RNA biosignatures test rapidly identifies bacterial infections in febrile newborns

A preliminary study has shown that RNA biosignatures can accurately distinguish whether a febrile newborn has a bacterial infection. If validated, a simple blood test could provide a fast, noninvasive diagnosis with better outcomes and lower treatment costs, according to a study published online August 23, 2016 in the Journal of the American Medical Association.

“The implications of these findings are potentially paradigm-changing,” said co-principal investigator Prashant Mahajan, MD, MPH, MBA, Professor of Emergency Medicine and Pediatrics at Wayne State University, in Detroit, MI.

“For 100 years, doctors have looked directly for bacteria in body fluids to make a diagnosis. We have now shown that genomic analysis to detect the response of the human immune system is also very accurate and potentially can be more rapid in determining if a young baby has a bacterial infection,” explained Dr. Mahajan, who is also Chief of Pediatric Emergency Medicine at Children’s Hospital of Michigan.

Currently, detecting serious bacterial infections in infants 2 months old and younger requires blood, urine, and cerebrospinal fluid (CSF) cultures—painful testing that can take a day or more to obtain results. Although fewer than 10% of newborns with fever who present to emergency departments are eventually found to have bacterial infections, many infants may be provisionally prescribed antibiotics and hospitalized until results of the cultures come back.

“Finding an accurate but less invasive method to determine if babies with fevers have bacterial infections is a ‘holy grail’ for emergency department physicians. This proof-of-concept study demonstrates that the evaluation of RNA biosignatures could one day be that tool,” said co-principal investigator Nate Kuppermann, MD, MPH, Professor and Chair of the Department of Emergency Medicine at University of California Davis School of Medicine, in Sacramento, CA.

This new method stems from the finding that microbial pathogens induce specific host responses (“RNA biosignatures”) that can be identified in blood leukocytes using microarray analyses. Studies have already shown this approach can distinguish bacterial from viral infections in older children and adults. But researchers questioned whether the immune systems of newborns are adequately developed to generate a detectable host response.

To find out, researchers at multiple centers in the Pediatric Emergency Care Applied Research Network (PECARN) put this question to the test. They measured RNA biosignatures in a convenience sample of 279 febrile infants 60 days or younger, of whom 89 had bacterial infections (confirmed by culture)—including 32 with bacteremia and 15 with urinary tract infections—and 190 had no infection. Nineteen healthy infants without fever were used as controls.

Their findings showed that the RNA biosignatures test detected bacterial infections with 87% sensitivity and 89% specificity compared to standard cultures. It also identified bacteremia with 94% sensitivity and 95% specificity. These results demonstrated that newborns’ immune systems did indeed generate a sufficient host response.

“Despite the young age of the babies in this study, they did carry robust RNA biosignatures,” explained co-principal investigator Octavio Ramilo, MD, Chief of Infectious Diseases at Nationwide Children's Hospital and Professor of Pediatrics at The Ohio State University, in Columbus, OH. “Regardless of whether they had a viral or bacterial infection, their immune systems were already programmed to respond with specific patterns.”

Following this study, the researchers now plan to corroborate their findings in a larger patient population and evaluate whether the RNA biosignature is stable at two different time points, thanks to a renewed five-year grant from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. They will also test a new RNA biosignatures polymerase chain reaction platform, which could provide faster results and be more applicable in clinical labs. The new study will also investigate whether the RNA biosignatures test can simultaneously detect bacterial and viral infection in a single patient.