Evaluation and Management of the Febrile Young Infant in the Emergency Department

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.

1. American College of Emergency Physicians Clinical Policies Committee, American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530-545. (Clinical practice guideline)
2. Huppler AR, Eickhoff JC, Wald ER. Performance of low-risk criteria in the evaluation of young infants with fever: review of the literature. Pediatrics. 2010;125(2):228-233. (Systematic review)
3. Schwartz S, Raveh D, Toker O, et al. A week-by-week analysis of the low-risk criteria for serious bacterial infection in febrile neonates. Arch Dis Child. 2009;94(4):287-292. (Retrospective; 449 patients)
4. Powell EC, Mahajan PV, Roosevelt G, et al. Epidemiology of bacteremia in febrile infants aged 60 days and younger. Ann Emerg Med. 2018;71(2):211-216. (Prospective; 4778 patients)
5. McCarthy PL, Sharpe MR, Spiesel SZ, et al. Observation scales to identify serious illness in febrile children. Pediatrics. 1982;70(5):802-809. (Retrospective; 312 patients)
6. Nigrovic LE, Mahajan PV, Blumberg SM, et al. The Yale Observation Scale Score and the risk of serious bacterial infections in febrile infants. Pediatrics. 2017;140(1). (Prospective; 4591 patients)
7. Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile, 4-to 8-week-old infants. Pediatrics. 1990;85(6):1040-1043. (Prospective; 126 patients)
8. Selbst SM, Friedman MJ, Singh SB. Epidemiology and etiology of malpractice lawsuits involving children in US emergency departments and urgent care centers. Pediatr Emerg Care. 2005;21(3):165-169. (Retrospective; 2283 claims)
9. Baskin MN, O’Rourke EJ, Fleisher GR. Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J Pediatr. 1992;120(1):22-27. (Prospective; 503 patients)
10. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med. 1993;329(20):1437-1441. (Prospective; 747 patients)
11. Jaskiewicz JA, McCarthy CA, Richardson AC, et al. Febrile infants at low risk for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. Pediatrics. 1994;94(3):390-396. (Prospective; 1005 patients)
12. Gomez B, Mintegi S, Bressan S, et al. Validation of the “Step-by-Step” approach in the management of young febrile infants. Pediatrics. 2016;138(2). (Prospective; 2185 patients)
13. Kuppermann N, Dayan PS, Levine DA, et al. A clinical prediction rule to identify febrile infants 60 days and younger at low risk for serious bacterial infections. JAMA Pediatr. 2019;173(4):342-351. (Prospective; 1821 patients)
14. Kimberlin DW, Whitley RJ. Neonatal herpes: what have we learned. Semin Pediatr Infect Dis. 2005;16(1):7-16. (Review)
15. Burstein B, Dubrovsky A, Greene A, et al. National survey on the impact of viral testing for the ED and inpatient management of febrile young infants. Hosp Pediatr. 2016;6(4):226-233. (Cross-sectional; 330 providers)
16. Wilson CB. Immunologic basis for increased susceptibility of the neonate to infection. J Pediatr. 1986;108(1):1-12. (Review)
17. Herr SM, Wald ER, Pitetti RD, et al. Enhanced urinalysis improves identification of febrile infants ages 60 days and younger at low risk for serious bacterial illness. Pediatrics. 2001;108(4):866-871. (Retrospective; 344 patients)
18. Lin DS, Huang SH, Lin CC, et al. Urinary tract infection in febrile infants younger than eight weeks of age. Pediatrics. 2000;105(2):E20. (Prospective; 162 patients)
19. Biondi EA, Lee B, Ralston SL, et al. Prevalence of bacteremia and bacterial meningitis in febrile neonates and infants in the second month of life: a systematic review and meta-analysis. JAMA Netw Open. 2019;2(3):e190874. (Systematic review and meta-analysis)
20. Biondi E, Evans R, Mischler M, et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132(6):990-996. (Cross-sectional; 181 patients)
21. Greenhow TL, Hung YY, Herz AM, et al. The changing epidemiology of serious bacterial infections in young infants. Pediatr Infect Dis J. 2014;33(6):595-599. (Cross-sectional; 881 patients)
22. Watt K, Waddle E, Jhaveri R. Changing epidemiology of serious bacterial infections in febrile infants without localizing signs. PLoS One. 2010;5(8):e12448. (Cross-sectional; 668 patients)
23. Fortunov RM, Hulten KG, Hammerman WA, et al. Community-acquired Staphylococcus aureus infections in term and near-term previously healthy neonates. Pediatrics. 2006;118(3):874-881. (Retrospective; 89 patients)
24. Greenhow TL, Hung YY, Herz AM. Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics. 2012;129(3):e590-e596. (Retrospective; 4255 patients)
25. Leazer R, Erickson N, Paulson J, et al. Epidemiology of cerebrospinal fluid cultures and time to detection in term infants. Pediatrics. 2017;139(5). (Cross-sectional; 410 patients)
26. King RL, Lorch SA, Cohen DM, et al. Routine cerebrospinal fluid enterovirus polymerase chain reaction testing reduces hospitalization and antibiotic use for infants 90 days of age or younger. Pediatrics. 2007;120(3):489-496. (Retrospective; 478 patients)
27. Flagg EW, Weinstock H. Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics. 2011;127(1):e1-e8. (Retrospective; 395 patients)
28. Long SS, Pool TE, Vodzak J, et al. Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. Pediatr Infect Dis J. 2011;30(7):556-561. (Case series; 32 patients)
29. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37(2):666-688. (Clinical practice guideline)
30. Muma BK, Treloar DJ, Wurmlinger K, et al. Comparison of rectal, axillary, and tympanic membrane temperatures in infants and young children. Ann Emerg Med. 1991;20(1):41-44. (Prospective; 224 patients)
31. Stoll BJ, Hansen NI, Sanchez PJ, et al. Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817-826. (Prospective; 389 patients)
32. Committee on Infectious Diseases, Committee on Fetus and Newborn, Baker CJ, et al. Policy statement-Recommendations for the prevention of perinatal group B streptococcal (GBS) disease. Pediatrics. 2011;128(3):611-616. (Policy statement)
33. Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289(2):203-209. (Prospective; 58,362 patients)
34. Jackson GL, Rawiki P, Sendelbach D, et al. Hospital course and short-term outcomes of term and late preterm neonates following exposure to prolonged rupture of membranes and/or chorioamnionitis. Pediatr Infect Dis J. 2012;31(1):89-90. (Retrospective; 812 patients)
35. Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108(2):223-229. (Prospective; 186 patients)
36. Pickert CB, Moss MM, Fiser DH. Differentiation of systemic infection and congenital obstructive left heart disease in the very young infant. Pediatr Emerg Care. 1998;14(4):263-267. (Retrospective; 85 patients)
37. Hui C, Neto G, Tsertsvadze A, et al. Diagnosis and management of febrile infants (0-3 months). Evid Rep Technol Assess (Full Rep). 2012(205):1-297. (Evidence report)
38. Valente JH, Mace SE, Gemme SR, et al. Clinical policy for well-appearing infants and children younger than 2 years of age presenting to the emergency department with fever. Ann Emerg Med. 2016;67(5):625-639. (Policy statement)
39. Aronson PL, McCulloh RJ, Tieder JS, et al. Application of the Rochester criteria to identify febrile infants with bacteremia and meningitis. Pediatr Emerg Care. 2019;35(1):22-27. (Retrospective; 82 patients)
40. Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med. 1999;153(5):508-511. (Retrospective; 254 patients)
41. Aronson PL, Wang ME, Shapiro ED, et al. Risk stratification of febrile infants Pediatrics. 2018;142(6). (Case-control; 384 patients)
42. Scarfone R, Murray A, Gala P, et al. Lumbar puncture for all febrile infants 29-56 days old: a retrospective cohort reassessment study. J Pediatr. 2017;187:200-205. (Retrospective; 1188 patients)
43. Pingree EW, Kimia AA, Nigrovic LE. The effect of traumatic lumbar puncture on hospitalization rate for febrile infants 28 to 60 days of age. Acad Emerg Med. 2015;22(2):240-243. (Cross-sectional; 929 patients)
44. Paxton RD, Byington CL. An examination of the unintended consequences of the rule-out sepsis evaluation: a parental perspective. Clin Pediatr (Phila). 2001;40(2):71-77. (Cross-sectional; 60 parents)
45. Chua KP, Neuman MI, McWilliams JM, et al. Association between clinical outcomes and hospital guidelines for cerebrospinal fluid testing in febrile infants aged 29-56 days. J Pediatr. 2015;167(6):1340-1346. (Retrospective; 80,074 patients)
46. Aronson PL, Thurm C, Alpern ER, et al. Variation in care of the febrile young infant <90 days in US pediatric emergency departments. Pediatrics. 2014;134(4):667-677. (Retrospective; 35,070 patients)
47. Tzimenatos L, Mahajan P, Dayan PS, et al. Accuracy of the urinalysis for urinary tract infections in febrile infants 60 days and younger. Pediatrics. 2018;141(2). (Prospective; 4147 patients)
48. Hsiao AL, Chen L, Baker MD. Incidence and predictors of serious bacterial infections among 57-to 180-day-old infants. Pediatrics. 2006;117(5):1695-1701. (Prospective; 429 patients)
49. Cruz AT, Mahajan P, Bonsu BK, et al. Accuracy of complete blood cell counts to identify febrile infants 60 days or younger with invasive bacterial infections. JAMA Pediatr. 2017;171(11):e172927. (Prospective; 4313 patients)
50. Woll C, Neuman MI, Aronson PL. Management of the febrile young infant: update for the 21st century. Pediatr Emerg Care. 2017;33(11):748-753. (Review)
51. 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. (Prospective; 2047 patients)
52. Baker MD, Bell LM, Avner JR. The efficacy of routine outpatient management without antibiotics of fever in selected infants. Pediatrics. 1999;103(3):627-631. (Prospective; 422 patients)
53. Dewan M, Zorc JJ, Hodinka RL, et al. Cerebrospinal fluid enterovirus testing in infants 56 days or younger. Arch Pediatr Adolesc Med. 2010;164(9):824-830. (Retrospective; 1231 patients)
54. Aronson PL, Lyons TW, Cruz AT, et al. Impact of enteroviral polymerase chain reaction testing on length of stay for infants 60 days old or younger. J Pediatr. 2017;189:169-174. (Retrospective; 19,953 patients)
55. Wallace SS, Lopez MA, Caviness AC. Impact of enterovirus testing on resource use in febrile young infants: a systematic review. Hosp Pediatr. 2017;7(2):96-102. (Systematic review)
56. Hawkes MT, Vaudry W. Nonpolio enterovirus infection in the neonate and young infant. Paediatr Child Health. 2005;10(7):383-388. (Review)
57. Seiden JA, Zorc JJ, Hodinka RL, et al. Lack of cerebrospinal fluid pleocytosis in young infants with enterovirus infections of the central nervous system. Pediatr Emerg Care. 2010;26(2):77-81. (Retrospective; 154 patients)
58. Bennett S, Harvala H, Witteveldt J, et al. Rapid simultaneous detection of enterovirus and parechovirus RNAs in clinical samples by one-step real-time reverse transcription-PCR assay. J Clin Microbiol. 2011;49(7):2620-2624. (Laboratory)
59. Cabrerizo M, Trallero G, Pena MJ, et al. Comparison of epidemiology and clinical characteristics of infections by human parechovirus vs. those by enterovirus during the first month of life. Eur J Pediatr. 2015;174(11):1511-1516. (Prospective; 84 patients)
60. Levine DA, Platt SL, Dayan PS, et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics. 2004;113(6):1728-1734. (Prospective; 1248 patients)
61. Bonadio W, Huang F, Nateson S, et al. Meta-analysis to determine risk for serious bacterial infection in febrile outpatient neonates with RSV infection. Pediatr Emerg Care. 2016;32(5):286-289. (Meta-analysis; 789 patients)
62. Krief WI, Levine DA, Platt SL, et al. Influenza virus infection and the risk of serious bacterial infections in young febrile infants. Pediatrics. 2009;124(1):30-39. (Prospective; 1091 patients)
63. Blaschke AJ, Korgenski EK, Wilkes J, et al. Rhinovirus in febrile infants and risk of bacterial infection. Pediatrics. 2018;141(2). (Cross-sectional; 4037 patients)
64. Mahajan P, Browne LR, Levine DA, et al. Risk of bacterial coinfections in febrile infants 60 days old and younger with documented viral infections. J Pediatr. 2018;203:86-91. (Prospective; 4778 patients)
65. Ralston S, Hill V, Waters A. Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis: a systematic review. Arch Pediatr Adolesc Med. 2011;165(10):951-956. (Systematic review)
66. McDaniel CE, Ralston S, Lucas B, et al. Association of diagnostic criteria with urinary tract infection prevalence in bronchiolitis: a systematic review and meta-analysis. JAMA Pediatr. 2019;173(3):269-277. (Systematic review and meta-analysis)
67. Byington CL, Reynolds CC, Korgenski K, et al. Costs and infant outcomes after implementation of a care process model for febrile infants. Pediatrics. 2012;130(1):e16-e24. (Quasi-experimental; 8431 patients)
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)
69. Crain EF, Bulas D, Bijur PE, et al. Is a chest radiograph necessary in the evaluation of every febrile infant less than 8 weeks of age? Pediatrics. 1991;88(4):821-824. (Prospective; 242 patients)
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)
87. Bonadio WA, Hegenbarth M, Zachariason M. Correlating reported fever in young infants with subsequent temperature patterns and rate of serious bacterial infections. Pediatr Infect Dis J. 1990;9(3):158-160. (Retrospective; 292 patients)
88. Mintegi S, Gomez B, Carro A, et al. Invasive bacterial infections in young afebrile infants with a history of fever. Arch Dis Child. 2018;103(7):665-669. (Retrospective; 1123 patients)
89. Ramgopal S, Janofsky S, Zuckerbraun NS, et al. Risk of serious bacterial infection in infants aged </=60 days presenting to emergency departments with a history of fever only. J Pediatr. 2019;204:191-195. (Prospective secondary analysis; 3825 patients)
90. Aronson PL, Shabanova V, Shapiro ED, et al. A prediction model to identify febrile infants ≤60 days at low risk of invasive bacterial infection. Pediatrics. 2019. (Case-control; 543 patients)
91. Li YW, Zhou LS, Li X. Accuracy of tactile assessment of fever in children by caregivers: a systematic review and meta-analysis. Indian Pediatr. 2017;54(3):215-221. (Systematic review and meta-anaylsis)
92. Tebruegge M, Pantazidou A, Curtis N. Question 1. How common is co-existing meningitis in infants with urinary tract infection? Arch Dis Child. 2011;96(6):602-606. (Systematic review, brief)
93. Tebruegge M, Pantazidou A, Clifford V, et al. The age-related risk of co-existing meningitis in children with urinary tract infection. PLoS One. 2011;6(11):e26576. (Cross-sectional; 748 patients)
94. Thomson J, Cruz AT, Nigrovic LE, et al. Concomitant bacterial meningitis in infants with urinary tract infection. Pediatr Infect Dis J. 2017;36(9):908-910. (Retrospective; 1737 patients)
95. Young B, Nguyen T, Alibaster A, et al. The prevalence of meningitis in febrile infants 29-60 days with positive urinalysis. Hosp Pediatr. 2018;8(8):e20170254. (Retrospective; 1174 patients)
96. McCulloh RJ, Fouquet SD, Herigon J, et al. Development and implementation of a mobile device-based pediatric electronic decision support tool as part of a national practice standardization project. J Am Med Inform Assoc. 2018;25(9):1175-1182. (Descriptive)
97. Cruz AT, Freedman SB, Kulik DM, et al. Herpes simplex virus infection in infants undergoing meningitis evaluation. Pediatrics. 2018;141(2). (Cross-sectional; 26,533 patients)
98. Lopez-Medina E, Cantey JB, Sanchez PJ. The mortality of neonatal herpes simplex virus infection. J Pediatr. 2015;166(6):1529-1532. (Case series; 13 patients)
99. Curfman AL, Glissmeyer EW, Ahmad FA, et al. Initial presentation of neonatal herpes simplex virus infection. J Pediatr. 2016;172:121-126. (Case series; 49 patients)
100. Caviness AC, Demmler GJ, Almendarez Y, et al. The prevalence of neonatal herpes simplex virus infection compared with serious bacterial illness in hospitalized neonates. J Pediatr. 2008;153(2):164-169. (Retrospective; 5817 patients)
101. Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med. 1991;324(7):450-454. (Prospective; 202 patients)
102. Shah SS, Aronson PL, Mohamad Z, et al. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128(6):1153-1160. (Retrospective; 1086 patients)
103. Long SS. In defense of empiric acyclovir therapy in certain neonates. J Pediatr. 2008;153(2):157-158. (Editorial)
104. Van TT, Mongkolrattanothai K, Arevalo M, et al. Impact of a rapid herpes simplex virus PCR assay on duration of acyclovir therapy. J Clin Microbiol. 2017;55(5):1557-1565. (Cross-sectional; 363 patients)
105. Brower L, Schondelmeyer A, Wilson P, et al. Testing and empiric treatment for neonatal herpes simplex virus: challenges and opportunities for improving the value of care. Hosp Pediatr. 2016;6(2):108-111. (Editorial)
106. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108(2):230-238. (Prospective and retrospective; 195 patients)
107. Mahajan P, Kuppermann N, Mejias A, et al. Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. JAMA. 2016;316(8):846-857. (Prospective; 298 patients)
108. Schnadower D, Kuppermann N, Macias CG, et al. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126(6):1074-1083. (Retrospective; 1895 patients)
109. Bonsu BK, Harper MB. Utility of the peripheral blood white blood cell count for identifying sick young infants who need lumbar puncture. Ann Emerg Med. 2003;41(2):206-214. (Retrospective; 5353 patients)