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Preliminary Communication
Innovations in Health Care Delivery
August 23/30, 2016

Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children

Author Affiliations
  • 1Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom
  • 2Translational Paediatrics and Infectious Diseases Section, Department of Paediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain
  • 3Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Healthcare Research Institute of Santiago de Compostela and Universidade de Santiago de Compostela, Spain
  • 4Department of Pediatrics, University of California San Diego, La Jolla
  • 5Rady Children’s Hospital San Diego, San Diego, California
  • 6Emma Children’s Hospital, Department of Paediatric Haematology, Immunology and Infectious Diseases, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
  • 7Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, and Instituto de Ciencias Forenses, Grupo de Medicina Xenómica, Spain
  • 8Department of Paediatrics, University of Oxford, Oxford, United Kingdom
  • 9National Institute of Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom
  • 10National Institute of Health Research Wellcome Trust Clinical Research Facility, University of Southampton, Southhampton, United Kingdom
  • 11University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
  • 12Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, Department of Blood Cell Research, University of Amsterdam, Amsterdam, the Netherlands
  • 13Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia
JAMA. 2016;316(8):835-845. doi:10.1001/jama.2016.11236

Importance  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.

Design, Setting, and Participants  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.

Exposures  A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.

Main Outcomes and Measures  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 and Relevance  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.