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Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx

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Biomedicine & Pharmacotherapy


journal homepage: www.elsevier.com/locate/biopha

Procalcitonin: The marker of pediatric bacterial infection


Mohammad Yousef Memara,b, Mojtaba Varshochia, Behrooz Shokouhic,

Mohammad Asgharzadehd, Hossein Samadi Kafild,
a
Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
b
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
c
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
d
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Timely recognition of systemic bacterial infections in pediatric care setting is the basis for effective treatment
Immunologic marker and control. This review provides an overview of procalcitonin (PCT) as an early marker for the detection of
Pediatric infection severe, invasive bacterial infection in children. Almost all articles on biochemical property and clinical studies in
Procalcitonin PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of
Sepsis
bacterial infections were examined. Various methods and analyzers are currently available for the evaluation of
Bacteria
PCT. Employment of PCT in the identification of neonatal bacterial infection is a complex process in some
conditions. Age specific cut-off, underlying syndrome, and maternal antibiotics usage should be considered when
PCT is to be applied in neonates. PCT might be false-negative in these conditions. However, if used appro-
priately, it can lead to a higher specificity than other immunologic markers. Due to its correlation with the
severity of infection, PCT can consequently be used as a prognostic indicator especially for sepsis and urinary
tract infection. It is, therefore, a practical supplementary means for the identification of bacterial infections in
pediatric health settings.

1. Introduction concerning clinicians as a predisposing aspect, PCT levels can be a fast


and sensitive scheme for determining the existence of bacterial infec-
Rapid identification and management of systemic bacterial infec- tion so as to assist more cautious selection of appropriate therapy [10].
tions are fundamental in neonates, infants, and children. Indeed, a It is crucial to limit the use of antibiotics to decrease the expansion of
postponement in the treatment of severe bacterial infections may have a antibiotic resistant bacteria, reduce complications and expenses, and
poor outcome. Distinguishing between a severe bacterial infection and prevent unnecessary admittance to hospitals for the use of parental
a localized bacterial or a viral infection can be highly critical in treat- antibiotics in viral infections [1]. This review was done in order to
ment options [1]. Sometimes, it is a challenge even for highly experi- optimize the potential clinical applications of this important marker in
enced pediatricians [1]. Procalcitonin (PCT), the precursor molecule of pediatric infections. To achieve this objective, almost all articles on
calcitonin, is a 116-amino-acid peptide without a recognized hormonal biochemical property and clinical studies in PubMed and Scopus da-
property [2]. Serum levels of PCT are low or untraceable in the serum of tabases regarding their use in pediatric infections and the use of PCT as
healthy individuals [3]. Severe generalized bacterial infections with a marker of bacterial infections were examined.
systemic appearances are coupled with elevated serum PCT. In com-
parison with viral infections, localized bacterial infections or the in- 2. Procalcitonin
flammatory response of non-infectious source do not, or only fairly,
boost PCT levels [2,4]. This boost is frequently associated with the Although PCT is the precursor for calcitonin, their biologic beha-
severity of illness and mortality [5,6]. PCT has not proved helpful in viors are noticeably different [11]. In C cells of the thyroid gland and K
differentiating bacterial infection intensive care unit (ICU) patients cells of the lung, increased levels of serum calcium concentrations or
because its levels in these conditions increase [7–9]. Since resistance to neoplastic altering result in the transcription of PCT genes. Conse-
antibiotics among bacteria is a significant public health trouble, and quently, the ribosomal synthesis of the 13 kD 116-amino-acid PCT
indiscriminate administration of antimicrobial drugs has been molecule arises, with the successive cleavage of amino acids 60 to 91


Corresponding author.
E-mail address: Kafilhs@tbzmed.ac.ir (H.S. Kafil).

https://doi.org/10.1016/j.biopha.2017.11.149
Received 10 November 2017; Received in revised form 20 November 2017; Accepted 29 November 2017
0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article as: Memar, M.Y., Biomedicine & Pharmacotherapy (2017), https://doi.org/10.1016/j.biopha.2017.11.149
M.Y. Memar et al. Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx

Fig. 1. Procalcitonin: structure and synthesis: Procalcitonin


(PCT) is the precursor of Calcitonin. Site of development is
the calc-1 gene on chromosome 11 of the human genome.
After translation from CT-DNA into mRNA, the first transla-
tion product is pre-procalcitonin, which then changes by
different modification steps into PCT [92].

yielding calcitonin (Fig. 1) [12–14]. The discovery of elevated PCT le- in calcitonin [14]. PCT levels increase in patients suffering from neu-
vels in patients who have undergone thyroidectomy suggests an origin roendocrine tumors (i.e., medullary thyroid cancer) and small cell
other than PCT [5]. The exact sites of PCT creation are unidentified, but cancer of the lung carcinoid tumor. This increase is associated with an
it is thought that liver is the chief location. In addition, mRNA of PCT elevated level of calcitonin. Therefore, in this condition the simulta-
were detected in other tissues such as lung, kidney and testis. Data neous increase of both PCT and calcitonin indicates the presence of
collected from some studies indicate that hepatocytes following sti- tumors and is independent of infection [9]. PCT elevated levels in this
mulation with tumor necrosis factor-α (TNF-α) and interleukin-6 IL-6, patient might be associated with false positive indication of infection
and peripheral blood mononuclear cells following stimulation with li- and inappropriate treatments.
popolysaccharides (LPS) start the expression of PCT [15–17]. This PCT concentration increases from 3 to 4 h, reaches climax at about
synthesis appears to be modulated by LPS and pro-inflammatory med- 6 h and then plateau for up to 24 h [16]. PCT is degraded by particular
iators TNF-α, interleukin-1b (IL-1b), interleukin-2 (IL-2), and IL-6. In protease and has a half-life of 25–30 h [14]. Serum PCT concentrations
vitro and animal models of bacterial infection or endotoxin exposure decline quickly for the duration of antibiotic therapy, and serial assays
induce the expression of PCT and other calcitonin precursors by prac- are practical in order to check the response to treatment [21]. PCT was
tical experiments in all tested tissues and organs. The first report of indicated to be of superior prognostic value for microbial infections and
increased serum PCT concentrations in sepsis was by Assicot in 1993 mortality than several medical variables used in the description of
[5]. The precise function of PCT is still unclear. It is a protein that is systemic inflammatory response syndrome (abnormal temperature, ta-
induced during inflammation. From an evolutionary perspective, it chycardia, tachypnea, and abnormal white blood cell counts) [22].
must have a physiological role. PCT plays a hypothetical role in the Persistently, increased PCT concentration indicates the continuous ex-
metabolism of calcium, the cytokine network and modulation of NO istence of infection.
synthesis. It also plays a ‘non-steroidal analgesic role. Further studies
are required to exactly demonstrate physiological role of PCT [9,14]. A 3. Method of measurement
correlation between PCT and the calcium metabolism has not been
demonstrated. However, septic patients often suffer from hypo- Diverse methods and analyzers are presently accessible for the as-
calcemia, but the levels of calcium and PCT do not correlate con- sessment of PCT. None of the currently accessible PCT measurement
siderably. The hypothetical effect of PCT in calcium metabolism during methods, whether in research or market, completely identifies 116-
sepsis is based on the constructional similarity of PCT and calcitonin. amino acid PCT peptide. The majority of assays distinguish portions of
PCT contains the amino acid sequence of calcitonin. However, the si- PCT and the adjoined section of calcitonin (CT) and calcitonin-carboxyl
milarity of the primary structure of the protein chains is less con- peptide-I [21]. By an extremely sensitive assay for PCT, the in-
siderable than the distinct differences in secondary and tertiary con- vestigators described normal PCT levels in non-infected individual as
figuration. A disulphide bridge between cystein residue at positon 1 and 0.033 ± 0.003 ng/mL [9]. One of the first, and still generally em-
7 forms a circle of seven amino acids at N-terminus of calcitonin. This ployed, methods is the immunoluminometric PCT detection. This assay
circle together with hydroxylated proline at C-terminus organize the has a practical sensitivity of 0.5 ng/mL, with a recognition limit (eva-
binding site with a high affinity to the calcitonin receptor. In PCT, the luation of analytical sensitivity), calculated by indistinctness outline,
N-terminal fragment is preserved preventing the creation of this bridge. assessed as being 0.08 ng/mL. Whereas this manual detection will dis-
This illustrates the common experimental results in which plasmatic tinguish notably high serum levels of PCT, it may not be sensitive en-
PCT has no affinity with the calcitonin receptors [18]. In healthy in- ough to assay slightly or moderately increased PCT levels through early
dividuals, circulating levels of PCT are very low, typically under 0.1 ng/ phase of infections. Thus, studies exploring the clinical usefulness of
mL. In viral infections and inflammatory reactions, PCT concentrations PCT by the immunoluminometric PCT assay (LUMItest®) may be subject
increase up to 1.5 ng/mL, but in bacterial infection levels may to inaccuracy; PCT levels reported as 0.5 ng/mL are not certain yet,
go > 100,000 times normal levels [19,20]. considering the fact that the practical sensitivity of 0.5 ng/mL exceeds
Bacterial infections induce PCT expression and release into the average standard rate by more than 10-fold. The subsequent production
systemic circulation. This expression is not associated with an increase of commercially accessible PCT measurement is based on the principle

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M.Y. Memar et al.

Table 1
Overview of some studies investigating the PCT as indicator in different type of pediatric infection.

Type of infection: Study diseign PTC cut-off (ng/mL) Study population Main finding Refs.

sepsis prospective 0.5–2, 2.1–10 and > 10 Thirty‐eight neonates with clinical, suspected and proven sepsis Usefulness of the PCT to establish an early identification of neonatal [85]
sepsis
prospective 0.5 185 premature infants in the neonatal ICU PCT in combination with serum amyloid A(SAA) is appropriate in [86]
finding and follow-up of sepsis in preterm infants
Prospective cohort 0.5 183 neonates with clinical sepsis PCT is not adequately trustworthy to be the sole indicator of neonatal [87]
sepsis. It would be helpful as part of full sepsis assessment.

Bacteremia among children prospective 0.1–2.0 159 hospitalized children with pneumonia PCT may be practical in recognizing bacteraemia among children [88]
hospitalized with CAP
Clinical sepsis in febrile neutropenic prospective 0.55–1.15 Thirty-two patients with a PCT is sensitive and specific early indicator of bacteremia in children [72]
children with cancer with FN. Serial detection improve the indicative accuracy of PCT,
Bacterial infections in pediatric prospective 0.5 43 febrile neutropenic episodes from 29 patients. After 24–148 h, PCT was considerably increased during bacterial [19]
oncology patients infection. Mucositis did not cause significant changes in PCT levels.
Meningitis Retrospective cohort 0.3 198 patients The PCT level is a strong predictor for differentiate between bacterial [45]
and aseptic meningitis.

3
retrospective cohort 0.5 167 patients PCT had prognostic value to differentiate between bacterial and [42]
aseptic meningitis.

Osteomyelitis prospective 0.5 339 patients(1 month to 14years) PCT is not a good screening test for identifying skeletal infection in [37]
children.
Fever without localising signs prospective 0.9 124 patients younger of 3 years whit fever without localizing signs. PCT offers a suitable sensitivity and specificity in predicting severe [64]
bacterial infections in children with fever without localising signs.
Acute pyelonephritis prospective 0.5 64 patients aged 2 weeks to 3 years, admitted to pediatric The admission PCT test has a high sensitivity and specificity for [61]
department with febrile UTI. differencing acute pyelonephritis from lower UTI in infants and
children.
Case series 0.5 One-hundred patients aged 1 month–14 years old with A semi-quantitative rapid test for PCT has a high sensitivity and [63]
documented UTI specificity for the differentiation of

Community acquired pneumonia Prospective 1 88 patients (aged 2 months to 13 years) admitted to hospital for PCT concentration, with a [52]
severe community acquired febrile pneumonia
Prospective 0.5 119 children admitted for radiographically documented CAP aged PCT is not able to predict the extent of chest X-ray infiltration and [89]
1 year to 14 years, without chronic diseases. ultimately the severity of the

Predicts Response to Beta-Lactam Retrospective cohort 0.3-10 125 consecutive children aged 1 month to 16 years who PCT is the best independent biologic predictor of favourable response [90]
to beta-lactam therapy in children
Shorten Antibiotic Therapy in Prospective Serial PCT 126 term and near-term infants suspected early-onset sepsis in the Serial PCT determinations allow shortening the duration of antibiotic [91]
Suspected Neonatal determinations first 3 days of life and treated with empiric antibiotic therapy therapy in term and near-term infants with suspected early-onset
sepsis.
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M.Y. Memar et al. Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx

of time-resolved amplified cryptate emission (TRACE) technology. This 5. Meningitis


particular assay uses a sheep polyclonal anti-calcitonin antibody and a
monoclonal anti-Catacalcin antibody, whereby PCT molecules bind to Bacterial meningitis, an inflammation of the meninges, affects the
these antibodies. The antibodies are labeled with fluorescent tracers, pia, arachnoid, and subarachnoid space. It occurs in reaction to bacteria
europium cryptate (donor) and XL665 (acceptor), and the creation of and bacterial products. This disease has been a significant reason of
the PCT–antibody composite results in an energy transport between the mortality and morbidity in neonates and children. However, mortality
two tracers which is accompanied by an amplification. This particular and morbidity vary by age and geological region of the patient and the
PCT evaluation has a diagnostic sensitivity of 0.019 ng/mL, while the causative pathogen [38,39]. In emergency cases, direct Cerebral Spinal
functional assay sensitivity has been evaluated as 0.06 ng/mL. Addi- Fluid (CSF) assessment gives data of bacterial meningitis in only
tional commercial assays by Siemens Healthcare Diagnostics Company, 50–80% of cases [40]. It is well known that other techniques applied for
Tarrytown Company, NY Company, and Roche Diagnostics company, identification, such as Polymerase Chain Reaction (PCR), im-
Indianapolis Company and IN Company are in development. PCT®-Q munological, and biochemical methods have their own restrictions
(BRAHMS, Thermo Scientific, Germany) is a point-of-care application [41]. PCT is a practical supplementary variable for distinguishing
of PCT; nevertheless, this test is not approved for use in the United bacterial from non-bacterial meningitis. Acute meningitis is pre-
States of America (USA) by the Food and Drug Administration (FDA). dominantly aseptic (82–94%) and in some cases bacterial (6–18%).
This test has the advantage of near-patient testing and can detect cir- Aseptic meningitis includes a syndrome of meningeal inflammation in
culating PCT levels within 30 min without the need for a complex which common bacterial pathogens cannot be recognized in the CSF,
analyzer or calibration [21]. Usually, a PCT level ≥0.5 ng/mL is con- which can induce limitations spontaneously. Bacterial meningitis is
sidered to be positive for the diagnosis of a bacterial infection [23,24] sometimes fatal and commonly associated with severe neurological
(Table 1). complications, especially when the diagnosisand treatment are late
The semi-quantitative PCT test may be a poor tool for the sequential [42,43]. In patients with non-bacterial meningitis, PCT value does not
evaluation of a patient’s condition because the test kit provides only an increase even in cases of viral sepsis. Elevated PCT levels indicate a
estimate of serum PCT levels [23,25]. Since most available PCT assays bacterial source with high specificity (Table 1), but false-negative re-
currently use antibodies directed towards internal epitopes of PCT, they sults can happen. PCT assessment have been reported to be a reliable
are unable to detect their amino-terminal variants [21]. tool for differentiation between viral and bacterial meningitis in chil-
dren, but have not been systematically explored in adults [44]. De-
4. Sepsis and septic arthritis termination of PCT level had 99% sensitivity (95% confidence interval,
97%–100%) and 83% specificity (95% confidence interval, 76%–90%)
Bacterial sepsis is the most frequent fatality reason in infants and for differentiation between bacterial and aseptic meningitis [45]. In
children in both developing and developed countries [26,27]. Early addition to PCT concentration in serum, PCT level in CSF can be very
recognition of the absence of infection would reduce the number of practical in the recognition of bacterial meningitis from viral meningitis
children started on antibiotics, shorten the duration of hospitalization, and other noninfectious syndromes. Determination of PCT in CSF offers
and minimize the probability for appearance of resistant organisms supplementary data to the clinician and authorizes the option for in-
[27,28]. Timely diagnosis and treatment with suitable antimicrobial itiating antibiotic therapy, both of which are necessary in managing
chemotherapy is of paramount importance to decrease morbidity and bacterial meningitis [41]. Henry et al.′s meta-analysis demonstrates
mortality associated with sepsis [14]. It has been reported that the that serum PCT evaluation is a highly valid and influential test for
concentration of PCT is more significantly elevated in children with speedily distinguishing between bacterial and viral meningitis in chil-
sepsis than in controls. PCT is reported as an appropriate indicator of dren [46].
bacterial sepsis [27,29] (Table 1). PCT offers improved specificity
compared to C- reactive protein (CRP) and serum amyloid A(SAA) for 6. Community-acquired pneumonia
distinguishing between viral and bacterial etiologies of fever, with si-
milar sensitivity [27,29]. PCT offers better sensitivity and specificity Community-acquired pneumonia (CAP), caused by viruses, ‘typical’
than CRP to differentiate between invasive and noninvasive infections respiratory bacteria (such as Streptococcus pneumoniae) or ‘atypical’
[29,30]. respiratory bacteria (such as Mycoplasma pneumoniae and Chlamydia
In early inception sepsis, PCT offers a sensitivity of 92.6% and a pneumoniae) is a frequent local infection in childhood [47]. Pneumonia
specificity of 97.5%. PCT appears to be a very specific and sensitive is an important cause of fatality for children around the world, ac-
indicator of early-onset neonatal sepsis and, therefore PCT determina- counting for about 30% of all childhood deaths. A particular pathogen
tions are detected in the subsequent 24 h. In late-onset sepsis (3–30 is not identified in most cases, but both viruses mainly respiratory
days), PCT provides a sensitivity and specificity of 100% in the detec- syncytial and influenza viruses and bacteria, especially S. pneumoniae
tion of bacterial sepsis [31]. Although it had a high specificity for and Haemophilus influenzae, are significant pathogens [48]. Numerous
neonatal infection, CRP was often normal early in the course of sepsis bacteria and viruses and their mixtures can cause this infection, but
[32,33]. Franz demonstrated that a combination of IL-8 and CRP was a there is an absence of speedy and commercially accessible diagnostic
more useful marker than PCT for the diagnosis of bacterial infection tests for most agents, which may clarify why the etiology is infrequently
[34]. recognized in clinical practice and why antibiotic therapy is empirical
Infections of bones and/or joints are infrequent but potentially in the majority of cases. Up to 60% of the cases are viral infections, thus
serious emergencies that are associated with considerable mortality and unnecessary and useless antibiotic therapy may often be administrated
morbidity. Postponed or insufficient treatment can result in irreparable [49,50]. Microbe-specific diagnosis, based on culture of blood, fluid, or
joint destruction, and case fatality rate is estimated to be almost 11%. samples obtained directly from the focus of infection in the lungs, is
Thus, early identification as well as quick and efficient treatment are possible only in a small minority of CAP cases. In papers published over
fundamental for avoiding severe outcomes. However, septic arthritis the last 15–20 years, serological tests based on antigen, antibody and
may be complicated to identify in particular conditions and in certain immune complex detection have been used for microbe-specific diag-
populations, such as among children and the elderly [35]. Aviel et al. nosis of CAP in children [47,51].
reported PCT to be a helpful indicator in the diagnosis of osteomyelitis, Several studies are available on describing the detection of lower
but not in septic [36]. Because of its low sensitivity, PCT cannot be respiratory infection etiology using PCT as a marker (Table 1). How-
applied as a screening marker for diagnosis of skeletal infections in ever, the findings of these studies are not in agreement. Moulin et al.
children, with the conventional cut-off of 0.5 ng/mL [37]. described that PCT concentration, with a threshold of 1 μg/l, is more

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M.Y. Memar et al. Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx

sensitive and specific and has greater positive and negative prognostic laboratory indicators that could correctly distinguish severe bacterial
values than CRP, IL-6, or White blood cells (WBC) count for differ- infection from localized or viral infections in young children with fevers
entiating bacterial and viral causes of CAP in untreated children ad- without a source, but a reliable indicator has not been recognized yet
mitted to hospitals as emergency cases [52]. Results of Toikka et al.′s [65–67]. Many clinical studies have dealt with this difficulty and the
study indicated the quantity of serum PCT, CRP, and Interleukin-6 (IL- combination of a clinical scoring system such as that of MaCarthy with
6) has little value in the differentiation of bacterial and viral pneumonia a total and deferential leukocyte count and detection of the in-
in children. However, in some patients with very high serum PCT, CRP, flammatory marker are used as screening techniques [64,68,69].
or IL-6 values, bacterial pneumonia is possible [53]. Galetto-Lacour Compared to generally applied screening means including IL-6, IL-8,
described that the association of increased PCT with a positive pneu- and IL-1 receptor antagonist, PCT and CRP present a superior sensitivity
mococcal urinary antigen is a strong predictor of pneumococcal -CAP and specificity in predicting severe bacterial infection in children with
[54]. Zhu et al. indicated that PCT level in peripheral blood is a sig- fever without localizing signs [64,65,69]. In an evaluation of regularly
nificant diagnostic indicator of pediatric bacterial infections and a used screening means such as clinical McCarthy, Lacour et al. reported
sensitive marker of difference between bacterial and non-bacterial that the total and deferential leukocyte count and CRP as well as other
pneumonia, therefore being of great importance for clinical and dif- inflammatory indicators such as IL-6, IL-1Ra, and IL-8, PCT offer a
ferential diagnosis [55]. Other studies showed that the PCT-guided slightly better sensitivity (93%) and specificity (78%) in forecasting a
treatment of supposed lower respiratory tract infection substantially severe bacterial infection in children with fever without localizing
decreased antibiotic administration without compromising clinical or signs, and may be used alone in primary screening [64]. Results of a
laboratory outcomes [10]. Massimiliano et al. confirmed earlier studies meta-analysis study carried by Chia-Hung et al. indicated PCT is better
representing that serum PCT is incapable to discriminate between than CRP for detecting serious bacterial infection among children with
bacterial and viral CAP in children, the conclusion being similar in both fever without source [65]. Fever is not only observed in the course of
ambulatory and hospitalized children at different ages [47]. Serum PCT bacterial or viral infections, but can be a symptom of some non-in-
is more elevated in invasive bacterial infections, such as bacterial me- fectious medical disorders such as autoimmune, malignant, or throm-
ningitis or septicemia, than in less invasive localized bacterial infec- boembolic diseases. Traditional indicators with sufficient sensitivity
tions, such as Urinary tract infections (UTIs) or pneumonia [47]. The and specificity are important in the discrimination between infectious
quantity of serum PCT seems to be valuable in the evaluation of the and non-infectious causes of fever and in making treatment decisions.
severity of pneumonia, when data have to be deduced together with PCT seems to be the most helpful laboratory marker for this purpose,
other clinical illumination (such as general circumstance, findings in particularly for the differentiation between infectious causes of fever
clinical assessment and in chest radiographs) and with other non-spe- and autoimmune, autoinflammatory, and malignant disorders [70]
cific host-response indicators (such as WBC count and CRP) [47]. (Table 1).

7. Urinary tract infections 9. Bacterial infection in neutropenic cancer patients with fever

Up to 7% of girls and 2% of boys will have an indicative, culture- Cancer patients treated with chemotherapy often have a phase with
confirmed UTI by six years of age [56,57]. Findings of UTI are often not neutropenia and a reduced immune response to bacterial pathogens. As
straightforward in pediatric application. Infection of the lower area is an outcome of high morbidity and mortality caused by bacteremia in
more likely to extend to the upper tract and kidneys in children than in these patients, the standard treatment throughout fever is hospital ad-
adults [1,58,59]. The unclear character of symptoms among febrile mittance and intravenous broad-spectrum antibiotics for at least 5 days
infants and young children provides the clinical discrimination of upper [71]. Early identification of sepsis in patients with febrile neutropenia
and lower UTI complications. However, true identification and early remains complicated due to unclear clinical and laboratory signs of
therapy of sever pyelonephritis are vital due to its involvement with infection [72,73]. The most generally used inflammatory marker, CRP,
renal scarring [60]. PCT quantity might be a practical and useful in- is relatively slow to increase, and several sequential detections are es-
dicator for the identification of sever pyelonephritis in infants and sential for the most precise identification of infection [74]. Kitanovski,
children [61]. Several studies described that the assessment of PCT test et al.′s result advocates that IL-6 and PCT are more sensitive and spe-
has a high sensitivity and specificity for distinguishing acute pyelone- cific early markers of bacteremia/clinical sepsis than CRP in children
phritis from lower UTI compared with other markers in infants and with febrile neutropenic and children with cancer [72]. Plasma PCT
children. The median PCT level was reported to be significantly higher concentrations at fever onset should be used and interpreted with
in the acute pyelonephritis [60–63]. PCT assessment might be a prac- caution in febrile patients with chemotherapy-related neutropenia [71].
tical indicator for the identification of UTIs. However, the accurate Martinez-Albarran et al. reported that PTC has 72.2% sensitivity and
position of this biomarker would possibly need to be refined for pe- 80.5% specificity in pediatric patients with cancer and febrile neu-
diatrics societies so that they agree on an illustration of the order and tropenia. These researchers described PCT as an accurate marker of
time of examinations after these infections [60]. The quick semi- bacterial infection in neutropenic children, while CRP may be a better
quantitative detection for PCT could be helpful for the management of screening examination in emergency cases [75].
children with febrile UTI in the pediatric emergency department (ED)
where the quantitative assessment procedures of the marker may not be 10. Monitoring of antibiotic therapy
available [63]. PCT value might be a helpful and practical tool for the
identification of severe pyelonephritis in infants and children, and offer PCT is a relatively novel and pioneering indicator of bacterial in-
informed conclusions about parenteral or oral antibiotic therapy in fection that has numerous potential applications in the pediatric
these patients (Table 1). emergency department (ED) [76,77]. PCT is described as an admirable
indicator in distinguishing invasive infections in ED. It can even make
8. Fever without localizing signs early diagnosis of invasive infections if the fever is developed in less
than 12 hs. PCT yields enhanced specificity than CRP for distinguishing
Fever without localizing signs in young children remains a com- between the viral and bacterial etiology of the fever. In addition, PCT
plicated diagnostic trouble, since clinical signs and symptoms are fre- provides improved sensibility and specificity than CRP to differentiate
quently unreliable predictors of severe bacterial infection which needs between invasive and noninvasive infections [29]. Day by day succes-
rapid therapeutic interference with intravenous antibiotic therapy [64]. sive PCT detection may be a valuable parameter in monitoring the ef-
For decades, researchers have made efforts to introduce clinical or ficiency of antibiotic administration in burn ICU patients [78]. The

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M.Y. Memar et al. Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx

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nity-acquired pneumonia: correlation with etiology and prognosis, Infection 28 (2)
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[25] M. Meisner, F.-M. Brunkhorst, H.-B. Reith, J. Schmidt, H.-G. Lestin, K. Reinhart,
Clinical experiences with a new semi-quantitative solid phase immunoassay for
There is no funding to declare. rapid measurement of procalcitonin, Clin. Chem. Lab. Med. 38 (10) (2000)
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Ethical approval [26] R.S. Watson, J.A. Carcillo, Scope and epidemiology of pediatric sepsis, Pediatr. Crit.
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[27] A. Enguix, C. Rey, A. Concha, A. Medina, D. Coto, M.A. Diéguez, Comparison of
This article does not contain any studies with human participants or procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of
animals performed by any of the authors. bacterial sepsis in critically ill neonates and children, Intensive Care Med. 27 (1)
(2001) 211–215.
[28] N. Alizadeh, M.Y. Memar, S.R. Moaddab, H.S. Kafil, Aptamer-assisted novel tech-
Conflict of interest nologies for detecting bacterial pathogens, Biomed. Pharmacother. 93 (2017)
737–745.
[29] A.F. Lopez, C.L. Cubells, J.G. García, J.F. Pou, Procalcitonin in pediatric emergency
The authors declare that they have no conflicts of interest.
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,
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