Table of Contents

 

Untreated serious bacterial infections in febrile young infants can have severe outcomes. A full sepsis workup is often recommended, but it may not be necessary. This issue reviews the newer risk stratification algorithms, the need for routine versus selective cerebrospinal fluid testing, the role of viral testing, and diagnostic and therapeutic challenges. You will learn:

The types of serious bacterial infections and invasive bacterial infections that are most common in young infants

Key historical information to obtain including the exact temperature and the method by which it was obtained, the presence of associated viral symptoms, and the details of the patient’s birth (including the mother’s prenatal laboratory studies)

Various risk stratification criteria including the Rochester criteria, Philadelphia criteria, Boston criteria, Step-by-Step approach, and PECARN prediction tool

How to use the various risk stratification algorithms to determine which infants require a full sepsis workup

When viral testing (eg, enterovirus, parechovirus, respiratory syncytial virus, rhinovirus) is indicated

Which empiric antibiotic regimen is appropriate, based on the patient’s age and the most likely pathogens

How to manage the infant who had a reported fever at home but is afebrile in the emergency department

Testing and management strategies for patients with neonatal herpes simplex virus infection

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology and Pathophysiology
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History
   2. Physical Examination
9. Diagnostic Studies
   1. Risk Stratification
      1. Ill-Appearing Febrile Infants
      2. Well-Appearing Febrile Infants
         • Cerebrospinal Fluid Testing
      3. Febrile Infants Aged 57 to 89 Days
      4. Newer Biomarkers
      5. Newer Risk-Stratification Algorithms
   2. Situation-Specific Testing
      1. Testing for Enterovirus and Parechovirus
      2. Testing for Respiratory Viruses
      3. Other Diagnostic Testing
10. Application of Risk Stratification Criteria and Treatment
    1. Application of Risk Stratification Criteria
       1. Febrile Infants Aged ≤ 28 Days
       2. Febrile Infants Aged > 28 Days
    2. Empiric Antibiotic Therapy
11. Special Circumstances
    1. Fever at Home Reported but Afebrile in the Emergency Department
12. Controversies and Cutting Edge
    1. Need for CSF Testing For Infants with Abnormal Urinalysis
    2. American Academy of Pediatrics REVISE Project
    3. Neonatal Herpes Simplex Virus Infection
    4. RNA Biosignatures
13. Disposition
14. Summary
15. Risk Management Pitfalls in the Management of Febrile Infants
16. Time- and Cost-Effective Strategies
17. Case Conclusions
18. Clinical Pathways
    1. Clinical Pathway for Evaluation and Management of Febrile Neonates in the Emergency Department
    2. Clinical Pathway for Evaluation and Management of Febrile Young Infants Aged 29 to 56 Days in the Emergency Department
    3. Clinical Pathway for Evaluation and Management of Febrile Young Infants Aged 57 to 89 Days in the Emergency Department
19. Tables
    1. Table 1. Definitions Associated With Febrile Young Infants
    2. Table 2. Differential Diagnosis of the Febrile Young Infant
    3. Table 3. Components of a Full Sepsis Workup
    4. Table 4. Most Common Risk Stratification Criteria for Management of Febrile Young Infants
    5. Table 5. Clinical Presentation of Neonatal Herpes Simplex Virus Infection
20. References

Abstract

Among young infants presenting with fever, untreated serious bacterial infections can have severe outcomes, so a full sepsis workup is often recommended but may not be necessary. This issue reviews the use of novel diagnostic tools such as procalcitonin, C-reactive protein, and RNA biosignatures as well as new risk stratification tools such as the Step-by-Step approach and the Pediatric Emergency Care Applied Research Network prediction rule to determine which febrile young infants require a full sepsis workup and to guide the management of these patients in the emergency department. The most recent literature assessing the risk of concomitant bacterial meningitis with urinary tract infections and the role for viral testing, specifically herpes simplex virus and enterovirus, are also reviewed.

Case Presentations

A 20-day-old boy presents to the ED in August for evaluation of a rectal temperature of 38˚C (100.4˚F). The baby was born by spontaneous vaginal delivery at 39 weeks’ gestational age. The mother’s prenatal labs were normal, including negative screening for group B Streptococcus. The patient felt warm to the parents today but has otherwise been asymptomatic. The baby has been eating 3 ounces every 4 hours and making an appropriate amount of wet diapers. The physical examination is normal, including a flat anterior fontanel and good hydration. When you explain to the mother that the baby will need to undergo the full sepsis workup, including lumbar puncture, she starts asking you questions: Is all of that testing necessary? Since her baby appears well other than the fever, what is the probability that he has a serious infection? Can other infections besides bacterial infections cause a fever, and does the baby need testing to identify those infections? After the testing is completed, will the baby need to be admitted to the hospital?

A 40-day-old girl presents to the ED in January for evaluation of a rectal temperature of 38˚C (100.4˚F). The history and physical examination are similar to the infant you saw in August, except that she has nasal discharge and a cough. Which risk stratification algorithm should you use for this infant? Would your workup change if a respiratory swab was positive for respiratory syncytial virus?

Your next patient is a 50-day-old girl who also presents to the ED with a rectal temperature of 38˚C (100.4˚F). The history and physical examination are similar to the patient you just saw, except this patient does not have nasal discharge or a cough. You send routine blood and urine tests, and the urinalysis results are positive for leukocyte esterase, > 20 white blood cells/high-power field, and many bacteria. Does this baby require a lumbar puncture? What is the likelihood of concomitant bacterial meningitis with a urinary tract infection?

Introduction

Due to an immature immune system and pathogens often specific to the age group, the young infant (generally aged < 60-90 days, depending on the specific study or review) is at high risk for serious bacterial infections (SBIs); in particular, urinary tract infection (UTI), bacteremia, and bacterial meningitis. Consequently, the febrile young infant with a rectal temperature ≥ 38°C (100.4°F) is commonly encountered in the emergency department (ED).¹ The incidence of SBI in febrile infants aged < 90 days is 8% to 12.5%,² and it is nearly 20% in neonates (aged ≤ 28 days).³ The incidence of potentially life-threatening bacteremia and/or bacterial meningitis (ie, invasive bacterial infection [IBI]) is approximately 2%.⁴

Due to their lack of social responsiveness (eg, social smile) and verbal cues, even well-appearing febrile young infants may harbor an SBI, in contrast to well-appearing febrile older infants and children who are at lower risk for IBI.⁵ Multiple studies have demonstrated that both observation scales and clinician suspicion for SBI are poorly predictive of bacterial infection in febrile infants.^6,7 Additionally, bacterial meningitis is the most common diagnosis involved in pediatric medical malpractice claims in the emergency department (ED).⁸

Over 2 decades ago, several risk stratification criteria were created to identify febrile young infants at low risk for SBI, and the criteria have been utilized to potentially avoid hospitalization of certain low-risk patients.^9-11 More recently, newer risk stratification algorithms that incorporate biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) have been developed and validated in febrile infants.^12,13

In addition to bacterial disease, the febrile infant aged ≤ 28 days is also at risk for neonatal herpes simplex virus (HSV) infection, a rare but life-threatening disease that is controversial in its workup and management.¹⁴ Other current controversies include the utility of the full sepsis workup in febrile young infants with identifiable sources of fever such as respiratory syncytial virus (RSV)¹⁵ and bronchiolitis, and the need for cerebrospinal fluid (CSF) testing in infants with presumptive UTI but who are otherwise at low risk for bacteremia and/or bacterial meningitis. Parents understandably question why invasive testing is recommended for their febrile baby, and the emergency clinician needs to clearly communicate the rationale behind the management of patients in this high-risk age group.

This issue of Pediatric Emergency Medicine Practice reviews the most up-to-date evidence for evaluation and management of febrile young infants, including the newer risk stratification algorithms, the need for routine versus selective CSF testing, the role of viral testing, and diagnostic and therapeutic challenges.

Critical Appraisal of the Literature

A literature search was performed in the PubMed database using multiple combinations of the search terms: febrile young infant, febrile infant, fever, low risk criteria, neonate, serious bacterial infection, invasive bacterial infection, neonatal herpes simplex virus, and infant less than 90 days old. In addition to reviewing articles included in the original version of this review published in 2013, all relevant articles published in or after 2013 were reviewed. Over 140 articles were reviewed, 109 of which were selected for inclusion. Emphasis was placed on reviewing the most important historical evidence, as well as recent studies with evidence that has been incorporated into clinical practice.

The body of research on the evaluation and management of febrile young infants is extensive and growing, but there is a paucity of randomized controlled trials, and there is no universally accepted clinical practice guideline. Additionally, IBIs (particularly bacterial meningitis) are rare in febrile young infants, so there are limited data on the precision of algorithms (eg, Rochester, Boston, and Philadelphia criteria) for the risk stratification of infants with an IBI. There are also limited data on the risk of adverse outcomes among infants who experience a delay in diagnosis of IBI. The Step-by-Step approach is a recently validated risk stratification algorithm, but this approach needs to be evaluated in certain populations of febrile young infants, such as infants with bronchiolitis. Additionally, the statistically derived and newly published Pediatric Emergency Care Applied Research Network (PECARN) prediction rule should, ideally, be further validated.

Risk Management Pitfalls in the Management of Febrile Infants

1. “The neonate had a fever, but he appeared to be well. I couldn’t justify doing the full sepsis workup, since there was little chance he had a serious infection.”

The prevalence of infection is too high for testing to be deferred. The febrile young infant is at high risk for an SBI, especially if he is aged ≤ 28 days, as nearly 1 in 5 febrile neonates will have an SBI.³ Additionally, the well-appearing febrile infant aged ≤ 60 days is also at risk, as 9.6% of these infants have an SBI and 1.8% have an IBI.⁶

5. “The mother denied any history of HSV, so I thought the 12-day-old neonate who looked ill likely had a bacterial infection and did not have neonatal HSV.”

The highest risk for transmission of neonatal HSV is babies born to mothers who have a primary infection at the time of delivery.³¹ The infection may be subclinical, so the mother may not know she has HSV when the baby presents to the ED. While the incidence of neonatal HSV is low,¹⁴ comprehensive HSV testing should be performed and empiric acyclovir therapy initiated in the ill-appearing, hypothermic, or seizing neonate, or when vesicles or a CSF pleocytosis with lymphocyte predominance are present.¹⁰⁵

9. “The 40-day-old febrile baby was very fussy on my exam, but the labs were normal, so he met the low-risk criteria, and I discharged him home.”

All of the low-risk criteria require the infant to be well-appearing on physical examination. (See Table 4.) Even with normal laboratory studies, if the infant is ill-appearing or has a focal infection, the baby should be hospitalized with initiation of empiric antibiotic therapy.

Tables

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of patients. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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68. Bramson RT, Meyer TL, Silbiger ML, et al. The futility of the chest radiograph in the febrile infant without respiratory symptoms. Pediatrics. 1993;92(4):524-526. (Prospective and retrospective; 361 patients)
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70. Fortunov RM, Hulten KG, Hammerman WA, et al. Evaluation and treatment of community-acquired Staphylococcus aureus infections in term and late-preterm previously healthy neonates. Pediatrics. 2007;120(5):937-945. (Retrospective; 126 patients)
71. Sakran W, Makary H, Colodner R, et al. Acute otitis media in infants less than three months of age: clinical presentation, etiology and concomitant diseases. Int J Pediatr Otorhinolaryngol. 2006;70(4):613-617. (Prospective; 68 patients)
72. Turner D, Leibovitz E, Aran A, et al. Acute otitis media in infants younger than two months of age: microbiology, clinical presentation and therapeutic approach. Pediatr Infect Dis J. 2002;21(7):669-674. (Retrospective; 137 patients)
73. Dagan R, Powell KR, Hall CB, et al. Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. J Pediatr. 1985;107(6):855-860. (Prospective; 148 patients)
74. Greenhow TL, Hung YY, Pantell RH. Management and outcomes of previously healthy, full-term, febrile infants ages 7 to 90 days. Pediatrics. 2016;138(6). (Retrospective; 1380 patients)
75. Mintegi S, Bressan S, Gomez B, et al. Accuracy of a sequential approach to identify young febrile infants at low risk for invasive bacterial infection. Emerg Med J. 2014;31(e1):e19-e24. (Prospective; 2470 patients)
76. Schelonka RL, Yoder BA, Hall RB, et al. Differentiation of segmented and band neutrophils during the early newborn period. J Pediatr. 1995;127(2):298-300. (Prospective; 94 patients)
77. Pantell RH, Newman TB, Bernzweig J, et al. Management and outcomes of care of fever in early infancy. JAMA. 2004;291(10):1203-1212. (Prospective; 3066 patients)
78. Mintegi S, Gomez B, Martinez-Virumbrales L, et al. Outpatient management of selected young febrile infants without antibiotics. Arch Dis Child. 2017;102(3):244-249. (Prospective; 1472 patients)
79. Pruitt CM, Neuman MI, Shah SS, et al. Factors associated with adverse outcomes among febrile young infants with invasive bacterial infections. J Pediatr. 2019;204:177-182. (Retrospective; 350 patients)
80. Woll C, Neuman MI, Pruitt CM, et al. Epidemiology and etiology of invasive bacterial infection in infants J Pediatr. 2018. (Cross-sectional; 442 patients)
81. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA. 2007;297(1):52-60. (Retrospective; 3295 patients)
82. Byington CL, Rittichier KK, Bassett KE, et al. Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. Pediatrics. 2003;111(5 Pt 1):964-968. (Retrospective; 1298 patients)
83. Dehority W. Use of vancomycin in pediatrics. Pediatr Infect Dis J. 2010;29(5):462-464. (Review)
84. Thomson J, Sucharew H, Cruz AT, et al. Cerebrospinal fluid reference values for young infants undergoing lumbar puncture. Pediatrics. 2018;141(3). (Cross-sectional; 7766 patients)
85. Lyons TW, Cruz AT, Freedman SB, et al. Correction of cerebrospinal fluid protein in infants with traumatic lumbar punctures. Pediatr Infect Dis J. 2017;36(10):1006-1008. (Retrospective; 2880 patients)
86. Ouchenir L, Renaud C, Khan S, et al. The epidemiology, management, and outcomes of bacterial meningitis in infants. Pediatrics. 2017;140(1). (Retrospective; 113 patients)
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