Northwestern Medicine scientists, working with the Pediatric Emergency Care Applied Research Network (PECARN), recently assessed whether an RNA biosignature of the body’s response to infection could distinguish if infants 60 days or younger with fever were experiencing a serious bacterial infection.
The results, published in the Journal of the American Medical Association, show how RNA biosignatures may be an alternative – and more accurate – method to identify infants with bacterial infections. Using RNA biosignatures could help clinicians target therapies for patients with or without infections and avoid invasive diagnostic procedures, antibiotics and hospitalization.
“To date, we have only been able to determine if a young infant with a fever has a bacterial infection using invasive testing of blood, urine and spinal fluid,” said co-author Elizabeth Alpern, MD, professor of Pediatrics. “In this preliminary study, we were able to identify RNA biosignatures (the body’s response to infection) from a blood test alone that could distinguish infants with and without a bacterial infection.”
From December 2008 to December 2010, 1,883 infants were enrolled and, of those, 279 RNA samples were analyzed. They found 89 positive bacterial cultures and 190 negative bacterial cultures
Sixty-six classifier genes distinguished infants with and without bacterial infections with 87 percent sensitivity (the ability to identify those with the disease) and 89 percent specificity (the ability to identify those without the disease). Ten classifier genes distinguished infants with the presence of bacteria in the blood from those without bacterial infections with 94 percent sensitivity and 95 percent specificity. The RNA biosignature method was also shown to be comparable to standard bacterial culture tests.
Elizabeth Powell, MD, ’89 ’91 GME, MPH, professor of Pediatrics, was the site principal investigator for the study and supervised it in the Ann & Robert H. Lurie Children’s Hospital of Chicago.
Elizabeth Powell, MD, ’89 ’91 GME, MPH, professor of Pediatrics, was the site principal investigator for the study and supervised it at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
“The PECARN network and Lurie Children’s Hospital are conducting a follow-up study to help refine the test and improve the ability for this test to be brought into clinical practice,” Powell said. “We thank the parents whose infants were treated in the Emergency Department and who agreed to participate in the study.”
PECARN, the first federally funded national network for research on pediatric emergencies and Emergency Medical Services for Children (EMSC), was established to facilitate to research in the care of acutely ill and injured children.
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