Prospective validation of a transcriptomic severity classifier among patients with suspected acute infection and sepsis in the emergency department

Abstract

Background and importance: mRNA-based host response signatures have been reported to improve sepsis diagnostics. Meanwhile, prognostic markers for the rapid and accurate prediction of severity in patients with suspected acute infections and sepsis remain an unmet need. IMX-SEV-2 is a 29-host-mRNA classifier designed to predict disease severity in patients with acute infection or sepsis.

Objective: Validation of the host-mRNA infection severity classifier IMX-SEV-2.

Design, settings and participants: Prospective, observational, convenience cohort of emergency department (ED) patients with suspected acute infections.

Outcome measures and analysis: Whole blood RNA tubes were analyzed using independently trained and validated composite target genes (IMX-SEV-2). IMX-SEV-2-generated risk scores for severity were compared to the patient outcomes in-hospital mortality and 72-h multiorgan failure.

Main results: Of the 312 eligible patients, 22 (7.1%) died in hospital and 58 (18.6%) experienced multiorgan failure within 72 h of presentation. For predicting in-hospital mortality, IMX-SEV-2 had a significantly higher area under the receiver operating characteristic (AUROC) of 0.84 [95% confidence intervals (CI), 0.76-0.93] compared to 0.76 (0.64-0.87) for lactate, 0.68 (0.57-0.79) for quick Sequential Organ Failure Assessment (qSOFA) and 0.75 (0.65-0.85) for National Early Warning Score 2 (NEWS2), ( P = 0.015, 0.001 and 0.013, respectively). For identifying and predicting 72-h multiorgan failure, the AUROC of IMX-SEV-2 was 0.76 (0.68-0.83), not significantly different from lactate (0.73, 0.65-0.81), qSOFA (0.77, 0.70-0.83) or NEWS2 (0.81, 0.75-0.86).

Conclusion: The IMX-SEV-2 classifier showed a superior prediction of in-hospital mortality compared to biomarkers and clinical scores among ED patients with suspected infections. No improvement for predicting multiorgan failure was found compared to established scores or biomarkers. Identifying patients with a high risk of mortality or multiorgan failure may improve patient outcomes, resource utilization and guide therapy decision-making.

Fig. 1

Flowchart of patient enrollment and outcomes. In total 312 of 317 patients enrolled met the inclusion criteria and were treated and diagnosed according to the standard of care by physicians blinded to the IMX-SEV-2 severity score results. Patient clinical outcomes were recorded from medical records.

Fig. 2

IMX-SEV-2 shows ability to separate patients with in-hospital mortality vs. survival or discharge. Distribution of IMX-SEV-2 severity scores segmented by in-hospital mortality vs. survival and/or discharge. Horizontal lines indicate the preset threshold cutoffs which divide the score into three interpretation bands: high (≥0.157), moderate (0.042–0.157) and low severity (<0.042).

Fig. 3

Performance of the IMX-SEV-2 severity score compared with other prognostic markers. Receiver operating characteristic (ROC) for distinguishing (a) in-hospital mortality, and (b) 72-h multiorgan failure. (c) Area under the receiver operating characteristics (AUROCs) with 95% confidence intervals for in-hospital mortality, and 72-h multiorgan for IMX-SEV-2 compared to other clinical markers.

Fig. 4

Performance of interpretation bands for in-hospital mortality. Performance of IMX-SEV-2, qSOFA, lactate and NEWS2 bands for predicting in-hospital mortality (a–d). IMX-SEV-2 bands are generated using the predefined thresholds. NEWS2 bands are defined as low risk (0–4), medium risk (5–6, and/or ≥3 in any single category) and high risk (≥7). Lactate results are presented for the 301 patients with concentrations measured at presentation.

Fig. 5

Performance of interpretation bands for multiorgan failure. Performance of IMX-SEV-2, qSOFA, lactate and NEWS2 bands for identifying and predicting 72-h multiorgan failure (a–d). IMX-SEV-2 bands are generated using the predefined thresholds. NEWS2 bands are defined as low risk (0–4), medium risk (5–6, and/or ≥3 in any single category) and high risk (≥7). Lactate results are presented for the 301 patients with concentrations measured at presentation.