In this study, it was confirmed that WBC and CRP, as well as PCT, are useful in assessing the risk of SBI in infants aged 3 months or less who visit the emergency room due to fever. To date, the Rochester, Philadelphia, and Boston criteria are frequently referenced to evaluate the risk of bacterial infection in infants under 3 months of age with fever(6-9). In all of these criteria, WBC and urinalysis are common evaluation criteria along with blood tests, chest x-ray, CSF, stool tests, etc. that are selectively used. In the pediatric emergency room unit of this research hospital, these criteria had been modified to determine the disposition of infants less than 3 months of age with fever (Figure 1). This study is meaningful in that it evaluated the usefulness of PCT, which was not included in the classic three criteria or the research hospital protocol, and confirmed that PCT is useful for predicting SBI with or without conventional laboratory tests in children less than 3 months old with fever.
Specifically, in this study, there were few SBIs except UTIs among patients enrolled over a period of 18 months. The first reason for this is Korea's high medical accessibility. Korea, especially Seoul, has excellent medical accessibility as the hospital density reaches 30 times that of the United States.(14) In fact, the duration of fever in patients included in this study was 3 hours (interquartile range, IQR 1.5–9.0 hours). In a similar study published by Ruud G. Nijman et al., SBIs were reported to affect 16% of the infants, but the median fever period was 2 days before presentation (IQR 1–4 days) (15). It is believed that when the time from fever onset to treatment is shortened it can prevent the actual transition to SBI. One more thing to consider is that CRP and PCT do not detect SBI well at the very beginning, so their sensitivity and negative predictive value may decrease (16, 17). This study showed sufficient diagnostic accuracy to discriminate SBI even in patients who visited the hospital after the median value of 3 hours, so it could be confirmed that CRP and PCT are useful in predicting SBI even in areas with high medical accessibility.
The second reason for the small number of SBIs is Korea's extensive national vaccination program. A recent study reported the prevalence and disease entities causing SBI in infants can change in response to the promotion of immunization (18). In Korea, the 13-valent pneumococcal conjugate vaccine (PCV13) has been designated as a mandatory national vaccination since 2014 and Haemophilus influenzae type b (Hib) since 2013, maintaining a vaccination rate of over 97% (19). Their use is thought to have helped prevent lower respiratory tract infections, which are a significant cause of SBI (20-22). In addition, bacillus Calmette–Guérin (BCG) vaccination is also an essential national vaccination, and the transdermal or intradermal vaccination rate is maintained over 98% (19). This might induce an immune response that improves innate immunity and decreases susceptibility to invasive non-TB infection (23, 24).
There were more boys in the SBI group that participated in this study. This is thought to be because most of the SBIs were UTIs, and among infants, males are more susceptible to UTIs (25). However, sex was not statistically significant in multivariate logistic regression analysis in predicting SBI.
In some recent studies, the cutoff value of PCT was set to 0.3 ng/mL by reflecting the study subjects' Youden's index, but in most studies, 0.5 ng/mL was set as the cutoff value when confirming the association between PCT and SBI(13, 26, 27). The reason that the cutoff value of PCT was set to 0.3 ng/mL in this study is that the value showed the highest Youden's index in the ROC curve and the most similar sensitivity/specificity to the existing classification criteria, CRP ≥2.0 mg/dL (CRP ≥2.0 mg/dL, 49.2/89.8; PCT ≥0.3 ng/mL, 54.1/87.5). As the PCT cutoff value increased, the specificity improved, but the sensitivity decreased and the overall accuracy tended to decrease (PCT ≥0.4 ng/mL, 39.3/90.6; PCT ≥0.5 ng/mL, 37.7/92.6). For this reason, in this study, the cutoff of PCT was set to 0.3 ng/mL.
The limitations of this study are that the total number of enrolled patients was as small as 317 and that it was a retrospective study. Also, most of the patients had UTIs. Given the relatively small prevalence of bacteremia, bacterial central nerve system (CNS) infections and bacterial pneumonia, it is necessary to include a wider variety of disease entities through larger studies. In addition, it is necessary to conduct a prospective study that actually classifies patients using the new classification system based on the research results to predict the risk of SBI. Good criteria to more effectively classify patients aged less than 3 months with fever, which consume a lot of medical care, need to be established.
In conclusion, PCT is useful for predicting SBI in children aged 3 months or less who visit the emergency room with a fever, and it is helpful to improve the diagnostic accuracy even when combined with WBC and CRP.