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JAMA. 2016 Aug 23-30;316(8):846-57. doi: 10.1001/jama.2016.9207.

Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger.

Author information

1
Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, Detroit.
2
Departments of Emergency Medicine and Pediatrics, University of California, Davis, School of Medicine, Sacramento.
3
Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus.
4
Benaroya Research Institute, Virginia Mason and Sidra Medical and Research Center, Seattle, Washington, and Doha, Qatar.
5
Department of Pediatrics, University of Utah, Salt Lake City.
6
Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania7Now at Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
7
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland.
8
Division of Emergency Medicine, Department of Pediatrics, Children's National Medical Center, George Washington School of Medicine and Health Sciences, Washington, DC.
9
Division of Pediatric Emergency Medicine, Alfred I. DuPont Hospital for Children, Nemours Children's Health System, Wilmington, Delaware.
10
Department of Pediatrics, Jacobi Medical Center, Albert Einstein College of Medicine, New York, New York.
11
Section of Emergency Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.
12
Department of Emergency Medicine, Hurley Medical Center and University of Michigan, Flint.
13
Departments of Emergency Medicine and Pediatrics, University of Rochester Medical Center, Rochester, New York.
14
Departments of Pediatrics and Emergency Medicine, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee.
15
Section of Emergency Medicine, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University, Columbus.
16
Sections of Emergency Medicine and Infectious Diseases, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston.
17
Division of Emergency Medicine, Department of Pediatrics, Columbia University College of Physicians & Surgeons, New York, New York.
18
Division of Emergency Medicine, Department of Pediatrics, University of Maryland Medical Center, Baltimore.
19
Department of Pediatrics, Primary Children's Medical Center, University of Utah, Salt Lake City.
20
Department of Emergency Medicine, Helen DeVos Children's Hospital of Spectrum Health, Grand Rapids, Michigan22Now with the Departments of Emergency Medicine and Pediatrics, Western Michigan University Homer Stryker, MD, School of Medicine, Kalamazoo.
21
Department of Pediatrics, St Louis Children's Hospital, Washington University, St Louis, Missouri24Now with the Division of Pediatric Emergency Medicine, University of California San Francisco School of Medicine.
22
Department of Pediatrics, Bellevue Hospital New York University Langone Center, New York.
23
Department of Pediatrics, Women and Children's Hospital of Buffalo, State University of New York at Buffalo.
24
Department of Emergency Medicine and Pediatrics, Hasbro Children's Hospital and Brown University, Providence, Rhode Island.
25
Department of Pediatrics, Bellevue Hospital New York University Langone Center, New York28Now with the Department of Emergency Medicine, Phoenix Children's Hospital, Phoenix, Arizona.
26
Department of Pediatrics, Boston Children's Hospital, Harvard University, Boston, Massachusetts.
27
Division of Emergency Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
28
Departments of Emergency Medicine and Pediatrics, University of Michigan, Ann Arbor.
29
Department of Pediatrics, Children's Hospital Colorado, University of Colorado-Denver, Aurora.
30
Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
31
Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee35Now with Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora.
32
Department of Pediatrics, Bellevue Hospital, New York University Langone Medical Center, New York.
33
Department of Emergency Medicine, University of California, Davis School of Medicine, Sacramento.
34
Division of Pediatric Emergency Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Abstract

IMPORTANCE:

Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach.

OBJECTIVE:

To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections.

DESIGN, SETTING, AND PARTICIPANTS:

Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.

EXPOSURE:

RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections.

MAIN OUTCOMES AND MEASURES:

Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores.

RESULTS:

Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43).

CONCLUSIONS AND RELEVANCE:

In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

PMID:
27552618
PMCID:
PMC5122927
DOI:
10.1001/jama.2016.9207
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mejias reports receiving personal fees from Abbvie, Novartis, and Janssen and grants from Gilead, Alios, and Janssen. Dr Ramilo reports receiving personal fees from HuMabs, Abbvie, Janssen, Medimmune, and Regeneron and grants from Janssen. All these fees and grants were not related to the current work. No other disclosures were reported.

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