Diagnostic Performance of AAP-Recommended Inflammatory Markers in Febrile Infants Aged 60 Days or Younger

This is the authors' abstract. We don't add key points for this paper.

Approximately 2% of febrile infants aged 60 days or younger have invasive bacterial infections (IBIs).1 To risk stratify well-appearing febrile infants aged 22 to 60 days, the 2021 American Academy of Pediatrics (AAP) clinical practice guideline (CPG) recommends 2 inflammatory marker (IM)–based strategies based on availability of procalcitonin (PCT): (1) PCT and absolute neutrophil count (ANC) or (2) maximum temperature (Tmax), ANC, and C-reactive protein (CRP).2 However, these combinations of IMs have not been directly compared in a multicenter study. We aimed to validate and compare the performance characteristics of the AAP CPG recommended risk stratification strategies for detecting IBI.We conducted a secondary analysis of the dataset from the Reducing Excessive Variability in Infant Sepsis Evaluation II (REVISE II), a quality improvement initiative that included infants aged 8 to 60 days with temperature of at least 38 °C who were evaluated at one of 106 sites from November 1, 2020, to October 31, 2022.3 Sites included freestanding (n = 35) and non-freestanding children’s hospitals (n = 37) and general hospitals (n = 34). For inclusion in this analysis, infants required a documented temperature and performance of a blood culture.4 Exclusion criteria mirrored those in the CPG,2,3 including ill appearance, which was based on emergency department physical examination documentation.5 Infants were classified as having IBI if an a priori defined pathogen was identified in blood culture (bacteremia) and/or in cerebrospinal fluid culture (bacterial meningitis) with a treatment course for IBI. We classified indeterminate organisms by consensus. Additional details are described in the parent study.3The data collection form listed normal and abnormal IM values per the AAP CPG; participating sites chose the appropriate option. We calculated the sensitivity, specificity, negative predictive value (NPV), and negative likelihood ratio (LR) for identification of IBI, stratified by AAP CPG age group, in 2 combinations: PCT + ANC and Tmax + ANC + CRP. As an exploratory analysis, we also assessed PCT+ANC+CRP. If all IMs in the combination were obtained, or at least 1 IM in the combination was abnormal (regardless of other IMs obtained), infants were included in that group. Infants could be included in more than 1 IM combination. Performance characteristics were calculated using Stata version 18.0 (StataCorp, Inc, College Station, TX). The study was deemed exempt by the AAP institutional review board.Of 13 262 infants who met eligibility criteria, 12 846 (96.9%) had blood cultures and were included, 292 (2.3%) of whom had IBIs. Characteristics of included infants are described in Supplemental Table 1. For identification of IBI in infants aged 22 to 60 days, both risk stratification strategies had high sensitivity (≥95%) and NPV (≥99.8%) and low negative LRs (≤0.12), though the sensitivity varied by age group (Table 1). Specificity was highest for PCT + ANC (63.2% in infants 22–60 days). Most false negatives were for bacteremia (Supplemental Table 2). When limited to infants who had all IMs obtained in the combination, the specificity of both combinations was slightly higher (Supplemental Table 3). Addition of CRP to PCT + ANC reduced specificity (Supplemental Table 4). Two infants with meningitis aged 22 to 60 days would have been misclassified as low risk by either PCT+ANC (1 infant) or Tmax + ANC + CRP (1 infant); both infants were hospitalized (Table 2).This multicenter study validates the use of the AAP-recommended risk stratification strategies for well-appearing febrile infants aged 22 to 60 days and increases the generalizability of prior studies4,6 by inclusion of infants evaluated at both children’s and general hospitals. Both AAP CPG recommended risk stratification strategies have high sensitivity for identifying febrile infants with IBIs. PCT + ANC had the highest specificity, with fewer infants being classified as non–low risk potentially resulting in fewer lumbar punctures and hospitalizations. Although 2 infants aged 22 to 60 days with meningitis would have been misclassified as low risk (1 by PCT+ANC and 1 by Tmax+ANC+CRP), both were hospitalized which may indicate that other factors raised the suspicion of meningitis (eg, clinical appearance). Further investigation is needed to assess outcomes of the rare infants with IBIs misclassified as low risk and to further evaluate the use of these strategies in infants aged 8 to 21 days.Limitations include those inherent in retrospective data collection, including potential infant misclassification as well appearing. Laboratory results were collected in a binary manner of normal vs abnormal, limiting additional analyses to assess different cutoff values. Additionally, we used ANC of greater than 4000/mm3 as our cutoff for the Tmax + ANC + CRP group. It is possible that sensitivity would be lower and specificity higher if 5200/mm3 was used, as is recommended when PCT is unavailable.5In conclusion, the AAP-recommended risk stratification strategies for febrile infants are excellent at ruling out IBI. Clinicians can have confidence in not obtaining lumbar punctures in low-risk infants. With higher specificity, use of PCT + ANC can potentially result in less resource utilization and harm.The authors acknowledge all the sites and site team members that collected data for this study as part of the AAP REVISE II QI Collaborative.