Reevaluate the Evaluation of Febrile Infants?

The Pediatric Emergency Care Applied Research Network (PECARN) has worked for the past decade to both evaluate new technologies and reevaluate standard of care for fever and infections. In a recent JAMA Pediatrics paper, the group revealed important findings: traditional complete blood cell (CBC) thresholds — with standard cutoffs for white blood cell count, absolute neutrophil count and platelet count — do not effectively identify very young infants with invasive bacterial infections.

“The majority of young babies presenting with acute fever are going to have something pretty benign, but a small group can have a serious infection. It’s important to identify that needle in the haystack,” says Octavio Ramilo, MD, chief of the Division of Infectious Diseases at Nationwide Children’s and an author on the publication. “We thought babies with higher white cell counts were more likely to have serious bacterial infections, but it turns out this standard lab test was not as helpful as we thought.”

PECARN’s investigators at 26 hospitals nationwide prospectively evaluated 4,313 previously healthy infants younger than 2 months of age who presented to emergency departments with fever. All babies had blood cultures and either cerebrospinal fluid cultures or a 7-day follow-up visit to confirm the cause and course of their fever. Standard CBC cutoff values were not accurate predictors of invasive bacterial infections, correctly identifying only 7-27 percent of true cases.

Even when the research team optimized CBC thresholds using the new data from study participants, including CBC values from 97 babies with confirmed invasive bacterial infections, the cutoffs could not discriminate between infants with and without invasive bacterial infections with high accuracy.

“It’s possible that CBCs used to be better predictive measures than they are now,” suggests Dr. Ramilo. “The causes of fever and infection in these young infants have changed over the last few decades. Vaccines and new protocols for treating infants born to mothers with fever may be making it even more challenging to detect which babies have severe bacterial infections.”

Despite the newfound shortcoming of this common lab test, Dr. Ramilo expects physicians will still use CBCs as part of their standard work-up — he just recommends they do so with a greater understanding of the limitations.

“We know now that CBCs can’t be relied on in isolation to make decisions,” says Dr. Ramilo, who is also a principal investigator in the Center for Vaccines and Immunity at Nationwide Children’s. “This study proves we need to develop new tools for identifying babies with serious infections more quickly and precisely.”

PECARN already has such efforts underway. The group’s 2016 JAMA publication announced their collective progress toward the use of transcriptomics — RNA biosignatures — to identify babies with bacterial infections with up to 90 percent accuracy. The researchers are currently validating the tests in a larger cohort to improve and prepare it for clinical practice.

References:

1. Cruz AT, Mahajan P, Bonsu BK, Bennett JE, Levine DA, Alpern ER, Nigrovic LE, Atabaki SM, Cohen DM, VanBuren JM, Ramilo O, Kuppermann N; Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network. Accuracy of complete blood cell counts to identify febrile infants 60 days or younger with invasive bacterial infections. JAMA Pediatrics. 2017 Nov 6;171(11):e172927.
2. Mahajan P, Kuppermann N, Mejias A, Suarez N, Chaussabel D, Casper TC, Smith B, Alpern ER, Anders J, Atabaki SM, Bennett JE, Blumberg S, Bonsu B, Borgialli D, Brayer A, Browne L, Cohen DM, Crain EF, Cruz AT, Dayan PS, Gattu R, Greenberg R, Hoyle JD Jr, Jaffe DM, Levine DA, Lillis K, Linakis JG, Muenzer J, Nigrovi LE, Powell EC, Rogers AJ, Roosevelt G, Ruddy RM, Saunders M, Tunk MG, Tzimenatos L, Vitale M, Dean JM, Ramilo O; Pediatric Emergency Care Applied Research Network (PECARN). Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. JAMA. 2016 Aug 23-30;316(8):846-57.

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