학술논문
Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.
Document Type
Academic Journal
Author
Tsalik EL; Durham Veterans Affairs Health Care System, Durham, NC.; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC.; Department of Biostatistics and Informatics, Duke University, Durham, NC.; Duke Clinical Research Institute, Durham, NC.; BioFire Diagnostics, LLC, Salt Lake City, UT.; Duke Regional Hospital, Durham, NC.; Institute for Medical Research, Durham, NC.; University of North Carolina Medical Center, Chapel Hill, NC.; Drexel University, Philadelphia, PA.; Rady Children's Institute for Genomic Medicine, San Diego, CA.; Henry Ford Hospital System, Detroit, MI.; University of South Alabama Health University Hospital, Mobile, AL.; Henao R; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Department of Biostatistics and Informatics, Duke University, Durham, NC.; Duke Clinical Research Institute, Durham, NC.; Montgomery JL; BioFire Diagnostics, LLC, Salt Lake City, UT.; Nawrocki JW; BioFire Diagnostics, LLC, Salt Lake City, UT.; Aydin M; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Lydon EC; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Ko ER; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Duke Regional Hospital, Durham, NC.; Petzold E; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Nicholson BP; Institute for Medical Research, Durham, NC.; Cairns CB; University of North Carolina Medical Center, Chapel Hill, NC.; Drexel University, Philadelphia, PA.; Glickman SW; University of North Carolina Medical Center, Chapel Hill, NC.; Quackenbush E; University of North Carolina Medical Center, Chapel Hill, NC.; Kingsmore SF; Rady Children's Institute for Genomic Medicine, San Diego, CA.; Jaehne AK; Henry Ford Hospital System, Detroit, MI.; Rivers EP; Henry Ford Hospital System, Detroit, MI.; Langley RJ; University of South Alabama Health University Hospital, Mobile, AL.; Fowler VG; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC.; Duke Clinical Research Institute, Durham, NC.; McClain MT; Durham Veterans Affairs Health Care System, Durham, NC.; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC.; Department of Biostatistics and Informatics, Duke University, Durham, NC.; Duke Clinical Research Institute, Durham, NC.; BioFire Diagnostics, LLC, Salt Lake City, UT.; Duke Regional Hospital, Durham, NC.; Institute for Medical Research, Durham, NC.; University of North Carolina Medical Center, Chapel Hill, NC.; Drexel University, Philadelphia, PA.; Rady Children's Institute for Genomic Medicine, San Diego, CA.; Henry Ford Hospital System, Detroit, MI.; University of South Alabama Health University Hospital, Mobile, AL.; Crisp RJ; BioFire Diagnostics, LLC, Salt Lake City, UT.; Ginsburg GS; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Burke TW; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Hemmert AC; BioFire Diagnostics, LLC, Salt Lake City, UT.; Woods CW; Durham Veterans Affairs Health Care System, Durham, NC.; Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC.; Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC.; Department of Biostatistics and Informatics, Duke University, Durham, NC.; Duke Clinical Research Institute, Durham, NC.; BioFire Diagnostics, LLC, Salt Lake City, UT.; Duke Regional Hospital, Durham, NC.; Institute for Medical Research, Durham, NC.; University of North Carolina Medical Center, Chapel Hill, NC.; Drexel University, Philadelphia, PA.; Rady Children's Institute for Genomic Medicine, San Diego, CA.; Henry Ford Hospital System, Detroit, MI.; University of South Alabama Health University Hospital, Mobile, AL.
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0355501 Publication Model: Print Cited Medium: Internet ISSN: 1530-0293 (Electronic) Linking ISSN: 00903493 NLM ISO Abbreviation: Crit Care Med Subsets: MEDLINE
Subject
Language
English
Abstract
Objectives: Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test.
Design: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.
Setting: Four U.S. emergency departments.
Patients: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.
Interventions: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.
Measurements and Main Results: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.
Conclusions: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.
Competing Interests: Dr. Tsalik received in-kind support from BioFire Diagnostics by way of consumables and test instruments; received funding from Predigen, Inc.. BioFire, Inc. provided in-kind support for test development reagents used in this study. Drs. Tsalik, Henao, McClain, Ginsburg, Burke, and Woods disclosed filing for a patent pertaining to the signatures discussed in this study (WO 2017/004390 A1). Dr. Montgomery was an employee of BioFire Diagnostics, LLC. Dr. Nawrocki disclosed he has shares in BioMérieux. Dr. Lydon was supported by the Eugene A. Stead Scholarship from Duke University School of Medicine and the Infectious Diseases Society of America Medical Scholars Program. Drs. Tsalik, Ginsburg, and Woods disclosed that they are cofounders of Predigen, Inc. Drs. Tsalik, Ko, Petzold, Cairns, Kingsmore, Fowler, Ginsburg, Burke, and Woods received support for article research from the National Institutes of Health (NIH). Drs. Nawrocki and Hemmert received funding from BioFire Diagnostics, LLC.; and disclosed that they are employees of BioFire Diagnostics, LLC. Dr. Cairns is a consultant for BioMérieux, Inc. Dr. Ko’s institution received funding from the Antibiotic Resistance Leadership Group; disclosed the off-label product use of diagnostic tests. Dr. Petzold received support for article research from the Defense Advanced Research Projects Agency (DARPA) (NIH National Institute of Allergy and Infectious Diseases (NIAID) U01AI066569 and UM1AI104681 U.S. DARPA contract—N66001-09-C2082). Dr. Cairns’ institution received funding from the NIH (NIAID) and the DARPA; and received funding from BioMérieux. Dr. Kingsmore’s institution received funding from the NIH. Dr. Fowler received funding from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Basilea, and Janssen; received funding from Basilea, Affinergy, Janssen, Basilea, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Destiny, UpToDate; Stock options Valanbio; a patent for sepsis diagnosis (US9850539B2). Dr. McClain disclosed he has patents pending on diagnostic signatures for respiratory infections. Dr. Crisp was an employee of BioFire Diagnostics and is currently an employee of BioMérieux, Inc. Dr. Ginsburg’s institution received funding from DARPA; received support for article research from the Bill & Melinda Gates Foundation. Dr. Burke is a consultant for and holds equity in Predigen, Inc. Dr. Burke’s institution received funding from the NIH; received funding from Predigen, Inc.; disclosed he is a coinventor on patents pending on Molecular Methods to Diagnose and Treat Respiratory Infections. Dr. Hemmert disclosed the off-label product use of BioFire FilmArray System. The remaining authors have disclosed that they do not have any potential conflicts of interest.
(Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)
Design: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.
Setting: Four U.S. emergency departments.
Patients: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.
Interventions: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.
Measurements and Main Results: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.
Conclusions: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.
Competing Interests: Dr. Tsalik received in-kind support from BioFire Diagnostics by way of consumables and test instruments; received funding from Predigen, Inc.. BioFire, Inc. provided in-kind support for test development reagents used in this study. Drs. Tsalik, Henao, McClain, Ginsburg, Burke, and Woods disclosed filing for a patent pertaining to the signatures discussed in this study (WO 2017/004390 A1). Dr. Montgomery was an employee of BioFire Diagnostics, LLC. Dr. Nawrocki disclosed he has shares in BioMérieux. Dr. Lydon was supported by the Eugene A. Stead Scholarship from Duke University School of Medicine and the Infectious Diseases Society of America Medical Scholars Program. Drs. Tsalik, Ginsburg, and Woods disclosed that they are cofounders of Predigen, Inc. Drs. Tsalik, Ko, Petzold, Cairns, Kingsmore, Fowler, Ginsburg, Burke, and Woods received support for article research from the National Institutes of Health (NIH). Drs. Nawrocki and Hemmert received funding from BioFire Diagnostics, LLC.; and disclosed that they are employees of BioFire Diagnostics, LLC. Dr. Cairns is a consultant for BioMérieux, Inc. Dr. Ko’s institution received funding from the Antibiotic Resistance Leadership Group; disclosed the off-label product use of diagnostic tests. Dr. Petzold received support for article research from the Defense Advanced Research Projects Agency (DARPA) (NIH National Institute of Allergy and Infectious Diseases (NIAID) U01AI066569 and UM1AI104681 U.S. DARPA contract—N66001-09-C2082). Dr. Cairns’ institution received funding from the NIH (NIAID) and the DARPA; and received funding from BioMérieux. Dr. Kingsmore’s institution received funding from the NIH. Dr. Fowler received funding from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Basilea, and Janssen; received funding from Basilea, Affinergy, Janssen, Basilea, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Destiny, UpToDate; Stock options Valanbio; a patent for sepsis diagnosis (US9850539B2). Dr. McClain disclosed he has patents pending on diagnostic signatures for respiratory infections. Dr. Crisp was an employee of BioFire Diagnostics and is currently an employee of BioMérieux, Inc. Dr. Ginsburg’s institution received funding from DARPA; received support for article research from the Bill & Melinda Gates Foundation. Dr. Burke is a consultant for and holds equity in Predigen, Inc. Dr. Burke’s institution received funding from the NIH; received funding from Predigen, Inc.; disclosed he is a coinventor on patents pending on Molecular Methods to Diagnose and Treat Respiratory Infections. Dr. Hemmert disclosed the off-label product use of BioFire FilmArray System. The remaining authors have disclosed that they do not have any potential conflicts of interest.
(Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)