Background: Fever without source in infants less than three months old presents a difficult diagnostic dilemma for ED physicians.  Over the past 25 years several algorithms have been developed to help guide clinicians, most notably the Rochester, Philadelphia and Boston Criteria, in determining which infants require admission vs. outpatient management.  These studies were designed published between 1992 and 1994 prior to the wide spread use of HiB and pneumococcal vaccines in children, maternal GBS screening and the development of many new biomarkers. 

The Step-by-Step approach to febrile infants was developed by a European group of pediatric emergency physicians with the objective of identifying low risk infants who could be safely managed as outpatients without lumbar puncture or empiric antibiotic treatment. The algorithm was designed using retrospective data and this study attempts to prospectively validate it.

Clinical Question:

How does the “Step-by-Step” approach to febrile infants compare to the Rochester criteria or the “Lab-score” method in identifying infants 90 days or younger with a fever of unknown source to be at a low risk of invasive bacterial infections?

Design:

Multi-center prospective study including 11 European pediatric emergency departments (8 Spanish, 2 Italian and 1 Swiss).

Population:

Infants 90 days old or younger with “fever without a source” defined as objective temperature of > 38C at home or in the ED without a clear source on history or physical exam, more specifically pulmonary exam findings or history of diarrhea.

Exclusion Criteria:

• Patients without fever in the ER and only subjective fevers at home
• Clear source of fever identified on careful history and physical exam
• Absence of 1 or more of the mandatory ancillary tests (Blood culture, Urine Culture, Urine dipstick, PCT, CRP or WBC)
• Refusal of the parents to consent

Intervention:

Application of the “Step-by-Step” approach:

Control:

The step-by-step approach was compared against two established algorithms for assessing the febrile infant:
1) The Rochester Criteria:

Infants 60 days or younger with temp >38C who met the following criteria were discharged without empiric antibiotics

• Full term, no underlying disease w/o perinatal antibiotics or prolonged perinatal hospitalization
• Well appearing infant without focal signs of infection
• WBC between 5,000 and 15,000
• Absolute Bands  <1,500
• UA <10 WBCs/hpf
• Stool <5 WBCs/hpf

2) Lab-Score

Infants 90 days or younger with objective temp >38C at home or in ED and with fever without source were assigned 0-9 points based on the following criteria.  A score of 3 or higher was found to have moderate sensitivity and specificity for invasive bacterial infections (sensitivity ranging from 86% to 94% and a specificity from 78% to 83%).

• CRP >= 40mg/L but <100mg/L +2 points
• CRP >= 100mg/L +4 points
• PCT >0.5ng/ml but <2.0ng/ml +2 points
• PCT >2.0ng/ml +4 points
  UA + Leukesteras or Nitrites +1 point

Outcome (primary):

Detection of an invasive bacterial infection (IBI) defined by having a positive blood culture or positive CSF or non-IBI defined as infant with positive stool or urine cultures but without positive blood or CSF cultures.

Primary Results

• 2635 infants 90 days or younger with a Fever without source
  • 177 (6.7%) visits the study was either not offered or the parents refused
  • 273 (10%) visits lacked the appropriate data
• 2185 (83%) infants were enrolled in the study
  • 504 (23.1%) were diagnosed with bacterial infection
    • 87 (3.9%) invasive bacterial infection
    • 417 (19.1%) non invasive bacterial infection
• 6 of the 7 IBIs missed by the “Step-by-Step” approach had fevers for <2 hours and 3, fever was not the primary complaint but instead first noticed in the ED

Strengths:

• Well conducted multicenter prospective study

Limitations:

• Absolute bands, a metric in the Rochester criteria, was not available in all patients
• The rule includes subjective criteria, “Abnormal pediatric assessment triangle” & “Ill-appearing” without inter-rater reliability comparison
• The availability of procalcitonin is not currently universal, limiting the applicability of the study
• Data collected in 11 European Pediatric Emergency Departments therefore the use in other patient populations or settings other then dedicated pediatric EDs should be cautioned.
• Prevalence of SBI was similar to previous European studies but higher then those reported in US studies, specifically the rate of UTIs
• The “Step-by-Step” approach was not compared to the Philadelphia criteria, the most used criteria in the US (20% of practioners) due to the need to LP all infants under 60 days
• Rochester study was designed to screen infants younger then 60 days (not 90)

Author’s Conclusions:
“ We validated the Step by Step as a valuable tool for the management of infants with fever without source in the emergency department and confirmed its superior accuracy in identifying patients at low risk of IBI, compared with the Rochester criteria and the Lab-score.”

Our Conclusions:
The febrile infant can be a diagnostic/management challenge for the emergency medicine physician.  The “Step-by-Step” approach to identifying infants at risk for potentially life threatening invasive bacterial infections has a 92.0% & 99.3% sensitivity and negative predictive value making it a reliable clinical decision instrument which avoids invasive studies such as lumbar punctures.  The study found that its sensitive is primarily limited by onset of fever, specifically fevers starting <2 hours from presentation.  When factoring this into detecting infants at risk for IBIs a sensitivity of 99.9% can be achieved.

Clinical Bottom Line  & Potential Impact to Current Practice:

The Step-by-Step approach to assessing febrile infants has excellent sensitivity and NPV but should be used with caution in infants presenting within 2 hours of onset of fever and in infants 21-28 days of age.

Guest Post By:

Kevin Carey, MD
PGY4 Resident EM
NYU/Bellvue Hospital

For More on this Topic Checkout:

• Ken Milne at The SGEM: SGEM # 171: Step-by-Step Approach to the Febrile Infant

References:

1. Gomez B et al. Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants. Pediatrics 2016; 138(2). [Epub Ahead of Print]. PMID: 27382134

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)