1 (SDF-1), (C) soluble vascular endothelial growth factor receptor 1 (sFLT-1), and (D) vascular endothelial growth factor (VEGF). Data presented as median (25%, 75%) with * denoting statistical significance set at P < 0.05. Dotted black line represents median biomarker levels in matched control subjects.

FIGURE 5.

Receiver operator curves (ROC) curves for multivariate models predicting CCI and Zubrod. (A) ROC for models predicting CCI at day 4 with and without biomarkers, and (B) ROC for models predicting Zubrod 4/5 at day 7 with and without biomarkers.