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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E227299 |
| Journal | JAMA network open |
| Volume | 5 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 14 2022 |
Funding
Conflict of Interest Disclosures: Dr Henao reported receiving personal fees from Biomeme and Infinia ML and owning a patent for methods to diagnose and treat acute respiratory infections outside the submitted work. Dr Jaehne reported receiving grants from Henry Ford Hospital during the conduct of the study. Dr Allen reported receiving a travel grant from the Henry Ford Health System during the conduct of the study. Dr Jayaprakash reported receiving grants from Abbott and the National Institutes of Health (NIH) outside the submitted work. Dr Wang reported receiving grants from the NIH during the conduct of the study and personal fees from the American College of Emergency Physicians for service as the editor in chief of the Journal of the American College of Emergency Physicians Open outside the submitted work. Dr Amanullah reported receiving grants from the NIH during the conduct of the study. Dr May reported receiving grants (via the University of California, Davis) from the NIH during the conduct of the study and grants (via the University of California, Davis) and speaking honoraria from Inflammatix outside the submitted work. Dr Ampofo reported receiving grants (via the University of Utah) from the National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study; grants (via the University of Utah) from the Centers for Disease Control and Prevention, Merck & Co, the NIAID, and the State of Utah; collaborating with BioFire Diagnostics on a grant from the NIH; and serving on the scientific advisory board of Merck & Co outside the submitted work. Dr Jhaveri reported receiving grants from Saol Therapeutics; personal fees from AstraZeneca, Dynavax Technologies, and Seqirus; and an editorial stipend from Elsevier outside the submitted work. Ms Komarow reported receiving grants from the Division of Microbiology and Infectious Disease of the NIAID, NIH during the conduct of the study. Dr Evans reported receiving grants from the NIAID during the conduct of the study and personal fees from Genentech and Microbiotix outside the submitted work. Dr Ginsburg reported owning equity in Biomeme during the conduct of the study, receiving grants from the NIH, and owning a patent for bacterial viral discrimination (licensed to Biomeme) outside the submitted work. Dr McClain reported receiving grants from Duke University during the conduct of the study and having a patent pending for molecular signatures of acute respiratory infections outside the submitted work. Dr Burke reported receiving grants from the NIH during the conduct of the study, owning equity in and serving as a consultant for Biomeme, and having a patent pending for methods to diagnose and treat acute respiratory infections outside the submitted work. Dr Woods reported receiving personal fees from Biomeme during the conduct of the study and owning a patent for methods to diagnose and treat acute respiratory infections outside the submitted work. Dr Tsalik reported receiving personal fees from Biomeme during the conduct of the study and owning a patent for methods to diagnose and treat acute respiratory infections outside the submitted work. No other disclosures were reported. Funding/Support: This study was supported by grant UM1AI104681 from the NIAID of the NIH (Dr Tsalik) and in-kind support from BioFire Diagnostics (test reagents and instruments) and bioMérieux (kits to measure procalcitonin levels).
ASJC Scopus subject areas
- General Medicine