Video Abstract
To derive and internally validate a prediction model for the identification of febrile infants ≤60 days old at low probability of invasive bacterial infection (IBI).
We conducted a case-control study of febrile infants ≤60 days old who presented to the emergency departments of 11 hospitals between July 1, 2011 and June 30, 2016. Infants with IBI, defined by growth of a pathogen in blood (bacteremia) and/or cerebrospinal fluid (bacterial meningitis), were matched by hospital and date of visit to 2 control patients without IBI. Ill-appearing infants and those with complex chronic conditions were excluded. Predictors of IBI were identified with multiple logistic regression and internally validated with 10-fold cross-validation, and an IBI score was calculated.
We included 181 infants with IBI (155 [85.6%] with bacteremia without meningitis and 26 [14.4%] with bacterial meningitis) and 362 control patients. Twenty-three infants with IBI (12.7%) and 138 control patients (38.1%) had fever by history only. Four predictors of IBI were identified (area under the curve 0.83 [95% confidence interval (CI): 0.79–0.86]) and incorporated into an IBI score: age <21 days (1 point), highest temperature recorded in the emergency department 38.0–38.4°C (2 points) or ≥38.5°C (4 points), absolute neutrophil count ≥5185 cells per μL (2 points), and abnormal urinalysis results (3 points). The sensitivity and specificity of a score ≥2 were 98.8% (95% CI: 95.7%–99.9%) and 31.3% (95% CI: 26.3%–36.6%), respectively. All 26 infants with meningitis had scores ≥2.
Infants ≤60 days old with fever by history only, a normal urinalysis result, and an absolute neutrophil count <5185 cells per μL have a low probability of IBI.
Comments
RE: Performing LP in the Evaluation of the Febrile Young Infant
I read with interest the recently published study1 entitled “A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of Invasive Bacterial Infection”. It seeks to determine criteria to accurately identify febrile young infants [FYI] at “acceptably” low risk for serious bacterial infections [SBI]. Criteria do not include performing CSF analysis. Results show that all 26 infants with bacterial meningitis [BM] studied had an IBI Score >2. The authors concluded that “using an IBI Score <2 to define low risk could have a significant impact by reducing lumbar punctures and hospitalization in neonates with a low probability of IBI.”
It is concerning that this recommendation suggests to clinicians that BM risk in the FYI can accurately be determined without CSF analysis, even in those aged younger than 4 weeks old.
There appear to be several shortcomings in methodology that impair accurately reaching this conclusion:
1] Inclusion criteria for study included “non-ill appearing infants”. Yet this determination was not standardized, and it is unclear if grading was performed by experienced attending-level or relatively inexperienced resident physicians. Clinical appearance, although an essential component to the evaluation, is notoriously difficult to accurately grade in the FYI, in large part due to patient neurologic immaturity; a prior study showed that only 3 of 4 FYI with SBI “appeared to be ill” as graded by PEM attending physicians.2 The fact that all 26 infants with BM studied were judged by a physician to be “not ill appearing” supports this.1
2] Traditionally, parental report of having measured fever per rectum is considered indicative of the febrile state; and therefore actionable as such. An IBI Score factor used to recommend eliminating performance of LP is caretaker history of fever/patient afebrile in the ED. Yet this has been shown to lack validity as an accurate distinguisher for a lower risk subset - by a prior study documenting 20% with a history of fever who were afebrile in the ED who then manifested fever per rectum during their subsequent 48 hour hospitalization.3 It is also unclear how many study patients received antipyretics prior to evaluation, and whether a standard number of multiple rectal temperatures were performed during the ED stay.
Another recently published study4 likewise proposed SBI low risk criteria for FYI which did not include CSF analysis [10 patients with BM]. Although ED temperatures are not specified, it is of note that 2 infants with BM met the criteria of normal urinalysis and CBC ANC <4090/mm3.
In both studies, the implication is that a non-LP protocol utilizing surrogate blood test results [CBC ANC, serum procalcitonin] can reliably determine SBI risk [including BM]. Just as one would not solely use ancillary blood test results to determine UTI risk without performing urinalysis, clinicians should remember that the sole method to conclusively diagnose the most serious SBI, namely BM, is CSF analysis. A relatively small sample size of 36 FYI with BM in combining these 2 studies should prompt caution that further analysis with greater patient numbers is essential before recommending eliminating LP in the outpatient evaluation of the FYI.
References
1. Aronson P, Shabanova V, Shapiro E, et al: A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of Invasive Bacterial Infection. Pediatrics 2019 Jun 5. pii: e20183604. doi: 10.1542/peds.2018-3604.
2. Bonadio, WA, Hennes, H, Smith, D, et al: Reliability Of Observation Variables In Distinguishing Infectious Outcome Of Febrile Young Infants. Pediatr Infect Dis J 1993;12:111-114.
3. Bonadio WA, Hegenbarth M, Zachariason M: Correlating Reported Fever In Young Infants With Subsequent Temperature Patterns And Rate Of Serious Bacterial Infections. Pediatr Infect Dis J 1990;9:158-160.
4. Kuppermann N, Dayan P, Levine D; et al: A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections. JAMA Pediatr 2019;173(4):342-351.