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Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

  • Author(s): Anderson, Brian J
  • Calfee, Carolyn S
  • Liu, Kathleen D
  • Reilly, John P
  • Kangelaris, Kirsten N
  • Shashaty, Michael GS
  • Lazaar, Aili L
  • Bayliffe, Andrew I
  • Gallop, Robert J
  • Miano, Todd A
  • Dunn, Thomas G
  • Johansson, Erik
  • Abbott, Jason
  • Jauregui, Alejandra
  • Deiss, Thomas
  • Vessel, Kathryn
  • Belzer, Annika
  • Zhuo, Hanjing
  • Matthay, Michael A
  • Meyer, Nuala J
  • Christie, Jason D
  • et al.
Abstract

BACKGROUND:Enrichment 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. METHODS:In 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 RESULTS:An 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. CONCLUSIONS:Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

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