Evaluation of a Multivalent Transcriptomic Metric for Diagnosing Surgical Sepsis and Estimating Mortality Among Critically Ill Patients

Abstract

Importance: Rapid and accurate discrimination of sepsis and its potential severity currently require multiple assays with slow processing times that are often inconclusive in discerning sepsis from sterile inflammation.

Objective: To analyze a whole-blood, multivalent, host-messenger RNA expression metric for estimating the likelihood of bacterial infection and 30-day mortality and compare performance of the metric with that of other diagnostic and prognostic biomarkers and clinical parameters.

Design, setting, and participants: This prospective diagnostic and prognostic study was performed in the surgical intensive care unit (ICU) of a single, academic health science center. The analysis included 200 critically ill adult patients admitted with suspected sepsis (cohort A) or those at high risk for developing sepsis (cohort B) between July 1, 2020, and July 30, 2021.

Exposures: Whole-blood sample measurements of a custom 29-messenger RNA transcriptomic metric classifier for likelihood of bacterial infection (IMX-BVN-3) or 30-day mortality (severity) (IMX-SEV-3) in a clinical-diagnostic laboratory setting using an analysis platform (510[k]-cleared nCounter FLEX; NanoString, Inc), compared with measurement of procalcitonin and interleukin 6 (IL-6) plasma levels, and maximum 24-hour sequential organ failure assessment (SOFA) scores.

Main outcomes and measures: Estimated sepsis and 30-day mortality performance.

Results: Among the 200 patients included (124 men [62.0%] and 76 women [38.0%]; median age, 62.5 [IQR, 47.0-72.0] years), the IMX-BVN-3 bacterial infection classifier had an area under the receiver operating characteristics curve (AUROC) of 0.84 (95% CI, 0.77-0.90) for discriminating bacterial infection at ICU admission, similar to procalcitonin (0.85 [95% CI, 0.79-0.90]; P = .79) and significantly better than IL-6 (0.67 [95% CI, 0.58-0.75]; P < .001). For estimating 30-day mortality, the IMX-SEV-3 metric had an AUROC of 0.81 (95% CI, 0.66-0.95), which was significantly better than IL-6 levels (0.57 [95% CI, 0.37-0.77]; P = .006), marginally better than procalcitonin levels (0.65 [95% CI, 0.50-0.79]; P = .06), and similar to the SOFA score (0.76 [95% CI, 0.62-0.91]; P = .48). Combining IMX-BVN-3 and IMX-SEV-3 with procalcitonin or IL-6 levels or SOFA scores did not significantly improve performance. Among patients with sepsis, IMX-BVN-3 scores decreased over time, reflecting the resolution of sepsis. In 11 individuals at high risk (cohort B) who subsequently developed sepsis during their hospital course, IMX-BVN-3 bacterial infection scores did not decline over time and peaked on the day of documented infection.

Conclusions and relevance: In this diagnostic and prognostic study, a novel, multivalent, transcriptomic metric accurately estimated the presence of bacterial infection and risk for 30-day mortality in patients admitted to a surgical ICU. The performance of this single transcriptomic metric was equivalent to or better than multiple alternative diagnostic and prognostic metrics when measured at admission and provided additional information when measured over time.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Brakenridge reported receiving joint academic-industry Department of Health and Human Services Biomedical Advanced Research and Development Authority (BARDA) funding from Inflammatix Inc during the conduct of the study. Dr Chen reported being an employee and stock option holder of Inflammatix Inc during the conduct of the study and outside the submitted work. Dr Midic reported being an employee and stockholder of Inflammatix Inc during the conduct of the study and outside the submitted work. Dr Darden reported receiving grants from the National Institute of General Medical Sciences during the conduct of the study. Dr Fenner reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Wacker reported being an employee and stock option holder of Inflammix Inc during the conduct of the study and outside the submitted work. Dr Liesenfeld reported being an employee and holder of stock options of Inflammix Inc during the conduct of the study and outside the submitted work. Dr Sweeney reported receiving grants from BARDA Division of Research, Innovation, and Ventures (DRIVe); being an employee and shareholder during the conduct of the study and outside the submitted work; and being the licensed inventor on several patents pending and issued that cover the InSep test. Dr Moldawer reported a subcontract on BARDA grant to Inflammatix Inc during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram for Study Design

aInclusion criteria consisted of intensive care unit (ICU) admission from the emergency department nontrauma, postoperative ICU admission, ICU transfer from the emergency department for severe trauma (patients with Injury Severity Scores >15, hemorrhagic shock, and/or severe chest trauma), and inpatient transfer from ward to ICU. bSamples for analysis (procalcitonin and interleukin 6 levels and transcriptomic metric classifiers for the likelihood of bacterial or viral infection and 30-day mortality) were obtained within 6 hours. cScheduled sampling day was within a 24-hour window.

Figure 2.. Transcriptomic Metric Classifiers for the Likelihood of Bacterial or Viral Infection (IMX-BVN-3) and 30-day Mortality (Severity) (IMX-SEV-3) Scores

A, Cohort A included patients with suspected sepsis. B, Cohort B included patients at high risk of developing sepsis. C, The crossover cohort included patients at high risk who subsequently developed sepsis. Data are presented in standard box plot format as medians, IQRs, and outliers.

Figure 3.. Area Under the Receiver Operating Characteristics Curve (AUROC) for Discrimination for Bacterial Infection and 30-Day Mortality

Measurements were obtained among all critically ill patients within 12 hours of intensive care unit admission (day 0). A, Total white blood cell (WBC) count. B, Same-day maximum sequential organ failure assessment (SOFA) score as clinically available comparison metrics. IL-6 indicates interleukin 6.

Figure 4.. Trends of Transcriptomic Metric Classifiers for the Likelihood of Bacterial or Viral Infection (IMX-BVN-3) Scores

The crossover cohort included 11 patients considered to be at high risk who developed sepsis after admission to the surgical intensive care unit. A, Rise in IMX-BVN-3 scores peaking on the day of sepsis identification and then declining with subsequent intervention. B, Concurrent procalcitonin levels in the same patients. The trends (red lines) are presented using loess smoothing curves with 95% CIs (shaded regions). Dotted lines and points illustrate individual patient values.