Using AAP Guidelines for Managing Febrile Infants Without C-Reactive Protein and Procalcitonin

This study was approved by the Kaiser Permanente Northern California (KPNC) institutional review board. Informed consent was waived.

This study retrospectively examined the performance of the AAP CPG in 2527 febrile infants aged 8 to 60 days evaluated in KPNC emergency departments (EDs) from 2010 to 2019. Using the cohort of infants meeting the AAP CPG inclusion criteria (Supplemental Table 6), the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for IBI were calculated for each age group (with Wilson score 95% CIs), along with the percentage of infants recommended to undergo invasive interventions which include lumbar puncture (LP), parenteral antibiotics, and hospitalization. These parameters were then compared with those of the Roseville, Rochester, Philadelphia, and Boston protocols, as published in Nguyen et al 2021, whose patient cohort overlapped significantly with the current study.⁷  Parameters for the Philadelphia and Boston protocols for infants aged <28 days were calculated using data from the current study cohort. These 4 protocols do not use CRP and PCT for their risk stratification. Although the AAP CPG includes separate recommendations for infants aged 8 to 21 days and 22 to 28 days, for comparability across protocols, these groups were combined and comparisons were made across 2 groups: infants aged <28 days and infants aged 29 to 60 days.

We recognize that the AAP deliberately allows for the exercise of clinical judgement with regard to medical interventions and hospitalizations. Where the AAP CPG allows clinical discretion (eg, “may” perform an intervention), the data were analyzed twice, as if the most conservative choices were selected and as if the least conservative choices were selected, and the results of both analyses reported as a range. Where the AAP CPG allows clinical discretion (eg, “need not” perform an intervention), the data were analyzed to include the least conservative option. Most conservative was defined as pursuing the most invasive interventions and least conservative was defined as pursuing the fewest invasive interventions. Most clinicians and families seek to minimize invasive interventions not considered absolutely necessary. Statistical analyses were performed using SAS 9.4 (SAS Institute, Inc, Cary, NC).

Within the KPNC system, obtaining a rapid CRP result has only recently become possible in the EDs, but is still not available for outpatient medical clinics. PCT rapid result is currently not available in any KPNC ED or outpatient medical clinic. Therefore, most infants in this retrospective cohort lacked these test results. In accordance with the CPG’s recommendation, for infants aged 22 to 60 days without PCT, IMs were temperature >38.5°C and ANC >5200/mm³. A subset of febrile infants who had CRP results was analyzed separately. In addition, a subanalysis of the AAP CPG was performed using ANC >5200/mm³ as the sole IM.

KPNC is a large, integrated care system, with >4 million members receiving care in >40 pediatric clinics, 21 EDs, and 10 pediatric hospital wards in Northern California. As a closed health care system, most members receive all their care internally. KPNC uses an Epic-based complete electronic health record (EHR) fully deployed in 2010. This EHR captures encounters from a comprehensive network of inpatient, ED, and ambulatory care, as well as laboratory, pharmacy, and imaging records and data.

Infants born within KPNC presenting to a KPNC ED between 8 and 60 days of age were included if they had temperature ≥38°C measured by any method within 4 hours of arrival to an ED or measured by any method at a medical clinic visit within 12 hours preceding ED arrival, and had a complete blood count (CBC), blood culture, and urinalysis (UA) obtained for that episode of illness. Although the AAP CPG includes infants with documented fever at home, we included only infants with fever documented in a medical setting. We chose to use only infants with fever documented in a medical setting given the heterogeneity of fever documentation and our previous finding that 9.3% of infants with a chief complaint or final diagnosis of fever did not have a documented fever.¹⁰  For patients who had multiple ED visits for the same febrile illness, only the first episodes were captured, whereas the subsequent visits were excluded. Patients were also excluded from the final cohort using the AAP CPG exclusion criteria (Supplemental Table 6).

See Supplemental Table 7.

Data were electronically extracted from the EHR and associated databases, and abstracted from the medical record via clinician review assisted by natural language processing. Data extracted included age in days and gestational age in weeks, maternal and neonatal infection history, comorbidity flag,¹¹  maximum temperature in the first 4 hours in the ED or in clinic visit within the 12 hours preceding arrival to ED, immunizations within 48 hours of ED visit, and laboratory test results during and before the ED visit (CBC with differential, UA, cultures, and CRP and PCT when available). A minority of patients had a CRP obtained and a very minimal number had PCT, so the PCT was excluded from further analysis. IBIs were defined by culture results (Supplemental Table 7). When necessary, medical record review was used to confirm the diagnosis of bacteremia and/or bacterial meningitis. Data manually abstracted by medical record review included well versus ill appearance, presence of a clinically identifiable focal bacterial infection, Herpes simplex virus infection, or clinical bronchiolitis, as documented in the treating physician’s examination and assessment.

There were 2527 infants who met enrollment criteria and who presented to a KPNC ED between 8 and 60 days of age with measured temperatures ≥38°C within 4 hours of ED arrival or measured in clinic within the 12 hours preceding arrival. Of these, 1937 had at least a CBC, blood culture, and UA obtained, and 1433 infants met the remaining AAP CPG inclusion criteria and comprised the final analytic cohort. There were 504 infants excluded using the AAP CPG exclusion criteria. See Table 1 for demographic information and Supplemental Table 6 for a breakdown of excluded infants by age and criterion. There were 60 (4.2%) cases of IBIs, 57 (4.0%) with bacteremia, and 9 (0.6%) with bacterial meningitis.

The sensitivity of the AAP CPG was 100% (95% CI 83.9%–100%) and the specificity was 0% (95% CI 0%–1.4%) among infants aged 8 to 21 days, all of whom are recommended to undergo complete evaluations which include LP, empirical parenteral antibiotics, and hospitalization.

Using the combination of ANC >5200/mm³ and temperature >38.5°C as positive IMs, among infants aged 22 to 28 days, the AAP CPG performed with a sensitivity of 88.9% (95% CI 51.8%–99.7%) and specificity of 40.4% (95% CI 33.2%–48.1%). Among infants aged 29 to 60 days, it performed with a sensitivity of 93.3% (95% CI 77.9%–99.2%) and specificity of 32.1% (29.1%–35.3%). (Table 2).

Out of 1433 infants with a total of 60 cases of IBIs, 3 (5%, 95% CI 1.04%–13.9%) cases of IBI were misidentified. All 3 misidentified IBI cases were infants with bacteremia. Case 1 was a 7-week-old infant with concurrent Influenza B and Escherichia coli bacteremia. Case 2 was a 27-day-old infant with group B Streptococcus agalactiae (GBS) bacteremia. Both cases had negative urine cultures. Case 3 was a 7-week-old infant with blood and urine cultures positive for GBS. No infants with meningitis were misidentified.

The AAP CPG recommends LP, empirical parenteral antibiotics, and hospitalization for all febrile infants aged 8 to 21 days. Ranges are reported because of the multiple management options built into the CPG. Using ANC >5200/mm³ and temperature >38.5°C as IMs, the AAP CPG recommends LP for 61% to 100% of infants aged 22 to 28 days and 0% to 69% of infants aged 29 to 60 days; parenteral antibiotics for 58% to 100% of infants aged 22 to 28 days and 56% to 69% of infants aged 29 to 60 days; and hospitalization for 65% to 100% of infants aged 22 to 28 days and 56% to 69% of infants aged 29 to 60 days (Table 3).

Within the cohort of 1433 infants, 435 infants (30.3%) had a CRP and only 14 (0.01%) had a PCT. Among those who had CRP done, there were 26 (6%) cases of IBI, with 332 (76.3%) having either ANC >5200/mm³ or temperature >38.5°C, or both. When the AAP CPG was applied to the 435 infants who had a CRP using only ANC and temperature as IMs, 1 case of IBI (a 27 day old infant with GBS bacteremia) was misclassified. With the addition of CRP >20 mg/L as IM, 10 additional infants were considered to have positive IMs, but the single case of IBI was still missed (Table 4).

Removing temperature >38.5°C and using ANC >5200/mm³ as the only positive IM led to a significant reduction in sensitivity: from 88.9% to 66.7% (95% CI 29.9%–92.5%) among infants aged 22 to 28 days (2 additional false negatives) and from 93.3% to 60.0% (95% CI 40.6%–77.3%) among infants aged 29 to 60 days (10 additional false negatives). There were 15 missed cases of IBI, 12 more than if temperature >38.5°C was also included as a positive IM. Removing temperature did lead to a notable improvement in specificity, to 73% (95% CI 65.9%–79.4%) among infants aged 22 to 28 days and 66.5% (95% CI 63.3%–69.5%) among infants aged 29 to 60 days (Supplemental Table 8).

Table 5 lists the performance characteristics and recommended interventions by the AAP CPG without CRP and PCT compared with the Roseville, Rochester, Philadelphia, and Boston protocols. For infants aged <28 days, the AAP CPG had a sensitivity of 96.7% (95% CI 82.8%–99.9%), which does not differ statistically from other protocols, whereas the specificity of 16.0% (95% CI 12.8%–19.8%) is better than the Philadelphia and Boston protocols, but worse than the Roseville and Rochester protocols. The AAP CPG recommends invasive interventions for 84% to 100% of infants aged <28 days compared with 100% of infants for the Philadelphia and Boston protocols, 56% to 70% for Roseville, and 51% for Rochester. Among infants aged 29 to 60 days, the AAP CPG performs with comparable sensitivity (93.3%, 95% CI 77.9%–99.2%) to the Roseville, Rochester, Philadelphia, and Boston protocols. The specificity of the AAP CPG, 32.1% (95% CI 29.1%–35.3%) is statistically inferior to all 4 of these protocols (95% CIs 47.9%–67.8%). The AAP CPG recommends invasive interventions for 0% to 69% of infants aged 29 to 60 days, compared with 51% to 100% for Philadelphia, 36% to 100% for Boston, 0% to 26% for Roseville, and 44% for Rochester.

The AAP CPG for the “Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old” is an evidence-based set of recommendations and algorithms for a widely studied clinical scenario. Although it addresses a variety of common clinical scenarios and provides guidance for the application of clinician judgment and shared decision-making, it does not address its application to clinical settings where CRP and PCT are not available with rapid turnaround. This study demonstrates that, using only the combination of ANC >5200/mm³ and temperature >38.5°C as IMs, the AAP CPG detects IBI with a high sensitivity but low specificity. Furthermore, whereas recent studies have downplayed the utility of temperature in favor of newer IMs such as PCT,^5,6  in this study, temperature was demonstrated to improve sensitivity when these markers were not available.

Without the new biomarkers of CRP and PCT, the AAP CPG increases the rate of potentially unneeded interventions without increasing sensitivity. The 5 protocols compared in this study (Roseville, Rochester, Philadelphia, Boston, and the AAP CPG) demonstrated statistically equivalent sensitivity, with overlapping CIs ranging from 73.5% to 99.9% (Fig 2). The specificity of the AAP CPG is statistically inferior in both age groups to comparison protocols, except for the Philadelphia and Boston protocols for infants aged <29 days. Compared with the Philadelphia and Boston protocols, the AAP CPG spares up to 42% of interventions in infants aged 22 to 28 days by using IMs for risk stratification instead of universally recommending LP, antibiotics, and hospitalization; for older infants, the AAP CPG recommends fewer LPs but more hospital admissions. Compared with the Rochester and Roseville protocols, the AAP CPG recommends more interventions across all age groups.

The risks of testing, hospitalization, and treatment are relatively small, but occur at high frequency. A study by Baker in 1993 reported an 18.9% risk of infiltration of an intravenous line and a 0.4% risk of drug-related rash.³  DeAngelis in 1983 reported complications in 19.5% of hospitalizations, ranging from intravenous infiltrates, fluid overload, accidental antibiotic overdose, and iatrogenic fever (high isolete temperature) to “distraught mother.”¹²  DeAngelis’ study also reported a significant number of contaminated cerebrospinal fluid cultures, contaminated blood cultures, repeated attempts at lumbar puncture, and other “diagnostic misadventures,” all familiar to emergency physicians and pediatric hospitalists. Byington in 2012 found the average cost of hospitalization for a febrile infant at 1 US academic institution to be $7178 in 2007.¹³  The sum of iatrogenic events, complications, and financial costs are not trivial, increasing the burden on an already overtaxed medical system, especially in the era of the coronavirus disease 2019 pandemic. In addition, such interventions undoubtedly heighten anxiety and pose a financial burden for families.

KPNC is a large, integrated health care system with a robust EHR extending back a decade, providing a large and consistently documented trove of clinical data. The major limitation of this study is that it was not adequately powered to address the contribution of CRP and PCT; however, we are not disputing the use of either PCT or CRP in the approach to the febrile infant, because both have been studied in thousands of febrile infants and the specificity was 60% (Pediatric Emergency Care Applied Research Network)⁶  and 46.9% (Step-by-Step),⁵  respectively, in those studies. Rather, our aim was to describe the use of the AAP CPG in the absence of CRP and PCT. In addition, we raise awareness of using IMs in settings which have not been validated in varying infant populations.

Although the AAP CPG contributes an extensive set of evidence-based recommendations for the management of the well-appearing, febrile, young infant, the application of its algorithms in clinical settings without ready availability of CRP or PCT may lead to increased interventions without improved sensitivity for detecting IBI. The authors of the CPG point out that “the recommendations in this guideline do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.” Until these tests become more widely available, community settings without readily available CRP or PCT may experience limited benefit from the AAP CPG.

When CRP and PCT testing are not available, the AAP CPG algorithms performed with high sensitivity but low specificity for detecting IBI in 8- to 60-day old febrile infants. Compared with some other protocols not utilizing CRP and PCT, the AAP CPG may recommend more invasive interventions while detecting IBI with similar sensitivity. Further studies may inform best practices to reduce unnecessary interventions.

We thank Dr Nathan Kuppermann for his insightful review of the manuscript.

AAP

American Academy of Pediatrics

ANC

absolute neutrophil counts

CBC

complete blood count

CI

confidence interval

CPG

Clinical Practice Guideline

CRP

C-reactive protein

ED

emergency department

EHR

electronic health record

GBS

group B Streptococcus agalactiae

IBI

invasive bacterial infection

IM

inflammatory marker

KPNC

Kaiser Permanente Northern California

LP

lumbar puncture

PCT

procalcitonin

UA

urinalysis