Title

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Authors

Emily R. Ko, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Ricardo Henao, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Katherine Frankey, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Elizabeth A. Petzold, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Pamela D. Isner, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Anja K. Jaehne, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Nakia Allen, Department of Pediatrics, Henry Ford Hospital System, Detroit, Michigan.
Jayna Gardner-Gray, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Gina Hurst, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Jacqueline Pflaum-Carlson, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Namita Jayaprakash, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Emanuel P. Rivers, Department of Emergency Medicine, Henry Ford Hospital System, Detroit, Michigan.
Henry Wang, McGovern Medical University of Texas Health, Houston.
Irma Ugalde, McGovern Medical University of Texas Health, Houston.
Siraj Amanullah, Department of Emergency Medicine, Alpert Medical School of Brown University, Hasbro Children's Hospital, Providence, Rhode Island.
Laura Mercurio, Department of Emergency Medicine, Alpert Medical School of Brown University, Hasbro Children's Hospital, Providence, Rhode Island.
Thomas H. Chun, Department of Emergency Medicine, Alpert Medical School of Brown University, Hasbro Children's Hospital, Providence, Rhode Island.
Larissa May, Department of Emergency Medicine, University of California, Davis.
Robert W. Hickey, Division of Pediatric Emergency Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
Jacob E. Lazarus, Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Shauna H. Gunaratne, Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Daniel J. Pallin, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Guruprasad Jambaulikar, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
David S. Huckins, Department of Emergency Medicine, Newton-Wellesley Hospital, Boston, Massachusetts.
Krow Ampofo, Department of Pediatrics, University of Utah, Salt Lake City.
Ravi Jhaveri, Department of Pediatrics, University of North Carolina at Chapel Hill.
Yunyun Jiang, The Biostatistics Center, George Washington University, Rockville, Maryland.
Lauren Komarow, The Biostatistics Center, George Washington University, Rockville, Maryland.
Scott R. Evans, The Biostatistics Center, George Washington University, Rockville, Maryland.
Geoffrey S. Ginsburg, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
L Gayani Tillekeratne, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.
Micah T. McClain, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina.

Document Type

Journal Article

Publication Date

4-1-2022

Journal

JAMA network open

Volume

5

Issue

4

DOI

10.1001/jamanetworkopen.2022.7299

Abstract

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship. Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI. Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc. Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection. Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Department

Biostatistics and Bioinformatics

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