SGEM#171: Step-by-Step Approach to the Febrile Infant

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Date: February 27th, 2017

Reference: Gomez et al. Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants. Pediatrics 2016.

Guest Skeptic: Dr. Anthony Crocco is a Pediatric Emergency Physician and is the Medical Director & Division Head of the Division of Pediatric Emergency at McMaster’s Children’s Hospital. He is also the creator of SketchyEBM.

Case: A 25-day-old girl presents with fever. There is no history of congestion, cough, vomiting, diarrhea, shortness of breath or any other focus for her infection. She looks well on exam and her vitals are normal except for a rectal temperature of 38.3C. She is less than 28 days old and you wonder how much of a work up to do (full septic workup, intravenous antibioticsadmission to hospital, blood and urine tests)?

Background: Fever without source in infants less than three months old represents a significant diagnostic dilemma for clinicians. Several criteria had been developed previously, including the Rochester (Jaskiewicz et al 1994), Boston (Baskin et al 1992) and Philadelphia (Baker et al 1993) criteria to help clinicians stratify the risk of significant bacterial infections.

These criteria, however, are out-dated in our current era of vaccinations, but to date, have represented our best option. A new algorithm has been developed by a European group of pediatric emergency physicians called the “Step-by-Step” approach.

Mintegi et al did a retrospective study of this “Step-by-Step” approach in 2014. They concluded: A sequential approach to young febrile infants based on clinical and laboratory parameters, including procalcitonin, identifies better patients more suitable for outpatient management. (EMJ 2014).

Clinical Question: In infants 90 days or younger of age with fever without focus, how does the “Step-by-Step” approach compare to using the Rochester criteria or using the “Lab-score” method in identifying patients at low risk of invasive bacterial infections (IBI)?

Reference: Gomez et al. Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants. Pediatrics 2016.

Population: Infants 90 days old or younger with fever without source (FWS)
- FWS was defined as a temperature measured at home or at the Pediatric Emergency Department ≥38°C, in patients with a normal physical examination and no respiratory signs/symptoms or a diarrheal process.
- Excluded if clear source of fever identified after history and physical examination, no fever on arrival and fever that had only been subjectively assessed by parents, absence of one or more of the mandatory ancillary tests, and refusal of the caregivers or parents to participate.
Intervention: Use of the “Step-by-Step” approach
Comparison: Use of the Rochester criteria and the “Lab-score” method
Outcome: Performance metrics to identify patients at low risk of invasive bacterial infection (defined as positive blood culture or CSF culture). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood (LR+) and negative likelihood ratio (LR-).

Author’s Conclusions: “The Step-by-Step approach revealed a high sensitivity, being more accurate than the Rochester criteria and the Lab-score at identifying children at low risk of IBI, and appears to be a useful tool for the management of the febrile infant in the ED. However, as no perfect tool exists, the Step by Step is not 100% sensitive and physicians should use caution especially when assessing infants with very short fever evolution. For this subgroup of patients, we strongly advise for an initial period of close observation and monitoring in the ED, even when all the complementary test values are normal”.

Quality Checklist for Clinical Decision Rules (Tools):

The study population included or focused on those in the emergency department: Yes. This was a multi-center study that recruited patients from eleven Pediatric Emergency Departments.
The patients were representative of those with the problem: Yes
All important predictor variables and outcomes were explicitly specified: Yes
This is a prospective, multicenter study including a broad spectrum of patients and clinicians (level II): No. All centers were Pediatric Emergency Departments and thus generalizability to the care given at non-Pediatric Emergency Department centers must be cautioned.
Clinicians interpret individual predictor variables and score the clinical decision rule reliably and accurately: Unsure. Although most of the clinical decision instruments involve objective laboratory data, two criteria “abnormal pediatric assessment triangle” and “ill appearing” are both subjective assessments. There was no discussion around the inter-rater reliability of these two metrics.
This is an impact analysis of a previously validated CDR (level I): No
For Level I studies, impact on clinician behavior and patient-centric outcomes is reported: Yes
The follow-up was sufficiently long and complete. Yes. There was a follow-up at one month post-presentation to ensure data capture.
The effect was large enough and precise enough to be clinically significant: Yes

Key Results: There were 2,185 patients included in the study with 87 (4%) being diagnosed with an invasive bacterial infection. The median age was 47 days with 60% being male.

The Step-by-Step approach had the lowest prevalence of significant bacterial infections in their “low risk” group: 1.1% (95%CI 0.5-1.8) compared with the Rochester criteria 2.1% (95%CI 1.2-3.0) and the Lab-score 10.8% (95%CI 9.4-12.3).

In terms of identifying invasive bacterial infection, defined as a positive blood culture or CSF culture, the Step-by-Step approach had better diagnostic metrics compared to the Rochester criteria and Lab-score (see above).

Overall this is a well-conducted prospective multi-center study. The Step-by-Step approach to fever without source in infants 90 days or younger is better than the Rochester criteria and Lab-score.

External Validity: This study was conducted in eight Spanish, two Italian and one Swiss pediatric emergency departments. Thus, we must be cautions when extrapolating the results to our own work environments.
Most Important Metric: The Lab score did outperform the Rochester criteria and the “Step-by-Step” approach in terms of specificity, positive predictive value (PPV) and positive Likelihood Ratio (LR). However, with a clinical decision instrument for infants with fever without focus, our primary interest is in ensuring that we not sending home infants with significant bacterial infections, invasive or non-invasive. The metrics that are most important include sensitivity, negative predictive value (NPV) and negative Likelihood Ratio. The Lab-score method did very poorly with these metrics, and as such is not a contender for a clinical decision instrument in this circumstance. The Rochester criteria had better sensitivity, NPV and negative LR but the best results were seen with the Step-by-Step approach (Sensitivity 92%, NPV 99.3% and negative LR 0.17).
Subjective Criteria: Most of the criteria used in the Step-by-Step approach were objective (age, leukocyturia, procalcitonin, CRP and ANC). However, there were some subjective criteria. A well appearing infant was defined by a normal Pediatric Assessment Triangle (PAT). The PAT has some subjective components. Additionally, not all of the participating sites systematically used the PAT and documentation in the medical record was used to determine if the infant was well-appearing.
Procalcitonin: The one major limitation with application of this research is availability of timely procalcitonin measurement. This test is not currently universally available in a clinically relevant time-frame, an essential component of the Step-by-Step approach.
Age and Duration of Fever: This is something the authors comment on in their paper. The Step-by-Step approach uses 21 days and younger as a cut-off for being high risk. However, of the seven patients that were missed by the Step-by-Step approach, four were between the ages of 22 and 28 days. This makes us very worried about all infants less than 28 days not just 21 days. Secondly, six of the seven patients missed by the Step-by-Step approach had fevers lasting less than two hours suggesting the biomarkers may not have had time to rise and flag the child as high risk. We worry about children presenting really early in their illness and whether they need a period of observation in the emergency department or very strict follow-up.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusion.

SGEM Bottom Line: If you have availability of serum procalcitonin measurement in a clinically-relevant time frame, the Step-by-Step approach to fever without source in infants 90 days old or younger is better than using the Rochester criteria or Lab-score methods. With the caveat that you should be careful with infants between 22-28 days old or those who present within two hours of fever onset.

Case Resolution: In this case, since procalcitonin was not available and the child was less than 28 days old, the clinician did a full septic workup, started intravenous antibiotics and admitted the child to pediatrics. The infant was sent home two days later when the blood, urine and CSF cultures came back negative. You set up a meeting with laboratory services at your hospital to discuss getting procalcitonin testing.

Clinically Application: For infants 90 days old or younger in an environment where procalcitonin testing is available, the Step-by-Step approach to fever without source is currently the best clinical decision instrument. We also suggest caution with infants between 22-28 days old and those with fever less than two hours.

What Do I Tell My Patient? Depending on availability of procalcitonin, we are going to use either the Rochester criteria or the Step-by-Step approach to help us decide if your child is at high risk of a invasive bacterial infection.

Keener Contest: Last weeks’ winner was super star nurse Brenda Palsa from South Huron Hospital in Exeter, Ontario. She knew that malaria was the number one cause of death among labourers constructing the Rideau Canal in Ottawa.

Listen to the podcast for this weeks’ question. If you know the answer then send it to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed: Don’t Forget the Bubbles – A New Approach to Febrile Infants