A 29-MRNA HOST RESPONSE WHOLE-BLOOD SIGNATURE IMPROVES PREDICTION OF 28-DAY MORTALITY AND 7-DAY INTENSIVE CARE UNIT CARE IN ADULTS PRESENTING TO THE EMERGENCY DEPARTMENT WITH SUSPECTED ACUTE INFECTION AND/OR SEPSIS

Abstract

Background: Risk stratification of emergency department patients with suspected acute infections and/or suspected sepsis remains challenging. We prospectively validated a 29-messenger RNA host response classifier for predicting severity in these patients. Methods: We enrolled adults presenting with suspected acute infections and at least one vital sign abnormality to six emergency departments in Greece. Twenty-nine target host RNAs were quantified on NanoString nCounter and analyzed with the Inflammatix Severity 2 (IMX-SEV-2) classifier to determine risk scores as low, moderate, and high severity. Performance of IMX-SEV-2 for prediction of 28-day mortality was compared with that of lactate, procalcitonin, and quick sequential organ failure assessment (qSOFA). Results: A total of 397 individuals were enrolled; 38 individuals (9.6%) died within 28 days. Inflammatix Severity 2 classifier predicted 28-day mortality with an area under the receiver operator characteristics curve of 0.82 (95% confidence interval [CI], 0.74-0.90) compared with lactate, 0.66 (95% CI, 0.54-0.77); procalcitonin, 0.67 (95% CI, 0.57-0.78); and qSOFA, 0.81 (95% CI, 0.72-0.89). Combining qSOFA with IMX-SEV-2 improved prognostic accuracy from 0.81 to 0.89 (95% CI, 0.82-0.96). The high-severity (rule-in) interpretation band of IMX-SEV-2 demonstrated 96.9% specificity for predicting 28-day mortality, whereas the low-severity (rule-out) band had a sensitivity of 78.9%. Similarly, IMX-SEV-2 alone accurately predicted the need for day-7 intensive care unit care and further boosted overall accuracy when combined with qSOFA. Conclusions: Inflammatix Severity 2 classifier predicted 28-day mortality and 7-day intensive care unit care with high accuracy and boosted the accuracy of clinical scores when used in combination.

Trial registration: ClinicalTrials.gov NCT00329582.

Fig. 1

Inflammatix Severity 1 demonstrates the ability to accurately predict 28-day mortality in patients with sepsis. The distribution of the IMX-SEV-2 severity scores is presented, stratified by the clinical outcome of 28-day mortality (death) versus survival (nondeath). The red dashed horizontal lines indicate the threshold values, which stratify the severity score into three result interpretation bands: high risk, moderate risk, and low severity. The full horizontal lines within each box plot represent the median IMX-SEV-2 score, and all data points are included.

Fig. 2

Prognostic performance of the IMX-SEV-2 severity interpretation bands and lactate concentrations for prediction of 28-day mortality. Test performance is shown as patients in band as well as sensitivity, specificity, and likelihood ratio for each interpretation or concentration band. A, The IMX-SEV-2 severity score stratified by predetermined cutoffs into interpretation bands for the overall cohort and (B) lactate stratified by blood concentration. LR, likelihood ratio.

Fig. 3

Composite risk prediction accuracies combining IMX-SEV-2 interpretation bands with clinical scores or lactate for predicting 28-day mortality. Accuracy of risk prediction using readouts of patients in band, likelihood ratio, sensitivity, and specificity when combining dichotomous qSOFA scores (low ≤2 vs. high ≥2) with IMX-SEV-2 severity interpretation bands (low, moderate, high) (A) or lactate concentrations (high, ≥4; moderate, 2–4; and low, ≤2 mmol/L (B). Graphical depiction of risk prediction for 28-day mortality comparing pretest probability with sequential integration of dichotomous qSOFA scores and IMX-SEV-2 interpretation bands (C) or lactate concentrations (D). Area under the receiver operating characteristics for qSOFA combined with IMX-SEV-2 or biomarkers lactate or PCT using logistic regression to predict 28-day mortality (E). Area under the receiver operating characteristics for SOFA combined with IMX-SEV-2 or biomarkers lactate or PCT using logistic regression to predict 28-day mortality (F). *The IMX-SEV-2 performance subgroup analysis was restricted to individuals for whom the comparator biomarker data were available. NA, not applicable.

Fig. 4

Area under the receiver operating characteristic curve of IMX-SEV-2 for prediction of ICU care within 7 days compared with lactate, PCT, day 0 qSOFA, and day 0 SOFA. *The IMX-SEV-2 performance subgroup analysis was restricted to individuals for whom the comparator biomarker data were available. NA, not applicable.

Fig. 5

Accuracy of composite risk prediction using sequential integration of qSOFA plus IMX-SEV-2 interpretation bands (A) or qSOFA and lactate concentrations (B) for prediction of ICU care within 7 days.