Evaluation of the Febrile Infant

August 2019



You are moonlighting in your local, community ED when the parents of a 26-dayold
female infant bring their daughter in for evaluation of fever. The child felt
warm to the touch this morning and her mother checked a rectal temperature,
which was 100 degrees F. Later that day, they checked temperature again and it
was 101. The child has still been breastfeeding well, nursing for 30 to 45 minutes
every 2 to 3 hours.

She was born via spontaneous vaginal delivery at 38 weeks EGA with no known
complications. The mother believes her GBS was negative. The patient was
discharged home with mom and has been doing well until today. No siblings in
the house.

On exam, the infant is well-appearing with no focus of infection on exam. You
discuss with the parents that you want to proceed with urine, blood, and CSF
testing, given the baby’s young age. Both parents are concerned about the
lumbar puncture and wonder if you can limit your work up to blood and urine
studies. You wonder if there are any clinical decision rules or strategies,
including procalcitonin, that could help you determine the patient’s risk of a
serious bacterial infection, and to help determine whether or not the LP is
absolutely necessary. You begin to research the literature to see what evidence
there is…

PICO Question

Population: Infants < 60 days of age presenting to the emergency department
with a fever of 38℃ or higher without a clear source of infection.

Intervention: Procalcitonin testing and use of clinical decision rules

Comparison: Standard of care

Outcome: Incidence of serious bacterial infection (SBI) or invasive bacterial
infection (IBI)

Search Strategy

Attending pediatric emergency physicians from St. Louis Children’s Hospital selected the most relevant articles from the recent literature.  No formal search strategy was employed.


Article 1: England JT, Del Vecchio MT, Aronoff SC.  Use of serum procalcitonin in evaluation of febrile infants:  a meta-analysis of 2317 patients.  J Emerg Med. 2014 Dec;47(6):682-8
Answer Key

Article 2:  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 Jan;170(1):62-9

Article 3:  Gomez B, Mintegi S. Bressan S. Da Dalt L, Gervaix A, Lacroix L; European Group for Validation of the Step-by-Step Approach.  Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants.  Pediatrics.  2016 Aug;138(2).

Article 4: Kupperman N, Dayan PS, Levine DA, et al: Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN) A Clinical Prediction Rule to Identify Febrile Infants 60 Days and Younger at Low Risk for Serious Bacterial Infections.  JAMA Pediatr.  2019  Apr 1;173(4):342-351

Bottom Line

Procalcitonin (PCT) has been proposed as a marker of bacterial infection in
many settings, including in the differentiation of viral upper respiratory infection
from pneumonia and the differentiation of sepsis from noninfectious systemic
inflammatory response. While its use has remained controversial, this
association with bacterial infection has since led investigators to study its utility in
the evaluation of the febrile neonate. One particular practical clinical implication
would be in whether PCT could be used to safely determine which febrile
neonates do not need to have LP’s done, but could also be extended to those
that do not need to be admitted to the hospital for IV antibiotics.

Several studies have looked at the association between elevated PCT and the
presence of a serious bacterial infection in febrile neonates. A meta-analysis of
such studies (England 2014) demonstrated a statistically significant association
between elevated PCT and the diagnosis of a serious bacterial infection (SBI),
with a relative risk of 3.97 (95% CI 3.41 to 4.62). While thought-provoking, the
associated likelihood ratios (LR+ = 2.83, LR- = 0.54) suggest that PCT alone
should not be used to differentiate SBI from non-bacterial illness in this
population. This does, however, suggest that its use in conjunction with other
clinical and laboratory findings may be useful.

A subsequent study (Milcent 2016) found that PCT performed better than creactive
protein (CRP), absolute neutrophil count (ANC), and the white blood cell
count (WBC) at diagnosing SBI and invasive bacterial infection (IBI), with much
better negative likelihood ratios than found in the meta-analysis (0.3, 95% CI 0.2
to 0.5; and 0.1, 95% CI 0.03 to 0.4 for these entities, respectively).

Given that PCT alone is insufficient to safely rule out an SBI or IBI in a febrile
neonate, others have attempted to find a place for PCT as part of a clinical
decision rule to increase our diagnostic accuracy in the evaluation of the febrile
neonate, using other clinical and laboratory findings to aid in diagnosis. The
“Step by Step” approach (Mintegi 2014) is an algorithm that involves clinical assessment, age, presence of leukocyturia, PCT level, CRP, and ANC to
evaluate for the risk of an IBI. This approach was found to have a LR+ of 1.73
(95% CI 1.61-1.85) and LR- of 0.17 (0.08-0.35) when validated prospectively in
11 pediatric emergency departments in Europe (Gomez 2016). Given this
negative LR, this approach appears to be useful in ruling out an IBI, particularly
among low and moderate-risk infants presenting with fever.

Another clinical decision rule was recently derived and validated using a
prospective cohort enrolled in the PECARN network (Kupperman 2019). The
rule, as derived, included a negative urinalysis, ANC of 4000/μL or lower, and a
serum PCT 0.5 ng/mL or lower. If all conditions were met, the rule missed only
1.2% of cases of SBI in the derivation cohort and 2.3% in the validation cohort.
The corresponding negative likelihood ratios were 0.02 (95% CI 0.003-0.14) and
0.04 (95% CI 0.01-0.15), suggesting that this rule could result in a significant
reduction in the probability of an SBI when negative. Unfortunately, the derivation
and validation cohorts in this study were nearly identical and did not involve
febrile infants cared for in the community setting by non-pediatric emergency
physicians. It will need further validation in other settings and patient populations
prior to widespread use.

The evaluation of the febrile infant remains difficult. Despite significant reductions
in the risk of SBI and IBI with improved vaccination (Koshy 2010, Whitney 2003,
Balmer 2002), there remains a high risk of morbidity and mortality in this patient
population. The promise of a new test (PCT) to help evaluate these patients has
led to much research; despite its clear association with bacterial illness in febrile
neonates, PCT seems most likely to be useful as part of an algorithmic approach
or clinical decision rule. The PECARN rule seems promising, and further
validation will hopefully lead to further reductions in hospital admission and
lumbar puncture in febrile neonates.