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Pediatrics. 2018 Dec; 142(6): e20181879.
Published online 2018 Nov 30. doi:10.1542/peds.2018-1879
PMCID: PMC6317769
PMID: 30425130
Paul L. Aronson, MD,
a,b Marie E. Wang, MD, MPH,c Eugene D. Shapiro, MD,a,d Samir S. Shah, MD, MSCE,e,f Adrienne G. DePorre, MD,g Russell J. McCulloh, MD,g,h Christopher M. Pruitt, MD,i Sanyukta Desai, MD,f Lise E. Nigrovic, MD, MPH,j Richard D. Marble, MD,k Rianna C. Leazer, MD,l Sahar N. Rooholamini, MD, MPH,m Laura F. Sartori, MD,n Fran Balamuth, MD, PhD, MSCE,o,p Christopher Woll, MD,a,b Mark I. Neuman, MD, MPH,j and for the Febrile Young Infant Research Collaborative
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In this multicenter study, we evaluate the performance characteristics of theRochester and modified Philadelphia criteria for risk stratification of febrileinfants with bacteremia and/or bacterial meningitis.
Abstract
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OBJECTIVES:
To evaluate the Rochester and modified Philadelphia criteria for the riskstratification of febrile infants with invasive bacterial infection (IBI)who do not appear ill without routine cerebrospinal fluid (CSF) testing.
METHODS:
We performed a case-control study of febrile infants ≤60 days oldpresenting to 1 of 9 emergency departments from 2011 to 2016. For eachinfant with IBI (defined as a blood [bacteremia] and/or CSF [bacterialmeningitis] culture with growth of a pathogen), controls without IBI werematched by site and date of visit. Infants were excluded if they appearedill or had a complex chronic condition or if data for any component of theRochester or modified Philadelphia criteria were missing.
RESULTS:
Overall, 135 infants with IBI (118 [87.4%] with bacteremia without meningitisand 17 [12.6%] with bacterial meningitis) and 249 controls were included.The sensitivity of the modified Philadelphia criteria was higher than thatof the Rochester criteria (91.9% vs 81.5%; P = .01), butthe specificity was lower (34.5% vs 59.8%; P < .001).Among 67 infants >28 days old with IBI, the sensitivity of both criteriawas 83.6%; none of the 11 low-risk infants had bacterial meningitis. Of 68infants ≤28 days old with IBI, 14 (20.6%) were low risk per theRochester criteria, and 2 had meningitis.
CONCLUSIONS:
The modified Philadelphia criteria had high sensitivity for IBI withoutroutine CSF testing, and all infants >28 days old with bacterialmeningitis were classified as high risk. Because some infants withbacteremia were classified as low risk, infants discharged from theemergency department without CSF testing require close follow-up.
What’s Known on This Subject:
The Rochester and modified Philadelphia criteria do not include routinecerebrospinal fluid testing. Although these criteria have high sensitivity inthe risk stratification of febrile infants with serious bacterial infections,most studies had few infants with bacteremia and/or bacterial meningitis.
What This Study Adds:
The modified Philadelphia criteria were highly sensitive in the riskstratification of non–ill-appearing febrile infants with bacteremia, andno infants with bacterial meningitis were classified as low risk. Two infants≤28 days old with meningitis were classified as low risk by the Rochestercriteria.
Approximately 10% of febrile infants ≤60 days of age evaluated in the emergencydepartment (ED) have a serious bacterial infection.1 To identify infants who may be discharged from the ED afterinitial evaluation, the Rochester and Philadelphia criteria2–4 are widely used to stratify febrile infants on the basis oftheir risk of serious bacterial infection.5 Although these criteria have a reported sensitivity of >90%in the risk stratification of febrile infants with serious bacterial infections, thesestudies included mostly infants with urinary tract infections (UTIs), with relativelyfew infants with bacteremia and/or bacterial meningitis4 (ie, invasive bacterial infection [IBI]). Therefore, dataare limited regarding the precision of the Rochester and Philadelphia criteria in therisk stratification of infants with IBI.4 Additionally, with a changing epidemiology of IBI in febrileinfants since the development of these criteria >2 decades ago,6,7 the performance of these criteria needs to be reevaluatedperiodically.4,8
Given the rarity of bacterial meningitis in febrile infants >28 days of age who appearwell and the unclear benefit of routine cerebrospinal fluid (CSF) testing,9–11 some providers do not automatically perform CSFtesting in this age group, although practice varies substantially across hospitals.12,13 The Rochester criteria and the modified Philadelphiacriteria do not require routine CSF testing to classify febrile infants as being at alow or high risk for serious bacterial infection.2,9 Data regarding the performance characteristics of the Rochesterand modified Philadelphia criteria in a large sample of febrile infants ≤60 daysof age with IBI would inform the need for routine CSF testing in this population. Ourobjective was to evaluate the Rochester and modified Philadelphia criteria for the riskstratification of infants with IBI using a contemporary sample of febrile infants≤60 days of age evaluated in the ED.
Methods
Study Design
We analyzed data collected for a case-control study of febrile infants ≤60days of age evaluated in the ED at 1 of 11 children’s hospitals betweenJuly 1, 2011, and June 30, 2016. The current study was limited to the 9hospitals containing hematology laboratories that reported band counts becausethese were included in both the Rochester criteria and the modified Philadelphiacriteria. The study was approved by each site’s institutional reviewboard with permission for data sharing.
Cases
Infants ≤60 days of age with IBI were identified through query of eachhospital’s microbiology laboratory database or electronic medical recordsystem for blood and/or CSF cultures positive for a pathogen (defined apriori).7 Infants wereexcluded if the culture with positive results was documented in the medicalrecord to have been treated as a contaminant.7,14,15 Bacteremia was defined as growth of a pathogen ina blood culture. Bacterial meningitis was defined as growth of a pathogen in aCSF culture (with or without bacteremia) or growth of a pathogen in a bloodculture with concomitant CSF pleocytosis if antimicrobial agents wereadministered before CSF collection. CSF pleocytosis was defined as a CSF whiteblood cell (WBC) count of ≥20 cells per mm3 for infants≤28 days of age and ≥10 cells per mm3 for infants 29 to60 days of age.16
Infants with IBI were included as case patients if they presented either fromhome or from an outpatient clinic to the participating hospital’s ED (ie,were not transferred from another hospital) and if the following criteria weremet: (1) presence of fever (defined as a rectal temperature of≥38.0°C at home, in an outpatient clinic, or in the ED4), (2) no ill appearance asdocumented on the ED physical examination,17 and (3) absence of a complex chroniccondition.18,19 For all infants with IBI, medical records in the30 days after were reviewed to assess for a diagnosis of bacterialmeningitis.
Controls
Each case patient was matched by hospital and date of visit to 2 febrile infantcontrols. Potentially eligible controls were identified through a query of thePediatric Health Information System database for infants ≤60 days of agewith an ED visit to a participating hospital during the 5-year study period andwho had urine and blood cultures obtained. A query of the electronic medicalrecord system was performed at 1 site that did not contribute ED data to thePediatric Health Information System. For each case patient at a participatingsite, infants with the closest date of visit to the case patient were selectedas potential controls; if >2 infants were eligible on the basis of visitproximity, a random number generator was used to select which controls toinclude.
Medical records were reviewed for each potential control to determine thepresence of fever and to confirm eligibility. Controls were eligible if (1) theymet the same inclusion criteria as case patients, (2) their blood and/or CSFculture did not have growth of a pathogen, and (3) they had not receivedantibiotics within 7 days before the ED visit. For all controls, medical recordsfor the 30 days after the ED visit were reviewed to ensure that the infant wasnot diagnosed with an IBI. If a potentially eligible control was determined tobe ineligible after a medical record review, an infant with the next closestdate of visit was selected, with the process repeated until an eligible controlwas identified. Febrile infants with UTIs7,20,21 but without IBI were eligible for inclusion ascontrols.
Data Collection
For each case patient and control, we extracted the following data: demographics(age and sex); past medical history (including gestational age); clinicalappearance and presence of a localized infection; complete blood count,urinalysis, and CSF cell count; and bacterial culture results (urine, blood, andCSF). Study investigators at each site entered data into a secure ResearchElectronic Data Capture tool hosted at Yale University.22
Rochester and Modified Philadelphia Criteria
Table 1 lists the components of theRochester and modified Philadelphia criteria that classified an infant as lowrisk.9,23 For both criteria, thedefinition of a normal urinalysis was based on currently used urine dipstick andmicroscopy parameters.20 Bandcounts require performance of a manual differential on a complete blood count.Because performance of a manual differential is usually reflexively triggered byspecific parameters set on a hospital’s automated hematologyanalyzer,24 the band countwas recorded as 0 if only an automated differential was performed, and no bandswere reported. The immature-to-total (I/T) neutrophil ratio was defined as thepercentage of bands divided by the percentage of total neutrophils on a completeblood count. Infants were excluded from the primary analyses if data weremissing for any component of the Rochester or modified Philadelphia criteria(eg, gestational age, urinalysis, or peripheral WBC count).23
TABLE 1
Low-Risk Components for the Rochester and Modified PhiladelphiaCriteria
| Components | Rochester | ModifiedPhiladelphia |
|---|---|---|
| Demographics | N/Aa | Age >28 d |
| Past medical history | Previously healthyb | Previously healthyb |
| Physical examination | No skin or soft tissue infection | No skin or soft tissue infection |
| Laboratory | Normal urinalysisc;peripheral WBC count of ≥5000 and ≤15 000;absolute band count of ≤1500 bands per μL | Normal urinalysisc;peripheral WBC count of ≥5000 and ≤15 000;I/T ratio of <0.2d |
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N/A, not applicable.
aRochester criteria include infants ≤60 d of age without an agecutoff to define low risk.
bGestational age ≥37 wk; no previous ED visit, hospitalization,or evaluation for fever; no previous IBI or treatment withantibiotics; no other significant past medical history.
cUrine dipstick with no or trace leukocyte esterase, negativenitrites, and urine microscopy, with ≤5 WBCs per HPF or≤5 WBCs per mm3 on an enhanced urinalysis.
dBands-to-total neutrophil ratio.
Statistical Analyses
Categorical variables were described by using frequencies and percentages, anddistributions were compared by using a χ2 test. For theRochester and modified Philadelphia criteria, sensitivity and specificity werecalculated and reported with 95% confidence intervals (CIs). Because both theRochester and Philadelphia criteria have historically used ≤10 WBCs perhigh-power field (HPF) or ≤10 WBCs per mm3 on an enhancedurinalysis2,9,23 to define a normal urinalysis, analyses wererepeated by using this definition. Additionally, because the modifiedPhiladelphia criteria were developed for infants ≤56 days of age,9 analyses were repeated afterlimiting the sample to infants in this age range. Because of concerns regardingthe introduction of bias on the basis of the exclusion of infants with IBI, wealso calculated the sensitivity of the Rochester and modified Philadelphiacriteria after the inclusion of infants with missing data.
Statistical analyses were performed by using Stata data analysis and statisticalsoftware version 15.0 (Stata Corp, College Station, TX). A 2-tailedP value < .05 was considered statisticallysignificant.
Results
Study Sample
During the 5-year study period, 331 infants with IBI were evaluated in the EDs ofthe 9 participating hospitals. Eighty-six infants (26.0%) were excluded becauseof ill appearance, including 26 febrile infants who had bacterial meningitis. Ofthe infants with IBI who did not appear ill, 145 met inclusion criteria as casepatients and were matched to 290 controls. Because of missing data on clinicalor laboratory components of the Rochester and/or modified Philadelphia criteria,10 case patients and 41 controls were excluded, resulting in a final studysample of 135 case patients and 249 controls (Fig 1). Among the 135 infants with IBI, 118 (87.4%) had bacteremiawithout meningitis, and 17 (12.6%) had bacterial meningitis (with or withoutbacteremia). Of the 17 infants with bacterial meningitis, 7 (41.2%) were >28days of age.
FIGURE 1
Study population. a One infant was missing a urinalysis andcomplete blood count.
Sensitivity and Specificity of the Rochester and Modified PhiladelphiaCriteria
A higher proportion of febrile infants with IBI were ≤28 days of age andhad abnormal laboratory parameters compared with matched controls (Table 2). Sixty-one infants with IBI(45.2%) had a UTI compared with 15 controls (6.0%). Overall, 25 infants with IBI(18.5%; 95% CI: 12.4%–26.1%) were classified as low risk per theRochester criteria compared with 11 infants (8.1%; 4.1%–14.1%) who wereclassified as low risk per the modified Philadelphia criteria (difference:10.4%; 95% CI: 2.2%–18.6%).
TABLE 2
Characteristics of Case Patients and Controls
| Characteristic | Case Patients(N = 135), n (%) | Controls(N = 249), n (%) | P |
|---|---|---|---|
| Demographics | |||
| Age group, d | .01 | ||
| ≤28 | 68 (50.4) | 92 (37.0) | |
| 29–60 | 67 (49.6) | 157 (63.1) | |
| Female sex | 61 (45.2) | 102 (41.0) | .42 |
| Parameters of Rochestercriteria | |||
| Low risk | 25 (18.5) | 149 (59.8) | <.001 |
| Previouslyhealthya | 107 (79.3) | 206 (82.7) | .40 |
| Normalurinalysisb | 61 (45.2) | 219 (88.0) | <.001 |
| PeripheralWBC ≥5000 and ≤15 000 | 86 (63.7) | 200 (80.3) | <.001 |
| Normalabsolute band countc | 110 (81.5) | 240 (96.4) | <.001 |
| Parameters of modifiedPhiladelphia criteria | |||
| Low risk | 11 (8.1) | 86 (34.5) | <.001 |
| Previouslyhealthya | 107 (79.3) | 206 (82.7) | .40 |
| Normalurinalysisb | 61 (45.2) | 219 (88.0) | <.001 |
| PeripheralWBC ≥5000 and ≤15 000 | 86 (63.7) | 200 (80.3) | <.001 |
| Normal I/Tratiod | 103 (76.3) | 234 (94.0) | <.001 |
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aGestational age ≥37 wk; no previous ED visit, hospitalization,or evaluation for fever; no previous IBI or treatment withantibiotics; no other significant past medical history.
bUrine dipstick with no or trace leukocyte esterase, negativenitrites, and urine microscopy, with ≤5 WBCs per HPF or≤5 WBCs per mm3 on an enhanced urinalysis.
cAbsolute band count ≤1500.
dBands-to-total neutrophil ratio <0.2.
The sensitivity of the Rochester criteria was lower than the sensitivity of themodified Philadelphia criteria (81.5% vs 91.9%; P = .01), butthe specificity was higher (59.8% vs 34.5%; P < .001). Thecriteria performed similarly when restricted to infants 29 to 60 days of age(Table 3). Additionally, performanceof the modified Philadelphia criteria was similar when limited to infants≤56 days of age. By using the historical definition of ≤10 WBCsper HPF or ≤10 WBCs per mm3 to define a normal urinalysis, thesensitivities of both the Rochester and modified Philadelphia criteria werelower (74.8% and 88.2%, respectively), with a marginal increase in specificity(63.5% and 36.1%).
TABLE 3
Performance Characteristics of the Rochester and Modified PhiladelphiaCriteria for the Identification of IBI in Febrile Infants
| Sensitivity (95%CI) | Specificity (95%CI) | |
|---|---|---|
| Infants ≤60 d ofa*ge | ||
| Rochestercriteria | 81.5 (73.9–87.6) | 59.8 (53.5–66.0) |
| ModifiedPhiladelphia criteria | 91.9 (85.9–95.9) | 34.5 (28.6–40.8) |
| Infants ≤28 d ofa*ge | ||
| Rochestercriteria | 79.4 (67.9–88.3) | 64.1 (53.5–73.9) |
| ModifiedPhiladelphia criteriaa | 100 (94.7–100) | 0 (0–3.9) |
| Infants 29–60 d ofa*ge | ||
| Rochestercriteria | 83.6 (72.5–91.5) | 57.3 (49.2–65.2) |
| ModifiedPhiladelphia criteria | 83.6 (72.5–91.5) | 54.8 (46.6–62.7) |
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aAll infants ≤28 d of age were considered high risk per themodified Philadelphia criteria.
With the inclusion of the 10 infants with IBI who had missing data, an additional4 infants were classified as low risk by the Rochester criteria, including 1infant who was also classified as low risk per the modified Philadelphiacriteria. When including these infants in the analysis, the sensitivity of theRochester criteria was slightly lower overall (80.0%) and among infants 29 to 60days of age (81.7%), whereas the sensitivity of the modified Philadelphiacriteria was not materially different (91.7% overall and 83.1% among infants29–60 days of age).
Febrile Infants With IBI Classified as Low Risk
Of the 11 infants with IBI classified as low risk per the modified Philadelphiacriteria, none were diagnosed with bacterial meningitis (Table 4). Two of these infants had mild CSF pleocytosisafter traumatic lumbar punctures, and neither received an antimicrobialtreatment course for bacterial meningitis. The additional 14 infants with IBIwho were classified as low risk per the Rochester criteria were all ≤28days of age, including 2 infants with bacterial meningitis (Table 4). Both of these infants (≤28days of age with bacterial meningitis) would have been classified as high riskper the modified Philadelphia criteria because of an I/T ratio of≥0.2.
TABLE 4
Febrile Infants With IBI Classified as Low Risk per the Rochester andModified Philadelphia Criteria
| Age, d | Urinalysis WBC | Peripheral WBC | I/T Ratioa | Absolute Band Count | CSF WBC Count | CSF RBC Count | Urine Culture | Blood Culture | CSF Culture |
|---|---|---|---|---|---|---|---|---|---|
| Infants ≤28 d ofa*geb | |||||||||
| 3 | 0–5 | 8.6 | 0 | 0 | 35 | 3180 | No growth | Enterococcusfaecalis | No growth |
| 4 | 0–5 | 9.5 | 0.10 | 760 | 10 | 7150 | No growth | Escherichia coli | No growth |
| 10 | 0–5 | 10.6 | 0.02 | 212 | 16 | 13 | No growth | GBS | No growth |
| 11 | 0–5 | 13.0 | 0.15 | 1404 | 198 | 273 000 | No growth | Group AStreptococcus | No growth |
| 13 | Not performedc | 7.6 | 0 | 0 | 31 | 29 590 | No growth | Klebsiellapneumoniae | No growth |
| 17 | 0–5 | 11.2 | 0 | 0 | Not obtained | Not obtained | No growth | Salmonella spp | No growth |
| 18 | Not performedc | 9.6 | 0 | 0 | 9 | 4010 | No growth | Group AStreptococcus | No growth |
| 18 | 0–5 | 6.9 | 0.25 | 1035 | 1385 | 16 | No growth | Paenibacillus | Paenibacillus |
| 19 | 0–5 | 10.3 | 0 | 0 | 5 | 88 | Klebsiellaoxytoca | K oxytoca | No growth |
| 19 | 0–5 | 9.2 | 0.12 | 644 | 3 | 4 | No growth | GBS | No growth |
| 22 | 0–5 | 6.7 | 0.20 | 1146 | 1024 | 46 305 | Contaminant | Streptococcusgallolyticus | S gallolyticus |
| 24 | 0–5 | 11.8 | 0 | 0 | 6 | 738 | No growth | GBS | No growth |
| 24 | 0–5 | 9.1 | 0 | 0 | 120 | 2585 | No growth | GBS | No growth |
| 28 | Not performedc | 11.4 | 0 | 0 | 0 | 81 500 | No growth | Enterobacter | No growth |
| Infants 29–60 d ofa*ged | |||||||||
| 29 | 0–5 | 7.2 | 0.02 | 72 | Not obtained | Not obtained | No growth | GBS | No growth |
| 29 | 0–5 | 9.6 | 0 | 0 | 20 | 28 000 | No growth | Salmonella spp | No growth |
| 38 | 0–5 | 14.7 | 0 | 0 | 2 | 0 | No growth | GBS | No growth |
| 40 | Not performedc | 11.4 | 0 | 0 | 0 | 6750 | No growth | E faecalis | No growth |
| 41 | 0–5 | 6.5 | 0 | 0 | 4 | 0 | No growth | GBS | No growth |
| 47 | 0–5 | 9.4 | 0 | 0 | 1 | 1 | No growth | GBS | No growth |
| 50 | 0–5 | 10.4 | 0.10 | 830 | 1 | 13 | No growth | GBS | No growth |
| 50 | 0–5 | 9.6 | 0 | 0 | 4 | 1 | No growth | GBS | No growth |
| 53 | 0–5 | 6.7 | 0 | 0 | 4 | 36 | Contaminant | Salmonella spp | No growth |
| 55 | 0–5 | 11.1 | 0.15 | 1221 | 80 | 55 590 | No growth | GBS | No growth |
| 60 | 0–5 | 8.1 | 0 | 0 | 1 | 0 | No growth | E coli | No growth |
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GBS, group B Streptococcus; RBC, red blood cell.
aBands-to-total neutrophil ratio.
bLow risk per the Rochester criteria only.
cUrine dipstick with negative leukocyte esterase and negativenitrites.
dLow risk per the Rochester and modified Philadelphia criteria.
Of the 4 infants with IBI who had missing data and were classified as low riskper the Rochester criteria, 2 infants (ages 13 and 40 days) had group Bstreptococcal meningitis; both infants had a missing urinalysis. The 40-day-oldinfant had a peripheral WBC count of 15 000 cells per μL and anabsolute band count of 1200 bands per μL, with an I/T ratio of 0.2. The 1infant classified as low risk per the modified Philadelphia criteria was a55-day-old infant with group B streptococcal bacteremia and mild CSF pleocytosisafter a traumatic lumbar puncture; the infant was not treated for bacterialmeningitis.
Discussion
In this validation study that included a large multicenter sample of febrile infantswith IBI who did not appear ill, the modified Philadelphia criteria were highlysensitive in the risk stratification of infants with IBI. Importantly, no infantswith bacterial meningitis were classified as low risk. Although the Rochestercriteria had a similar sensitivity for IBI in febrile infants >28 days of age, 2infants ≤28 days of age with bacterial meningitis were classified as lowrisk. Our findings support the use of the modified Philadelphia criteria withoutroutine CSF testing for febrile infants in the second month of life.
Although only 0.2% of febrile infants 29 to 60 days of age who present to the ED havebacterial meningitis,6 manypediatric emergency medicine clinicians routinely perform CSF testing in this agegroup because of the high rate of neurologic sequelae and mortality associated withthis condition.25,26 However, performance of routineCSF testing in this age group is associated with higher costs, increasedhospitalization rates for otherwise low-risk infants, and significant stress forparents, all without a reduction in adverse outcomes compared with selective CSFtesting.10,13,27,28 Therefore, some have questioned the need for routineCSF testing in this age group. However, previous investigations in which theRochester and modified Philadelphia criteria were evaluated included few infantswith bacterial meningitis who did not appear ill.4,8,9,23
Our results inform this important issue by revealing that the modified Philadelphiacriteria had high sensitivity for IBI and classified all infants with bacterialmeningitis as high risk without routine CSF testing. Although 11 infants 29 to 60days of age were classified as low risk by the modified Philadelphia criteria, allthe infants had bacteremia without meningitis, and the 2 infants with CSFpleocytosis had traumatic lumbar punctures. Additionally, we excluded 26 febrileinfants with bacterial meningitis who appeared ill, all of whom would have beenclassified as high risk by the modified Philadelphia criteria because of their illappearance.9
The overall prevalence of IBI has been reported to be 2% in febrile infants.6 Therefore, among the thousands offebrile infants evaluated in the ED, few infants with IBI will be missed with use ofthese criteria. For instance, of 300 febrile infants >28 days of age who do notappear ill, 6 (2%) will have an IBI, and 1 of these 6 infants will be classified aslow risk by the modified Philadelphia criteria. Therefore, only 1 of 300 febrileinfants (0.3%) who do not appear ill will have an IBI, specifically with bacteremia,that will be missed with use of these criteria. Although the Rochester criteria hada similar sensitivity for IBI among infants 29 to 60 days of age, when includinginfants with missing data, 1 infant with bacterial meningitis in this age group wasclassified as low risk; our results favor the use of the modified Philadelphiacriteria. However, ultimately, clinicians must balance the rarity of bacterialmeningitis in febrile infants >28 days of age who do not appear ill and the risksof a lumbar puncture27,28 with the potential for serious neurologic sequelae ordeath if treatment is delayed.25,26 For infants treated with empirical antimicrobial therapywithout performance of CSF testing, there is potential for prolonged antimicrobialtherapy if the blood culture grows a pathogen and CSF pleocytosis is present on asubsequent lumbar puncture. Additionally, although infection with herpes simplexvirus is rare among febrile infants >28 days age,29,30 CSF testing should be obtained in this age group ifherpes simplex virus is suspected (eg, presence of vesicles or seizures).31
The prevalence of IBI is highest among febrile infants ≤28 days of age, and 1%of these infants will have bacterial meningitis.6 Although most infants in the first month of life whoare classified as low risk without CSF testing will not have an IBI, 2 infants withmeningitis in our study would have been missed by the Rochester criteria. Although arecently validated procalcitonin-based, low-risk algorithm that also does notinclude routine CSF testing (the step-by-step approach) uses an age cutoff of 21days instead of 28 days,32 in ourstudy, 3 infants with IBI, including 1 with bacterial meningitis, were between 22and 28 days of age and were classified as low risk per the Rochester criteria.Therefore, caution should be exercised in applying these criteria to febrile infants≤28 days of age.
The sensitivity and specificity of the modified Philadelphia criteria were similar tothose of the step-by-step approach.32 Because procalcitonin is not currently available at someUS hospitals, the modified Philadelphia criteria can be more widely implemented forthe risk stratification of febrile infants. However, these criteria should beprospectively tested against the step-by-step approach in a large cohort of febrileinfants. Additionally, although favorable outcomes have been reported for infantsmanaged as outpatients with the step-by-step approach,33 future investigation is needed to evaluateoutcomes with use of the modified Philadelphia criteria.
Our study has several limitations. First, data were collected through a medicalrecord review, and clinical variables, such as clinical appearance, may not beaccurately documented. However, we used a previously utilized definition of illappearance, and we only included infants who were not ill appearing.17 Second, although our searchstrategy for identifying case patients made it unlikely that we missed infants withIBI, we were unable to calculate the positive and negative predictive values of theRochester and modified Philadelphia criteria because we did not include all febrileinfants at study sites. Third, only 17 infants in our sample had bacterialmeningitis, reflecting the low prevalence of this condition among infants who do notappear ill. However, our study included the largest sample to date of febrileinfants ≤60 days of age with IBI who did not appear ill. Additionally,although we excluded 26 infants with bacterial meningitis who appeared ill, all ofthese infants would have been classified as high risk by both the Rochester andmodified Philadelphia criteria.9,23 Fourth, although we reviewed subsequent visits forcontrols, we cannot exclude the possibility that a control was diagnosed with IBI ata nonparticipating hospital. Fifth, although we excluded infants with IBI who hadmissing documentation of any component of the Rochester or modified Philadelphiacriteria, we included these infants in a sensitivity analysis. Sixth, the band countwas recorded as 0 if only an automated differential was performed on the completeblood count, and no bands were reported. Manual differentials are triggeredreflexively by a hospital’s automated hematology analyzer or on request froma clinician. It is therefore possible that some low-risk infants with IBI and 0bands would have been classified as high risk if a manual differential had beenperformed, which may have resulted in an underestimation of the sensitivity of thecriteria. Lastly, we only included infants who presented to EDs at participatingchildren’s hospitals, and our results may not be generalizable to othersettings, particularly community-based EDs.
Conclusions
The modified Philadelphia criteria, which does not include routine CSF testing,classifies most febrile infants with IBI as high risk. Because a few infants >28days of age with bacteremia were classified as low risk, febrile infants dischargedfrom the ED without CSF testing should have close outpatient follow-up. Cautionshould be exercised in applying low risk criteria to infants ≤28 days of age.A prospective study is needed to confirm the safety of routinely omitting CSFtesting in low-risk febrile infants >28 days of age.
Acknowledgments
We thank the following collaborators in the Febrile Young Infant ResearchCollaborative for their contributions as group authors for this study: Elizabeth R.Alpern, MD, MSCE, Northwestern University Feinberg School of Medicine (Chicago, IL);Whitney L. Browning, MD, Vanderbilt University School of Medicine (Nashville, TN);Elana A. Feldman, MD, Lucile Packard Children’s Hospital Stanford (Palo Alto,CA); Katie L. Hayes, BS, Children’s Hospital of Philadelphia (Philadelphia,PA); Catherine E. Lumb, BS, University of Alabama School of Medicine (Birmingham,AL); Christine E. Mitchell, BSN, Children’s Hospital of Philadelphia(Philadelphia, PA); Nipam Shah, MBBS, MPH, University of Alabama at Birmingham(Birmingham, AL); Sarah J. Shin, BSN, Children’s Hospital of Philadelphia(Philadelphia, PA); and Derek J. Williams, MD, MPH, Vanderbilt University School ofMedicine (Nashville, TN).
Glossary
| CI | confidence interval |
| CSF | cerebrospinal fluid |
| ED | emergency department |
| HPF | high-power field |
| IBI | invasive bacterial infection |
| I/T | immature-to-total |
| UTI | urinary tract infection |
| WBC | white blood cell |
Footnotes
Contributed by
Dr Aronson conceptualized and designed the study, supervised data collectionlocally and nationally, performed the data analyses, interpreted the data,drafted the initial manuscript, and reviewed and revised the manuscriptcritically for important intellectual content; Dr Wang contributed to the designof the study, collected local data, interpreted the data, and reviewed andrevised the manuscript critically for important intellectual content; DrsShapiro and Shah contributed to the design of the study, interpreted the data,and reviewed and revised the manuscript critically for important intellectualcontent; Drs DePorre, McCulloh, Pruitt, Desai, Nigrovic, Marble, Leazer,Rooholamini, Sartori, Balamuth, and Woll collected local data, interpreted thedata, and reviewed and revised the manuscript critically for importantintellectual content; Dr Neuman contributed to the conceptualization and designof the study, collected local data, interpreted the data, and reviewed andrevised the manuscript critically for important intellectual content; and allauthors approved the final manuscript as submitted and agree to be accountablefor all aspects of the work.
FINANCIAL DISCLOSURE: The authors have indicated they have nofinancial relationships relevant to this article to disclose.
FUNDING: Supported, in part, by Clinical and Translational ScienceAwards grants KL2 TR001862 (to Drs Aronson and Shapiro) and UL1TR0001863 (to DrShapiro) from the National Center for Advancing Translational Science, acomponent of the National Institutes of Health. The content is solely theresponsibility of the authors and does not represent the official views of theNational Institutes of Health. Funded by the National Institutes of Health(NIH).
POTENTIAL CONFLICT OF INTEREST: Dr Shapiro has served as an expertwitness in malpractice cases involving the evaluation of febrile children; theother authors have indicated they have no potential conflicts of interest todisclose.
COMPANION PAPER: A companion to this article can be found online atwww.pediatrics.org/cgi/doi/10.1542/peds.2018-2861.
References
1. Huppler AR,Eickhoff JC,Wald ER.Performance of low-risk criteria in the evaluation of younginfants with fever: review of the literature.Pediatrics.2010;125(2):228–233 [PubMed] [Google Scholar]
2. Dagan R,Powell KR,Hall CB,Menegus MA.Identification of infants unlikely to have serious bacterialinfection although hospitalized for suspected sepsis.J Pediatr.1985;107(6):855–860 [PubMed] [Google Scholar]
3. Baker MD,Bell LM,Avner JR.Outpatient management without antibiotics of fever inselected infants.N Engl J Med.1993;329(20):1437–1441 [PubMed] [Google Scholar]
4. Hui C,Neto G,Tsertsvadze A, et al..Diagnosis and management of febrile infants (0-3months).Evid Rep Technol Assess (Full Rep).2012;(205):1–297 [PMC free article] [PubMed] [Google Scholar]
5. Meehan WP III,Fleegler E,Bachur RG.Adherence to guidelines for managing the well-appearingfebrile infant: assessment using a case-based, interactivesurvey.Pediatr Emerg Care.2010;26(12):875–880 [PubMed] [Google Scholar]
6. Powell EC,Mahajan PV,Roosevelt G, et al.; FebrileInfant Working Group of the Pediatric Emergency Care Applied ResearchNetwork (PECARN) . Epidemiology ofbacteremia in febrile infants aged 60 days and younger.Ann Emerg Med.2018;71(2):211–216 [PMC free article] [PubMed] [Google Scholar]
7. Woll C,Neuman MI,Pruitt CM, et al.; FebrileYoung Infant Research Collaborative .Epidemiology and etiology of invasive bacterial infection ininfants ≤60 days old treated in emergencydepartments.J Pediatr.2018;200:210–217.e1 [PMC free article] [PubMed] [Google Scholar]
8. Garra G,Cunningham SJ,Crain EF.Reappraisal of criteria used to predict serious bacterialillness in febrile infants less than 8 weeks of age.Acad Emerg Med.2005;12(10):921–925 [PubMed] [Google Scholar]
9. Scarfone R,Murray A,Gala P,Balamuth F.Lumbar puncture for all febrile infants 29-56 days old: aretrospective cohort reassessment study.J Pediatr.2017;187:200–205.e1 [PMC free article] [PubMed] [Google Scholar]
10. Chua KP,Neuman MI,McWilliams JM,Aronson PL; Febrile YoungInfant Research Collaborative .Association between clinical outcomes and hospital guidelinesfor cerebrospinal fluid testing in febrile infants aged 29-56days.J Pediatr.2015;167(6):1340–1346.e9 [PMC free article] [PubMed] [Google Scholar]
11. Aronson PL,McCulloh RJ,Tieder JS, et al.; FebrileYoung Infant Research Collaborative .Application of the Rochester criteria to identify febrileinfants with bacteremia and meningitis [published online ahead of printFebruary 5, 2018].Pediatr Emerg Care. doi: 10.1097/PEC.0000000000001421 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
12. Aronson PL,Thurm C,Alpern ER, et al.; FebrileYoung Infant Research Collaborative .Variation in care of the febrile young infant <90 days inUS pediatric emergency departments [published correction appears inPediatrics. 2015;135(4):775].Pediatrics.2014;134(4):667–677 [PubMed] [Google Scholar]
13. Aronson PL,Thurm C,Williams DJ, et al.; FebrileYoung Infant Research Collaborative .Association of clinical practice guidelines with emergencydepartment management of febrile infants ≤56 days ofa*ge.J Hosp Med.2015;10(6):358–365 [PMC free article] [PubMed] [Google Scholar]
14. Biondi E,Evans R,Mischler M, et al..Epidemiology of bacteremia in febrile infants in the UnitedStates.Pediatrics.2013;132(6):990–996 [PubMed] [Google Scholar]
15. Leazer R,Erickson N,Paulson J, et al..Epidemiology of cerebrospinal fluid cultures and time todetection in term infants.Pediatrics.2017;139(5):e20163268. [PubMed] [Google Scholar]
16. Kestenbaum LA,Ebberson J,Zorc JJ,Hodinka RL,Shah SS.Defining cerebrospinal fluid white blood cell count referencevalues in neonates and young infants.Pediatrics.2010;125(2):257–264 [PMC free article] [PubMed] [Google Scholar]
17. Baskin MN,Goh XL,Heeney MM,Harper MB.Bacteremia risk and outpatient management of febrile patientswith sickle cell disease.Pediatrics.2013;131(6):1035–1041 [PubMed] [Google Scholar]
18. Feudtner C,Hays RM,Haynes G,Geyer JR,Neff JM,Koepsell TD.Deaths attributed to pediatric complex chronic conditions:national trends and implications for supportive careservices.Pediatrics.2001;107(6). Available at:www.pediatrics.org/cgi/content/full/107/6/e99 [PubMed] [Google Scholar]
19. Feudtner C,Feinstein JA,Zhong W,Hall M,Dai D.Pediatric complex chronic conditions classification systemversion 2: updated for ICD-10 and complex medical technology dependence andtransplantation.BMC Pediatr.2014;14:199. [PMC free article] [PubMed] [Google Scholar]
20. Tzimenatos L,Mahajan P,Dayan PS, et al.; PediatricEmergency Care Applied Research Network(PECARN) . Accuracy of the urinalysis forurinary tract infections in febrile infants 60 days andyounger.Pediatrics.2018;141(2):e20173068. [PMC free article] [PubMed] [Google Scholar]
21. Schroeder AR,Newman TB,Wasserman RC,Finch SA,Pantell RH.Choice of urine collection methods for the diagnosis ofurinary tract infection in young, febrile infants.Arch Pediatr Adolesc Med.2005;159(10):915–922 [PubMed] [Google Scholar]
22. Harris PA,Taylor R,Thielke R,Payne J,Gonzalez N,Conde JG.Research electronic data capture (REDCap)–ametadata-driven methodology and workflow process for providing translationalresearch informatics support.J Biomed Inform.2009;42(2):377–381 [PMC free article] [PubMed] [Google Scholar]
23. Jaskiewicz JA,McCarthy CA,Richardson AC, et al.; FebrileInfant Collaborative Study Group .Febrile infants at low risk for serious bacterialinfection–an appraisal of the Rochester criteria and implications formanagement.Pediatrics.1994;94(3):390–396 [PubMed] [Google Scholar]
24. Guarner J,Atuan MA,Nix B, et al..Process to evaluate hematological parameters that reflex tomanual differential cell counts in a pediatric institution.Clin Lab.2010;56(1–2):21–27 [PubMed] [Google Scholar]
25. Lebel MH,McCracken GH Jr. Delayedcerebrospinal fluid sterilization and adverse outcome of bacterialmeningitis in infants and children.Pediatrics.1989;83(2):161–167 [PubMed] [Google Scholar]
26. Okike IO,Johnson AP,Henderson KL, et al.; neoMenStudy Group . Incidence, etiology,and outcome of bacterial meningitis in infants aged <90 days in theUnited Kingdom and Republic of Ireland: prospective, enhanced, nationalpopulation-based surveillance.Clin Infect Dis.2014;59(10):e150–e157 [PubMed] [Google Scholar]
27. Pingree EW,Kimia AA,Nigrovic LE.The effect of traumatic lumbar puncture on hospitalizationrate for febrile infants 28 to 60 days of age.Acad Emerg Med.2015;22(2):240–243 [PubMed] [Google Scholar]
28. Paxton RD,Byington CL.An examination of the unintended consequences of the rule-outsepsis evaluation: a parental perspective.Clin Pediatr (Phila).2001;40(2):71–77 [PubMed] [Google Scholar]
29. Long SS,Pool TE,Vodzak J,Daskalaki I,Gould JM.Herpes simplex virus infection in young infants during 2decades of empiric acyclovir therapy.Pediatr Infect Dis J.2011;30(7):556–561 [PubMed] [Google Scholar]
30. Cruz AT,Freedman SB,Kulik DM, et al.; HSV StudyGroup of the Pediatric Emergency Medicine Collaborative ResearchCommittee . Herpes simplex virusinfection in infants undergoing meningitis evaluation.Pediatrics.2018;141(2):e20171688. [PMC free article] [PubMed] [Google Scholar]
31. Kimberlin DW,Lin CY,Jacobs RF, et al.; NationalInstitute of Allergy and Infectious Diseases Collaborative AntiviralStudy Group . Natural history ofneonatal herpes simplex virus infections in the acyclovirera.Pediatrics.2001;108(2):223–229 [PubMed] [Google Scholar]
32. Gomez B,Mintegi S,Bressan S, DaDalt L,Gervaix A,Lacroix L; European Group forValidation of the Step-by-Step Approach .Validation of the “Step-by-Step” approach inthe management of young febrile infants.Pediatrics.2016;138(2):e20154381. [PubMed] [Google Scholar]
33. Mintegi S,Gomez B,Martinez-Virumbrales L,Morientes O,Benito J.Outpatient management of selected young febrile infantswithout antibiotics.Arch Dis Child.2017;102(3):244–249 [PubMed] [Google Scholar]
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