Abstract
BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.
Highlights
Sepsis carries a high mortality and has limited pharmacologic therapy [1]
Patient characteristics We enrolled 400 critically ill septic patients (Additional file 2: Figure S1); baseline characteristics are summarized in Soluble tumor necrosis factor receptor-1 The plasma soluble tumor necrosis factor receptor-1 (sTNFR1) concentration at intensive care unit (ICU) admission independently associated with mortality (OR [95% confidence interval (CI)] per 1-log increase 1.68 [1.23–2.28]; p = 0.001), and adding the sTNFR1 concentration to a clinical variable model for mortality improved model fit and marginally improved discrimination (Additional file 2: Table S1)
33.5% were sTNFR1-positive with a 17.8% unadjusted increased absolute risk of mortality, which was within the 95% CI of the risk differences (RD) in the derivation population (Table 2)
Summary
Sepsis carries a high mortality and has limited pharmacologic therapy [1]. A pipeline of therapies targeting inflammation, vascular regulation, and immune regulation are in development, often in tandem with the oncology, autoimmune, and cardiovascular spheres [2, 3]. Several fields have embraced enrichment strategies to refine patient selection for clinical trials, fostering the translation of experimental therapies [5,6,7,8]. This includes “prognostic enrichment,” selecting patients with a greater likelihood of having an outcome, and “predictive. We sought to develop a simple biomarker-based prognostic enrichment method for selecting high-risk patients for future sepsis trials. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors
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