children

Article
Usefulness of Procalcitonin in the Diagnosis of Bacterial
Infection in Immunocompetent Children
Hae Na Park 1 , Su Yeong Kim 1 , Na Mi Lee 1 , Dae Yong Yi 1 , Sin Weon Yun 1 , Soo Ahn Chae 1 , In Seok Lim 1 ,
Yong Kwan Lim 2 and Ji Young Park 1, *

1 Department of Pediatrics, Chung-Ang University Hospital, Seoul 06973, Korea

2 Department of Laboratory Medicine, Chung-Ang University Hospital, Seoul 06973, Korea
* Correspondence: jypark@caumc.or.kr

Abstract: Bacterial infections (BIs) need to be differentiated from non-BIs (NBIs) to enable prompt
administration of antibiotics. Therefore, inflammatory biomarkers are needed as they can accu-
rately identify BIs. This study evaluated the usefulness of procalcitonin (PCT) in the diagnosis
of BI in immunocompetent children. We retrospectively reviewed the medical records of pa-
tients <18 years who underwent PCT measurements between July 2012 and June 2019. In total,
474 patients were enrolled and divided into the BI (n = 205) and NBI groups (n = 269). The BI
group was subcategorized into the invasive BI (IBI; n = 94), mucosal BI (MBI; n = 31), toxigenic
BI (TBI; n = 23), and localized BI (LBI; n = 57) subgroups. The NBI group was further subcatego-
rized into the viral infection (VI; n = 118) and inflammatory disease groups (ID; n = 151). PCT was
compared with the levels of C-reactive protein (CRP), white blood cell (WBC), and erythrocyte
sedimentation rate (ESR). Between the BI and NBI groups, PCT (4.2 ± 16.9 vs. 1.1 ± 2.5 ng/mL;
p = 0.008) and ESR (39.1 ± 32.4 vs. 54.8 ± 28.2 mm/h; p < 0.001) were significantly different. Be-
tween the IBI and other groups, WBC (14,797 ± 7148 vs. 12,622 ± 5770 × 106 /L; p = 0.007), ESR
(35.3 ± 30.3 vs. 51.5 ± 30.3 mm/h; p < 0.001), and PCT (8.1 ± 23.8 vs. 1.0 ± 3.4 ng/mL; p = 0.005)
Citation: Park, H.N.; Kim, S.Y.; Lee,
N.M.; Yi, D.Y.; Yun, S.W.; Chae, S.A.;
were significantly different. However, none of the biomarkers were useful in differentiating BI from
Lim, I.S.; Lim, Y.K.; Park, J.Y. NBI. While WBC (area under curve (AUC) = 0.615, p = 0.003) and PCT (AUC = 0.640, p < 0.001) were
Usefulness of Procalcitonin in the useful, they fared poorly in differentiating IBI from other groups. Thus, additional studies are needed
Diagnosis of Bacterial Infection in to identify more accurate biomarkers capable of differentiating BIs, especially IBIs.
Immunocompetent Children.
Children 2022, 9, 1263. https:// Keywords: bacterial infections; child; procalcitonin
doi.org/10.3390/children9081263

Academic Editor: Anna Nilsson

Received: 10 June 2022 1. Introduction

Accepted: 18 August 2022
In pediatric patients, viral infections (VIs) are the main causes of infectious diseases.
Published: 21 August 2022
However, because clinicians find it troublesome to differentiate bacterial infections (BIs)
Publisher’s Note: MDPI stays neutral from VIs with initial clinical presentations for many conditions, empirical antibiotic therapy
with regard to jurisdictional claims in is administered. To avoid unnecessary antibiotic use, diagnostic inflammatory markers
published maps and institutional affil- that can suggest the occurrences of BIs quickly and accurately have been a requirement [1].
iations. Administration of antibiotics 1 h after visiting the emergency department could lower
mortality [2]. Thus, in addition to the clinician’s alertness to the clinical presentations, an
adequate inflammatory marker that suggests possible BI is needed. Inflammatory markers,
including white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), or C-reactive
Copyright: © 2022 by the authors.
protein (CRP) have been extensively used.
Licensee MDPI, Basel, Switzerland.
Procalcitonin (PCT), a pro-peptide of calcitonin, is normally secreted from the C-cells
This article is an open access article
of the thyroid gland [3]. It is usually secreted at a low serum concentration (<0.1 ng/mL) in
distributed under the terms and
conditions of the Creative Commons
normal adults and children after the neonatal period. In severe BI cases, PCT could increase
Attribution (CC BY) license (https://
from 0.5 ng/mL to 200 ng/mL. PCT rarely exceeds 1 ng/mL in cases of VI [4]. The half-life
creativecommons.org/licenses/by/ time of PCT is approximately 24 h [5]. Although the mechanism behind the elevation
4.0/). of PCT levels during BI is yet to be identified, the most extensively accepted hypothesis

Children 2022, 9, 1263. https://doi.org/10.3390/children9081263 https://www.mdpi.com/journal/children

Children 2022, 9, 1263 2 of 8

states that PCT is secreted from hematopoietic cells, parenchyma of the lung, or the liver by
proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and tissue necrosis factor α post
BI [6]. In South Korea, studies regarding PCT were initiated in the late 1990s [7,8]. Over the
past decades, PCT has gradually been introduced in the clinical praxis as an inflammatory
marker to differentiate various types of BI [9], and has been used along with other markers.
Although early studies have shown the potential of PCT in differentiating various types of
BI, recent studies have reported that PCT has no significant benefit when compared with
CRP [10,11]. However, PCT had been recently studied again as an inflammatory marker to
rule out invasive BI (IBI) [12,13].
Therefore, this study aims to evaluate the usefulness of PCT in the diagnosis of BI in
children, especially IBI, by comparing it with other inflammatory markers.

2. Materials and Methods

2.1. Participants and Definition of Patient Groups
This retrospective analysis was conducted among immunocompetent patients under
the age of 18 years who underwent a PCT test in the outpatient department or emergency
department or as inpatients on the day of their admission to the Chung-Ang University
Hospital between July 2012 and June 2019. The age group was classified into infants
(<1 year, toddlers (1–2 years), preschoolers (3–5 years), middle childhood (6–11 years), and
teenagers (12–17 years). We classified patients into BI and non-BI (NBI) groups, and further
categorized the BI group into four subgroups: IBI, mucosal BI (MBI), toxigenic BI (TBI),
and localized BI (LBI) according to the etiologies with final diagnosis.
The IBI group comprised patients in whom bacteria were identified by culture studies
in blood, urine collected through aseptic catheterization or cystocentesis, and cerebrospinal
fluid (CSF) samples [14]. The MBI group included patients with acute otitis media, acute
sinusitis, and group A streptococcal pharyngotonsillitis. In the TBI group, patients with scar-
let fever, staphylococcal scaled skin syndrome (4S), toxic shock syndrome (TSS), rheumatic
fever, and acute generalized exanthematous pustulosis were included. In the LBI group, pa-
tients with skin and soft tissue infection, deep neck infection, mastoiditis, intra-abdominal
infection, and bacterial enteritis were included. The NBI group was further divided into VI
and inflammatory disease (ID) subgroups. The VI group included patients in whom viruses
were detected through respiratory specimens, CSF, or stool, based on the polymerase chain
reaction (PCR) or rapid antigen test. Patients with combined bacterial and viral etiologies
were excluded. The ID group included patients with autoimmune or non-infectious IDs.
Patients in the ID group with positive bacterial or viral studies were also excluded.
This study was approved by the Institutional Review Board of Chung-Ang University
Hospital (no. 2004-002-19308). The review board waived the need for informed consent.

2.2. Study Design

All patients with data pertaining to PCT, CRP, WBC count, and ESR were included. We
considered additional laboratory tests depending on the patient’s symptoms and physical
examination. If a patient had gastrointestinal symptoms, such as vomiting and diarrhea, we
performed a stool virus antigen/PCR test or conducted a culture study. Nasopharyngeal
swabs were collected from patients with respiratory symptoms, such as cough, sputum, or
rhinorrhea, which were further processed for the detection of respiratory viruses (aden-
ovirus, respiratory syncytial virus A/B, Influenza A/B virus, parainfluenza virus 1/2/3/4,
rhinovirus A/B/C, metapneumovirus, enterovirus, coronavirus 229E/NL63/OC43, and
bocavirus 1/2/3/4) via PCT test. If patients exhibited signs of meningeal irritation or if
infants under 90 days had fever, they were subjected to CSF analysis with culture study
and PCR tests for enterovirus/herpes virus. The final diagnosis was made based on the
laboratory results. The presence of a single bacterial pathogen in stool specimens indicated
bacterial enteritis and the presence of a single viral pathogen in stool specimens indicated
viral enteritis. Patients with WBC count ≥5 (based on high-power microscopy) and single
bacterial pathogen ≥105 colony/mL (based on cultures) were diagnosed with urinary tract
Children 2022, 9, 1263 3 of 8

infection (UTI) Cases with WBC count ≥5 (based on high-power microscopy) and single
bacterial pathogens ≥105 colony forming unit/mL (based on cultures) were defined as
urinary tract infection (UTI). The presence of bacterial pathogens in CSF culture indicated
bacterial meningitis, while the presence of viral pathogens in CSF specimens, detected
via PCR test, indicated viral meningitis. Pathogenic single bacterial infection identified
by blood culture studies from more than two blood samples was defined as bacteremia.
Scarlet fever, 4S, TSS, and acute generalized exanthematous pustulosis were diagnosed by
their characteristic features. Rheumatic fever was diagnosed using Jones criteria. Group
A streptococcal pharyngotonsillitis was diagnosed only if confirmed by a positive rapid
antigen detection test or culture study. In our institute, the reference cut-off value and the
measuring range for PCT were 0.5 ng/mL and 0.05–200 ng/mL, respectively.

2.3. Statistical Analysis

Statistical software programs SPSS (version 26.0, IBM, Armonk, NY, USA) and Med-
Calc 12, were used for statistical analysis. Categorical variables were compared using
Pearson’s chi-square test. Continuous variables were compared using Student’s t-test and
one-way analysis of variance. Continuous variables are presented as means ± standard
deviations. A receiver operating characteristic (ROC) curve analysis was performed to
obtain appropriate cut-off values, sensitivity, and specificity of inflammatory markers. ROC
curve comparisons were also performed for each model set by using Delong’s test for two
correlated ROC curves. Confidence intervals (CI) at 95% were verified and p values < 0.05
were considered statistically significant.

3. Results
3.1. Demographics and Diagnosis of Patients
During the 7-year study period, 24,691 immunocompetent children under 18 years
of age visited our medical center. Among them, 3203 children underwent PCT tests in
our emergency department (n = 350), outpatient clinic (n = 577), and hospitalized ward
(n = 2276). Overall, 1567 cases were revealed to be follow-up cases and were excluded.
Additionally, 193 neonatal intensive care unit cases were excluded. Moreover, 952 children
who did not undergo PCR tests were excluded due to unclarified etiologies. Furthermore,
17 cases were excluded because they were combined BI/VI cases or were IDs with VIs.
Finally, 474 patients were enrolled in this study. All demographic data are listed in Table 1.
In total, 197 patients were females (41.6%) with a mean age of 3.7 ± 4.0 years. Among the
462 admitted patients, the mean duration of hospitalization was 6.7 ± 7.1 days.

Table 1. Comparison of demographics between bacterial infection and non-bacterial infection groups.

BI, NBI
p
n = 205 (%) VI, n = 118 (%) ID, n = 151 (%)
114 (42.4) 0.679
Sex, female 83 (40.5)
49 (41.5) 65 (43.0) 0.889
3.4 ± 3.0 0.057
Age, years † 4.2 ± 5.0
2.9 ± 2.6 3.8 ± 3.2 0.027
5.3 ± 2.7 <0.001
Hospitalization days † 8.7 ± 10.1
5.1 ± 3.1 5.5 ± 2.4 <0.001
Abbreviations: BI; bacterial infection, NBI; nonbacterial infection, VI; viral infection, ID; inflammatory disease.
† Theses variables are presented as means ± standard deviations.

Two-hundred and five patients (43.2%) were classified into the BI group and 269
(56.8%) into the NBI group. The BI group was further subclassified into the IBI (n = 94;
45.9%), LBI (n = 57; 27.8%), MBI (n = 31; 15.1%), and TBI groups (n = 23; 11.2%). The NBI
group was subclassified into the ID (n = 151; 56.1%) and VI groups (n = 118; 43.9%). The
IBI group included patients with UTI (n = 73; 77.7%), bacteremia (n = 12; 12.8%), bone
Children 2022, 9, 1263 4 of 8

and joint infections (n = 5; 5.3%), and meningitis (n = 4; 4.3%). The MBI group included
patients with acute otitis media or sinusitis (n = 23; 74.2%) and group A streptococcus
pharyngotonsillitis (n = 8; 25.8%). The TBI group consisted of patients with scarlet fever
(n = 12; 52.2%), 4S (n = 7; 30.4%), and TSS (n = 2; 8.7%); one patient (4.4%) had rheumatic
fever and another had acute generalized exanthematous pustulosis. The LBI group included
patients with skin and soft tissue infections (n = 21; 36.2%), acute cervical lymphadenitis
(n = 14; 24.1%), intra-abdominal infection (n = 13; 22.4%), bacterial enteritis (n = 6; 10.3%),
deep-neck infections (n = 2; 3.5%), and mastoiditis (n = 2; 3.5%). In the ID group, Kawasaki
disease was the most common (n = 137; 90.7%), followed by Kikuchi–Fujimoto disease
(n = 8; 5.3%), juvenile rheumatoid arthritis (n = 5; 3.3%), and ulcerative colitis (n = 1; 0.7%).
The number of females in the BI and NBI groups was 83 (40.5%) and 114 (42.4%),
respectively, with no significant differences between the groups (p = 0.679). Between
the two groups, there was no significant difference in age (BI: 4.2 ± 5.0 years,
NBI: 3.4 ± 3.0 years; p = 0.057); however, a significantly longer hospitalization was ob-
served in the patients in the BI group (8.7 ± 10.1 days) than those in the NBI group
(5.3 ± 2.7 days; p < 0.001). There was no statistical sex-based difference among the BI, VI,
and ID groups (females in BI: 83 [40.5%], in VI: 49 [41.5%], in ID: 65 [43.0%]; p = 0.889);
however, significant differences were noted with respect to age (BI: 4.2 ± 5.0, VI: 2.9 ± 2.6,
ID: 3.8 ± 3.2 years; p = 0.027) and duration of hospitalization (BI: 8.7 ± 10.1, VI: 5.1 ± 3.1,
ID: 5.5 ± 2.4 days; p < 0.001). Upon comparison of the three groups, age differences
were observed between the BI and VI groups (p = 0.020). Additionally, differences in
the duration of hospitalization were observed between the BI and VI groups and the BI
and ID groups (all p < 0.001). (Table 1) When comparing the IBI group with the other
groups, sex-based differences were not observed (p = 0.342). However, the mean age was
lower (1.5 ± 3.3 vs. 4.3 ± 4.0 years; p < 0.001) and the mean duration of hospitalization was
higher in the IBI group (10.1 ± 11.0 vs. 5.8 ± 5.3 days; p = 0.001). A comparison among
the BI subgroups revealed no significant difference with respect to sex (p = 0.360). The
mean age and hospitalization duration were significantly different among the BI subgroups
(p < 0.001 and p = 0.033, respectively). Detailed comparisons among the BI subgroups
revealed that the mean age of patients in the IBI group (1.5 ± 3.3 years) was significantly
lower than that of patients in MBI (4.4 ± 4.5 years, p = 0.008), TBI (5.8 ± 3.9 years, p < 0.001),
and LBI groups (7.8 ± 5.5 years, p < 0.001). Patient age in the MBI and LBI groups was
also significantly different (p = 0.002). The mean duration of hospitalization was different
between the IBI and MBI groups (10.1 ± 11.0 vs. 3.8 ± 1.7 days, p = 0.026). The mean
duration of hospitalization was 6.6 ± 4.3 days in the TBI group and 7.8 ± 5.5 days in the
LBI group.

3.2. Analysis of Inflammatory Markers in Studied Groups

The mean value was 13,053 ± 6121 × 106 /L for WBC, 61.9 ± 64.4 mg/L for CRP,
48.1 ± 31.0 mm/h for ESR, and 2.4 ± 11.4 ng/mL for PCT. The mean values of inflamma-
tory biomarkers by groups and subgroups are listed in Table 2. Among the inflammatory
markers, there was a significant difference in PCT (BI: 4.2 ± 16.9, NBI: 1.1 ± 2.5 ng/mL;
p = 0.008) and ESR (BI: 39.1 ± 32.4, NBI: 54.8 ± 28.2 mm/h; p < 0.001) between the BI
and NBI groups. When comparing the differences in inflammatory markers among the
BI, VI, and ID groups, there were significant differences in WBC, CRP, ESR, and PCT
(p = 0.017, <0.001, <0.001, and 0.011, respectively). WBC values were significantly different
between the VI and ID groups (11,767 ± 6207 vs. 13,890 ± 5378 × 106 /L; p = 0.013). CRP
values were also significantly different in each group (BI: 61.4 ± 69.8, VI: 40.7 ± 51.5,
ID: 79.0 ± 61.1 mg/L; all p < 0.05). ESR values in the ID group (61.4 ± 28.0 mm/h) were
significantly different from that in the VI (38.3 ± 21.4 mm/h; p < 0.001) and BI groups
(39.1 ± 32.4 mm/h; p < 0.001). The PCT values in the BI group (4.2 ± 16.9 ng/mL) were
different from that in the VI (1.0 ± 3.3 ng/mL; p = 0.040) and ID groups (1.1 ± 1.7 ng/mL;
p = 0.026). When compared, the WBC count (14,797 ± 7148 vs. 12,622 ± 5770 × 106 /L;
p = 0.007) and PCT (8.1 ± 23.8 vs. 1.0 ± 3.4 ng/mL; p = 0.005) were found to be higher
Children 2022, 9, 1263 5 of 8

in the IBI group than in the other groups. Additionally, ESR was lower (35.3 ± 30.3
vs. 51.5 ± 30.3 mm/h; p < 0.001) in the IBI group than in the other groups, while CRP
in the IBI group was not significantly different from the other groups (69.3 ± 77.6 vs.
60.0 ± 60.6 mg/L; p = 0.207). When analyzing the inflammatory markers among the BI sub-
groups, there were significant differences in WBC count and PCT (p = 0.011 and p = 0.025,
respectively); however, CRP and ESR did not yield any significant difference (p = 0.060 and
0.357, respectively). Additionally, WBC count (14,797 ± 7148 vs. 11,941 ± 6203 × 106 /L)
and PCT comparisons (8.1 ± 23.8 vs. 0.6 ± 1.1 ng/mL) between the IBI and LBI groups
yielded significant differences (all p = 0.040).

Table 2. Comparisons of inflammatory markers among studied groups.

WBC CRP ESR PCT

106 /L mg/L mm/h ng/mL
Bacterial infection (BI) 13,177 ± 6484 61.4 ± 69.8 39.1 ± 32.4 4.2 ± 16.9
IBI 14,797 ± 7148 69.3 ± 77.6 35.3 ± 30.3 8.1 ±23.8
MBI 11,976 ± 5127 36.8 ± 44.8 44.5 ± 30.9 0.4 ± 0.8
TBI 11,241 ± 4350 41.9 ± 69.3 34.0 ± 32.7 2.6 ± 10.8
LBI 11,941 ± 6203 69.0 ± 15.1 45.3 ± 36.7 0.6 ± 1.1
Nonbacterial infection (NBI) 12,959 ± 5841 62.2 ± 60.1 54.8 ± 28.2 1.1 ± 2.5
VI 11,767 ± 6207 40.7 ± 51.5 38.3 ± 21.4 1.0 ± 3.3
ID 13,890 ± 5378 79.0 ± 61.1 61.4 ± 28.0 1.1 ± 1.7
Abbreviations: WBC; white blood cell, CRP; C-reactive protein, ESR; erythrocyte sedimentation rate, PCT;
procalcitonin, IBI; invasive bacterial infection, MBI; mucosal bacterial infection, TBI; toxigenic bacterial infection,
LBI; localized bacterial infection, VI; viral infection, ID; inflammatory diseases. Bold numbers indicated the
statistical differences.

There were significant differences according to the age groups between the BI and
NBI groups and among the BI subgroups (all p < 0.001). Among infants, ESR alone was
different between the BI and NBI groups (31.4 ± 27.6 vs. 48.1 ± 24.6 mm/h, p = 0.008) and
the IBI and other groups (31.6 ± 27.5 vs. 46.1 ± 25.7 mm/h, p = 0.019). Among toddlers, no
biomarker showed significant differences between the BI and NBI groups or the IBI and
other groups (all p > 0.05). Among preschoolers, ESR was different between the BI and NBI
(38.3 ± 34.8 vs. 58.1 ± 29.5 mm/h, p = 0.013) groups, while WBC was different between the
IBI and other groups (19,295 ± 4280 vs. 12,782 ± 5206 × 106 /L, p = 0.015). Among middle
childhood and teenagers, there was no difference between the BI and NBI groups or the IBI
and other groups (all p > 0.05).

3.3. Comparisons of Accuracy and Cut-Off Values of Inflammatory Markers

The ROC curves were constructed by differentiating the BI and NBI groups. The
areas under the curve (AUCs) were 0.495 for WBC, 0.443 for CRP, 0.335 for ESR, and 0.498
for PCT. All these markers were insignificant in distinguishing between the BI and NBI
groups. (Table 3 and Figure 1A) However, when comparing AUCs between the IBI and
other groups, PCT (0.640, 95% CI: 0.562–0.719, p < 0.001), WBC (0.615, 95% CI: 0.532–0.698,
p = 0.003), and CRP (0.508, 95% 0.434–0.581, p = 0.843) were determined to be useful
markers; however, CRP outcomes were not statistically significant. The optimal cut-off
values were 15,860 × 106 /L for WBC (sensitivity: 46.8%, specificity: 76.3%) and 1.8 ng/mL
for PCT (sensitivity: 39.4%, specificity: 87.1%). However, PCT and WBC yielded poor
accuracy (Table 3 and Figure 1B).
 (sensitivity: 39.4%, specificity: 87.1%). However, PCT and WBC yielded poor accuracy
(Table 3 and Figure 1B).

Table 3. Comparison of area under curve values between bacterial infection and nonbacterial infec-
tion groups.
Children 2022, 9, 1263 6 of 8
AUC 95% CI p Cut-Off Sensitivity Specificity
BI–NBI
WBC3. Comparison of0.495
Table area under 0.430-0.560 0.876 bacterial
curve values between 16530 infection
71.2and nonbacterial
22.7
infection
CRP groups. 0.443 0.380–0.506 0.075 4.1 20.8 89.5
ESR AUC 0.335 95% 0.274–0.395
CI p <0.001Cut-Off34.0 Sensitivity
54.6 74.4
Specificity
PCT
BI–NBI 0.498 0.433–0.563 0.958 4.6 84.9 5.6
IBI–other
WBC groups 0.495 0.430-0.560 0.876 16530 71.2 22.7
CRP 0.443 0.380–0.506 0.075 4.1 20.8 89.5
WBC
ESR 0.335 0.6150.274–0.395
0.532–0.698
<0.001 0.003 34.0
15860 46.8
54.6 74.476.3
PCT
CRP 0.498 0.5080.433–0.563
0.434–0.5810.958 0.843 4.645.2 84.9
55.3 5.6 52.8
IBI–other groups
ESR
WBC 0.615 0.3360.532–0.698
0.262–0.4110.003 <0.001 15860
44.0 68.6
46.8 76.358.4
CRP
PCT 0.508 0.6400.434–0.581
0.562–0.7190.843 <0.001 45.21.8 55.3
39.4 52.887.1
ESR 0.336 0.262–0.411 <0.001 44.0 68.6 58.4
Abbreviations:
PCT AUC;0.640
area under the curve, CI:<0.001
0.562–0.719 confidence interval,
1.8 BI; bacterial
39.4 infection, 87.1NBI; non-
bacterial infection, WBC; white blood cell, CRP; C-reactive protein, ESR; erythrocyte sedimentation
Abbreviations: AUC; area under the curve, CI: confidence interval, BI; bacterial infection, NBI; nonbacterial
rate, PCT; WBC;
infection, procalcitonin.
white blood cell, CRP; C-reactive protein, ESR; erythrocyte sedimentation rate, PCT; procalcitonin.

(a) (b)
Figure 1.1.Comparison
Figure Comparisonof ofreceiver operatingcharacteristic
receiver operating characteristiccurve
curve analyses
analyses of inflammatory
of inflammatory markers
markers
between the (a) bacterial infection and nonbacterial infection group, and between the
between the (a) bacterial infection and nonbacterial infection group, and between the (b) invasive (b) invasive
bacterial
bacterialinfection
infectiongroup and all
group and allother
othergroups.
groups. Abbreviations:
Abbreviations: WBC,WBC, white
white bloodblood cell;C-reactive
cell; CRP, CRP, C-reac-
tive protein; ESR, erythrocyte sedimentation rate; PCT, procalcitonin.
protein; ESR, erythrocyte sedimentation rate; PCT, procalcitonin.

4. 4. Discussion
Discussion
InInthis
thisretrospective
retrospective study,
study, we
we compared
comparedinflammatory
inflammatory biomarker
biomarker levels in children
levels in children
with BI and NBI and reported that PCT and ESR were significantly different in these groups.
with BI and NBI and reported that PCT and ESR were significantly different in these
WBC, ESR, and PCT yielded significant differences, which aided in the differentiation of IBI
groups. WBC, ESR, and PCT yielded significant differences, which aided in the differen-
from other infections. However, ROC analysis revealed that none of the four inflammatory
tiation of IBI from other infections. However, ROC analysis revealed that none of the four
markers were useful in differentiating BI from NBI. However, WBC and PCT were useful in
inflammatory
differentiatingmarkers
IBI fromwere
other useful in but
infections differentiating
yielded poorBI from NBI.
accuracy basedHowever, WBC and
on ROC analysis.
PCT were useful in differentiating IBI from other infections but yielded
ESR was not shown to be useful in the ROC analysis. Additionally, WBC and PCT yielded poor accuracy
based on ROC analysis. ESR was not shown to be
lower sensitivity but higher specificity than CRP and ESR. useful in the ROC analysis. Addition-
ally, WBC
Given and PCT
that PCT yielded
can be lower
measuredsensitivity but higher
to differentiate specificity
patients with LBIthan
or CRP andthose
VI from ESR.
withGiven
severethat PCT
BI [9], canstudies
many be measured
have beento published
differentiate patients
in support of with LBI or VI from
this hypothesis. those
Accord-
ing to several studies, PCT reflects the severity of BI and is more elevated
with severe BI [9], many studies have been published in support of this hypothesis. Ac- in cases of severe
BI. Additionally,
cording to several astudies,
study with
PCT175 children
reflects the revealed
severity ofthat
BIpatients with septic
and is more elevatedshock had of
in cases
higher
severe BI.PCT levels than those
Additionally, withwith
a study no infection, VI, orrevealed
175 children LBI and that
that PCT values
patients were
with further
septic shock
increased in patients with severe BI [15]. Harbarth et al. measured PCT levels in patients
with systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic
shock. PCT levels were found to be significantly different among the four groups, and more
severe infections were found to be associated with higher PCT values [16]. Simon et al.
Children 2022, 9, 1263 7 of 8

demonstrated that PCT was more effective than CRP for differentiating BIs in patients with
SIRS admitted to the pediatric intensive care unit [17]. Moreover, Casado et al. concluded
that PCT was superior to CRP or WBC count in children with sepsis, even in infants [18].
A study conducted on infants observed better sensitivity and specificity for PCT than
CRP [7]. In pediatric patients with suspected UTIs, PCT was effective in differentiating
upper UTIs [8]. In a previous study that compared VI and BI in children (ages: 1–36 months)
who visited the emergency room with fever, CRP and PCT exhibited similar sensitivity for
the diagnosis of BI; however, the specificity of PCT was better. In differentiating IBI, PCT
showed better sensitivity and specificity than CRP [1].
Conversely, some studies have argued that there was no significant difference in the
efficacy of PCT compared with those of other inflammatory indicators, especially CRP.
According to a study wherein non-infectious patients and infectious patients admitted to
ICU were compared, PCT had lower sensitivity, specificity, and AUC than CRP, and the
authors concluded that PCT had low-diagnostic efficacy [19]. In addition, some studies
revealed that among children who visited the emergency room with fever, CRP was more
convenient and sensitive as an indicator for predicting severe BI in comparison with
PCT [20]. A study on malnourished children also concluded that CRP was a useful marker
to identify patients at risk for death [21]. Additionally, in another study, PCT was more
sensitive and specific than CRP in patients with bacterial sepsis [12]. A study, conducted
in febrile children under the age of 3 years showed that PCT was a more accurate marker
than WBC, absolute neutrophil, and band count in children with serious BI [22].
The limitations of this study are that it was conducted in a single center. As such, the
number of enrolled patients was limited. Secondly, the number of patients per group and
the diagnoses were uneven owing to the retrospective nature of the study. Lastly, there may
be a possibility of misclassification of bacterial respiratory infections as VI, especially single
boca-viral infections. However, all four patients who were diagnosed with pneumonia
or bronchiolitis improved without the administration of antimicrobials. However, this
study has strengths in that BIs were divided into four groups, and analyses were conducted
between their classified subgroups. In addition, we compared and analyzed the findings
from patients with inflammatory diseases in a manner similar to previous studies.
This study utilized retrospective analysis. Accordingly, there was a possibility of
selection bias as the PCT tests were not performed in all patients. Additional, well-designed
studies are required to identify newer and more accurate biomarkers to discriminate
between BI and IBI prospectively.
In conclusion, a comparison of mean values revealed that PCT and ESR were the
most useful inflammatory markers to differentiate BI from NBI and IBI from other types of
infection. Though the PCT value proved to be useful, it had poor accuracy.

Author Contributions: Conceptualization, H.N.P. and J.Y.P.; methodology, H.N.P.; software, J.Y.P.;
validation, D.Y.Y., S.W.Y. and S.A.C.; formal analysis, J.Y.P.; investigation, J.Y.P.; resources, S.Y.K.
and N.M.L.; data curation, H.N.P.; writing—original draft preparation, H.N.P.; writing—review and
editing, J.Y.P. and Y.K.L.; visualization, J.Y.P.; supervision, I.S.L.; project administration, J.Y.P.; funding
acquisition, J.Y.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by Chung-Ang University Research Grants in 2022.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki and was approved by the Institutional Review Board of Chung-Ang University Hospital
(no. 2004-002-19803).
Informed Consent Statement: Patient consent was waived due to the retrospective nature of the
study based on medical record reviews.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Children 2022, 9, 1263 8 of 8

References
1. Fernandez, L.A.; Luaces, C.C.; Garcia, J.J.; Fernandez, P.J. Procalcitoninin pediatric emergency departments for the early diagnosis
of invasive bacterial infections in febrile infants: Results of a multicenter study and utility of a rapid qualitative test for this
marker. Pediatr. Infect. Dis. J. 2003, 22, 895–903.
2. Mehanic, S.; Baljic, R. The importance of serum procalcitonin in diagnosis and treatment of serious bacterial infections and sepsis.
Mater. Sociomed. 2013, 25, 277–281. [CrossRef] [PubMed]
3. Reinhart, K.; Karzai, W.; Meisner, M. Procalcitonin as a marker of the systemic inflammatory response to infection. Intensive Care
Med. 2000, 26, 1193–1200. [CrossRef] [PubMed]
4. Gendrel, D.; Bohuon, C. Procalcitonin as a marker of bacterial infection. Pediatr. Infect. Dis. J. 2000, 19, 679–687. [CrossRef]
[PubMed]
5. Meisner, M.; Schmidt, J.; Huttner, H.; Tschaikowsky, K. The natural elimination rate of procalcitonin in patients with normal and
impaired renal function. Intensive Care Med. 2000, 26, S212–S216. [CrossRef]
6. Matwiyoff, G.N.; Prahl, J.D.; Miller, R.J.; Carmichael, J.J.; Amundson, D.E.; Seda, G.; Daheshia, M. Immune regulation of
procalcitonin: A biomarker and mediator of infection. Inflamm. Res. 2012, 61, 401–409. [CrossRef] [PubMed]
7. Kim, E.K.; Lee, B.S.; Lee, J.A.; Jo, H.S.; Park, J.D.; Kim, B.I.; Choi, J.H. Clinical availability of serum procalcitonin level in the
diagnosis of neonatal bacterial infection. J. Korean Soc. Neonatol. 2001, 8, 211–221.
8. Kim, D.W.; Chung, J.Y.; Koo, J.W.; Kim, S.W.; Han, T.H. Usefulness of serum procalcitonin test for the diagnosis of upper urinary
tract infection in children. Korean J. Pediatr. 2006, 49, 87–92. [CrossRef]
9. Assicot, M.; Gendrel, D.; Carsin, H.; Raymond, J.; Guilbaud, J.; Bohuon, C. High serum procalcitonin concentrations in patients
with sepsis and infection. Lancet 1993, 341, 515–518. [CrossRef]
10. Park, I.H.; Lee, S.H.; Yu, S.T.; Oh, Y.K. Serum procalcitonin as a diagnostic marker of neonatal sepsis. Korean J. Pediatr. 2014, 57,
451–456. [CrossRef]
11. Nijman, R.G.; Moll, H.A.; Smit, F.J.; Gervaix, A.; Weerkamp, F.; Vergouwe, Y.; De Rijke, Y.B.; Oostenbrink, R. C-reactive
protein, procalcitonin and the lab-score for detecting serious bacterial infections in febrile children at the emergency department:
A prospective observational study. Pediatr. Infect. Dis. J. 2014, 33, e273–e279. [CrossRef] [PubMed]
12. Huang, X.; Wang, J.; Li, H. Diagnostic and prognostic values of serum procalcitonin and C-reactive protein in patients of bacterial
sepsis. Zhonghua Yi Xue Za Zhi 2014, 94, 2106–2109. [PubMed]
13. Sakha, K.; Husseini, M.B.; Seyyedsadri, N. The role of the procalcitonin in diagnosis of neonatal sepsis and correlation between
procalcitonin and C-reactive protein in these patients. Pak. J. Biol. Sci. 2008, 11, 1785–1790. [CrossRef]
14. Nijman, R.G.; Oostenbrink, R.; Moll, H.A.; Casals-Pascual, C.; von Both, U.; Cunnington, A.; De, T.; Eleftheriou, I.; EMonts, M.;
Kohlmaier, B.; et al. A novel framework for phenotyping children with suspected or confirmed infection for future biomarker
studies. Front. Pediatr. 2021, 9, 688272. [CrossRef]
15. Hatherill, M.; Tibby, S.M.; Sykes, K.; Turner, C.; Murdoch, I.A. Diagnostic markers of infection: Comparison of procalcitonin with
C reactive protein and leucocyte count. Arch. Dis. Child 1999, 81, 417–421. [CrossRef]
16. Harbarth, S.; Holeckova, K.; Froidevaux, C.; Pittet, D.; Ricou, B.; Grau, G.E.; Vadas, L.; Pugin, J. Diagnostic value of procalcitonin,
interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am. J. Respir. Crit. Care Med. 2001, 164,
396–402. [CrossRef]
17. Simon, L.; Saint-Louis, P.; Amre, D.K.; Lacroix, J.; Gauvin, F. Procalcitonin and C-reactive protein as markers of bacterial infection
in critically ill children at onset of systemic inflammatory response syndrome. Pediatr. Crit. Care Med. 2009, 9, 407–413. [CrossRef]
[PubMed]
18. Casado, F.J.; Blanco, Q.A.; Asensio, J.; Arranz, E.; Garrote, J.A.; Nieto, M. Serum procalcitonin in children with suspected sepsis:
A comparison with C-reactive protein and neutrophil count. Pediatr. Crit. Care Med. 2003, 4, 190–195. [CrossRef] [PubMed]
19. Ugarte, H.; Silva, E.; Mercan, D.; De Mendonca, A.; Vincent, J.L. Procalcitonin used as a marker of infection in the intensive care
unit. Crit. Care Med. 1999, 27, 498–504. [CrossRef]
20. Andreola, B.; Bressan, S.; Callegaro, S.; Liverani, A.; Plebani, M.; Da Dalt, L. Procalcitonin and C-reactive protein as diagnostic
markers of severe bacterial infections in febrile infants and children in the emergency department. Pediatr. Infect. Dis. J. 2007, 26,
672–677. [CrossRef]
21. Page, A.L.; De Rekeneire, N.; Sayadi, S.; Aberrane, S.; Janssens, A.C.; Dehoux, M.; Baron, E. Diagnostic and prognostic value of
procalcitonin and C-reactive protein in malnourished children. Pediatrics 2014, 133, e363–e370. [CrossRef] [PubMed]
22. Mahajan, P.; Grzybowski, M.; Chen, X.; Kannikeswaran, N.; Stanley, R.; Singal, B.; Hoyle, J., Jr.; Borgialli, D.; Duffy, E.;
Kuppermann, N. Procalcitonin as a marker of serious bacterial infections in febrile children younger than 3 years old. Acad.
Emerg. Med. 2014, 21, 171–179. [CrossRef] [PubMed]