Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children

Herberg, Jethro A., Kaforou, Myrsini, Wright, Victoria J., Shailes, Hannah, Eleftherohorinou, Hariklia, Hoggart, Clive J., Cebey-Lopez, Miriam, Carter, Michael J., Janes, Victoria A., Gormley, Stuart, Shimizu, Chisato, Tremoulet, Adriana H., Barendregt, Anouk M., Salas, Antonio, Kanegaye, John, Pollard, Andrew J., Faust, Saul N., Patel, Sanjay, Kuijpers, Taco, Martinon-Torres, Federico, Burns, Jane C., Coin, Lachlan J. M. and Levin, Michael (2016) Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children. The Journal of the American Medical Association, 316 8: 835-845. doi:10.1001/jama.2016.11236


Author Herberg, Jethro A.
Kaforou, Myrsini
Wright, Victoria J.
Shailes, Hannah
Eleftherohorinou, Hariklia
Hoggart, Clive J.
Cebey-Lopez, Miriam
Carter, Michael J.
Janes, Victoria A.
Gormley, Stuart
Shimizu, Chisato
Tremoulet, Adriana H.
Barendregt, Anouk M.
Salas, Antonio
Kanegaye, John
Pollard, Andrew J.
Faust, Saul N.
Patel, Sanjay
Kuijpers, Taco
Martinon-Torres, Federico
Burns, Jane C.
Coin, Lachlan J. M.
Levin, Michael
Title Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children
Journal name The Journal of the American Medical Association   Check publisher's open access policy
ISSN 1538-3598
0098-7484
Publication date 2016-08-23
Year available 2016
Sub-type Article (original research)
DOI 10.1001/jama.2016.11236
Open Access Status Not yet assessed
Volume 316
Issue 8
Start page 835
End page 845
Total pages 11
Place of publication Chicago, IL, United States
Publisher American Medical Association
Language eng
Subject 2700 Medicine
Abstract 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 infectionwas 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.
Formatted abstract
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.
Keyword Medicine, General & Internal
General & Internal Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID DMPED P26077
V1401
EC-GA 279185
RSRO 54990
PI10/00540
10 PXIB 918 184 PR
U54-HL108460
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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