A Novel 29-Messenger RNA Host-Response Assay From Whole Blood Accurately Identifies Bacterial and Viral Infections in Patients Presenting to the Emergency Department With Suspected Infections: A Prospective Observational Study

Abstract

Objectives: The rapid diagnosis of acute infections and sepsis remains a serious challenge. As a result of limitations in current diagnostics, guidelines recommend early antimicrobials for suspected sepsis patients to improve outcomes at a cost to antimicrobial stewardship. We aimed to develop and prospectively validate a new, 29-messenger RNA blood-based host-response classifier Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) to determine the likelihood of bacterial and viral infections.

Design: Prospective observational study.

Setting: Emergency Department, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany.

Patients: Three hundred twelve adult patients presenting to the emergency department with suspected acute infections or sepsis with at least one vital sign change.

Interventions: None (observational study only).

Measurements and main results: Gene expression levels from extracted whole blood RNA was quantified on a NanoString nCounter SPRINT (NanoString Technologies, Seattle, WA). Two predicted probability scores for the presence of bacterial and viral infection were calculated using the IMX-BVN-2 neural network classifier, which was trained on an independent development set. The IMX-BVN-2 bacterial score showed an area under the receiver operating curve for adjudicated bacterial versus ruled out bacterial infection of 0.90 (95% CI, 0.85-0.95) compared with 0.89 (95% CI, 0.84-0.94) for procalcitonin with procalcitonin being used in the adjudication. The IMX-BVN-2 viral score area under the receiver operating curve for adjudicated versus ruled out viral infection was 0.83 (95% CI, 0.77-0.89).

Conclusions: IMX-BVN-2 demonstrated accuracy for detecting both viral infections and bacterial infections. This shows the potential of host-response tests as a novel and practical approach for determining the causes of infections, which could improve patient outcomes while upholding antimicrobial stewardship.

Conflict of interest statement

Drs. Bauer’s, Kappert’s, Galtung’s, Lehmann’s, Tauber’s, and Somasundaram’s institution received funding from Inflammatix and Gentian AS. Dr. Kappert’s and Tauber’s institution received funding from Deutsche Forschungsgemeinschaft, Stiftung für Pathobiochemie und Molekulare Diagnostik, and Deutsche Stiftung Innere Medizin. Drs. Wacker, Liesenfeld, Buturovic, Cheng, Sweeney, and Luethy disclosed that they are employees of and option shareholders in Inflammatix.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

Figures

Figure 1.

Study flowchart. To assess the diagnostic performance of our index test, IMX-BVN-2, we enrolled 317 patients presenting to the emergency department (ED) with clinically suspected acute infection. After excluding five patients, our final cohort of 312 patients had whole blood samples tested with Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) on the NanoString nCounter (NanoString Technologies, Seattle, WA) platform. To establish infection status, a two-physician expert panel reviewed data from medical charts (which included PCT results) while blinded to IMX-BVN-2 results. The physicians gave each patient assessments for the presence of bacterial infection and presence of viral infection based a 4-point scale (Ruled Out, Unlikely, Probable, and Proven). These assessments were then translated into binary “present” and “absent” adjudications for the presence of bacterial infection and presence of viral infection using two adjudication methods: a conservative consensus adjudication (CA) method and a liberal forced adjudication (FA). Finally, IMX-BVN-2 bacterial and viral score performance was determined by comparing results with CA and FA infection statuses. CRP = C-reactive protein, PCR = polymerase chain reaction, PCT = procalcitonin.

Figure 2.

Distribution of Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) bacterial and viral scores segmented by adjudicated infection statuses established using forced adjudication (FA) and consensus adjudication (CA). Distribution of IMX-BVN-2 bacterial scores segmented by expert panel adjudicated infection status using A, FA and B, CA. Distribution of IMX-BVN-2 viral scores segmented by expert panel adjudicated infection status using C, FA and D, CA. Horizontal lines indicate threshold cutoffs that divide each score into the four results interpretation bands: Very Unlikely, Unlikely, Possibly, and Very Likely. p values indicate statistically significant differences in IMX-BVN-2 scores between each pair of patient infection status groups using Welch t test for equal means. CA

Figure 3.

Performance of Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) after applying previously established cutoffs to segment scores into clinically actionable results interpretation bands, using consensus adjudication (CA) infection status. Performance characteristics of the A, IMX-BVN-2 bacterial score, B, procalcitonin (PCT), and C, IMX-BVN-2 viral score when segmented into the results interpretation bands among patients with a known CA infection status. PCT was segmented into interpretation bands using cutoffs established in other studies (10). Formulas for calculating performance characteristics are outlined in Supplementary Table S10 (Supplemental Digital Content 13, http://links.lww.com/CCM/G503). Performance characteristics calculated under forced adjudication is provided in Supplementary Figure S4 (Supplemental Digital Content 12, http://links.lww.com/CCM/G502). Sens. = sensitivity, Spec. = specificity.