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
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Abstract
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Case Presentations
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Introduction
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Critical Appraisal of the Literature
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Etiology and Pathophysiology
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Differential Diagnosis
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Prehospital Care
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Emergency Department Evaluation
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History
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Physical Examination
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Diagnostic Studies
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Risk Stratification
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Ill-Appearing Febrile Infants
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Well-Appearing Febrile Infants
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Cerebrospinal Fluid Testing
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Febrile Infants Aged 57 to 89 Days
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Newer Biomarkers
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Newer Risk-Stratification Algorithms
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Situation-Specific Testing
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Testing for Enterovirus and Parechovirus
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Testing for Respiratory Viruses
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Other Diagnostic Testing
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Application of Risk Stratification Criteria and Treatment
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Application of Risk Stratification Criteria
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Febrile Infants Aged ≤ 28 Days
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Febrile Infants Aged > 28 Days
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Empiric Antibiotic Therapy
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Special Circumstances
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Fever at Home Reported but Afebrile in the Emergency Department
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Controversies and Cutting Edge
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Need for CSF Testing For Infants with Abnormal Urinalysis
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American Academy of Pediatrics REVISE Project
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Neonatal Herpes Simplex Virus Infection
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RNA Biosignatures
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Disposition
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Summary
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Risk Management Pitfalls in the Management of Febrile Infants
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Time- and Cost-Effective Strategies
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Case Conclusions
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Clinical Pathways
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Clinical Pathway for Evaluation and Management of Febrile Neonates in the Emergency Department
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Clinical Pathway for Evaluation and Management of Febrile Young Infants Aged 29 to 56 Days in the Emergency Department
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Clinical Pathway for Evaluation and Management of Febrile Young Infants Aged 57 to 89 Days in the Emergency Department
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Tables
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Table 1. Definitions Associated With Febrile Young Infants
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Table 2. Differential Diagnosis of the Febrile Young Infant
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Table 3. Components of a Full Sepsis Workup
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Table 4. Most Common Risk Stratification Criteria for Management of Febrile Young Infants
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Table 5. Clinical Presentation of Neonatal Herpes Simplex Virus Infection
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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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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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Wilson CB. Immunologic basis for increased susceptibility of the neonate to infection. J Pediatr. 1986;108(1):1-12. (Review)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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Woll C, Neuman MI, Pruitt CM, et al. Epidemiology and etiology of invasive bacterial infection in infants J Pediatr. 2018. (Cross-sectional; 442 patients)
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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)
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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)
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Dehority W. Use of vancomycin in pediatrics. Pediatr Infect Dis J. 2010;29(5):462-464. (Review)
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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)
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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)
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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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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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Long SS. In defense of empiric acyclovir therapy in certain neonates. J Pediatr. 2008;153(2):157-158. (Editorial)
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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)
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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)
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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)
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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)
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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)
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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)
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Points and Pearls Excerpt
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Multiple studies have demonstrated that observation scales and clinician suspicion for severe bacterial infection (SBI) are poorly predictive of bacterial infection in febrile infants.
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Neonates have the highest prevalence of SBI and invasive bacterial infection. Febrile neonates should have a full sepsis workup and be hospitalized and treated with empiric antibiotic therapy.
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At a minimum, order urine studies for the febrile infant aged 57 to 89 days, with a strong consideration to blood testing as well, as these patients are still at risk for a urinary tract infection.
Most Important References
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* 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)
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* 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)
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* 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)
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American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Pediatric Fever, Mace SE, Gemme SR. 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)
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* Aronson PL, Wang ME, Shapiro ED, et al. Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture. Pediatrics. (Case-control; 384 patients)
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The Rochester criteria for febrile infants determine whether or not febrile infants are at low risk for serious bacterial infection. The Step-by-Step approach to febrile infants identifies febrile infants aged ≤ 90 days who are at low risk for invasive bacterial infections. The PECARN rule for low-risk febrile infants predicts the risk for urinary tract infection, bacteremia, or bacterial meningitis in febrile infants aged ≤ 60 days.
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Rochester Criteria for Febrile Infants
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Step-by-Step Approach to Febrile Infants
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PECARN Rule for Low-Risk Febrile Infants
Rochester Criteria for Febrile Infants
Introduction
The Rochester criteria for febrile infants determine whether or not febrile infants are at low risk for serious bacterial infection.
Points & Pearls
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While the validation study for the Rochester criteria included infants aged ≤ 60 days, in clinical practice, infants aged < 28 days often are not considered to be at low risk, due to their age.
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Premature infants should be assessed based on their corrected age (eg, for an infant born at 30 weeks gestational age, subtract 7 weeks from the chronologic age).
Why and When to Use, Next Steps and Advice
Why to Use
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The Rochester criteria identify infants who are at low risk for SBI (defined as bacteremia, meningitis, osteomyelitis, suppurative arthritis, soft tissue infections [cellulitis, abscess, mastitis, omphalitis], urinary tract infection, gastroenteritis, or pneumonia).
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Febrile infants aged ≤ 60 days may present with minimal signs and symptoms or may present similarly to those who have viral infections. The criteria can help identify SBI in these patients; the prevalence of SBI is 10% to 12% in this group, with urinary tract infections representing > 90% of these SBIs (Biondi 2013, Greenhow 2014).
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Use of the Rochester criteria may reduce overtesting and overtreatment of well-appearing febrile infants.
When to Use
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The Rochester criteria can be used for well-appearing infants aged ≤ 60 days who present to the ED for a chief complaint of fever ≥ 38ºC (100.4ºF), or who are found to have fever on presentation for another complaint.
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Ill-appearing infants should be redirected to the sepsis guidelines.
Next Steps
If the patient is at low risk for SBI according to the Rochester criteria (in the derivation study, SBI occurred in 1% of low-risk infants):
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Limited testing, including complete blood cell count, blood culture, urinalysis, and urine culture, is recommended.
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Febrile infants who are considered to be at low risk generally do not require antibiotics.
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It is generally safe to discharge these infants if there are no social concerns or questions about the caregiver’s ability to follow up with a primary care pediatrician.
If the patient is not considered to be at low risk for SBI according to the Rochester criteria (in the study, SBI occurred in 12.3% of infants who were identified as not at low risk):
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Further testing is required, including complete blood cell count, blood culture, urinalysis, urine culture, and cerebrospinal fluid testing.
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Empiric broad spectrum antibiotic coverage is indicated.
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Admission is recommended, pending negative cultures at 24 to 36 hours.
Advice
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Herpes simplex virus risk factors should be carefully assessed, including maternal history of herpes simplex virus infection or primary lesions at delivery, household contacts with lesions, vesicular rash, patient presentation with seizures, or pleocytosis on cerebrospinal fluid testing.
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A positive viral test result (eg, respiratory syncytial virus, influenza) reduces the likelihood of SBI by approximately 50%, but the risk of a concurrent SBI is not 0% (Greenhow 2014, Krief 2009).
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The gold standard for urine culture is a sample obtained via straight catheterization. “Bag” urine collection introduces the risk of specimen contamination with skin flora. If possible, blood, urine, and cerebrospinal fluid samples should be obtained before starting antibiotics.
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The differential diagnosis of febrile ill-appearing infants aged < 60 days should also include the following: congenital heart disease, metabolic disease (eg, galactosemia), congenital adrenal hyperplasia with adrenal crisis, and nonaccidental trauma.
Abbreviations: ED, emergency department; SBI, serious bacterial infection.
Calculator Review Authors
Laura Mercurio, MD
Department of Pediatric Emergency Medicine, Brown
University/Hasbro Children’s Hospital, Providence, RI
Evidence Appraisal
The Rochester criteria were first proposed by Dagan et al in 1985 at the University of Rochester Medical Center in New York. In 1994, Jaskiewicz et al validated the criteria by aggregating data from 3 prospective studies that were conducted between 1984 and 1992. Only infants aged ≤ 60 days who had rectal temperatures ≥ 38ºC (100.4ºF) at home or at presentation were included in the validation study. The clinical environments were an emergency department and a pediatric outpatient clinic.
The evaluation of each infant included global assessment, past medical history, physical examination (including for evidence of skin, soft tissue, bone, or joint infection), and laboratory assessment (including blood, urine, and cerebrospinal fluid studies). Chest x-ray and stool studies were only obtained if clinical symptoms were present. Of note, cerebrospinal fluid studies were not part of the Rochester risk stratification criteria. Each infant was then categorized as low risk or not low risk. Among 931 evaluable patients, 437 met all of the low-risk criteria and 511 did not.
The study’s main outcomes were bacteremia and a larger inclusive category of serious bacterial infection (SBI). SBI was defined as bacteremia, meningitis, osteomyelitis, suppurative arthritis, soft tissue infections (cellulitis, abscess, mastitis, omphalitis), urinary tract infection, gastroenteritis, or pneumonia. SBI was identified in 1% of the low-risk infants as compared to 12.3% of non–low-risk infants. The negative predictive value (NPV) of the low-risk criteria was 99.5% for bacteremia and 98.9% for SBI.
In 2012, Hui et al conducted a review of 84 studies to determine the diagnostic accuracy of screening tools for SBI and HSV in infants aged < 3 months. This review also examined the rela-tionship between viral testing and risk of SBI. The various clinical and laboratory criteria (including the Rochester, Philadelphia, Boston, and Milwaukee screening tools) demonstrated similar overall accuracy (84.4%-100% sensitivity; 93.7%-100% NPV) for identifying infants with SBI. The Rochester criteria were more accurate in neonates than in older infants, while the other screening tools were more accurate in older infants than in neonates.
In 2016, Gomez et al conducted a prospec-tive study including infants aged < 90 days who presented to 11 European pediatric emergency departments between September 2012 and August 2014. The study compared the accuracies of the new Step-by-Step approach, the Rochester criteria, and the Lab-score for identifying patients who are at low risk of invasive bacterial infection (IBI). For the study population, the sensitivity and NPV for ruling out IBI were 92.0% and 99.3%, respectively, for the Step-by-Step approach, 81.6% and 98.3% for the Rochester criteria, and 59.8% and 98.1% for the Lab-score. Some infants with IBIs were misclassified by each of the tools in the study: 7 by the Step-by-Step approach,16 by the Rochester criteria, and 35 by the Lab-score.
Calculator Creator
Ron Dagan, MD
References
Original/Primary Reference
Validation Reference
Other References
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Biondi E, Evans R, Mischler M, et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132(6):990-996.
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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.
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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.
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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.
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Biondi EA, Byington CL. Evaluation and management of febrile, well-appearing young infants. Infect Dis Clin North Am. 2015;29(3):575-585.
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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):e20154381.
Step-by-Step Approach to Febrile Infants
Introduction
The Step-by-Step approach to febrile infants identifies febrile infants aged ≤ 90 days who are at low risk for invasive bacterial infections.
Points & Pearls
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The Step-by-Step approach was developed with the goal of identifying febrile infants aged ≤ 90 days who are at low risk of invasive bacterial infection (defined as bacteremia or meningitis).
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It was only studied in previously healthy infants and does not apply to infants who have any prior medical history.
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The Step-by-Step approach should be used in previously healthy infants aged ≤ 90 days who present with fever without a source.
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In the original study by Mintegi et al (2014), “fever without a source” was defined as fever in an infant with an unremarkable physical examination and without signs or symptoms of a self-limiting viral illness such as bronchiolitis or gastroenteritis.
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Differences in the prevalence of invasive bacterial infection (IBI) versus noninvasive bacterial infection in each risk subgroup should also be taken into consideration when interpreting and applying the results of the original study.
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The Step-by-Step approach performs best when applied to infants with fever lasting > 2 hours because the rule relies on the detection of inflammatory markers (procalcitonin and C-reactive protein) that may take time to increase.
Why and When to Use, and Next Steps
Why to Use
The etiology of fever in infants aged ≤ 90 days can range from self-limiting viral illness (eg, bronchiolitis) to life-threatening IBI (eg, bacteremia or meningitis). The Step-by-Step approach can be used to rule out IBI with a high negative predictive value (99.3%). If IBI can be safely ruled out, these low-risk infants do not require hospital admission and intravenous antibiotics.
When to Use
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The Step-by-Step approach can be used in previously healthy infants aged ≤ 90 days who have a fever ≥ 38.0°C (≥ 100.4°F) documented at home or at presentation in the ED.
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Caution is advised when using the Step-by-Step approach in infants with a short duration of fever, as it takes time for serum inflammatory markers (eg, procalcitonin, to increase). Observation in the ED should be considered, even if laboratory values are initially normal.
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Caution is advised when using the Step-by-Step approach in infants aged 21 to 28 days, as the management of this age group remains controversial and the Step-by-Step algorithm did not perform optimally in this group. In the validation study by Gomez et al (2016), 4 out of the 7 patients (57%) who were not identified as high risk by the Step-by-Step approach but were diagnosed with an IBI were aged 21 to 28 days. Studies suggest that the prevalence of bacteremia may be higher in infants aged 21 to 28 days as compared to infants aged > 28 days, so a full sepsis workup is recommended for any infant aged < 28 days (Powell 2018).
Next Steps
Interpretation
Risk Group |
IBI Risk |
Recommendation |
Low |
0.7% |
Full sepsis workup is likely not needed. Consider a period of ED observation, especially if the fever lasts < 2 hours, and ensure outpatient follow-up with a pediatrician. |
Intermediate |
3.4% |
Full sepsis workup (including blood, urine, and cerebrospinal fluid cultures), initiation of broad-spectrum intravenous antibiotics, and inpatient hospital admission may be indicated, especially if the patient is aged 21 to 28 days. |
High |
8.1% |
Full sepsis workup (including blood, urine, and cerebrospinal fluid cultures), initiation of broad-spectrum intravenous antibiotics, chest x-ray, and inpatient hospital admission are recommended. |
Management of IBI in Infants:
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Prompt initiation of broad-spectrum antibiotics according to local guidelines is strongly recommended.
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Optimization of respiratory support and hemodynamics should be initiated if respiratory distress or signs of dehydration or shock are present.
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Inpatient hospital admission for a minimum of 36 to 48 hours is recommended if cultures remain negative. Studies indicate that if IBI is present, 96% of blood cultures will become positive within 36 hours and 99% will become positive within 48 hours (Biondi 2014, Biondi 2015).
Abbreviations: ED, emergency department; IBI, invasive bacterial infection
Calculator Review Authors
Emily Heikamp, MD, PhD
Department of Pediatrics, Section of Hematology-
Oncology, Baylor College of Medicine/Texas Children's
Hospital, Houston, TX
Critical Action
No decision rule should trump clinical gestalt. High suspicion for IBI in a febrile infant should warrant a full sepsis workup.
Evidence Appraisal
Gomez et al (2016) conducted a prospective validation study of previously derived criteria, which they applied to 2185 infants aged ≤ 90 days who presented to pediatric emergency departments at 11 European hospitals. Among this group, 3.9% were diagnosed with an IBI and 19.1% were diagnosed with a noninvasive bacterial infection such as urinary tract infection.
In a post-hoc analysis, the Step-by-Step approach demonstrated superior sensitivity and negative predictive value as compared to other risk assessment tools such as the Rochester criteria and the Lab-score (Shaughnessy 2016). Sensitivity and negative predictive value for ruling out IBI were 92.0% and 99.3% for the Step-by-Step approach, 81.6% and 98.3% for the Rochester criteria, and 59.8% and 98.1% for the Lab-score, respectively.
Calculator Creator
Santiago Mintegi, MD, PhD.
References
Original/Primary Reference
Validation Reference
Other References
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Aronson PL, Neuman MI. Should we evaluate febrile young infants step-by-step in the emergency department?. Pediatrics. 2016;138(2):e20161579.
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Shaughnessy AF. Step-By-Step approach to ruling out infant infection is accurate. Am Fam Physician. 2016;94(11):933.
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Dieckmann RA, Brownstein D, Gausche-Hill M. The pediatric assessment triangle: a novel approach for the rapid evaluation of children. Pediatr Emerg Care. 2010;26(4):312-315.
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Biondi EA, Byington CL. Evaluation and management of febrile, well-appearing young infants. Infect Dis Clin North Am. 2015;29(3):575-585.
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Biondi EA, Mischler MM, Jerardi KE, et al. Blood culture time to positivity in febrile infants with bacteremia. JAMA Pediatrics. 2014;168(9): 844-849.
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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.
PECARN Rule for Low-Risk Febrile Infants
Introduction
The PECARN rule for low-risk febrile infants predicts the risk for urinary tract infection, bacteremia, or bacterial meningitis in febrile infants aged ≤ 60 days.
Points & Pearls
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The PECARN (Pediatric Emergency Care Applied Research Network) prediction rule does not apply to ill-appearing infants. The rule is intended to be one directional: it may help rule out serious bacterial infection (SBI) in patients who are “low risk,” but the converse is not true (ie, patients who are “not low risk” according to the rule do not necessarily have an SBI).
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Infants with signs of shock or who are otherwise ill-appearing or unstable should be considered at to be at high risk for SBI and in most cases should have blood, urine, and cerebrospinal fluid cultures performed. This clinical prediction rule would not apply to such patients.
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A serum procalcitonin level is required for the PECARN prediction rule, but this test may not be rapidly available in all settings.
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The majority of infants aged ≤ 60 days are unvaccinated and have immature immune systems.
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Infants aged < 28 days warrant special attention, as they are at elevated risk for herpes meningoencephalitis as well as a more rapid progression of disease. These patients almost always require admission for close monitoring along with a full sepsis workup, including lumbar puncture.
Why and When to Use, Next Steps and Advice
Why to Use
A physical examination alone is unreliable in ruling out SBI in febrile infants. The PECARN prediction rule may help to decrease unnecessary admissions and/or lumbar punctures. It can be used to help determine the disposition of some well-appearing infants who have reliable access to follow-up with a primary care pediatrician or in the same ED in 24 hours, or whose caregivers can be relied upon to return the patient to the ED if a pending culture has a positive result.
When to Use
Use the PECARN prediction rule in well-appearing infants aged ≤ 60 days, to stratify the risk of SBI (defined as urinary tract infection, bacteremia, or bacterial meningitis).
Next Steps
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Patients predicted to be at low risk for SBI might be able to be safely discharged from the ED, as long as follow up with a primary care pediatrician or in the same ED can be reasonably well assured.
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The decision to admit a febrile infant is multifactorial. Lack of reliable follow-up care may necessitate admission.
Advice
Some well-appearing infants considered to be at low risk for SBI may be suitable for discharge from the ED with follow-up with their primary care pediatrician or in the same ED in 24 hours for reassessment, as opposed to the traditional practice of admitting all febrile infants aged 0 to 60 days.
Abbreviations: ED, emergency department; PECARN, Pediatric Emergency Care Applied Research Network; SBI, serious bacterial infection.
Calculator Review Authors
Derek Tam, MD, MPH
Department of Pediatrics, Maimonides Medical Center,
Brooklyn, NY
Hector Vazquez, MD
Department of Emergency Medicine, Maimonides
Medical Center, Brooklyn, NY
Christopher Tainter, MD, RDMS
Department of Anesthesiology, Division of Critical
Care, Department of Emergency Medicine, University of
California San Diego, San Diego, CA
Critical Action
Consider a critical congenital heart defect (and empiric prostaglandin treatment) in a neonate who presents in shock.
Evidence Appraisal
The derivation study by Kuppermann et al (2019) included 1896 previously healthy febrile infants aged ≤ 60 days who had a serum procalcitonin level test at the time of their sepsis evaluation; participants whose procalcitonin samples were lost or mislabeled were excluded. The overall cohort was 1821 patients (908 in the derivation sample and 913 in the validation sample). The primary outcome was the presence or absence of an SBI, defined as urinary tract infection, bacteremia, or bacterial meningitis.
The prediction rule had a sensitivity of 98.8% (95% confidence interval [CI], 92.5%-99.9%) in the derivation study and 97.7% sensitivity (95% CI, 91.3%- 99.6%) in the validation study. The negative predictive value for SBI was 99.8% (95% CI, 98.8%-100.0%) and 99.6% (95% CI, 98.4%- 99.9%) in the derivation and validation studies, respectively. Because the validation study was not conducted independently, there is a risk of diminished external validity.
The benefits of using this rule are: (1) unnecessary admissions may be decreased and (2) unnecessary lumbar punctures may be avoided. A key difference in this prediction rule as compared to other similar rules is that the sensitivity remained high despite the fact that lumbar puncture results were not used as criteria in the rule. However, there is a low prevalence of bacterial meningitis in the general population due to the use of Haemophilus influenzae type B and pneumococcal vaccinations, so there were few cases of bacterial meningitis included in this study’s data set.
Finally, 3 infants in the study were misclassified by the prediction rule as being at low risk but had SBIs (2 had a urinary tract infection and 1 had Enterobacter cloacae bacteremia). All 3 were treated appropriately based on culture results and had uneventful clinical courses.
Calculator Creator
Nathan Kuppermann, MD, MPH
References
Original/Primary Reference
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