When infants exhibiting fever and no clear source of infection visit the Emergency Department (ED) or outpatient department (OPD), doctors must diagnose serious bacterial infection (SBI) as soon as possible and determine appropriate next steps. Infants younger than 3 months have the highest risk of SBI such as bacterial meningitis, bacteremia, and urinary tract infection (UTI). Infants between 1 and 3 months of age presenting with fever for unknown reasons are reported to have SBI rates of up to 9% [1-5]. In many studies, the procalcitonin (PCT) test is reported to be superior to other tests in predicting SBI in children [4,6-12]. However, some reports indicate that it is no different from other tests [13-17].

In this study, we investigated if the PCT test is superior to testing for other biomarkers in predicting SBI in febrile infants with no clear source of infection. In addition, we investigated if the PCT test could better predict SBI when combined with tests for other biomarkers. We focused on infants between 1 and 3 months of age and reviewed their medical records for our assessments.

We analyzed the medical record of 336 febrile infants between 1 and 3 months of age with no clear source of infection. Of the 336 febrile infants, 212 (63.1%) were male. Mean age at diagnosis was 59.5±24.5 days, gestational age was 38.8±1.3 weeks, and birth weight was 3,200±431 g. Type of delivery of SBI group did not differ from that of non-SBI group (cesarean section 50.5% vs. vaginal delivery 49.5%, P=0.659). However, the maximal body temperature of SBI group (39.0℃±0.5℃) was higher than that of non-SBI (38.6℃±0.5℃, P<0.05). Ninety-five infants (28.3%) visited the hospital OPD and 241 (71.7%) visited the ER. Three hundred eight infants (91.7%) were admitted. The mean length of stay was 5.7±2.6 days. The onset of fever until arrival at the hospital was clearly noted in 191 patients. Of 191 patients, the mean duration of fever at home was 6.3±6.8 hours. Among the 336 cases, 38 (11.3%) were classified as definitive SBI. Of the 38 SBI patients, 3 patients were UTI sepsis caused by Escherichia coli, 1 patient was meningitis caused by Streptococcus agalactiae, and 34 patients were UTI (Table 1). Of the 34 patients of UTI, E. coli was the most commonly found pathogen, appearing in 33 cases; S. agalactiae was found in 1 case. There were no cases of definitive SBI with complication.

Mean laboratory values in SBI patients were PCT 6.4±11.9 ng/mL, CRP 3.8±2.6 mg/dL, WBC 12,882±6,568/μL, ANC 6,984±4,675/μL, and PLT 382.5±102.1×10³/μL. In comparison, the mean values in the non-SBI group were PCT 0.3±1.2 ng/mL, CRP 1.3±1.6 mg/dL, WBC 11,591±5,299/μL, ANC 4,888±3,661/μL, and PLT 397.5±121.1×10³/μL. There were significant differences in PCT, CRP, and ANC between SBI and non-SBI groups (P<0.001) (Table 2).

The sensitivity of the SBI group was PCT 43.6%, CRP 92.3%, WBC 15.4%, ANC 97.4%, and PLT 51.3%. As well, the specificity of the SBI group was PCT 92.6%, CRP 25.3%, WBC 91.9%, ANC 5.1%, and PLT 52.2%.

However, the accuracy of the SBI group was 86.9% for PCT followed by 83.0% for WBC. If combined the biomarkers, PCT+WBC was revealed as the highest specificity and accuracy (98.3% and 88.1%), followed by PCT+CRP (93.6% and 87.2%) and PCT+ANC (92.9% and 86.9%, Table 3).

Predicted AUCs on receiver operating characteristic (ROC) curve were 77.0% for PCT and 80.8% for CRP, indicating that PCT and CRP were not different. The AUCs for biomarker combinations were 85.4% for PCT+CRP, 77.2% for PCT+WBC, 81.3% for PCT+ANC, 80.1% for CRP+WBC, and 81.6% for CRP+ANC. The highest AUC was confirmed as combination with PCT and CRP whether single biomarker or two combined biomarkers (Fig. 1). The cutoff values on our ROC curve were confirmed as PCT 0.5 ng/mL, CRP 0.49 mg/dL, WBC 19,500/μL, ANC 1,300/μL, and PLT 400.5×10³/μL.

The probability of SBI without an apparent source is reported to be up to 12% for infants less than 28 days old and up to 9% for infants between 1 and 3 months of age [4]. Decades of research and debate have been dedicated not only to determining the likelihood of SBI causing fever in infant, but also to establishing treatment guidelines for such instances. Clinical examination alone is not sufficient to exclude SBI as a diagnosis. The Philadelphia and Rochester Criteria in combination with laboratory screening test results are used to assess SBI in patients. Sensitivity is reported to be 98% for the Philadelphia Criteria and 92% for the Rochester; reported NPVs are 97.1% and 97.3%, respectively [20,21]. However, because accurately determining SBI in febrile infants is difficult, testing for several clinical biomarkers is used in conjunction with routine laboratory evaluation and clinical suspicion. The additional biomarker tests include those of peripheral WBC count, ANC, and CRP, which have sensitivities ranging from 45 to 79% and specificities ranging from 78% to 79% [4].

In 1993, Assicot et al. (quoted from [22]) reported that patients with SBI had high serum concentration of PCT, a calcitonin peptide without hormonal function. During infection or inflammation, plasma PCT concentration is known to both increases and return to normal more rapidly than CRP level [23]. PCT level was also observed to increase faster than CRP level 6 hours after the onset of severe inflammatory response syndrome [24]. For these reasons, the PCT test is considered a useful tool in early diagnosis of infection or inflammations. Other studies have investigated whether PCT is a useful biomarker to distinguish between viral infection and SBI. PCT was found to distinguish between bacterial and viral meningitis [8,25,26] and to identify SBI in infants more accurately than classic screening tests [6]. However, one report noted that PCT level might not be reliable in diagnosing bacterial meningitis after neurosurgery [16]. Another report found that serum PCT concentration is not a good indicator of bacterial ventriculoperitoneal shunt infection [17]. In pediatric patients visiting emergency departments or primary care, PCT testing was found to be superior to measuring WBC count, but similar to measuring CRP [15].

Several Korean studies have focused on PCT. Hur et al. [27] performed the PCT and CRP simultaneously on single blood samples from 1,270 patients with blood culture-positive sepsis. They reported that the diagnostic utility of the PCT was superior to evaluation of CRP level. However, in diagnosing neonatal bacterial infection, the PCT was found to be more expensive, with comparably acceptable specificity and similar or better sensitivity than the CPR [28]. Serum PCT level has been reported as a highly effective early diagnostic marker for neonatal bacterial infection, but is not as reliable a marker as CRP [29,30]. Kim et al. [31] reported that there is no diagnostic value in measuring serum PCT concentration determine bacterial infection in febrile infants 6 months of age or younger. Yang et al. [32] reported similar sensitivities and specificities for serum CRP and serum PCT in diagnosing acute pyelonephritis (APN) in infants 12 months of age or younger. However, the sensitivity and specificity for APN diagnosis increased when PCT was combined with CRP and erythrocyte sedimentation rate.

In this study, sex and age at diagnosis in SBI group differed from those of non-SBI group because of large percentage of UTI or UTI sepsis in SBI group. Of 38 SBI patients, 34 had UTI and 3 had UTI sepsis. 76.5% of UTI group and 66.6% of bacteremia were 61–90 days old infants. Also, UTI were frequently diagnosed in male in infants.

This study had some limitations. First, we could not represent the entire infant population in Korea when assessing SBI, because this study was conducted using medical records from a single hospital. Second, determining the severity of SBI was difficult because few were found to have sepsis and meningitis among the definitive SBI patients. Third, we collected urine using urine bags rather than catheterization, increasing the likelihood of contamination.

Even with these limitations, our study offers a significant comparative analysis of biomarkers that can predict SBI in infants between 1 and 3 months of age who are vulnerable to infection and who visit the pediatric ED with fever.

In conclusion, PCT was shown as lower sensitivity than CRP, but higher specificity and accuracy than CRP for identifying SBI in febrile infants between 1 and 3 months of age. A combination of PCT and CRP showed the highest AUC than the other combination of biomarkers. Therefore, we suggested the predictor of SBIs for PCT or combination of PCT and CRP which were more accurate and specific biomarker to rule out the SBI.