[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Figure.
Receiver Operating Characteristic Curves and Optimal Complete Blood Cell Count Parameter Thresholds
Receiver Operating Characteristic Curves and Optimal Complete Blood Cell Count Parameter Thresholds

Total white blood cell count (A), absolute neutrophil count (B), and platelet count (C) for identifying young febrile infants aged 0 to 28 days and 29 to 60 days with invasive bacterial infections. Black squares represent the optimal cutoffs; counts are in  × 103 cells/µL. To convert absolute neutrophil count and white blood cell count to × 109 per liter, multiply by 0.001; to convert platelet count to × 109 per liter, multiply by 1.

Table 1.  
Demographics of the 4313 Infants in the Study Population
Demographics of the 4313 Infants in the Study Population
Table 2.  
Pathogens Causing Invasive Bacterial Infections in Infants Aged 0 to 60 Days
Pathogens Causing Invasive Bacterial Infections in Infants Aged 0 to 60 Days
Table 3.  
Comparision of Complete Blood Cell Count Parameters Between Infants With and Without Invasive Bacterial Infections
Comparision of Complete Blood Cell Count Parameters Between Infants With and Without Invasive Bacterial Infections
Table 4.  
Test Characteristics of CBC Parameters for Identifying Infants With Invasive Bacterial Infections
Test Characteristics of CBC Parameters for Identifying Infants With Invasive Bacterial Infections
1.
Gorelick  MH, Alpern  ER, Alessandrini  EA.  A system for grouping presenting complaints: the pediatric emergency reason for visit clusters.  Acad Emerg Med. 2005;12(8):723-731.PubMedGoogle ScholarCrossref
2.
Gomez  B, Mintegi  S, Bressan  S, Da Dalt  L, Gervaix  A, Lacroix  L; European Group for Validation of the Step-by-Step Approach.  Validation of the “Step-by-Step” approach in the management of young febrile infants.  Pediatrics. 2016;138(2):e20154381.PubMedGoogle ScholarCrossref
3.
Schnadower  D, Kuppermann  N, Macias  CG,  et al; American Academy of Pediatrics Pediatric Emergency Medicine Collaborative Research Committee.  Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia.  Pediatrics. 2010;126(6):1074-1083.PubMedGoogle ScholarCrossref
4.
Shah  AP, Cobb  BT, Lower  DR,  et al.  Enhanced versus automated urinalysis for screening of urinary tract infections in children in the emergency department.  Pediatr Infect Dis J. 2014;33(3):272-275.PubMedGoogle ScholarCrossref
5.
Schroeder  AR, Chang  PW, Shen  MW, Biondi  EA, Greenhow  TL.  Diagnostic accuracy of the urinalysis for urinary tract infection in infants <3 months of age.  Pediatrics. 2015;135(6):965-971.PubMedGoogle ScholarCrossref
6.
Mahajan  P, Grzybowski  M, Chen  X,  et al.  Procalcitonin as a marker of serious bacterial infections in febrile children younger than 3 years old.  Acad Emerg Med. 2014;21(2):171-179.PubMedGoogle ScholarCrossref
7.
Milcent  K, Faesch  S, Gras-Le Guen  C,  et al.  Use of procalcitonin assays to predict serious bacterial infection in young febrile infants.  JAMA Pediatr. 2016;170(1):62-69.PubMedGoogle ScholarCrossref
8.
Ivaska  L, Niemelä  J, Leino  P, Mertsola  J, Peltola  V.  Accuracy and feasibility of point-of-care white blood cell count and C-reactive protein measurements at the pediatric emergency department.  PLoS One. 2015;10(6):e0129920.PubMedGoogle ScholarCrossref
9.
Nijman  RG, Moll  HA, Smit  FJ,  et al.  C-reactive protein, procalcitonin and the lab-score for detecting serious bacterial infections in febrile children at the emergency department: a prospective observational study.  Pediatr Infect Dis J. 2014;33(11):e273-e279.PubMedGoogle ScholarCrossref
10.
Dagan  R, Powell  KR, Hall  CB, Menegus  MA.  Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis.  J Pediatr. 1985;107(6):855-860.PubMedGoogle ScholarCrossref
11.
Bachur  RG, Harper  MB.  Predictive model for serious bacterial infections among infants younger than 3 months of age.  Pediatrics. 2001;108(2):311-316.PubMedGoogle ScholarCrossref
12.
Baker  MD, Bell  LM, Avner  JR.  Outpatient management without antibiotics of fever in selected infants.  N Engl J Med. 1993;329(20):1437-1441.PubMedGoogle ScholarCrossref
13.
Lukacs  SL, Schrag  SJ.  Clinical sepsis in neonates and young infants, United States, 1988-2006.  J Pediatr. 2012;160(6):960-5.e1.PubMedGoogle ScholarCrossref
14.
Schrag  SJ, Farley  MM, Petit  S,  et al.  Epidemiology of invasive early-onset neonatal sepsis, 2005-2014.  Pediatrics. 2016;138(6):e20162013.PubMedGoogle ScholarCrossref
15.
Aronson  PL, Thurm  C, Alpern  ER,  et al; Febrile Young Infant Research Collaborative.  Variation in care of the febrile young infant <90 days in US pediatric emergency departments.  Pediatrics. 2014;134(4):667-677.PubMedGoogle ScholarCrossref
16.
Jain  S, Cheng  J, Alpern  ER,  et al.  Management of febrile neonates in US pediatric emergency departments.  Pediatrics. 2014;133(2):187-195.PubMedGoogle ScholarCrossref
17.
Bonsu  BK, Chb  M, Harper  MB.  Identifying febrile young infants with bacteremia: is the peripheral white blood cell count an accurate screen?  Ann Emerg Med. 2003;42(2):216-225.PubMedGoogle ScholarCrossref
18.
De  S, Williams  GJ, Hayen  A,  et al.  Value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.  Arch Dis Child. 2014;99(6):493-499.PubMedGoogle ScholarCrossref
19.
Yo  C-H, Hsieh  P-S, Lee  S-H,  et al.  Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis.  Ann Emerg Med. 2012;60(5):591-600.PubMedGoogle ScholarCrossref
20.
Seigel  TA, Cocchi  MN, Salciccioli  J,  et al.  Inadequacy of temperature and white blood cell count in predicting bacteremia in patients with suspected infection.  J Emerg Med. 2012;42(3):254-259.PubMedGoogle ScholarCrossref
21.
Bleeker  SE, Derksen-Lubsen  G, Grobbee  DE, Donders  ART, Moons  KGM, Moll  HA.  Validating and updating a prediction rule for serious bacterial infection in patients with fever without source.  Acta Paediatr. 2007;96(1):100-104.PubMedGoogle ScholarCrossref
22.
Van den Bruel  A, Thompson  MJ, Haj-Hassan  T,  et al.  Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review.  BMJ. 2011;342:d3082.PubMedGoogle ScholarCrossref
23.
Connelly  MA, Shimizu  C, Winegar  DA,  et al.  Differences in GlycA and lipoprotein particle parameters may help distinguish acute kawasaki disease from other febrile illnesses in children.  BMC Pediatr. 2016;16(1):151.PubMedGoogle ScholarCrossref
24.
Kim  BK, Yim  HE, Yoo  KH.  Plasma neutrophil gelatinase-associated lipocalin: a marker of acute pyelonephritis in children.  Pediatr Nephrol. 2017;32(3):477-484.PubMedGoogle ScholarCrossref
25.
Herberg  JA, Kaforou  M, Wright  VJ,  et al; IRIS Consortium.  Diagnostic accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children.  JAMA. 2016;316(8):835-845.PubMedGoogle ScholarCrossref
26.
Mahajan  P, Kuppermann  N, Mejias  A,  et al; Pediatric Emergency Care Applied Research Network (PECARN).  Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger.  JAMA. 2016;316(8):846-857.PubMedGoogle ScholarCrossref
27.
Bonsu  BK, Harper  MB.  A low peripheral blood white blood cell count in infants younger than 90 days increases the odds of acute bacterial meningitis relative to bacteremia.  Acad Emerg Med. 2004;11(12):1297-1301.PubMedGoogle ScholarCrossref
28.
Wiedmeier  SE, Henry  E, Sola-Visner  MC, Christensen  RD.  Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system.  J Perinatol. 2009;29(2):130-136.PubMedGoogle ScholarCrossref
29.
Metz  CE.  Basic principles of ROC analysis.  Semin Nucl Med. 1978;8(4):283-298.PubMedGoogle ScholarCrossref
30.
Vermont  J, Bosson  JL, François  P, Robert  C, Rueff  A, Demongeot  J.  Strategies for graphical threshold determination.  Comput Methods Programs Biomed. 1991;35(2):141-150.PubMedGoogle ScholarCrossref
31.
Greenhow  TL, Hung  YY, Herz  AM, Losada  E, Pantell  RH.  The changing epidemiology of serious bacterial infections in young infants.  Pediatr Infect Dis J. 2014;33(6):595-599.PubMedGoogle ScholarCrossref
32.
Greenhow  TL, Hung  YY, Herz  AM.  Changing epidemiology of bacteremia in infants aged 1 week to 3 months.  Pediatrics. 2012;129(3):e590-e596.PubMedGoogle ScholarCrossref
33.
Nosrati  A, Ben Tov  A, Reif  S.  Diagnostic markers of serious bacterial infections in febrile infants younger than 90 days old.  Pediatr Int. 2014;56(1):47-52.PubMedGoogle ScholarCrossref
34.
McGowan  JE  Jr, Bratton  L, Klein  JO, Finland  M.  Bacteremia in febrile children seen in a “walk-in” pediatric clinic.  N Engl J Med. 1973;288(25):1309-1312.PubMedGoogle ScholarCrossref
35.
Kuppermann  N, Fleisher  GR, Jaffe  DM.  Predictors of occult pneumococcal bacteremia in young febrile children.  Ann Emerg Med. 1998;31(6):679-687.PubMedGoogle ScholarCrossref
36.
Mischler  M, Ryan  MS, Leyenaar  JK,  et al.  Epidemiology of bacteremia in previously healthy febrile infants: a follow-up study.  Hosp Pediatr. 2015;5(6):293-300.PubMedGoogle ScholarCrossref
37.
Ouchenir  L, Renaud  C, Khan  S,  et al.  The epidemiology, management, and outcomes of bacterial meningitis in infants.  Pediatrics. 2017;140(1):e20170476.PubMedGoogle ScholarCrossref
38.
Pereira  C, Dias  A, Oliveira  H, Rodrigues  F.  Escherichia coli bacteraemia in a pediatric emergency service (1995-2010) [in Portuguese].  Acta Med Port. 2011;24(suppl 2):207-212.PubMedGoogle Scholar
39.
Herz  AM, Greenhow  TL, Alcantara  J,  et al.  Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine.  Pediatr Infect Dis J. 2006;25(4):293-300.PubMedGoogle ScholarCrossref
40.
Kuppermann  N.  Occult bacteremia in young febrile children.  Pediatr Clin North Am. 1999;46(6):1073-1109.PubMedGoogle ScholarCrossref
41.
Peña  BM, Harper  MB, Fleisher  GR.  Occult bacteremia with group B streptococci in an outpatient setting.  Pediatrics. 1998;102(1, pt 1):67-72.PubMedGoogle ScholarCrossref
42.
Crocetti  M, Moghbeli  N, Serwint  J.  Fever phobia revisited: have parental misconceptions about fever changed in 20 years?  Pediatrics. 2001;107(6):1241-1246.PubMedGoogle ScholarCrossref
43.
Schmitt  BD.  Fever phobia: misconceptions of parents about fevers.  Am J Dis Child. 1980;134(2):176-181.PubMedGoogle ScholarCrossref
44.
Hall  KK, Lyman  JA.  Updated review of blood culture contamination.  Clin Microbiol Rev. 2006;19(4):788-802.PubMedGoogle ScholarCrossref
45.
Weddle  G, Jackson  MA, Selvarangan  R.  Reducing blood culture contamination in a pediatric emergency department.  Pediatr Emerg Care. 2011;27(3):179-181.PubMedGoogle ScholarCrossref
46.
Gander  RM, Byrd  L, DeCrescenzo  M, Hirany  S, Bowen  M, Baughman  J.  Impact of blood cultures drawn by phlebotomy on contamination rates and health care costs in a hospital emergency department.  J Clin Microbiol. 2009;47(4):1021-1024.PubMedGoogle ScholarCrossref
47.
Garges  HP, Moody  MA, Cotten  CM,  et al.  Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters?  Pediatrics. 2006;117(4):1094-1100.PubMedGoogle ScholarCrossref
48.
Nigrovic  LE, Kuppermann  N, Malley  R; Bacterial Meningitis Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics.  Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era.  Acad Emerg Med. 2008;15(6):522-528.PubMedGoogle ScholarCrossref
49.
Stoll  ML, Rubin  LG.  Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a Children’s Hospital Emergency Department and Urgent Care Center.  Arch Pediatr Adolesc Med. 2004;158(7):671-675.PubMedGoogle ScholarCrossref
50.
Kuppermann  N, Walton  EA.  Immature neutrophils in the blood smears of young febrile children.  Arch Pediatr Adolesc Med. 1999;153(3):261-266.PubMedGoogle ScholarCrossref
51.
Connell  TG, Rele  M, Cowley  D, Buttery  JP, Curtis  N.  How reliable is a negative blood culture result? volume of blood submitted for culture in routine practice in a children’s hospital.  Pediatrics. 2007;119(5):891-896.PubMedGoogle ScholarCrossref
52.
Driscoll  AJ, Deloria Knoll  M, Hammitt  LL,  et al; PERCH Study Group.  The effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumonia.  Clin Infect Dis. 2017;64(suppl 3):S368-S377.PubMedGoogle ScholarCrossref
Original Investigation
November 6, 2017

Accuracy of Complete Blood Cell Counts to Identify Febrile Infants 60 Days or Younger With Invasive Bacterial Infections

Author Affiliations
  • 1Sections of Pediatric Emergency Medicine and Pediatric Infectious Diseases, Baylor College of Medicine, Houston, Texas
  • 2Departments of Emergency Medicine and Pediatrics, University of Michigan, Ann Arbor
  • 3Division of Emergency Medicine, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University, Columbus
  • 4Division of Pediatric Emergency Medicine, Alfred I. DuPont Hospital for Children, Nemours Children’s Health System, Wilmington, Delaware
  • 5Department of Emergency Medicine and Pediatrics, New York University Langone Medical Center, Bellevue Hospital Center, New York, New York
  • 6Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 7Division of Emergency Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 8Division of Emergency Medicine, Department of Pediatrics, Children’s National Medical Center, Washington, DC
  • 9Department of Pediatrics, University of Utah, Salt Lake City
  • 10Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children’s Hospital and The Ohio State University, Columbus
  • 11Departments of Emergency Medicine and Pediatrics, University of California, Davis Health, Sacramento
JAMA Pediatr. 2017;171(11):e172927. doi:10.1001/jamapediatrics.2017.2927
Key Points

Question  What is the accuracy of complete blood count parameters at routinely used thresholds in identifying young febrile infants with bacteremia or bacterial meningitis in the pneumococcal conjugate vaccine era?

Findings  In this cohort of 4313 febrile infants aged 0 to 60 days, 97 (2.2%) had bacteremia or bacterial meningitis. Sensitivities were low for white blood cell counts less than 5000/µL (sensitivity, 10%; specificity, 91%), white blood cell count ≥15 000/µL (sensitivity, 27%; specificity, 87%), and absolute neutrophil count ≥10 000/µL (sensitivity, 18%; specificity, 96%).

Meaning  No complete blood cell count parameter at routinely used thresholds in isolation identified infants with bacteremia or bacterial meningitis with sufficient accuracy to substantially assist clinical decision making.

Abstract

Importance  Clinicians often risk stratify young febrile infants for invasive bacterial infections (IBIs), defined as bacteremia and/or bacterial meningitis, using complete blood cell count parameters.

Objective  To estimate the accuracy of individual complete blood cell count parameters to identify febrile infants with IBIs.

Design, Setting, and Participants  Planned secondary analysis of a prospective observational cohort study comprising 26 emergency departments in the Pediatric Emergency Care Applied Research Network from 2008 to 2013. We included febrile (≥38°C), previously healthy, full-term infants younger than 60 days for whom blood cultures were obtained. All infants had either cerebrospinal fluid cultures or 7-day follow-up.

Main Outcomes and Measures  We tested the accuracy of the white blood cell count, absolute neutrophil count, and platelet count at commonly used thresholds for IBIs. We determined optimal thresholds using receiver operating characteristic curves.

Results  Of 4313 enrolled infants, 1340 (31%; 95% CI, 30% to 32%) were aged 0 to 28 days, 2412 were boys (56%), and 2471 were white (57%). Ninety-seven (2.2%; 95% CI, 1.8% to 2.7%) had IBIs. Sensitivities were low for common complete blood cell count parameter thresholds: white blood cell count less than 5000/µL, 10% (95% CI, 4% to 16%) (to convert to 109 per liter, multiply by 0.001); white blood cell count ≥15 000/µL, 27% (95% CI, 18% to 36%); absolute neutrophil count ≥10 000/µL, 18% (95% CI, 10% to 25%) (to convert to  × 109 per liter, multiply by 0.001); and platelets <100  × 103/µL, 7% (95% CI, 2% to 12%) (to convert to × 109 per liter, multiply by 1). Optimal thresholds for white blood cell count (11 600/µL), absolute neutrophil count (4100/µL), and platelet count (362 × 103/µL) were identified in models that had areas under the receiver operating characteristic curves of 0.57 (95% CI, 0.50-0.63), 0.70 (95% CI, 0.64-0.76), and 0.61 (95% CI, 0.55-0.67), respectively.

Conclusions and Relevance  No complete blood cell count parameter at commonly used or optimal thresholds identified febrile infants 60 days or younger with IBIs with high accuracy. Better diagnostic tools are needed to risk stratify young febrile infants for IBIs.

Introduction

Febrile infants 60 days and younger are routinely evaluated in emergency departments (ED) for serious bacterial infections including urinary tract infections (UTIs), bacteremia, and bacterial meningitis.1 Urinary tract infections are common bacterial infections2,3 and the urinalysis is a highly sensitive, noninvasive, readily available, rapid turnaround test to facilitate diagnosis.4,5 Although novel serum biomarkers are being evaluated to aid the clinician to reliably detect the presence of invasive bacterial infections (IBIs, defined by bacteremia or bacterial meningitis),6-9 the lack of reliable physical examination findings and nonspecific symptoms add to the diagnostic uncertainty for IBI.3

Several algorithms and guidelines have been used to help risk stratify young febrile infants for IBIs.10-12 These algorithms were developed prior to the introduction of the pneumococcal conjugate vaccines, although this vaccine predominantly affects older infants. In addition, screening of pregnant women for group B streptococcus and provision of intrapartum antibiotic chemoprophylaxis has led to IBI becoming less common in the well-appearing febrile young infant,13,14 making risk stratification even more challenging. While there is substantial variation in the laboratory evaluation of young febrile infants,15,16 the most commonly obtained test is the complete blood cell count (CBC). Smaller studies have demonstrated suboptimal performance characteristics of CBC parameters including the peripheral white blood cell (WBC) count and absolute neutrophil count (ANC) for IBI.17-22 However, this needs further validation in larger prospective cohorts of young febrile infants. Serum inflammatory markers, such as procalcitonin and C-reactive protein, can more accurately predict which young infants have IBIs.6,7,19 However, these newer biomarkers are still being validated and are not readily available in all EDs.23-26 Therefore, the ease and tradition of obtaining CBCs has led clinicians to continue to use CBC parameters in algorithms to help risk stratify young febrile infants.

Given the changing epidemiology of IBIs, we conducted a prospective study in which we enrolled a large, geographically diverse cohort of febrile infants and conducted a planned subanalysis to determine the performance of the CBC to identify febrile infants 60 days and younger with IBIs.

Methods
Study Design, Setting, and Population

Quiz Ref IDThis was a planned secondary analysis of a prospectively enrolled cohort of young febrile infants evaluated in 26 EDs in the Pediatric Emergency Care Applied Research Network between 2008 and 2013. In the parent study, we evaluated the association of host gene expression patterns with bacterial infections.26 Infants aged 60 days or younger were enrolled if they had documented temperatures of 38°C or higher and blood cultures were obtained. In addition to blood cultures, all infants had either cerebrospinal fluid (CSF) cultures obtained or telephone follow-up within 7 days of the ED visit to ascertain whether any patient had missed or developed bacterial meningitis. We excluded infants who were critically ill (eg, requiring emergent interventions such as intubation, cardiopulmonary resuscitation, or use of vasoactive medication), premature (completed gestational age <37 weeks), received antibiotics in the 4 days preceding the ED visit, or had major congenital malformations or comorbid medical conditions (eg, inborn errors of metabolism, congenital heart disease, chronic lung disease, immunosuppression or immunodeficiencies, or indwelling catheters or shunts). We also excluded previously enrolled infants and infants for whom the presence of bacteremia or meningitis was unknown. In addition, for this subanalysis, we excluded children whose CBC components were missing as well as febrile infants with urinary tract infections without IBIs. However, infants with urinary tract infections who also had either bacteremia and/or bacterial meningitis were included. Institutional review board approval was obtained at each site, and written consent was obtained from the guardian of each enrolled patient.

Study Definitions

We defined bacteremia and bacterial meningitis as growth of a single pathogen in blood and CSF cultures, respectively. Organisms classified a priori as contaminants included Bacillus non-cereus/non-anthracis, diphtheroids, Lactobacillus, Micrococcus, coagulase-negative staphylococci, and viridans group streptococci.

Quiz Ref IDWe defined leukocytosis as a WBC count 15 000 cells/µL or greater and leukopenia as a WBC count less than 5000 cells/µL (to convert to × 109 per liter, multiply by 0.001). Neutrophilia was defined as an ANC greater than 10 000 cells/µL (to convert to × 109 per liter, multiply by 0.001). These thresholds were chosen a priori because these are the thresholds used by several existing algorithms to risk stratify young febrile infants.10-12,27 Thrombocytosis was defined as a platelet count 450 × 103 cells/µL or greater (to convert to  × 109 per liter, multiply by 1). Thrombocytopenia was evaluated at 2 different platelet count thresholds: less than 100  × 103 cells/µL and less than 150   × 103 cells/µL.28 Band counts were not routinely available and therefore were not analyzed.

Outcome Measures

Quiz Ref IDThe primary outcome measures were the test characteristics of the WBC count, ANC, and platelet count to identify infants with IBIs.

Statistical Analyses

We summarized categorical variables with counts and percentages and continuous measures with medians, interquartile ranges (IQRs), means, and standard deviations. For each CBC parameter analyzed, we reported sensitivity, specificity, positive predictive value, and negative predictive value for the commonly used thresholds. We also analyzed likelihood ratios with 95% confidence intervals. We constructed receiver operating characteristic (ROC) curves and determined an optimal cutoff value for each CBC parameter through minimizing the sensitivity, specificity coordinate pair from the point (1,1), also known as the Euclidean method.29,30 We calculated areas under the ROC curves (AUC), and based on prior work, we defined AUCs of less than 0.7 as having poor discriminatory value; AUCs of 0.7 to 0.8 as minimally accurate; AUCs of 0.8 to 0.9 as having good accuracy; and AUCs of greater than 0.9 as having excellent accuracy.17 We used SAS, version 9.4 software (SAS Institute) for analyses. P values less than .05 were considered significant, and all tests were 2-sided.

Results
Study Population

Of the 4795 infants included in the main study, 4313 (90.7%) met inclusion criteria for this analysis (eFigure in the Supplement). Lumbar punctures were attempted in 3384 infants (78.5%) and were successful in 3324 (98.2%). The demographic characteristics of the study population are described in Table 1. The median age was 38 days (IQR, 25-48 days).

Invasive Bacterial Infections

Ninety-seven infants (2.2%; 95% CI, 1.8% to 2.7%) had IBIs; 73 of 4313 (1.7%; 95% CI, 1.4% to 2.1%) with isolated bacteremia and 24 (0.6%; 95% CI, 0.4% to 0.8%) with bacterial meningitis. Of the 24 infants with meningitis, 11 also had documented bacteremia. Invasive bacterial infections were identified in 57 of 1340 infants 28 days and younger (4.3%; 95% CI, 3.2% to 5.3%) and in 40 of 2973 infants aged 29 to 60 days (1.4%; 95% CI, 1.0% to 1.8%). Pathogens isolated are listed in Table 2.

Accuracy of CBC Parameters in Identifying Infants With IBIs

No CBC parameters reliably distinguished between infants with and without IBIs (Table 3). While children with IBIs did have higher WBC counts, ANCs, and lower platelet counts, there was not a threshold for these parameters at which IBI could be reliably predicted (Figure). The test characteristics of CBC parameters at various commonly used thresholds and optimal thresholds are presented in Table 4. Even at the optimal ANC threshold of 4100 cells/µL, one-third of infants with IBIs would have been missed. All CBC parameters had low sensitivity and high negative predictive values at commonly used thresholds. Low positive predictive values were in part owing to the low prevalence of IBIs. Using widely accepted normal ranges for WBC counts (5000 to 14 900 cells/µL) or an ANC of less than 10  × 103 cells/µL would have missed 61 (63%) and 80 (82%) of infants with IBIs, respectively.

We constructed ROC curves for each individual laboratory predictor variable for infants aged 0 to 28 days and infants aged 29 to 60 days separately (Figure). Complete blood cell count test characteristics were not improved when only infants older than 28 days were considered. No single CBC parameter at any threshold had both good sensitivity and good specificity. The WBC count, ANC, and platelet count each had poor discriminatory value.

Discussion

Our analysis of a large, prospectively enrolled, geographically diverse cohort of febrile infants 60 days and younger likely represents the epidemiology of the bacterial pathogens responsible for bacteremia and bacterial meningitis. Of greater importance, our findings demonstrate that Quiz Ref IDindividual parameters of the CBC have poor discriminatory ability in identifying which young febrile infants have IBIs.

A minority of infants with IBIs had abnormal WBC counts. This finding is consistent with other studies evaluating young febrile infants, where peripheral leukocytosis was seen in fewer than one-half of infants with bacteremia and in a minority of infants with bacterial meningitis.31,32 We also evaluated the ability of the platelet count to identify infants with IBIs because platelets are an acute-phase reactant, and few data exist on the accuracy of platelet counts in risk stratifying young infants for IBIs.33 However, neither thrombocytosis nor thrombocytopenia, as can be seen with overwhelming infections, were sufficiently accurate. While we would expect the positive predictive value to decline and the negative predictive value to increase as the prevalence of bacteremia and bacterial meningitis decline, sensitivity and specificity of the CBC parameters should not be influenced by declining prevalence rates. One possible explanation for the CBC’s poor performance is the change of pathogens causing bacterial meningitis and bacteremia in young infants. In the pre–pneumococcal conjugate vaccine era, leukocytosis was commonly seen in older infants with Haemophilus and pneumococcal bacteremia.34,35 However, pathogens more commonly identified in the modern era may produce less of an inflammatory response by the host. A 2015 retrospective study of episodes of bacteremia in previously healthy febrile infants 90 days and younger receiving care in 17 children’s hospitals found that Escherichia coli, group B streptococcus, and Staphylococcus aureus were among the most common bacteria isolated,36 and that E coli and group B streptococcus accounted for almost two-thirds of bacterial meningitis cases in infants aged 0 to 90 days.37E coli bacteremia is less likely to be associated with peripheral leukocytosis than pneumococcal bacteremia in infants and toddlers,38-40 and 1 study of infants with late-onset group B streptococcus bacteremia found that only 45% had abnormal WBC counts.40,41

Another possible explanation for why CBC parameters poorly identified infants with IBIs is that infants in our cohort may have presented earlier in the natural histories of their infections than in previous studies. In 2001, investigators42 compared parental perceptions of childhood fever with a previous study conducted in 198043 and found that in the more contemporary era, parents were more apt to check their children’s temperatures more often, worry more about seizures as a complication of pyrexia, have bloodwork performed on their children during febrile illnesses, and seek care in an ED. These concerns regarding fever may well translate into seeking care earlier in the course of an infant’s illness. One 2016 study2 found that no single CBC or inflammatory parameter or combination of parameters had optimal sensitivity for identifying infants with IBIs who had pyrexia of short durations.2 Additionally, in this study, CBCs were evaluated at one point, and the parameters may have been more accurate had CBCs been obtained later into an infant’s illness.

Complete blood cell count parameters also had suboptimal specificity for identifying infants with IBIs in our cohort. While most febrile neonates are hospitalized and administered empirical parenteral antibiotics while awaiting culture results, accurate identification of low-risk infants in the second month of life would enable reduction in resource use, costs to families, and unnecessary antibiotic exposure. However, given the low incidence of IBIs, most abnormal CBC results will not be associated with the presence of IBI. Our data add to previous literature on the poor accuracy of CBCs in identifying young febrile infants with IBIs17-22 and questions how CBC parameters, particularly the ANC, may be integrated into newer guidelines. Rather than using CBC parameters in isolation, an approach that combines certain CBC parameters (ie, the ANC) with other laboratory tests, such as the urinalysis, procalcitonin, and/or C-reactive protein (when available), may help risk stratify these febrile infants more effectively.2

Quiz Ref IDRecognition that CBC parameters in isolation have poor ability to discriminate young febrile infants with and without IBIs has important implications for ED practice. Some hospital algorithms recommend only sending blood cultures in febrile infants if the WBC or ANC parameters are abnormal. The rationale is to decrease the frequency of blood culture contamination, which has historically been noted in 2% to 11% of blood cultures obtained from children in the ED.44-46 However, this practice would also miss most young febrile infants with IBIs. Two studies15,16 have described practice variation in terms of cultures obtained in young febrile infants, finding that even among 0- to 28-day-old neonates, fewer than two-thirds to three-quarters have blood, urine, and CSF cultures obtained.15,16 Another belief is that most infants with bacterial meningitis will have concomitant bacteremia and will thus have positive blood cultures even if CSF is not obtained at the time of the initial visit. While this was true for Haemophilus influenzae, data from the early 2000s indicate that bacteremia is only documented in 46% to 60% of infants with bacterial meningitis,47,48 consistent with our findings in this study.

Limitations

This study has some limitations. Data were collected from a convenience sample of febrile infants evaluated in the EDs of large academic children’s hospitals, and the results may thus not be generalizable to community EDs. However, the frequency of bacteremia and meningitis were similar to that described in previously published studies,31,32,39,40,48,49 and we do not have a biological hypothesis why the accuracy of the CBC would be different in different settings. Critically ill-appearing infants were not enrolled in this study, possibly leading to spectrum bias. However, most risk-stratification tools aim to identify infants at low risk for IBI, not those at high risk, and critical appearance is more important than any laboratory value for identifying those at high risk. There are some data on the utility of band counts in predicting bacteremia in this age group,50 but we were unable to assess the utility of relative or absolute bandemia for identifying those with IBIs given variation in band count availability across study EDs. Bacterial cultures were considered the reference standard for analyses, despite recognition that falsely negative cultures51 can occur owing to sporadic bacteremia or if low blood volumes are inoculated into blood culture bottles. One 2017 study found that for each additional 1 mL of blood culture volume collected, microbial yield increased by 0.5% in children with pneumonia.52

Conclusions

Complete blood cell count parameters had poor accuracy in distinguishing febrile infants 60 days and younger with and without invasive bacterial infections in the postpneumococcal conjugate vaccine era, although the ANC had the highest sensitivity. Physicians who use CBC thresholds in an attempt to risk stratify febrile young infants may be falsely reassured by normal CBC parameters. When used in isolation, either at commonly used thresholds or at the optimal thresholds identified here, CBC parameters have at best modest discriminatory ability. In an era where better screening tests exist to identify infants with IBIs, we need to question our continual reliance on a test whose greatest strength may simply be in its ready availability in clinical practice.

Back to top
Article Information

Corresponding Author: Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Ste A2210, Houston, TX 77030 (acruz@bcm.edu).

Accepted for Publication: July 6, 2017.

Correction: This article was corrected on January 8, 2018, to correct an error in the Key Points section of the text.

Published Online: September 11, 2017. doi:10.1001/jamapediatrics.2017.2927

Author Contributions: Dr VanBuren had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mahajan, Ramilo, Kuppermann.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cruz.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cruz, VanBuren.

Obtained funding: Mahajan, Ramilo, Kuppermann.

Administrative, technical, or material support: Cruz, Mahajan, Ramilo, Kuppermann.

Supervision: Mahajan, Ramilo, Kuppermann.

Conflict of Interest Disclosures: Dr Ramilo reports personal fees from Abbvie, Janssen, Regeneron, and Pfizer, and grants from Janssen. All these fees and grants are not related to the current work. No other disclosures are reported.

Funding/Support: The research reported in this publication was supported in part by grant H34MCO8509 from Health Resources and Services Administration, Emergency Services for Children and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award R01HD062477. This project is also supported in part by the Health Resources and Services Administration, Maternal and Child Health Bureau, and Emergency Medical Services for ChildrenNetwork Development Demonstration Program under cooperative agreements U03MC00008, U03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC22684, and U03MC22685.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The participating centers and investigators of the Pediatric Emergency Care Applied Research Network are:

Ann and Robert H. Lurie Children’s Hospital, Chicago, Illinois (Elizabeth C. Powell, MD, MPH); Bellevue Hospital Center, New York, New York (Deborah A. Levine, MD; Michael G. Tunik, MD); Boston Children’s Hospital, Boston, Massachusetts (Lise E. Nigrovic, MD, MPH); Children’s Hospital of Colorado (Genie Roosevelt, MD); Children’s Hospital of Michigan (Prashant Mahajan, MD, MPH, MBA); Children’s Hospital of Philadelphia, Pennsylvania (Elizabeth R. Alpern, MD, MSCE); Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (Melissa Vitale, MD); Children’s Hospital of Wisconsin (Lorin Browne, DO; Mary Saunders, MD); Children’s National Medical Center, Washington, DC (Shireen M. Atabaki, MD, MPH); Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (Richard M. Ruddy, MD); Hasbro Children’s Hospital, Providence, Rhode Island (James G. Linakis, MD, PhD); Helen DeVos Children's Hospital, Grand Rapids, Michigan (John D. Hoyle, Jr., MD); Hurley Medical Center, Flint, Michigan (Dominic Borgialli, DO, MPH); Jacobi Medical Center, New York, New York (Stephen Blumberg, MD; Ellen F. Crain, MD, PhD); Johns Hopkins Children’s Center, Baltimore, Maryland (Jennifer Anders, MD); Nationwide Children's Hospital, Columbus, Ohio (Bema Bonsu, MD; Daniel M. Cohen, MD); Nemours/Alfred I. DuPont Hospital for Children, New Castle County, Delaware (Jonathan E. Bennett, MD); New York Presbyterian-Morgan Stanley Children’s Hospital (Peter S. Dayan, MD, MSc); Primary Children’s Medical Center, Salt Lake City, Utah (Richard Greenberg, MD); St Louis Children’s Hospital, St Louis, Missouri (David M. Jaffe, MD; Jared Muenzer, MD); Texas Children’s Hospital, Houston, Texxas (Andrea T. Cruz, MD, MPH); University of California, Davis Medical Center (Nathan Kuppermann, MD, MPH; Leah Tzimenatos, MD); University of Maryland, College Park, Maryland (Rajender Gattu, MD); University of Michigan (Alexander J. Rogers, MD); University of Rochester, Rochester, New York (Anne Brayer, MD); and Women and Children’s Hospital of Buffalo, Buffalo, New York (Kathleen Lillis, MD).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by Health Resources and Services Administration, Health and Human Services, or the US government.

Additional Contributions: We thank the research coordinators in Pediatric Emergency Care Applied Research Network and the project staff at the Data Coordinating Center at the University of Utah. All were compensated by grants that supported the study.

References
1.
Gorelick  MH, Alpern  ER, Alessandrini  EA.  A system for grouping presenting complaints: the pediatric emergency reason for visit clusters.  Acad Emerg Med. 2005;12(8):723-731.PubMedGoogle ScholarCrossref
2.
Gomez  B, Mintegi  S, Bressan  S, Da Dalt  L, Gervaix  A, Lacroix  L; European Group for Validation of the Step-by-Step Approach.  Validation of the “Step-by-Step” approach in the management of young febrile infants.  Pediatrics. 2016;138(2):e20154381.PubMedGoogle ScholarCrossref
3.
Schnadower  D, Kuppermann  N, Macias  CG,  et al; American Academy of Pediatrics Pediatric Emergency Medicine Collaborative Research Committee.  Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia.  Pediatrics. 2010;126(6):1074-1083.PubMedGoogle ScholarCrossref
4.
Shah  AP, Cobb  BT, Lower  DR,  et al.  Enhanced versus automated urinalysis for screening of urinary tract infections in children in the emergency department.  Pediatr Infect Dis J. 2014;33(3):272-275.PubMedGoogle ScholarCrossref
5.
Schroeder  AR, Chang  PW, Shen  MW, Biondi  EA, Greenhow  TL.  Diagnostic accuracy of the urinalysis for urinary tract infection in infants <3 months of age.  Pediatrics. 2015;135(6):965-971.PubMedGoogle ScholarCrossref
6.
Mahajan  P, Grzybowski  M, Chen  X,  et al.  Procalcitonin as a marker of serious bacterial infections in febrile children younger than 3 years old.  Acad Emerg Med. 2014;21(2):171-179.PubMedGoogle ScholarCrossref
7.
Milcent  K, Faesch  S, Gras-Le Guen  C,  et al.  Use of procalcitonin assays to predict serious bacterial infection in young febrile infants.  JAMA Pediatr. 2016;170(1):62-69.PubMedGoogle ScholarCrossref
8.
Ivaska  L, Niemelä  J, Leino  P, Mertsola  J, Peltola  V.  Accuracy and feasibility of point-of-care white blood cell count and C-reactive protein measurements at the pediatric emergency department.  PLoS One. 2015;10(6):e0129920.PubMedGoogle ScholarCrossref
9.
Nijman  RG, Moll  HA, Smit  FJ,  et al.  C-reactive protein, procalcitonin and the lab-score for detecting serious bacterial infections in febrile children at the emergency department: a prospective observational study.  Pediatr Infect Dis J. 2014;33(11):e273-e279.PubMedGoogle ScholarCrossref
10.
Dagan  R, Powell  KR, Hall  CB, Menegus  MA.  Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis.  J Pediatr. 1985;107(6):855-860.PubMedGoogle ScholarCrossref
11.
Bachur  RG, Harper  MB.  Predictive model for serious bacterial infections among infants younger than 3 months of age.  Pediatrics. 2001;108(2):311-316.PubMedGoogle ScholarCrossref
12.
Baker  MD, Bell  LM, Avner  JR.  Outpatient management without antibiotics of fever in selected infants.  N Engl J Med. 1993;329(20):1437-1441.PubMedGoogle ScholarCrossref
13.
Lukacs  SL, Schrag  SJ.  Clinical sepsis in neonates and young infants, United States, 1988-2006.  J Pediatr. 2012;160(6):960-5.e1.PubMedGoogle ScholarCrossref
14.
Schrag  SJ, Farley  MM, Petit  S,  et al.  Epidemiology of invasive early-onset neonatal sepsis, 2005-2014.  Pediatrics. 2016;138(6):e20162013.PubMedGoogle ScholarCrossref
15.
Aronson  PL, Thurm  C, Alpern  ER,  et al; Febrile Young Infant Research Collaborative.  Variation in care of the febrile young infant <90 days in US pediatric emergency departments.  Pediatrics. 2014;134(4):667-677.PubMedGoogle ScholarCrossref
16.
Jain  S, Cheng  J, Alpern  ER,  et al.  Management of febrile neonates in US pediatric emergency departments.  Pediatrics. 2014;133(2):187-195.PubMedGoogle ScholarCrossref
17.
Bonsu  BK, Chb  M, Harper  MB.  Identifying febrile young infants with bacteremia: is the peripheral white blood cell count an accurate screen?  Ann Emerg Med. 2003;42(2):216-225.PubMedGoogle ScholarCrossref
18.
De  S, Williams  GJ, Hayen  A,  et al.  Value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.  Arch Dis Child. 2014;99(6):493-499.PubMedGoogle ScholarCrossref
19.
Yo  C-H, Hsieh  P-S, Lee  S-H,  et al.  Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis.  Ann Emerg Med. 2012;60(5):591-600.PubMedGoogle ScholarCrossref
20.
Seigel  TA, Cocchi  MN, Salciccioli  J,  et al.  Inadequacy of temperature and white blood cell count in predicting bacteremia in patients with suspected infection.  J Emerg Med. 2012;42(3):254-259.PubMedGoogle ScholarCrossref
21.
Bleeker  SE, Derksen-Lubsen  G, Grobbee  DE, Donders  ART, Moons  KGM, Moll  HA.  Validating and updating a prediction rule for serious bacterial infection in patients with fever without source.  Acta Paediatr. 2007;96(1):100-104.PubMedGoogle ScholarCrossref
22.
Van den Bruel  A, Thompson  MJ, Haj-Hassan  T,  et al.  Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review.  BMJ. 2011;342:d3082.PubMedGoogle ScholarCrossref
23.
Connelly  MA, Shimizu  C, Winegar  DA,  et al.  Differences in GlycA and lipoprotein particle parameters may help distinguish acute kawasaki disease from other febrile illnesses in children.  BMC Pediatr. 2016;16(1):151.PubMedGoogle ScholarCrossref
24.
Kim  BK, Yim  HE, Yoo  KH.  Plasma neutrophil gelatinase-associated lipocalin: a marker of acute pyelonephritis in children.  Pediatr Nephrol. 2017;32(3):477-484.PubMedGoogle ScholarCrossref
25.
Herberg  JA, Kaforou  M, Wright  VJ,  et al; IRIS Consortium.  Diagnostic accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children.  JAMA. 2016;316(8):835-845.PubMedGoogle ScholarCrossref
26.
Mahajan  P, Kuppermann  N, Mejias  A,  et al; Pediatric Emergency Care Applied Research Network (PECARN).  Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger.  JAMA. 2016;316(8):846-857.PubMedGoogle ScholarCrossref
27.
Bonsu  BK, Harper  MB.  A low peripheral blood white blood cell count in infants younger than 90 days increases the odds of acute bacterial meningitis relative to bacteremia.  Acad Emerg Med. 2004;11(12):1297-1301.PubMedGoogle ScholarCrossref
28.
Wiedmeier  SE, Henry  E, Sola-Visner  MC, Christensen  RD.  Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system.  J Perinatol. 2009;29(2):130-136.PubMedGoogle ScholarCrossref
29.
Metz  CE.  Basic principles of ROC analysis.  Semin Nucl Med. 1978;8(4):283-298.PubMedGoogle ScholarCrossref
30.
Vermont  J, Bosson  JL, François  P, Robert  C, Rueff  A, Demongeot  J.  Strategies for graphical threshold determination.  Comput Methods Programs Biomed. 1991;35(2):141-150.PubMedGoogle ScholarCrossref
31.
Greenhow  TL, Hung  YY, Herz  AM, Losada  E, Pantell  RH.  The changing epidemiology of serious bacterial infections in young infants.  Pediatr Infect Dis J. 2014;33(6):595-599.PubMedGoogle ScholarCrossref
32.
Greenhow  TL, Hung  YY, Herz  AM.  Changing epidemiology of bacteremia in infants aged 1 week to 3 months.  Pediatrics. 2012;129(3):e590-e596.PubMedGoogle ScholarCrossref
33.
Nosrati  A, Ben Tov  A, Reif  S.  Diagnostic markers of serious bacterial infections in febrile infants younger than 90 days old.  Pediatr Int. 2014;56(1):47-52.PubMedGoogle ScholarCrossref
34.
McGowan  JE  Jr, Bratton  L, Klein  JO, Finland  M.  Bacteremia in febrile children seen in a “walk-in” pediatric clinic.  N Engl J Med. 1973;288(25):1309-1312.PubMedGoogle ScholarCrossref
35.
Kuppermann  N, Fleisher  GR, Jaffe  DM.  Predictors of occult pneumococcal bacteremia in young febrile children.  Ann Emerg Med. 1998;31(6):679-687.PubMedGoogle ScholarCrossref
36.
Mischler  M, Ryan  MS, Leyenaar  JK,  et al.  Epidemiology of bacteremia in previously healthy febrile infants: a follow-up study.  Hosp Pediatr. 2015;5(6):293-300.PubMedGoogle ScholarCrossref
37.
Ouchenir  L, Renaud  C, Khan  S,  et al.  The epidemiology, management, and outcomes of bacterial meningitis in infants.  Pediatrics. 2017;140(1):e20170476.PubMedGoogle ScholarCrossref
38.
Pereira  C, Dias  A, Oliveira  H, Rodrigues  F.  Escherichia coli bacteraemia in a pediatric emergency service (1995-2010) [in Portuguese].  Acta Med Port. 2011;24(suppl 2):207-212.PubMedGoogle Scholar
39.
Herz  AM, Greenhow  TL, Alcantara  J,  et al.  Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine.  Pediatr Infect Dis J. 2006;25(4):293-300.PubMedGoogle ScholarCrossref
40.
Kuppermann  N.  Occult bacteremia in young febrile children.  Pediatr Clin North Am. 1999;46(6):1073-1109.PubMedGoogle ScholarCrossref
41.
Peña  BM, Harper  MB, Fleisher  GR.  Occult bacteremia with group B streptococci in an outpatient setting.  Pediatrics. 1998;102(1, pt 1):67-72.PubMedGoogle ScholarCrossref
42.
Crocetti  M, Moghbeli  N, Serwint  J.  Fever phobia revisited: have parental misconceptions about fever changed in 20 years?  Pediatrics. 2001;107(6):1241-1246.PubMedGoogle ScholarCrossref
43.
Schmitt  BD.  Fever phobia: misconceptions of parents about fevers.  Am J Dis Child. 1980;134(2):176-181.PubMedGoogle ScholarCrossref
44.
Hall  KK, Lyman  JA.  Updated review of blood culture contamination.  Clin Microbiol Rev. 2006;19(4):788-802.PubMedGoogle ScholarCrossref
45.
Weddle  G, Jackson  MA, Selvarangan  R.  Reducing blood culture contamination in a pediatric emergency department.  Pediatr Emerg Care. 2011;27(3):179-181.PubMedGoogle ScholarCrossref
46.
Gander  RM, Byrd  L, DeCrescenzo  M, Hirany  S, Bowen  M, Baughman  J.  Impact of blood cultures drawn by phlebotomy on contamination rates and health care costs in a hospital emergency department.  J Clin Microbiol. 2009;47(4):1021-1024.PubMedGoogle ScholarCrossref
47.
Garges  HP, Moody  MA, Cotten  CM,  et al.  Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters?  Pediatrics. 2006;117(4):1094-1100.PubMedGoogle ScholarCrossref
48.
Nigrovic  LE, Kuppermann  N, Malley  R; Bacterial Meningitis Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics.  Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era.  Acad Emerg Med. 2008;15(6):522-528.PubMedGoogle ScholarCrossref
49.
Stoll  ML, Rubin  LG.  Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a Children’s Hospital Emergency Department and Urgent Care Center.  Arch Pediatr Adolesc Med. 2004;158(7):671-675.PubMedGoogle ScholarCrossref
50.
Kuppermann  N, Walton  EA.  Immature neutrophils in the blood smears of young febrile children.  Arch Pediatr Adolesc Med. 1999;153(3):261-266.PubMedGoogle ScholarCrossref
51.
Connell  TG, Rele  M, Cowley  D, Buttery  JP, Curtis  N.  How reliable is a negative blood culture result? volume of blood submitted for culture in routine practice in a children’s hospital.  Pediatrics. 2007;119(5):891-896.PubMedGoogle ScholarCrossref
52.
Driscoll  AJ, Deloria Knoll  M, Hammitt  LL,  et al; PERCH Study Group.  The effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumonia.  Clin Infect Dis. 2017;64(suppl 3):S368-S377.PubMedGoogle ScholarCrossref
×