title: Host gene expression classifiers diagnose acute respiratory illness etiology.
abstract: Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Emergency Medicine Service, Durham Veteran's Affairs Medical Center, Durham, NC 27705.|Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.
authors.forename: Ephraim L
authors.initials: EL
authors.lastname: Tsalik
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Department of Electrical & Computer Engineering, Duke University, Durham, NC 27708.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Henao
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Marshall
authors.initials: M
authors.lastname: Nichols
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Thomas
authors.initials: T
authors.lastname: Burke
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Duke Regional Hospital, Department of Medicine, Duke University, Durham, NC 27710.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Ko
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.|Section for Infectious Diseases, Medicine Service, Durham Veteran's Affairs Medical Center, Durham, NC 27705.
authors.forename: Micah T
authors.initials: MT
authors.lastname: McClain
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Hudson
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Anna
authors.initials: A
authors.lastname: Mazur
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.
authors.forename: Debra H
authors.initials: DH
authors.lastname: Freeman
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Tim
authors.initials: T
authors.lastname: Veldman
authors.affiliation: Immunology Division, Lovelace Respiratory Research Institute, Albuquerque, NM 87108.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599.
authors.forename: Eugenia B
authors.initials: EB
authors.lastname: Quackenbush
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599.
authors.forename: Seth W
authors.initials: SW
authors.lastname: Glickman
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599.|Department of Emergency Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Cairns
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI 48202.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Jaehne
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI 48202.
authors.forename: Emanuel P
authors.initials: EP
authors.lastname: Rivers
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Wayne State University, Detroit, MI 48202.
authors.forename: Ronny M
authors.initials: RM
authors.lastname: Otero
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.
authors.forename: Aimee K
authors.initials: AK
authors.lastname: Zaas
authors.affiliation: Rady Pediatric Genomic and Systems Medicine Institute, Rady Children's Hospital, San Diego, CA 92123.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Department of Electrical & Computer Engineering, Duke University, Durham, NC 27708.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Carin
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
authors.affiliation: Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, Durham, NC 27708.|Division of Infectious Diseases & International Health, Department of Medicine, Duke University, Durham, NC 27710.|Section for Infectious Diseases, Medicine Service, Durham Veteran's Affairs Medical Center, Durham, NC 27705.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D060085:Coinfection / Q000235:genetics / Q000382:microbiology / Q000821:virology; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012141:Respiratory Tract Infections / Q000175:diagnosis* / Q000235:genetics* / Q000382:microbiology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult