In this study, it was confirmed that PCT, as well as WBC and CRP, which are classic biomarkers, 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 have 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 is not included in the classic three criteria or the research hospital protocol, and it confirmed that PCT is useful for predicting SBI with or without the addition of conventional laboratory tests in children less than 3 months old with fever.
In this study, there were few SBIs except UTIs among patients enrolled over a period of 18 months. The epidemiology of bacterial infection in infants is changing worldwide. In particular, invasive bacterial infections are decreasing and the rate of UTIs is increasing [17, 18]. In the most recent study, the majority of SBIs were identified as UTIs . It was also confirmed that more than 30% of invasive bacterial infections were accompanied by a UTI . Although this study was conducted on a patient group, the majority of which had a UTI, since it did not deviate from the global trend, this might not introduce any bias in interpreting the results, but an accurate analysis is needed through the application of additional large-scale studies.
However, caution is needed in the interpretation of the results since the urine collection method used in this study applied a urine collection bag instead of suprapubic aspiration or transurethral catheterization. In the most recent studies, it has been confirmed that a urine collection bag is primarily used in the pediatric ED to reduce patient pain and complications associated with the collection procedure . In this study, in order to minimize contamination that may occur during urine collection using a collection bag, 2% chlorhexidine was used to sterilize the urethral opening three times or more by drawing a concentric circle, and after it had completely dried, the collection bag was attached. During the sterilization, traction of prepuce was performed for boys, and for girls, the wrinkles of the labium were spread. When urinating with feces passage, it was regarded as contaminated, so it was collected again. If even a little urine leaked out, it was considered exposed to external contamination and collected again. Only specimens identified above 100,000/CFU with a single organism in the urine culture were reported as positive. Although a UTI was defined only based on the bacterial culture results, there were no UTI patients without pyuria. Although being aware of the limitations of the urine collection bag method, it was chosen in order to avoid performing an invasive procedure, and all of the UTIs were accompanied by pyuria, minimizing false positives. In order to interpret the results accurately in additional research, it is necessary to actively use transurethral catheterization or suprapubic aspiration .
In this study, when PCT was applied together with WBC and CRP, the sensitivity, PPV, and NPV increased from 67.2, 29.3, and 88.7 to 80.3, 30.1, and 92.2, respectively. This may not seem very dramatic, and it may be interpreted as not being cost-effective as it increases unnecessary hospitalization. However, several studies in adults have already reported that the use of PCT is rather cost-effective to predict SBI [23-25]. Bacterial infection in infants can have serious consequences if adequate treatment is not provided. Nathan et al. prioritized the sensitivity of the prediction rule by specifying a relative cost of 100 to 1 for failure to identify an SBI vs incorrectly predicting an SBI . According to Carrie et al., although more hospitalization, lumbar puncture, and antibiotic treatment were performed while completing more diagnostic tests using augmented criteria, advanced viral PCR technology and changes in discharge criteria resulted in a reduced overall cost and length of stay, and a reduction in the unnecessary antibiotics duration . Therefore, it might be better to use PCT as a biomarker to minimize misclassification and to find a desirable combination of biomarkers and cutoff values through prospective research to reduce the total cost.
The median (IQR) fever duration of the patients in this study was 3 (1.5-9.0) hours, which was shorter than that of a similar study [27, 28]. According to previous studies, CRP and PCT do not detect SBI well at the very beginning of the infection, so their sensitivity and negative predictive value may decrease [29, 30]. This study showed sufficient diagnostic accuracy to discriminate SBI even in patients who visited the hospital after a median duration of 3 hours, so it could be confirmed that CRP and PCT are useful in predicting SBI even in areas with high medical accessibility. This result may act as a bias for applications with a longer fever duration. However, considering that the peak level of each biomarker is maintained for more than 24 hours, it will not act as a serious bias. In fact, Karen et al. and Olaciregui et al., and Borja et al. also reported the effectiveness of PCT regardless of fever onset increased. [10, 13, 31]. Therefore, even in cases with a longer febrile illness duration than in this study, it is considered that there might be no major bias in applying our results.
There were more boys in the SBI group in this study. This is thought to be because most of the SBIs were UTIs, and among infants, males are more susceptible to UTIs . However, sex was not statistically significant in multivariate logistic regression analysis in predicting an SBI.
The limitations of this study are that the total number of enrolled patients was only 317 and that it was a retrospective study. Also, most of the patients had UTIs. Given the relatively low 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 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.