title: Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.
abstract: OBJECTIVE
  Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.
  
  
  OBJECTIVE
  To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.
  
  
  METHODS
  Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.
  
  
  METHODS
  A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.
  
  
  METHODS
  Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group.
  
  
  RESULTS
  The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment.
  
  
  CONCLUSIONS
  This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Jethro A
authors.initials: JA
authors.lastname: Herberg
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Myrsini
authors.initials: M
authors.lastname: Kaforou
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Shailes
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Hariklia
authors.initials: H
authors.lastname: Eleftherohorinou
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Clive J
authors.initials: CJ
authors.lastname: Hoggart
authors.affiliation: Translational Paediatrics and Infectious Diseases Section, Department of Paediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain3Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Healthcare Research Institute of Santiago de Compostela and Universidade de Santiago de Compostela, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cebey-López
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Carter
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Janes
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Gormley
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla5Rady Children's Hospital San Diego, San Diego, California.
authors.forename: Chisato
authors.initials: C
authors.lastname: Shimizu
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla5Rady Children's Hospital San Diego, San Diego, California.
authors.forename: Adriana H
authors.initials: AH
authors.lastname: Tremoulet
authors.affiliation: Emma Children's Hospital, Department of Paediatric Haematology, Immunology and Infectious Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anouk M
authors.initials: AM
authors.lastname: Barendregt
authors.affiliation: Translational Paediatrics and Infectious Diseases Section, Department of Paediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain3Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Healthcare Research Institute of Santiago de Compostela and Universidade de Santiago de Compostela, Spain7Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, and Instituto de Ciencias Forenses, Grupo de Medicina Xenómica, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla5Rady Children's Hospital San Diego, San Diego, California.
authors.forename: John
authors.initials: J
authors.lastname: Kanegaye
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom9National Institute of Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: National Institute of Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southhampton, United Kingdom11University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Saul N
authors.initials: SN
authors.lastname: Faust
authors.affiliation: University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Patel
authors.affiliation: Emma Children's Hospital, Department of Paediatric Haematology, Immunology and Infectious Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands12Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, Department of Blood Cell Research, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Taco
authors.initials: T
authors.lastname: Kuijpers
authors.affiliation: Translational Paediatrics and Infectious Diseases Section, Department of Paediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain3Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Healthcare Research Institute of Santiago de Compostela and Universidade de Santiago de Compostela, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Martinón-Torres
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla5Rady Children's Hospital San Diego, San Diego, California.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
authors.affiliation: Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D000941:Antigens / Q000097:blood* / Q000235:genetics; D019540:Area Under Curve; D001424:Bacterial Infections / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002675:Child, Preschool; D060085:Coinfection / Q000175:diagnosis / Q000382:microbiology / Q000821:virology; D003598:Cytoskeletal Proteins / Q000097:blood* / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D005334:Fever / Q000097:blood / Q000382:microbiology* / Q000821:virology*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008297:Male; D011446:Prospective Studies; D012313:RNA / Q000032:analysis / Q000097:blood* / Q000235:genetics; D012306:Risk; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D014777:Virus Diseases / Q000150:complications / Q000175:diagnosis* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D000941:Antigens; D015415:Biomarkers; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; C065888:IFI44 protein, human; D012313:RNA