Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU

Abstract

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility.

Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults.

Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts.

Measurements and main results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity.

Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).

Keywords: RT-qPCR; classifier; infection; inflammation; sepsis.

Figures

Figure 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram for the complete clinical dataset (N = 447) used in validation of SeptiCyte LAB. Subject recruitment dates were as follows: MARS (Molecular Diagnosis and Risk Stratification of Sepsis), between June 2013 and November 2013; VENUS (Validation of Septic Gene Expression Using SeptiCyte), between May 2014 and April 2015; VENUS Supplement, between March 2016 and August 2016. LoD = limit of detection; N/A = not applicable; RPD = retrospective physician diagnosis.

Figure 2.

Receiver operating characteristic curves for SeptiScore, calculated for the complete clinical dataset. (A) Receiver operating characteristic curves. Unanimous retrospective physician diagnosis (RPD) (nsepsis = 121; nSIRS = 171; nexcluded = 155; area under the curve [AUC], 0.89; 95% confidence interval [CI], 0.85–0.93), consensus RPD (nsepsis = 180; nSIRS = 230; nexcluded = 37; AUC, 0.85; 95% CI, 0.81–0.89), and forced RPD (nsepsis = 202; nSIRS = 245; AUC, 0.82; 95% CI, 0.78–0.86). (B) Sensitivity, specificity as a function of cut point. Comparator = consensus RPD. The following SeptiScore band boundaries are indicated: band 1/2 boundary at 3.05, band 2/3 boundary at 4.45, and band 3/4 boundary at 5.95, as well as the Youden index (Y) at 5.1 (when sensitivity + specificity is maximized). SIRS = systemic inflammatory response syndrome.

Figure 3.

Positive correlation between SeptiScore and the probability of sepsis. In each panel the probability of sepsis is plotted against SeptiScore for four different SeptiScore ranges (bands). Each box-and-whisker plot indicates the median and the upper and lower 80% confidence interval bounds on sepsis probability for a particular band. The number of sepsis:systemic inflammatory response syndrome (SIRS) subjects in each band is indicated. (A) Unanimous retrospective physician diagnosis (RPD) (171 SIRS, 119 sepsis; 155 excluded). (B) Consensus RPD (230 SIRS; 180 sepsis; 37 indeterminates excluded). (C) Forced RPD (245 SIRS; 202 sepsis).

Figure 4.

Forward logistic regression models. No imputation of missing values was performed. (A) Consensus retrospective physician diagnosis (RPD) (n = 160), procalcitonin (PCT) included. (B) Forced RPD (n = 176), PCT included. (C) Unanimous RPD (n = 120), PCT included. For panels A–C, variables were added in the order A, B, C, D, E, F, and area under the curve (AUC) values were recalculated after each addition step. (D) Consensus RPD (n = 223), PCT excluded. (E) Forced RPD (n = 243), PCT excluded. (F) Unanimous RPD (n = 166), PCT excluded. For panels D–F, variables were added in the order A, D, G, H, I, J, and AUC values were recalculated after each addition step. Symbols, consistent with assignments in the online supplement, part 6, are as follows: A = SeptiScore; B = log2PCT; C = maximum white blood cell count; D = number of systemic inflammatory response syndrome criteria; E = minimum core temperature; F = minimum white blood cell count; G = maximum mean arterial pressure; H = race/ethnicity; I = maximum core temperature; J = sex.

Figure 5.

Area under the curve (AUC) distributions for logistic models. An exhaustive examination of all 16,383 possible logistic combinations of the following 14 variables was conducted: SeptiScore, procalcitonin, maximum glucose concentration, minimum white blood cell count, maximum white blood cell count, maximum mean arterial pressure, minimum core temperature, maximum core temperature, minimum heart rate, maximum heart rate, number of systemic inflammatory response syndrome criteria, age, sex, and race/ethnicity. No imputation of missing values was performed. The comparator was consensus retrospective physician diagnosis. Blue = models containing SeptiScore; green = models containing procalcitonin but not SeptiScore; red = models without SeptiScore or procalcitonin.