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Procalcitonin: The marker of pediatric bacterial infection
Biomedicine & Pharmacotherapy xxx (xxxx) xxx–xxx
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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 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Immunologic marker Pediatric infection Procalcitonin Sepsis Bacteria
Timely recognition of systemic bacterial infections in pediatric care setting is the basis for effective treatment and control. This review provides an overview of procalcitonin (PCT) as an early marker for the detection of severe, invasive bacterial infection in children. Almost all articles on biochemical property and clinical studies in PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of bacterial infections were examined. Various methods and analyzers are currently available for the evaluation of 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 appropriately, 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 infection so as to assist more cautious selection of appropriate therapy [10]. It is crucial to limit the use of antibiotics to decrease the expansion of antibiotic resistant bacteria, reduce complications and expenses, and prevent unnecessary admittance to hospitals for the use of parental antibiotics in viral infections [1]. This review was done in order to optimize the potential clinical applications of this important marker in pediatric infections. To achieve this objective, almost all articles on biochemical property and clinical studies in PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of bacterial infections were examined.
Rapid identification and management of systemic bacterial infections are fundamental in neonates, infants, and children. Indeed, a postponement in the treatment of severe bacterial infections may have a poor outcome. Distinguishing between a severe bacterial infection and a localized bacterial or a viral infection can be highly critical in treatment options [1]. Sometimes, it is a challenge even for highly experienced pediatricians [1]. Procalcitonin (PCT), the precursor molecule of calcitonin, is a 116-amino-acid peptide without a recognized hormonal property [2]. Serum levels of PCT are low or untraceable in the serum of healthy individuals [3]. Severe generalized bacterial infections with systemic appearances are coupled with elevated serum PCT. In comparison with viral infections, localized bacterial infections or the inflammatory response of non-infectious source do not, or only fairly, boost PCT levels [2,4]. This boost is frequently associated with the severity of illness and mortality [5,6]. PCT has not proved helpful in differentiating bacterial infection intensive care unit (ICU) patients because its levels in these conditions increase [7–9]. Since resistance to antibiotics among bacteria is a significant public health trouble, and indiscriminate administration of antimicrobial drugs has been
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2. Procalcitonin Although PCT is the precursor for calcitonin, their biologic behaviors are noticeably different [11]. In C cells of the thyroid gland and K cells of the lung, increased levels of serum calcium concentrations or neoplastic altering result in the transcription of PCT genes. Consequently, the ribosomal synthesis of the 13 kD 116-amino-acid PCT molecule arises, with the successive cleavage of amino acids 60 to 91
Corresponding author. E-mail address: Kafi[email protected] (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
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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 translation product is pre-procalcitonin, which then changes by different modification steps into PCT [92].
in calcitonin [14]. PCT levels increase in patients suffering from neuroendocrine tumors (i.e., medullary thyroid cancer) and small cell cancer of the lung carcinoid tumor. This increase is associated with an elevated level of calcitonin. Therefore, in this condition the simultaneous increase of both PCT and calcitonin indicates the presence of tumors and is independent of infection [9]. PCT elevated levels in this patient might be associated with false positive indication of infection and inappropriate treatments. PCT concentration increases from 3 to 4 h, reaches climax at about 6 h and then plateau for up to 24 h [16]. PCT is degraded by particular protease and has a half-life of 25–30 h [14]. Serum PCT concentrations decline quickly for the duration of antibiotic therapy, and serial assays are practical in order to check the response to treatment [21]. PCT was indicated to be of superior prognostic value for microbial infections and mortality than several medical variables used in the description of systemic inflammatory response syndrome (abnormal temperature, tachycardia, tachypnea, and abnormal white blood cell counts) [22]. Persistently, increased PCT concentration indicates the continuous existence of infection.
yielding calcitonin (Fig. 1) [12–14]. The discovery of elevated PCT levels in patients who have undergone thyroidectomy suggests an origin other than PCT [5]. The exact sites of PCT creation are unidentified, but it is thought that liver is the chief location. In addition, mRNA of PCT were detected in other tissues such as lung, kidney and testis. Data collected from some studies indicate that hepatocytes following stimulation with tumor necrosis factor-α (TNF-α) and interleukin-6 IL-6, and peripheral blood mononuclear cells following stimulation with lipopolysaccharides (LPS) start the expression of PCT [15–17]. This synthesis appears to be modulated by LPS and pro-inflammatory mediators TNF-α, interleukin-1b (IL-1b), interleukin-2 (IL-2), and IL-6. In vitro and animal models of bacterial infection or endotoxin exposure induce the expression of PCT and other calcitonin precursors by practical experiments in all tested tissues and organs. The first report of increased serum PCT concentrations in sepsis was by Assicot in 1993 [5]. The precise function of PCT is still unclear. It is a protein that is induced during inflammation. From an evolutionary perspective, it must have a physiological role. PCT plays a hypothetical role in the metabolism of calcium, the cytokine network and modulation of NO synthesis. It also plays a ‘non-steroidal analgesic role. Further studies are required to exactly demonstrate physiological role of PCT [9,14]. A correlation between PCT and the calcium metabolism has not been demonstrated. However, septic patients often suffer from hypocalcemia, but the levels of calcium and PCT do not correlate considerably. The hypothetical effect of PCT in calcium metabolism during sepsis is based on the constructional similarity of PCT and calcitonin. PCT contains the amino acid sequence of calcitonin. However, the similarity of the primary structure of the protein chains is less considerable than the distinct differences in secondary and tertiary configuration. A disulphide bridge between cystein residue at positon 1 and 7 forms a circle of seven amino acids at N-terminus of calcitonin. This circle together with hydroxylated proline at C-terminus organize the binding site with a high affinity to the calcitonin receptor. In PCT, the N-terminal fragment is preserved preventing the creation of this bridge. This illustrates the common experimental results in which plasmatic PCT has no affinity with the calcitonin receptors [18]. In healthy individuals, circulating levels of PCT are very low, typically under 0.1 ng/ mL. In viral infections and inflammatory reactions, PCT concentrations increase up to 1.5 ng/mL, but in bacterial infection levels may go > 100,000 times normal levels [19,20]. Bacterial infections induce PCT expression and release into the systemic circulation. This expression is not associated with an increase
3. Method of measurement Diverse methods and analyzers are presently accessible for the assessment of PCT. None of the currently accessible PCT measurement methods, whether in research or market, completely identifies 116amino acid PCT peptide. The majority of assays distinguish portions of PCT and the adjoined section of calcitonin (CT) and calcitonin-carboxyl peptide-I [21]. By an extremely sensitive assay for PCT, the investigators described normal PCT levels in non-infected individual as 0.033 ± 0.003 ng/mL [9]. One of the first, and still generally employed, methods is the immunoluminometric PCT detection. This assay has a practical sensitivity of 0.5 ng/mL, with a recognition limit (evaluation of analytical sensitivity), calculated by indistinctness outline, assessed as being 0.08 ng/mL. Whereas this manual detection will distinguish notably high serum levels of PCT, it may not be sensitive enough to assay slightly or moderately increased PCT levels through early phase of infections. Thus, studies exploring the clinical usefulness of PCT by the immunoluminometric PCT assay (LUMItest®) may be subject to inaccuracy; PCT levels reported as 0.5 ng/mL are not certain yet, considering the fact that the practical sensitivity of 0.5 ng/mL exceeds average standard rate by more than 10-fold. The subsequent production of commercially accessible PCT measurement is based on the principle 2
0.3
Retrospective cohort
3 0.5
Case series
Prospective
Shorten Antibiotic Therapy in Suspected Neonatal
Serial PCT determinations
0.3-10
0.5
Prospective
Retrospective cohort
1
Prospective
Predicts Response to Beta-Lactam
Community acquired pneumonia
0.5
prospective
Acute pyelonephritis
0.9
prospective
Fever without localising signs
0.5
prospective
Osteomyelitis
0.5
0.5
prospective
retrospective cohort
0.55–1.15
prospective
Clinical sepsis in febrile neutropenic children with cancer Bacterial infections in pediatric oncology patients Meningitis
0.1–2.0
0.5
Prospective cohort
prospective
0.5
prospective
Bacteremia among children
0.5–2, 2.1–10 and > 10
prospective
sepsis
PTC cut-off (ng/mL)
Study diseign
Type of infection:
126 term and near-term infants suspected early-onset sepsis in the first 3 days of life and treated with empiric antibiotic therapy
125 consecutive children aged 1 month to 16 years who
88 patients (aged 2 months to 13 years) admitted to hospital for severe community acquired febrile pneumonia 119 children admitted for radiographically documented CAP aged 1 year to 14 years, without chronic diseases.
One-hundred patients aged 1 month–14 years old with documented UTI
64 patients aged 2 weeks to 3 years, admitted to pediatric department with febrile UTI.
124 patients younger of 3 years whit fever without localizing signs.
339 patients(1 month to 14years)
167 patients
198 patients
43 febrile neutropenic episodes from 29 patients.
Thirty-two patients with a
159 hospitalized children with pneumonia
183 neonates with clinical sepsis
185 premature infants in the neonatal ICU
Thirty‐eight neonates with clinical, suspected and proven sepsis
Study population
Table 1 Overview of some studies investigating the PCT as indicator in different type of pediatric infection.
PCT is the best independent biologic predictor of favourable response to beta-lactam therapy in children Serial PCT determinations allow shortening the duration of antibiotic therapy in term and near-term infants with suspected early-onset sepsis.
PCT is not able to predict the extent of chest X-ray infiltration and ultimately the severity of the
PCT concentration, with a
PCT is not a good screening test for identifying skeletal infection in children. PCT offers a suitable sensitivity and specificity in predicting severe bacterial infections in children with fever without localising signs. The admission PCT test has a high sensitivity and specificity for differencing acute pyelonephritis from lower UTI in infants and children. A semi-quantitative rapid test for PCT has a high sensitivity and specificity for the differentiation of
PCT may be practical in recognizing bacteraemia among children hospitalized with CAP PCT is sensitive and specific early indicator of bacteremia in children with FN. Serial detection improve the indicative accuracy of PCT, After 24–148 h, PCT was considerably increased during bacterial infection. Mucositis did not cause significant changes in PCT levels. The PCT level is a strong predictor for differentiate between bacterial and aseptic meningitis. PCT had prognostic value to differentiate between bacterial and aseptic meningitis.
Usefulness of the PCT to establish an early identification of neonatal sepsis PCT in combination with serum amyloid A(SAA) is appropriate in finding and follow-up of sepsis in preterm infants PCT is not adequately trustworthy to be the sole indicator of neonatal sepsis. It would be helpful as part of full sepsis assessment.
Main finding
[91]
[90]
[89]
[52]
[63]
[61]
[64]
[37]
[42]
[45]
[19]
[72]
[88]
[87]
[86]
[85]
Refs.
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5. Meningitis
of time-resolved amplified cryptate emission (TRACE) technology. This particular assay uses a sheep polyclonal anti-calcitonin antibody and a monoclonal anti-Catacalcin antibody, whereby PCT molecules bind to these antibodies. The antibodies are labeled with fluorescent tracers, europium cryptate (donor) and XL665 (acceptor), and the creation of the PCT–antibody composite results in an energy transport between the two tracers which is accompanied by an amplification. This particular PCT evaluation has a diagnostic sensitivity of 0.019 ng/mL, while the functional assay sensitivity has been evaluated as 0.06 ng/mL. Additional commercial assays by Siemens Healthcare Diagnostics Company, Tarrytown Company, NY Company, and Roche Diagnostics company, Indianapolis Company and IN Company are in development. PCT®-Q (BRAHMS, Thermo Scientific, Germany) is a point-of-care application of PCT; nevertheless, this test is not approved for use in the United States of America (USA) by the Food and Drug Administration (FDA). This test has the advantage of near-patient testing and can detect circulating PCT levels within 30 min without the need for a complex analyzer or calibration [21]. Usually, a PCT level ≥0.5 ng/mL is considered to be positive for the diagnosis of a bacterial infection [23,24] (Table 1). The semi-quantitative PCT test may be a poor tool for the sequential evaluation of a patient’s condition because the test kit provides only an estimate of serum PCT levels [23,25]. Since most available PCT assays currently use antibodies directed towards internal epitopes of PCT, they are unable to detect their amino-terminal variants [21].
Bacterial meningitis, an inflammation of the meninges, affects the pia, arachnoid, and subarachnoid space. It occurs in reaction to bacteria and bacterial products. This disease has been a significant reason of mortality and morbidity in neonates and children. However, mortality and morbidity vary by age and geological region of the patient and the causative pathogen [38,39]. In emergency cases, direct Cerebral Spinal Fluid (CSF) assessment gives data of bacterial meningitis in only 50–80% of cases [40]. It is well known that other techniques applied for identification, such as Polymerase Chain Reaction (PCR), immunological, and biochemical methods have their own restrictions [41]. PCT is a practical supplementary variable for distinguishing bacterial from non-bacterial meningitis. Acute meningitis is predominantly aseptic (82–94%) and in some cases bacterial (6–18%). Aseptic meningitis includes a syndrome of meningeal inflammation in which common bacterial pathogens cannot be recognized in the CSF, which can induce limitations spontaneously. Bacterial meningitis is sometimes fatal and commonly associated with severe neurological complications, especially when the diagnosisand treatment are late [42,43]. In patients with non-bacterial meningitis, PCT value does not increase even in cases of viral sepsis. Elevated PCT levels indicate a bacterial source with high specificity (Table 1), but false-negative results can happen. PCT assessment have been reported to be a reliable tool for differentiation between viral and bacterial meningitis in children, but have not been systematically explored in adults [44]. Determination of PCT level had 99% sensitivity (95% confidence interval, 97%–100%) and 83% specificity (95% confidence interval, 76%–90%) for differentiation between bacterial and aseptic meningitis [45]. In addition to PCT concentration in serum, PCT level in CSF can be very practical in the recognition of bacterial meningitis from viral meningitis and other noninfectious syndromes. Determination of PCT in CSF offers supplementary data to the clinician and authorizes the option for initiating antibiotic therapy, both of which are necessary in managing bacterial meningitis [41]. Henry et al.′s meta-analysis demonstrates that serum PCT evaluation is a highly valid and influential test for speedily distinguishing between bacterial and viral meningitis in children [46].
4. Sepsis and septic arthritis Bacterial sepsis is the most frequent fatality reason in infants and children in both developing and developed countries [26,27]. Early recognition of the absence of infection would reduce the number of children started on antibiotics, shorten the duration of hospitalization, and minimize the probability for appearance of resistant organisms [27,28]. Timely diagnosis and treatment with suitable antimicrobial chemotherapy is of paramount importance to decrease morbidity and mortality associated with sepsis [14]. It has been reported that the concentration of PCT is more significantly elevated in children with sepsis than in controls. PCT is reported as an appropriate indicator of bacterial sepsis [27,29] (Table 1). PCT offers improved specificity compared to C- reactive protein (CRP) and serum amyloid A(SAA) for distinguishing between viral and bacterial etiologies of fever, with similar sensitivity [27,29]. PCT offers better sensitivity and specificity than CRP to differentiate between invasive and noninvasive infections [29,30]. In early inception sepsis, PCT offers a sensitivity of 92.6% and a specificity of 97.5%. PCT appears to be a very specific and sensitive indicator of early-onset neonatal sepsis and, therefore PCT determinations are detected in the subsequent 24 h. In late-onset sepsis (3–30 days), PCT provides a sensitivity and specificity of 100% in the detection of bacterial sepsis [31]. Although it had a high specificity for neonatal infection, CRP was often normal early in the course of sepsis [32,33]. Franz demonstrated that a combination of IL-8 and CRP was a more useful marker than PCT for the diagnosis of bacterial infection [34]. Infections of bones and/or joints are infrequent but potentially serious emergencies that are associated with considerable mortality and morbidity. Postponed or insufficient treatment can result in irreparable joint destruction, and case fatality rate is estimated to be almost 11%. Thus, early identification as well as quick and efficient treatment are fundamental for avoiding severe outcomes. However, septic arthritis may be complicated to identify in particular conditions and in certain populations, such as among children and the elderly [35]. Aviel et al. reported PCT to be a helpful indicator in the diagnosis of osteomyelitis, but not in septic [36]. Because of its low sensitivity, PCT cannot be applied as a screening marker for diagnosis of skeletal infections in children, with the conventional cut-off of 0.5 ng/mL [37].
6. Community-acquired pneumonia Community-acquired pneumonia (CAP), caused by viruses, ‘typical’ respiratory bacteria (such as Streptococcus pneumoniae) or ‘atypical’ respiratory bacteria (such as Mycoplasma pneumoniae and Chlamydia pneumoniae) is a frequent local infection in childhood [47]. Pneumonia is an important cause of fatality for children around the world, accounting for about 30% of all childhood deaths. A particular pathogen is not identified in most cases, but both viruses mainly respiratory syncytial and influenza viruses and bacteria, especially S. pneumoniae and Haemophilus influenzae, are significant pathogens [48]. Numerous bacteria and viruses and their mixtures can cause this infection, but there is an absence of speedy and commercially accessible diagnostic tests for most agents, which may clarify why the etiology is infrequently recognized in clinical practice and why antibiotic therapy is empirical in the majority of cases. Up to 60% of the cases are viral infections, thus unnecessary and useless antibiotic therapy may often be administrated [49,50]. Microbe-specific diagnosis, based on culture of blood, fluid, or samples obtained directly from the focus of infection in the lungs, is possible only in a small minority of CAP cases. In papers published over the last 15–20 years, serological tests based on antigen, antibody and immune complex detection have been used for microbe-specific diagnosis of CAP in children [47,51]. Several studies are available on describing the detection of lower respiratory infection etiology using PCT as a marker (Table 1). However, the findings of these studies are not in agreement. Moulin et al. described that PCT concentration, with a threshold of 1 μg/l, is more 4
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sensitive and specific and has greater positive and negative prognostic values than CRP, IL-6, or White blood cells (WBC) count for differentiating bacterial and viral causes of CAP in untreated children admitted to hospitals as emergency cases [52]. Results of Toikka et al.′s study indicated the quantity of serum PCT, CRP, and Interleukin-6 (IL6) has little value in the differentiation of bacterial and viral pneumonia in children. However, in some patients with very high serum PCT, CRP, or IL-6 values, bacterial pneumonia is possible [53]. Galetto-Lacour described that the association of increased PCT with a positive pneumococcal urinary antigen is a strong predictor of pneumococcal -CAP [54]. Zhu et al. indicated that PCT level in peripheral blood is a significant diagnostic indicator of pediatric bacterial infections and a sensitive marker of difference between bacterial and non-bacterial pneumonia, therefore being of great importance for clinical and differential diagnosis [55]. Other studies showed that the PCT-guided treatment of supposed lower respiratory tract infection substantially decreased antibiotic administration without compromising clinical or laboratory outcomes [10]. Massimiliano et al. confirmed earlier studies representing that serum PCT is incapable to discriminate between bacterial and viral CAP in children, the conclusion being similar in both ambulatory and hospitalized children at different ages [47]. Serum PCT is more elevated in invasive bacterial infections, such as bacterial meningitis or septicemia, than in less invasive localized bacterial infections, such as Urinary tract infections (UTIs) or pneumonia [47]. The quantity of serum PCT seems to be valuable in the evaluation of the severity of pneumonia, when data have to be deduced together with other clinical illumination (such as general circumstance, findings in clinical assessment and in chest radiographs) and with other non-specific host-response indicators (such as WBC count and CRP) [47].
laboratory indicators that could correctly distinguish severe bacterial infection from localized or viral infections in young children with fevers without a source, but a reliable indicator has not been recognized yet [65–67]. Many clinical studies have dealt with this difficulty and the combination of a clinical scoring system such as that of MaCarthy with a total and deferential leukocyte count and detection of the inflammatory marker are used as screening techniques [64,68,69]. Compared to generally applied screening means including IL-6, IL-8, and IL-1 receptor antagonist, PCT and CRP present a superior sensitivity and specificity in predicting severe bacterial infection in children with fever without localizing signs [64,65,69]. In an evaluation of regularly used screening means such as clinical McCarthy, Lacour et al. reported that the total and deferential leukocyte count and CRP as well as other inflammatory indicators such as IL-6, IL-1Ra, and IL-8, PCT offer a slightly better sensitivity (93%) and specificity (78%) in forecasting a severe bacterial infection in children with fever without localizing signs, and may be used alone in primary screening [64]. Results of a meta-analysis study carried by Chia-Hung et al. indicated PCT is better than CRP for detecting serious bacterial infection among children with fever without source [65]. Fever is not only observed in the course of bacterial or viral infections, but can be a symptom of some non-infectious medical disorders such as autoimmune, malignant, or thromboembolic diseases. Traditional indicators with sufficient sensitivity and specificity are important in the discrimination between infectious and non-infectious causes of fever and in making treatment decisions. PCT seems to be the most helpful laboratory marker for this purpose, particularly for the differentiation between infectious causes of fever and autoimmune, autoinflammatory, and malignant disorders [70] (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, cultureconfirmed UTI by six years of age [56,57]. Findings of UTI are often not straightforward in pediatric application. Infection of the lower area is more likely to extend to the upper tract and kidneys in children than in adults [1,58,59]. The unclear character of symptoms among febrile infants and young children provides the clinical discrimination of upper and lower UTI complications. However, true identification and early therapy of sever pyelonephritis are vital due to its involvement with renal scarring [60]. PCT quantity might be a practical and useful indicator for the identification of sever pyelonephritis in infants and children [61]. Several studies described that the assessment of PCT test has a high sensitivity and specificity for distinguishing acute pyelonephritis from lower UTI compared with other markers in infants and children. The median PCT level was reported to be significantly higher in the acute pyelonephritis [60–63]. PCT assessment might be a practical indicator for the identification of UTIs. However, the accurate position of this biomarker would possibly need to be refined for pediatrics societies so that they agree on an illustration of the order and time of examinations after these infections [60]. The quick semiquantitative detection for PCT could be helpful for the management of children with febrile UTI in the pediatric emergency department (ED) where the quantitative assessment procedures of the marker may not be available [63]. PCT value might be a helpful and practical tool for the identification of severe pyelonephritis in infants and children, and offer informed conclusions about parenteral or oral antibiotic therapy in these patients (Table 1).
Cancer patients treated with chemotherapy often have a phase with neutropenia and a reduced immune response to bacterial pathogens. As an outcome of high morbidity and mortality caused by bacteremia in these patients, the standard treatment throughout fever is hospital admittance and intravenous broad-spectrum antibiotics for at least 5 days [71]. Early identification of sepsis in patients with febrile neutropenia remains complicated due to unclear clinical and laboratory signs of infection [72,73]. The most generally used inflammatory marker, CRP, is relatively slow to increase, and several sequential detections are essential for the most precise identification of infection [74]. Kitanovski, et al.′s result advocates that IL-6 and PCT are more sensitive and specific early markers of bacteremia/clinical sepsis than CRP in children with febrile neutropenic and children with cancer [72]. Plasma PCT concentrations at fever onset should be used and interpreted with caution in febrile patients with chemotherapy-related neutropenia [71]. Martinez-Albarran et al. reported that PTC has 72.2% sensitivity and 80.5% specificity in pediatric patients with cancer and febrile neutropenia. These researchers described PCT as an accurate marker of bacterial infection in neutropenic children, while CRP may be a better screening examination in emergency cases [75]. 10. Monitoring of antibiotic therapy PCT is a relatively novel and pioneering indicator of bacterial infection that has numerous potential applications in the pediatric emergency department (ED) [76,77]. PCT is described as an admirable indicator in distinguishing invasive infections in ED. It can even make early diagnosis of invasive infections if the fever is developed in less than 12 hs. PCT yields enhanced specificity than CRP for distinguishing between the viral and bacterial etiology of the fever. In addition, PCT provides improved sensibility and specificity than CRP to differentiate between invasive and noninvasive infections [29]. Day by day successive PCT detection may be a valuable parameter in monitoring the efficiency of antibiotic administration in burn ICU patients [78]. The
8. Fever without localizing signs Fever without localizing signs in young children remains a complicated diagnostic trouble, since clinical signs and symptoms are frequently unreliable predictors of severe bacterial infection which needs rapid therapeutic interference with intravenous antibiotic therapy [64]. For decades, researchers have made efforts to introduce clinical or 5
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performance of a PCT-based algorithm may decrease antibiotic introduction in seriously ill, septic patients without compromising clinical outcome [79]. The use of serum PCT is applicable to identify invasive infection, to distinguish sepsis from noninfectious systemic inflammatory reaction conditions, and to guide antibiotic administration. Antibiotic treatment tailored to sequential PCT assessments may reduce the antibiotic exposure without increasing treatment failure [80].
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11. The appropriate use of PCT as a marker Application of PCT in the identification of neonatal infection is complicated, because some conditions such as respiratory distress syndrome, haemodynamic malfunction, and perinatal asphyxia can lead to elevated serum PCT levels that are not different from those of septic infants up to 48 h after the onset of clinical signs of distress or infection [33,81]. In addition, a physiological boost of PCT level has been documented up to 48 h postpartum [77,82]. Thus, the exercise of PCT as an indicator of neonatal bacterial infection is problematic in several aspects, and PCT cannot be presented as the gold standard [1]. Negative analytical assessment of PCT is not always 100%, and thus a low serum PCT level may falsely guide physicians. Nevertheless, PCT performs better than other accessible markers such as WBC and CRP. Its application might be preferable for identification of infections in the children.[1]. The decision of a single cut-off assessment will continue to be a predicament, since a zone of improbability will exist forever. For application in neonates, age specific indication values, underlying syndrome, and maternal administration of antibiotics should be taken into account. Because of biofilm-forming organisms and low-level inflammatory reactions, subacute types of infective endocarditis or prosthetic valve infective endocarditis may have diverse appearances, and PCT can be false-negative in these conditions [83]. PCT is influenced by a variety of infectious etiologies. In a comparison between Gram-negative and Gram-positives agents, PCT levels were described to be higher in Gram-negatives [84]. 12. Conclusion Application of PCT as an early indicator of bacterial infections in neonates, infants, and children results in appropriate general sensitivity and specificity. It can be considered as an additional tool for the identification of bacterial infections in this group of patients. In addition to favorable sensitivity and specificity, rapid kinetics and association with severity of infection are its other advantages in clinical practice. Funding There is no funding to declare. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Conflict of interest The authors declare that they have no conflicts of interest. References [1] A.M. van Rossum, R. Wulkan, A. Oudesluys-Murphy, Procalcitonin as an early marker of infection in neonates and children, Lancet Infect. Dis. 4 (10) (2004) 620–630. [2] W. Karzai, M. Oberhoffer, A. Meier-Hellmann, K. Reinhart, Procalcitonin—a new indicator of the systemic response to severe infections, Infection 25 (6) (1997) 329–334. [3] D. Gendrel, C. Bohuon, Procalcitonin, a marker of bacterial infection, Infection 25
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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 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Immunologic marker Pediatric infection Procalcitonin Sepsis Bacteria
Timely recognition of systemic bacterial infections in pediatric care setting is the basis for effective treatment and control. This review provides an overview of procalcitonin (PCT) as an early marker for the detection of severe, invasive bacterial infection in children. Almost all articles on biochemical property and clinical studies in PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of bacterial infections were examined. Various methods and analyzers are currently available for the evaluation of 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 appropriately, 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 infection so as to assist more cautious selection of appropriate therapy [10]. It is crucial to limit the use of antibiotics to decrease the expansion of antibiotic resistant bacteria, reduce complications and expenses, and prevent unnecessary admittance to hospitals for the use of parental antibiotics in viral infections [1]. This review was done in order to optimize the potential clinical applications of this important marker in pediatric infections. To achieve this objective, almost all articles on biochemical property and clinical studies in PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of bacterial infections were examined.
Rapid identification and management of systemic bacterial infections are fundamental in neonates, infants, and children. Indeed, a postponement in the treatment of severe bacterial infections may have a poor outcome. Distinguishing between a severe bacterial infection and a localized bacterial or a viral infection can be highly critical in treatment options [1]. Sometimes, it is a challenge even for highly experienced pediatricians [1]. Procalcitonin (PCT), the precursor molecule of calcitonin, is a 116-amino-acid peptide without a recognized hormonal property [2]. Serum levels of PCT are low or untraceable in the serum of healthy individuals [3]. Severe generalized bacterial infections with systemic appearances are coupled with elevated serum PCT. In comparison with viral infections, localized bacterial infections or the inflammatory response of non-infectious source do not, or only fairly, boost PCT levels [2,4]. This boost is frequently associated with the severity of illness and mortality [5,6]. PCT has not proved helpful in differentiating bacterial infection intensive care unit (ICU) patients because its levels in these conditions increase [7–9]. Since resistance to antibiotics among bacteria is a significant public health trouble, and indiscriminate administration of antimicrobial drugs has been
⁎
2. Procalcitonin Although PCT is the precursor for calcitonin, their biologic behaviors are noticeably different [11]. In C cells of the thyroid gland and K cells of the lung, increased levels of serum calcium concentrations or neoplastic altering result in the transcription of PCT genes. Consequently, the ribosomal synthesis of the 13 kD 116-amino-acid PCT molecule arises, with the successive cleavage of amino acids 60 to 91
Corresponding author. E-mail address: Kafi[email protected] (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
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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 translation product is pre-procalcitonin, which then changes by different modification steps into PCT [92].
in calcitonin [14]. PCT levels increase in patients suffering from neuroendocrine tumors (i.e., medullary thyroid cancer) and small cell cancer of the lung carcinoid tumor. This increase is associated with an elevated level of calcitonin. Therefore, in this condition the simultaneous increase of both PCT and calcitonin indicates the presence of tumors and is independent of infection [9]. PCT elevated levels in this patient might be associated with false positive indication of infection and inappropriate treatments. PCT concentration increases from 3 to 4 h, reaches climax at about 6 h and then plateau for up to 24 h [16]. PCT is degraded by particular protease and has a half-life of 25–30 h [14]. Serum PCT concentrations decline quickly for the duration of antibiotic therapy, and serial assays are practical in order to check the response to treatment [21]. PCT was indicated to be of superior prognostic value for microbial infections and mortality than several medical variables used in the description of systemic inflammatory response syndrome (abnormal temperature, tachycardia, tachypnea, and abnormal white blood cell counts) [22]. Persistently, increased PCT concentration indicates the continuous existence of infection.
yielding calcitonin (Fig. 1) [12–14]. The discovery of elevated PCT levels in patients who have undergone thyroidectomy suggests an origin other than PCT [5]. The exact sites of PCT creation are unidentified, but it is thought that liver is the chief location. In addition, mRNA of PCT were detected in other tissues such as lung, kidney and testis. Data collected from some studies indicate that hepatocytes following stimulation with tumor necrosis factor-α (TNF-α) and interleukin-6 IL-6, and peripheral blood mononuclear cells following stimulation with lipopolysaccharides (LPS) start the expression of PCT [15–17]. This synthesis appears to be modulated by LPS and pro-inflammatory mediators TNF-α, interleukin-1b (IL-1b), interleukin-2 (IL-2), and IL-6. In vitro and animal models of bacterial infection or endotoxin exposure induce the expression of PCT and other calcitonin precursors by practical experiments in all tested tissues and organs. The first report of increased serum PCT concentrations in sepsis was by Assicot in 1993 [5]. The precise function of PCT is still unclear. It is a protein that is induced during inflammation. From an evolutionary perspective, it must have a physiological role. PCT plays a hypothetical role in the metabolism of calcium, the cytokine network and modulation of NO synthesis. It also plays a ‘non-steroidal analgesic role. Further studies are required to exactly demonstrate physiological role of PCT [9,14]. A correlation between PCT and the calcium metabolism has not been demonstrated. However, septic patients often suffer from hypocalcemia, but the levels of calcium and PCT do not correlate considerably. The hypothetical effect of PCT in calcium metabolism during sepsis is based on the constructional similarity of PCT and calcitonin. PCT contains the amino acid sequence of calcitonin. However, the similarity of the primary structure of the protein chains is less considerable than the distinct differences in secondary and tertiary configuration. A disulphide bridge between cystein residue at positon 1 and 7 forms a circle of seven amino acids at N-terminus of calcitonin. This circle together with hydroxylated proline at C-terminus organize the binding site with a high affinity to the calcitonin receptor. In PCT, the N-terminal fragment is preserved preventing the creation of this bridge. This illustrates the common experimental results in which plasmatic PCT has no affinity with the calcitonin receptors [18]. In healthy individuals, circulating levels of PCT are very low, typically under 0.1 ng/ mL. In viral infections and inflammatory reactions, PCT concentrations increase up to 1.5 ng/mL, but in bacterial infection levels may go > 100,000 times normal levels [19,20]. Bacterial infections induce PCT expression and release into the systemic circulation. This expression is not associated with an increase
3. Method of measurement Diverse methods and analyzers are presently accessible for the assessment of PCT. None of the currently accessible PCT measurement methods, whether in research or market, completely identifies 116amino acid PCT peptide. The majority of assays distinguish portions of PCT and the adjoined section of calcitonin (CT) and calcitonin-carboxyl peptide-I [21]. By an extremely sensitive assay for PCT, the investigators described normal PCT levels in non-infected individual as 0.033 ± 0.003 ng/mL [9]. One of the first, and still generally employed, methods is the immunoluminometric PCT detection. This assay has a practical sensitivity of 0.5 ng/mL, with a recognition limit (evaluation of analytical sensitivity), calculated by indistinctness outline, assessed as being 0.08 ng/mL. Whereas this manual detection will distinguish notably high serum levels of PCT, it may not be sensitive enough to assay slightly or moderately increased PCT levels through early phase of infections. Thus, studies exploring the clinical usefulness of PCT by the immunoluminometric PCT assay (LUMItest®) may be subject to inaccuracy; PCT levels reported as 0.5 ng/mL are not certain yet, considering the fact that the practical sensitivity of 0.5 ng/mL exceeds average standard rate by more than 10-fold. The subsequent production of commercially accessible PCT measurement is based on the principle 2
0.3
Retrospective cohort
3 0.5
Case series
Prospective
Shorten Antibiotic Therapy in Suspected Neonatal
Serial PCT determinations
0.3-10
0.5
Prospective
Retrospective cohort
1
Prospective
Predicts Response to Beta-Lactam
Community acquired pneumonia
0.5
prospective
Acute pyelonephritis
0.9
prospective
Fever without localising signs
0.5
prospective
Osteomyelitis
0.5
0.5
prospective
retrospective cohort
0.55–1.15
prospective
Clinical sepsis in febrile neutropenic children with cancer Bacterial infections in pediatric oncology patients Meningitis
0.1–2.0
0.5
Prospective cohort
prospective
0.5
prospective
Bacteremia among children
0.5–2, 2.1–10 and > 10
prospective
sepsis
PTC cut-off (ng/mL)
Study diseign
Type of infection:
126 term and near-term infants suspected early-onset sepsis in the first 3 days of life and treated with empiric antibiotic therapy
125 consecutive children aged 1 month to 16 years who
88 patients (aged 2 months to 13 years) admitted to hospital for severe community acquired febrile pneumonia 119 children admitted for radiographically documented CAP aged 1 year to 14 years, without chronic diseases.
One-hundred patients aged 1 month–14 years old with documented UTI
64 patients aged 2 weeks to 3 years, admitted to pediatric department with febrile UTI.
124 patients younger of 3 years whit fever without localizing signs.
339 patients(1 month to 14years)
167 patients
198 patients
43 febrile neutropenic episodes from 29 patients.
Thirty-two patients with a
159 hospitalized children with pneumonia
183 neonates with clinical sepsis
185 premature infants in the neonatal ICU
Thirty‐eight neonates with clinical, suspected and proven sepsis
Study population
Table 1 Overview of some studies investigating the PCT as indicator in different type of pediatric infection.
PCT is the best independent biologic predictor of favourable response to beta-lactam therapy in children Serial PCT determinations allow shortening the duration of antibiotic therapy in term and near-term infants with suspected early-onset sepsis.
PCT is not able to predict the extent of chest X-ray infiltration and ultimately the severity of the
PCT concentration, with a
PCT is not a good screening test for identifying skeletal infection in children. PCT offers a suitable sensitivity and specificity in predicting severe bacterial infections in children with fever without localising signs. The admission PCT test has a high sensitivity and specificity for differencing acute pyelonephritis from lower UTI in infants and children. A semi-quantitative rapid test for PCT has a high sensitivity and specificity for the differentiation of
PCT may be practical in recognizing bacteraemia among children hospitalized with CAP PCT is sensitive and specific early indicator of bacteremia in children with FN. Serial detection improve the indicative accuracy of PCT, After 24–148 h, PCT was considerably increased during bacterial infection. Mucositis did not cause significant changes in PCT levels. The PCT level is a strong predictor for differentiate between bacterial and aseptic meningitis. PCT had prognostic value to differentiate between bacterial and aseptic meningitis.
Usefulness of the PCT to establish an early identification of neonatal sepsis PCT in combination with serum amyloid A(SAA) is appropriate in finding and follow-up of sepsis in preterm infants PCT is not adequately trustworthy to be the sole indicator of neonatal sepsis. It would be helpful as part of full sepsis assessment.
Main finding
[91]
[90]
[89]
[52]
[63]
[61]
[64]
[37]
[42]
[45]
[19]
[72]
[88]
[87]
[86]
[85]
Refs.
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5. Meningitis
of time-resolved amplified cryptate emission (TRACE) technology. This particular assay uses a sheep polyclonal anti-calcitonin antibody and a monoclonal anti-Catacalcin antibody, whereby PCT molecules bind to these antibodies. The antibodies are labeled with fluorescent tracers, europium cryptate (donor) and XL665 (acceptor), and the creation of the PCT–antibody composite results in an energy transport between the two tracers which is accompanied by an amplification. This particular PCT evaluation has a diagnostic sensitivity of 0.019 ng/mL, while the functional assay sensitivity has been evaluated as 0.06 ng/mL. Additional commercial assays by Siemens Healthcare Diagnostics Company, Tarrytown Company, NY Company, and Roche Diagnostics company, Indianapolis Company and IN Company are in development. PCT®-Q (BRAHMS, Thermo Scientific, Germany) is a point-of-care application of PCT; nevertheless, this test is not approved for use in the United States of America (USA) by the Food and Drug Administration (FDA). This test has the advantage of near-patient testing and can detect circulating PCT levels within 30 min without the need for a complex analyzer or calibration [21]. Usually, a PCT level ≥0.5 ng/mL is considered to be positive for the diagnosis of a bacterial infection [23,24] (Table 1). The semi-quantitative PCT test may be a poor tool for the sequential evaluation of a patient’s condition because the test kit provides only an estimate of serum PCT levels [23,25]. Since most available PCT assays currently use antibodies directed towards internal epitopes of PCT, they are unable to detect their amino-terminal variants [21].
Bacterial meningitis, an inflammation of the meninges, affects the pia, arachnoid, and subarachnoid space. It occurs in reaction to bacteria and bacterial products. This disease has been a significant reason of mortality and morbidity in neonates and children. However, mortality and morbidity vary by age and geological region of the patient and the causative pathogen [38,39]. In emergency cases, direct Cerebral Spinal Fluid (CSF) assessment gives data of bacterial meningitis in only 50–80% of cases [40]. It is well known that other techniques applied for identification, such as Polymerase Chain Reaction (PCR), immunological, and biochemical methods have their own restrictions [41]. PCT is a practical supplementary variable for distinguishing bacterial from non-bacterial meningitis. Acute meningitis is predominantly aseptic (82–94%) and in some cases bacterial (6–18%). Aseptic meningitis includes a syndrome of meningeal inflammation in which common bacterial pathogens cannot be recognized in the CSF, which can induce limitations spontaneously. Bacterial meningitis is sometimes fatal and commonly associated with severe neurological complications, especially when the diagnosisand treatment are late [42,43]. In patients with non-bacterial meningitis, PCT value does not increase even in cases of viral sepsis. Elevated PCT levels indicate a bacterial source with high specificity (Table 1), but false-negative results can happen. PCT assessment have been reported to be a reliable tool for differentiation between viral and bacterial meningitis in children, but have not been systematically explored in adults [44]. Determination of PCT level had 99% sensitivity (95% confidence interval, 97%–100%) and 83% specificity (95% confidence interval, 76%–90%) for differentiation between bacterial and aseptic meningitis [45]. In addition to PCT concentration in serum, PCT level in CSF can be very practical in the recognition of bacterial meningitis from viral meningitis and other noninfectious syndromes. Determination of PCT in CSF offers supplementary data to the clinician and authorizes the option for initiating antibiotic therapy, both of which are necessary in managing bacterial meningitis [41]. Henry et al.′s meta-analysis demonstrates that serum PCT evaluation is a highly valid and influential test for speedily distinguishing between bacterial and viral meningitis in children [46].
4. Sepsis and septic arthritis Bacterial sepsis is the most frequent fatality reason in infants and children in both developing and developed countries [26,27]. Early recognition of the absence of infection would reduce the number of children started on antibiotics, shorten the duration of hospitalization, and minimize the probability for appearance of resistant organisms [27,28]. Timely diagnosis and treatment with suitable antimicrobial chemotherapy is of paramount importance to decrease morbidity and mortality associated with sepsis [14]. It has been reported that the concentration of PCT is more significantly elevated in children with sepsis than in controls. PCT is reported as an appropriate indicator of bacterial sepsis [27,29] (Table 1). PCT offers improved specificity compared to C- reactive protein (CRP) and serum amyloid A(SAA) for distinguishing between viral and bacterial etiologies of fever, with similar sensitivity [27,29]. PCT offers better sensitivity and specificity than CRP to differentiate between invasive and noninvasive infections [29,30]. In early inception sepsis, PCT offers a sensitivity of 92.6% and a specificity of 97.5%. PCT appears to be a very specific and sensitive indicator of early-onset neonatal sepsis and, therefore PCT determinations are detected in the subsequent 24 h. In late-onset sepsis (3–30 days), PCT provides a sensitivity and specificity of 100% in the detection of bacterial sepsis [31]. Although it had a high specificity for neonatal infection, CRP was often normal early in the course of sepsis [32,33]. Franz demonstrated that a combination of IL-8 and CRP was a more useful marker than PCT for the diagnosis of bacterial infection [34]. Infections of bones and/or joints are infrequent but potentially serious emergencies that are associated with considerable mortality and morbidity. Postponed or insufficient treatment can result in irreparable joint destruction, and case fatality rate is estimated to be almost 11%. Thus, early identification as well as quick and efficient treatment are fundamental for avoiding severe outcomes. However, septic arthritis may be complicated to identify in particular conditions and in certain populations, such as among children and the elderly [35]. Aviel et al. reported PCT to be a helpful indicator in the diagnosis of osteomyelitis, but not in septic [36]. Because of its low sensitivity, PCT cannot be applied as a screening marker for diagnosis of skeletal infections in children, with the conventional cut-off of 0.5 ng/mL [37].
6. Community-acquired pneumonia Community-acquired pneumonia (CAP), caused by viruses, ‘typical’ respiratory bacteria (such as Streptococcus pneumoniae) or ‘atypical’ respiratory bacteria (such as Mycoplasma pneumoniae and Chlamydia pneumoniae) is a frequent local infection in childhood [47]. Pneumonia is an important cause of fatality for children around the world, accounting for about 30% of all childhood deaths. A particular pathogen is not identified in most cases, but both viruses mainly respiratory syncytial and influenza viruses and bacteria, especially S. pneumoniae and Haemophilus influenzae, are significant pathogens [48]. Numerous bacteria and viruses and their mixtures can cause this infection, but there is an absence of speedy and commercially accessible diagnostic tests for most agents, which may clarify why the etiology is infrequently recognized in clinical practice and why antibiotic therapy is empirical in the majority of cases. Up to 60% of the cases are viral infections, thus unnecessary and useless antibiotic therapy may often be administrated [49,50]. Microbe-specific diagnosis, based on culture of blood, fluid, or samples obtained directly from the focus of infection in the lungs, is possible only in a small minority of CAP cases. In papers published over the last 15–20 years, serological tests based on antigen, antibody and immune complex detection have been used for microbe-specific diagnosis of CAP in children [47,51]. Several studies are available on describing the detection of lower respiratory infection etiology using PCT as a marker (Table 1). However, the findings of these studies are not in agreement. Moulin et al. described that PCT concentration, with a threshold of 1 μg/l, is more 4
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sensitive and specific and has greater positive and negative prognostic values than CRP, IL-6, or White blood cells (WBC) count for differentiating bacterial and viral causes of CAP in untreated children admitted to hospitals as emergency cases [52]. Results of Toikka et al.′s study indicated the quantity of serum PCT, CRP, and Interleukin-6 (IL6) has little value in the differentiation of bacterial and viral pneumonia in children. However, in some patients with very high serum PCT, CRP, or IL-6 values, bacterial pneumonia is possible [53]. Galetto-Lacour described that the association of increased PCT with a positive pneumococcal urinary antigen is a strong predictor of pneumococcal -CAP [54]. Zhu et al. indicated that PCT level in peripheral blood is a significant diagnostic indicator of pediatric bacterial infections and a sensitive marker of difference between bacterial and non-bacterial pneumonia, therefore being of great importance for clinical and differential diagnosis [55]. Other studies showed that the PCT-guided treatment of supposed lower respiratory tract infection substantially decreased antibiotic administration without compromising clinical or laboratory outcomes [10]. Massimiliano et al. confirmed earlier studies representing that serum PCT is incapable to discriminate between bacterial and viral CAP in children, the conclusion being similar in both ambulatory and hospitalized children at different ages [47]. Serum PCT is more elevated in invasive bacterial infections, such as bacterial meningitis or septicemia, than in less invasive localized bacterial infections, such as Urinary tract infections (UTIs) or pneumonia [47]. The quantity of serum PCT seems to be valuable in the evaluation of the severity of pneumonia, when data have to be deduced together with other clinical illumination (such as general circumstance, findings in clinical assessment and in chest radiographs) and with other non-specific host-response indicators (such as WBC count and CRP) [47].
laboratory indicators that could correctly distinguish severe bacterial infection from localized or viral infections in young children with fevers without a source, but a reliable indicator has not been recognized yet [65–67]. Many clinical studies have dealt with this difficulty and the combination of a clinical scoring system such as that of MaCarthy with a total and deferential leukocyte count and detection of the inflammatory marker are used as screening techniques [64,68,69]. Compared to generally applied screening means including IL-6, IL-8, and IL-1 receptor antagonist, PCT and CRP present a superior sensitivity and specificity in predicting severe bacterial infection in children with fever without localizing signs [64,65,69]. In an evaluation of regularly used screening means such as clinical McCarthy, Lacour et al. reported that the total and deferential leukocyte count and CRP as well as other inflammatory indicators such as IL-6, IL-1Ra, and IL-8, PCT offer a slightly better sensitivity (93%) and specificity (78%) in forecasting a severe bacterial infection in children with fever without localizing signs, and may be used alone in primary screening [64]. Results of a meta-analysis study carried by Chia-Hung et al. indicated PCT is better than CRP for detecting serious bacterial infection among children with fever without source [65]. Fever is not only observed in the course of bacterial or viral infections, but can be a symptom of some non-infectious medical disorders such as autoimmune, malignant, or thromboembolic diseases. Traditional indicators with sufficient sensitivity and specificity are important in the discrimination between infectious and non-infectious causes of fever and in making treatment decisions. PCT seems to be the most helpful laboratory marker for this purpose, particularly for the differentiation between infectious causes of fever and autoimmune, autoinflammatory, and malignant disorders [70] (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, cultureconfirmed UTI by six years of age [56,57]. Findings of UTI are often not straightforward in pediatric application. Infection of the lower area is more likely to extend to the upper tract and kidneys in children than in adults [1,58,59]. The unclear character of symptoms among febrile infants and young children provides the clinical discrimination of upper and lower UTI complications. However, true identification and early therapy of sever pyelonephritis are vital due to its involvement with renal scarring [60]. PCT quantity might be a practical and useful indicator for the identification of sever pyelonephritis in infants and children [61]. Several studies described that the assessment of PCT test has a high sensitivity and specificity for distinguishing acute pyelonephritis from lower UTI compared with other markers in infants and children. The median PCT level was reported to be significantly higher in the acute pyelonephritis [60–63]. PCT assessment might be a practical indicator for the identification of UTIs. However, the accurate position of this biomarker would possibly need to be refined for pediatrics societies so that they agree on an illustration of the order and time of examinations after these infections [60]. The quick semiquantitative detection for PCT could be helpful for the management of children with febrile UTI in the pediatric emergency department (ED) where the quantitative assessment procedures of the marker may not be available [63]. PCT value might be a helpful and practical tool for the identification of severe pyelonephritis in infants and children, and offer informed conclusions about parenteral or oral antibiotic therapy in these patients (Table 1).
Cancer patients treated with chemotherapy often have a phase with neutropenia and a reduced immune response to bacterial pathogens. As an outcome of high morbidity and mortality caused by bacteremia in these patients, the standard treatment throughout fever is hospital admittance and intravenous broad-spectrum antibiotics for at least 5 days [71]. Early identification of sepsis in patients with febrile neutropenia remains complicated due to unclear clinical and laboratory signs of infection [72,73]. The most generally used inflammatory marker, CRP, is relatively slow to increase, and several sequential detections are essential for the most precise identification of infection [74]. Kitanovski, et al.′s result advocates that IL-6 and PCT are more sensitive and specific early markers of bacteremia/clinical sepsis than CRP in children with febrile neutropenic and children with cancer [72]. Plasma PCT concentrations at fever onset should be used and interpreted with caution in febrile patients with chemotherapy-related neutropenia [71]. Martinez-Albarran et al. reported that PTC has 72.2% sensitivity and 80.5% specificity in pediatric patients with cancer and febrile neutropenia. These researchers described PCT as an accurate marker of bacterial infection in neutropenic children, while CRP may be a better screening examination in emergency cases [75]. 10. Monitoring of antibiotic therapy PCT is a relatively novel and pioneering indicator of bacterial infection that has numerous potential applications in the pediatric emergency department (ED) [76,77]. PCT is described as an admirable indicator in distinguishing invasive infections in ED. It can even make early diagnosis of invasive infections if the fever is developed in less than 12 hs. PCT yields enhanced specificity than CRP for distinguishing between the viral and bacterial etiology of the fever. In addition, PCT provides improved sensibility and specificity than CRP to differentiate between invasive and noninvasive infections [29]. Day by day successive PCT detection may be a valuable parameter in monitoring the efficiency of antibiotic administration in burn ICU patients [78]. The
8. Fever without localizing signs Fever without localizing signs in young children remains a complicated diagnostic trouble, since clinical signs and symptoms are frequently unreliable predictors of severe bacterial infection which needs rapid therapeutic interference with intravenous antibiotic therapy [64]. For decades, researchers have made efforts to introduce clinical or 5
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performance of a PCT-based algorithm may decrease antibiotic introduction in seriously ill, septic patients without compromising clinical outcome [79]. The use of serum PCT is applicable to identify invasive infection, to distinguish sepsis from noninfectious systemic inflammatory reaction conditions, and to guide antibiotic administration. Antibiotic treatment tailored to sequential PCT assessments may reduce the antibiotic exposure without increasing treatment failure [80].
(3) (1997) 133–134. [4] J. Hedlund, L.-O. Hansson, Procalcitonin and C-reactive protein levels in community-acquired pneumonia: correlation with etiology and prognosis, Infection 28 (2) (2000) 68–73. [5] M. Assicot, C. Bohuon, D. Gendrel, J. Raymond, H. Carsin, J. Guilbaud, High serum procalcitonin concentrations in patients with sepsis and infection, Lancet 341 (8844) (1993) 515–518. [6] B. Muller, J.C. White, E.S. Nylén, R.H. Snider, K.L. Becker, J.F. Habener, Ubiquitous expression of the calcitonin-I gene in multiple tissues in response to sepsis 1, J. Clin. Endocrinol. Metab. 86 (1) (2001) 396–404. [7] B.M. Tang, G.D. Eslick, J.C. Craig, A.S. McLean, Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis, Lancet Infect. Dis. 7 (3) (2007) 210–217. [8] R. Agarwal, D.N. Schwartz, Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review, Clin. Infect. Dis. 53 (4) (2011) 379–387. [9] K.L. Becker, R. Snider, E.S. Nylen, Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations, Crit. Care Med. 36 (3) (2008) 941–952. [10] S. Al-Nakeeb, G. Clermont, Procalcitonin testing has the potential to reduce unnecessary antibiotic use in patients with suspected lower respiratory tract infections, Crit. Care 9 (3) (2005) 1–2. [11] K. Becker, E. Nylen, J. White, B. Muller, R. Snider Jr., Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors, J. Clin. Endocrinol. Metab. 89 (4) (2004) 1512–1525. [12] N. Aikawa, S. Fujishima, S. Endo, I. Sekine, K. Kogawa, Y. Yamamoto, S. Kushimoto, H. Yukioka, N. Kato, K. Totsuka, Multicenter prospective study of procalcitonin as an indicator of sepsis, J. Infect. Chemother. 11 (3) (2005) 152–159. [14] E. Carrol, A. Thomson, C. Hart, Procalcitonin as a marker of sepsis, Int. J. Antimicrob. Agents 20 (1) (2002) 1–9. [15] M. Oberhoffer, I. Stonans, S. Russwurm, E. Stonane, H. Vogelsang, U. Junker, L. Jäger, K. Reinhart, Procalcitonin expression in human peripheral blood mononuclear cells and its modulation by lipopolysaccharides and sepsis-related cytokines in vitro, J. Lab. Clin. Med. 134 (1) (1999) 49–55. [16] G. Groothuis, P. Limburg, H. ten Duis, H. Moshage, H. Hoekstra, J. Bijzet, J. Zwaveling, Procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro, Crit. Care Med. 28 (2000) 458–461. [17] M. Meisner, Pathobiochemistry and clinical use of procalcitonin, Clin. Chim. Acta 323 (1) (2002) 17–29. [18] P. Maruna, K. Nedelnikova, R. Gurlich, Physiology and genetics of procalcitonin, Physiol. Res. 49 (2000) S57–S62. [19] K.G. Miedema, E.S. de Bont, R.F.O. Elferink, M.J. van Vliet, C.S.O. Nijhuis, W.A. Kamps, W.J. Tissing, The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia, Support. Care Cancer 19 (10) (2011) 1593–1600. [20] M.S. Niederman, Biological markers to determine eligibility in trials for communityacquired pneumonia: a focus on procalcitonin, Clin. Infect. Dis. 47 (Supplement 3) (2008) S127–S132. [21] S. Riedel, Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis, Diagn. Microbiol. Infect. Dis. 73 (3) (2012) 221–227. [22] A.W. Bossink, A.J. Groeneveld, L.G. Thijs, Prediction of microbial infection and mortality in medical patients with fever: plasma procalcitonin, neutrophilic elastase-α1-antitrypsin, and lactoferrin compared with clinical variables, Clin. Infect. Dis. 29 (2) (1999) 398–407. [23] H. Oshita, J. Sakurai, M. Kamitsuna, Semi-quantitative procalcitonin test for the diagnosis of bacterial infection: clinical use and experience in Japan, J. 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11. The appropriate use of PCT as a marker Application of PCT in the identification of neonatal infection is complicated, because some conditions such as respiratory distress syndrome, haemodynamic malfunction, and perinatal asphyxia can lead to elevated serum PCT levels that are not different from those of septic infants up to 48 h after the onset of clinical signs of distress or infection [33,81]. In addition, a physiological boost of PCT level has been documented up to 48 h postpartum [77,82]. Thus, the exercise of PCT as an indicator of neonatal bacterial infection is problematic in several aspects, and PCT cannot be presented as the gold standard [1]. Negative analytical assessment of PCT is not always 100%, and thus a low serum PCT level may falsely guide physicians. Nevertheless, PCT performs better than other accessible markers such as WBC and CRP. Its application might be preferable for identification of infections in the children.[1]. The decision of a single cut-off assessment will continue to be a predicament, since a zone of improbability will exist forever. For application in neonates, age specific indication values, underlying syndrome, and maternal administration of antibiotics should be taken into account. Because of biofilm-forming organisms and low-level inflammatory reactions, subacute types of infective endocarditis or prosthetic valve infective endocarditis may have diverse appearances, and PCT can be false-negative in these conditions [83]. PCT is influenced by a variety of infectious etiologies. In a comparison between Gram-negative and Gram-positives agents, PCT levels were described to be higher in Gram-negatives [84]. 12. Conclusion Application of PCT as an early indicator of bacterial infections in neonates, infants, and children results in appropriate general sensitivity and specificity. It can be considered as an additional tool for the identification of bacterial infections in this group of patients. In addition to favorable sensitivity and specificity, rapid kinetics and association with severity of infection are its other advantages in clinical practice. Funding There is no funding to declare. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Conflict of interest The authors declare that they have no conflicts of interest. References [1] A.M. van Rossum, R. Wulkan, A. Oudesluys-Murphy, Procalcitonin as an early marker of infection in neonates and children, Lancet Infect. Dis. 4 (10) (2004) 620–630. [2] W. Karzai, M. Oberhoffer, A. Meier-Hellmann, K. Reinhart, Procalcitonin—a new indicator of the systemic response to severe infections, Infection 25 (6) (1997) 329–334. [3] D. Gendrel, C. Bohuon, Procalcitonin, a marker of bacterial infection, Infection 25
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