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Lo Sasso Bruna. and all legal disclaimers that apply to the journal pertain. Bellia Chiara.031 CCA 14122 To appear in: Clinica Chimica Acta Received date: Revised date: Accepted date: 3 July 2015 25 September 2015 30 September 2015 Please cite this article as: Giulia Bivona.1016/j. Ciaccio Marcello PII: DOI: Reference: S0009-8981(15)00440-4 doi: 10. Clinica Chimica Acta (2015). Please note that during the production process errors may be discovered which could affect the content. and review of the resulting proof before it is published in its final form.031 This is a PDF file of an unedited manuscript that has been accepted for publication.cca. Marcello Ciaccio.1016/j.2015.  Procalcitonin and community-acquired pneumonia (CAP) in children Bivona Giulia.09.cca. Luisa Agnello. typesetting.09. doi: 10. The manuscript will undergo copyediting. Bruna Lo Sasso. As a service to our customers we are providing this early version of the manuscript.2015. Chiara Bellia. Concetta Scazzone. Scazzone Concetta. . Agnello Luisa. Procalcitonin and community-acquired pneumonia (CAP) in children.

Agnello Luisa 1. Ciaccio Marcello 1. Dipartimento di Biopatologia e IP Biotecnologie Mediche. Scazzone Concetta 1. 129 90127 Palermo D Italy Fax +39 091 655 3275 TE Tel.ACCEPTED MANUSCRIPT Procalcitonin and community-acquired pneumonia (CAP) in children. Università degli studi di Palermo. SC R 2 UOC Medicina di Laboratorio-CoreLab. MD. Corresponding author: NU Marcello Ciaccio. Bivona Giulia 1. PhD Dipartimento di Biopatologia e Biotecnologie Mediche MA Università degli Studi di Palermo Via del Vespro. Lo Sasso Bruna 1.2 T 1 Sezione Biochimica Clinica e Medicina Molecolare. . AOUP Policlinico P. +39 091 6553296 AC CE P Email: marcello.ciaccio@unipa. Bellia Chiara 1. Giaccone.

T Community-Acquired pneumonia (CAP) has been studied extensively. TE Keywords Abbreviations CE P Procalcitonin. CRP: C-reactive protein. children. specifically its usefulness for distinguishing pneumococcal infections from viral and NU unknown infections. OR: odds ratio . for predicting severity and the correct antibiotic treatment. Among these infections. biomarkers.ACCEPTED MANUSCRIPT Abstract The role of procalcitonin (PCT) as a biomarker for sepsis in adults is well documented. AC AUC: area under the curve. further studies are needed to have better understanding of its role for pediatric CAP D management. CI: confidence interval. procalcitonin. community-acquired pneumonia. children. This paper focuses on the studies performed to identify the best inflammatory biomarker for CAP management. PCT. SC R The PubMed database and the Cochrane Library were used to search for the following keywords: CAP. Thirteen articles were studied to determine the role of PCT in CAP management. ROC: receiving operating characteristic. CAP: community-acquired pneumonia. while its role in infections affecting neonatal children remains controversial. pediatric CAP. and one of the most frequent causes of hospitalization in industrialized countries. MA Although there is an increase in studies confirming the usefulness of PCT in CAP management in children. ESR: erythrocyte sedimentation rate. because it’s the second IP cause of death in children in developing countries. PCT: procalcitonin. WBC: white blood cells.

The 13 remaining articles included 4 observational studies. procalcitonin. The main objective of several clinicians and investigators in this field has been to detect the cause of pneumonia: since bacterial Pneumonia cannot be completely differentiated on D the basis of clinical or chest radiograph findings. children. Background The physiological role of procalcitonin (PCT) remains unknown. 1 prospective control case study. 1 prospective single center randomized study. 1 prospective and descriptive study and 1 review. 2. and one of the most frequent causes of hospitalization in industrialized countries [4]. a protein containing 116 amino acids. Although the significance of serum PCT levels at MA diagnosis is observed in adult systemic inflammation. because it’s the second NU cause of death in children in developing countries. We limited the search to studies published in English. its relevance in pediatric CAP is still uncertain [5]. is normally produced by neuroendocrine cells in the thyroid and lungs at a very low T rate and it is undetectable in serum [1]. Forty-four hits were obtained from PubMed: 30 papers and 1 review that investigate the role of PCT in adults instead of in children were excluded. the same search was performed in the Cochrane Library and 2 articles. This study focuses on the role of PCT in pediatric CAP management. SC R The role of procalcitonin (PCT) as a biomarker for sepsis in adults is well documented. An additional 7 articles. synthesis and secretion of PCT become ubiquitous [2]. Community-Acquired pneumonia (CAP) has been studied extensively. Method AC The PubMed database and the Cochrane Library were used to search for the following keywords: CAP. 3. Inflammatory and infectious injuries stimulate IP overexpression of the CALC1 gene consequently increasing serum PCT. Successively. and that were conducted using clinical case studies. Under these pathologic conditions. 1 prospective cohort study.ACCEPTED MANUSCRIPT 1. 1 review and 2 clinical practice Guidelines were specifically searched for as references for this study’s “background”. were found. it was important to focus on the role of PCT CE P for assessing the severity of the disease and for managing the antibiotic treatment. while its role in infections affecting neonatal children remains controversial [3]. many efforts have been made with the goal to TE improve early detection of etiologic agents via biomarkers. “PCT and disease severity” and “PCT and antibiotic treatment” sections. Among these infections. 1 retrospective single center cohort study. 3 prospective studies. particularly referring to those molecules involved in the inflammatory process. PCT. PCT and CAP etiology . already taken from PubMed.

0. atypical bacterial infections and non-bacteraemic typical bacterial infections. 93%) at a threshold > 2ng/ml. two hypotheses emerged: one confirming the usefulness of PCT in distinguishing the T etiology of CAP. the maximum LR for positive results (15.83. 95% CI 0. the study by Lee et al [9] compared PCT levels and other inflammatory markers between AC bronchopneumonia and lobar pneumonia in 76 children (mean age: 3 years.6). Moulin et al [7] investigated the role of several markers for the rapid identification of bacterial vs viral pneumonia in 72 children (inpatients form the ages 2 months to 13 years).85. 27% inpatients). the Galetto-Lacour study [11] confirmed the role of PCT in differentiating the etiology of CAP. 95% CI 0. 89%. 95% CI 0. In 2010. in 126 children (inpatients from the ages of 1 month to 17 years).09 ng/ml vs. NU In 2001. IP In 2000. 54 mg/l p=0. with PCT values ≥1ng/ml and age ≥ 5.80). the sensitivity was 50% and the specificity was >80% for bacterial pneumonia. the other finding no usefulness.3) (LR+) was reached at a cut-off of 2 ng/ml.56 ng/ml. were determined to be independently predictive factors for bacterial CAP (distinction of bacterial from viral etiology of CAP: OR 4. In addition. other inflammatory markers”.16.0.99.ACCEPTED MANUSCRIPT Several Authors [6-14] have investigated the role of PCT as a serum marker for differentiating bacterial and viral CAP in children. the areas under the curves were calculated. elevated PCT and need of hospital care). and interleukin 6 (IL-6) (AUC 0. the three non specific markers of typical bacterial CE P CAP (alveolar infiltration.019) and a CRP (C-reactive SC R Protein) concentration (96mg/l vs.97) than CRP (AUC: 0. inpatients) PCT had a negative predictive value for differentiating bacteraemic infections from viral infections. particularly showing elevated PCT and CRP values to be strongly associated with .8 years. pneumococcal and atypical infections.93. The authors concluded that PCT and CRP values greatly overlapped.73- the Nascimento study [10] showed that in 95 children (aged 26 days to 4. specificity and likelihood ratio (LR). Results for the other inflammatory markers are reported below in the section “PCT vs. 0. finding MA that the PCT value of 1 ng/ml differentiates between bacterial infection and viral pneumonia more effectively (AUC: 0. PCT was useful to differentiate between bacterial and viral infection (58%). D The study by Korppi [8] assessed the value of the clinical features in CAP for differentiating the TE etiology between viral.0. Recently. Using PCT > 2ng/ml. By comparing these characteristics in 101 children (mean age: 4 years. p= 0. Generally.45-0. In 2010. CI 95% 1.08). PCT AUC at the time of admission was 0.84.1. (respectively 95%. inpatients) and investigated the test performance by plotting a Receiver Operating Characteristic curve (ROC). 95% CI 0. the study by Toikka et al [6] showed that patients with bacterial pneumonia had a significantly higher PCT (median 2. individually or combined with other inflammatory markers. expressed in terms of sensitivity.

which were the 25th.5% inpatients) with CAP.5. PCT concentration showed significant . The highest sensitivity was 55% at the 0. With regards to assessing CAP severity via PCT concentrations.0.6. in 2007 Don [20] conducted a prospective study performed on 100 children (mean age: 3. However. 75th and 90th percentile levels.0 ng/ml. Specifically. 50th. mycoplasma/chlamydia. OR: 19.0 ng/ml were tested as screening limits between pneumococcal.ACCEPTED MANUSCRIPT pneumococcal CAP (OR: 23. 18 and 35. TE In the study that included 190 children (aged 0-15. > 5 years: 37%. 26% inpatients) with the goal to evaluate the level of PCT while assessing severity of CAP.5). it IP could be useful to point out the results obtained by Korppi.39 ng/ml) and the mixed pneumococcal infections (0. in the cases of bacterial infections. The results were similar when the single strain pneumococcal infections (0. viral.7 years. The ROC curve showed no cut-off limit with a good sensitivity and specificity for distinguishing between pneumococcal and viral pneumonia (AUC of D serum PCT for differentiating viral from bacterial infections: 0. T In order to discuss the studies with contradicting results [12-14] to the ones previously described. only few Authors [17-19] have looked into the relationship between PCT values and severity for pediatric infectious diseases.49 ng/ml) were analyzed separately. or bacterial sepsis.4. which initially focused on the hypotheses that excluded the role of PCT in distinguishing the infection etiology. such as meningococcal disease and urinary tract infections. 30. PCT values of 0. 95% CI: 5-117. Korppi [13] found no differences between pneumococcal. 4. PCT and disease severity While the relationship between PCT and severity or prognosis has been thoroughly investigated in adults during either systemic infections or CAP [15-16]. viral and unknown pneumonia. no difference between pneumococcal. 95% CI: 5-75. corresponding respectively to 0. 19% inpatients). which is irrelevant. The research by Don et al [14] found no association between PCT levels and etiology in 68 children AC (< 5 years: 63%.0 and 2. the Authors suggested that elevated PCT or CRP values are stronger predictors of pneumococcal CAP when associated with a positive pneumococcal urinary antigen. viral and unknown etiology CE P infections. and for negative results 0. expressed in terms of needing hospital treatment and presence of an alveolar infiltration on chest radiograph. The Likelihood Ratio (LR) for positive results was 2. 1. in 2001. respectively). mixed and unknown CAP patient subgroups was reported in 119 children from a sample of 132 children (mean age: 3 years. The highest specificity MA (88%) was reached at 1. inpatients). at all cut-offs. at a SC R later stage the role of PCT was proven to be useful. as seen above [11-13]. NU 1. Specifically. there is an association between high PCT levels and poor prognosis.5 ng/ml cut-off level. in terms of PCT values.8 ng/ml.6. Particularly.

6.7 ng/ml. The study design implied that all patients were divided into two subgroups: a PCT-guided therapy group. two research groups [6. The study found that the PCT group received significantly fewer courses of antibiotics (85. used PCT measurements to guide antibiotic treatment choices.87) were significantly higher (p< 0. respectively). inpatients) treated with beta lactam in monotherapy. and experienced fewer adverse effects to antibiotic treatment (3. 1-9. Since no biological predictor of clinical response to beta lactam treatment is available. Since each study has been carried out using different methodological approaches. specificity.25 ng/ml).2-2. p=0.0012). individually and in combination. to target Streptococcus pneumoniae. p< 0. In 95% of children with bacterial pneumococcal CAP.8 % vs 100%. from the enrollment criteria to laboratory analysis.31-1. The European and American guidelines [21-22] recommend beta lactam treatment as the first choice in hospitalized children of all ages.ACCEPTED MANUSCRIPT difference in inpatients compared to outpatients (p< 0.1 years.2%. as well as for detecting etiologic features. neutrophil D count and CRP. p<0. rather than without.7 ng/ml. Specifically. IP 5.05).05).4. with the goal to identify the best predictor of clinical response in terms of diagnostic performance (sensitivity.96 days. PCT and antibiotic treatment Antibiotic treatment of CAP in children remains mostly empirical because the identification of SC R etiologic pathogen is difficult in pediatric patients.9% vs 25. apyrexia is NU reached within 48 hours of antibiotic treatment.002. in 2012 Cohen et al [23] performed a retrospective study on 125 MA CAP children (mean age: 3. 0. A multivariate analysis identified PCT and neutrophil count as more reliable predictors than WBC count and CRP CE P (p< 0. likelihood ratio and predictive value) among PCT. other inflammatory markers A great effort has been made in order to assess the role of PCT and other inflammatory non specific markers.54-22. AC The former underwent antibiotic therapy based on PCT values ( 0. PCT levels were significantly higher in children with. by assessing the diagnostic characteristics at different thresholds for each one. WBC count. or in predicting clinical response to antibiotic treatment. a TE response to beta lactam treatment (3.37 vs 10. PCT levels in alveolar CAP (25th-75th percentile: 0. 0. was exposed to antibiotics for less time (5. vs 0. p<0.14] have tested the diagnostic performance of the above-mentioned predictors with the goal to identify the best one. in CAP management. and an evidence-based therapy group. different . Likewise.04).05).04 vs 0.06 and 0.05). PCT vs.13.0003) than levels in interstitial T CAP (25th-75th percentile: 0. An Italian [24] study performed on 319 children (aged 1 month to 14 years.9. in assessing disease prognosis and severity. inpatients).

while the sensitivities with these cut-off values were 50% for PCT. and Moulin [7]. WBC. However. 31% for CRP and 34% for IL-6. The Authors concluded that elevated CRP. As seen before. in TE relation to its usefulness in differentiating viral from bacterial etiology among children with bacteraemic CAP.14 for distinguishing a pneumococcal from viral etiology. and chest radiographic findings for differentiating pneumococcal from viral etiology in 132 children (inpatients from the ages of 1 month to 5 years). CRP. and 3. WBC: 15. viral CAP. The areas under the ROC curves were compared for all of the markers. WBC count and ESR and the etiology of pneumonia. Don et al [14] evaluated the role of the main inflammatory markers. showing IP PCT to be more accurate than IL6. Korppi [25] investigated the role of the combination of four inflammatory markers (PCT.7 for separating pneumococcal from viral CAP. The results were T similar when analyzing the comparison between PCT and IL-6 diagnostic performances.02). chose to evaluate IL-6 in addition to PCT and CRP. CRP >150ng/ml or IL6>40 SC R pg/ml. it had a LR+ of 4.4 in atypical vs. In 2004.04 PCT vs CRP. the sensitivity. Toikka [6]. while it was 3. 75th and 90th percentile values of each marker. When considering PCT alone at 75th percentile (18 ng/ml). In particular. 14]. AC by analyzing the association between five different combinations of PCT. 90mm/h) and WBC at 75th percentile (22cellsx10/L) were significantly associated with the etiology of the infection.003 for PCT vs IL-6. the results of Toikka showed that using PCT > 2ng/ml. values of ESR at 50th and 75th percentile (60 mm/h. D The study by Nascimento-Carvalho [10] evaluated the cytokine IFN- in addition to PCT. The Authors concluded that the presence of IFN- did not add any diagnostic value to PCT in distinguishing between the different etiological groups. 10. CRP.91 for distinguishing atypical from viral CAP. except WBC count: p<0. PCT and WBC had no significant association with the etiology of CAP. excluding cytokines. in 2001. in 2000. PCT: 1 ng/ml. the results reported by NU Moulin showed that the concentration PCT.34 cells x 109/L. Toikka found that CRP and PCT values greatly overlapped. in order to assess the etiology of CAP. the likelihood ratio for positive results (LR+) was 2. 50th. IL6 or white blood cell MA count for differentiating bacterial and viral causes of community-acquired pneumonia. Using the 25th. The results showed that for all four of the marker values > 50th percentile (CRP: 101 mg/L. with a threshold of 2 ng/ml. The results showed an association between the presence of detectable IFN- and CE P PCT<2ng/ml (p< 0. 12. while they conflicted when comparing PCT and CRP. the specificity was >80% for bacterial pneumonia for all the markers. ESR). ESR: 65mm/hr).ACCEPTED MANUSCRIPT cut-offs have been used to assess the diagnostic performance of each marker and to eventually identify the best predictor [6. However. is more sensitive and specific and has greater positive and negative predictive values than CRP. In 2009. specificity and likelihood ratio for . and p< 0.

evaluated by the need for hospital treatment and NU the presence of an alveolar infiltration on chest radiograph. Unfortunately. Cohen [23] performed an analysis of predictors (PCT. or for predicting prognosis of the disease. based on the likelihood ratio value. Nevertheless. and TE assessed the usefulness of PCT compared with the three others markers. leading to controversial results. such as the soluble urokinase plasminogen activator receptor (suPAR). Currently. and that there was a MA good correlation between PCT and CRP (r= 0.ACCEPTED MANUSCRIPT positive results were calculated and. CRP. however in this case there is still no definitive data [26. and to its limited availability. given that it’s a predictor of pneumococcal pneumonia. PCT and CRP have been AC carefully studied and compared. Lee et al [9] T obtained similar results when comparing the same markers in children with lobar pneumonia. The Authors concluded that there was no sensitive and specific combination of these markers that could be used in the clinical pediatric practice.72). They IP found that LR of PCT for diagnosis of lobar pneumonia was maximum at a cut-off value of 2 ng/ml. LR being higher than the CRP level at a cut-off of 6 mg/L (6. was associated with a significant elevation of the average serum PCT concentrations compared to outpatients. most of them involve children with uncomplicated CAP. In addition.59). Among the biomarkers. Conclusion The management of CAP in children still requires useful laboratory tools either for detecting the etiology agent. especially in terms of detection of a pneumococcal infection [29. with regards to D the role of inflammatory markers in predicting clinical response to antibiotic treatment. the most accurate combination was selected. it’s still unknown whether there is an advantage in severe and complicated CAP. WBC (r= 0. 30]. the use of CRP in clinical practice has not been replaced by PCT. other markers for inflammation have been proposed for CAP diagnosis and management. the most recent data showed PCT to be the best performance diagnostic marker. 28]. probably due to its higher cost compared CRP.43). the study by Don [20] showed that the severity of pneumonia. the studies reported in this review have some limitations: firstly. with the goal to start the correct antibiotic treatment sooner and to reduce antibiotic courses. there is an increase in results confirming the usefulness . ESR and WBC count in assessing disease severity. furthermore. 27. WBC count and ESR).8). As mentioned previously. CE P 7. sample sizes are small. With regards the role of PCT. Overall. Thus.9) and the ESR at a cut-off of 30 SC R mm/hr (6. PCT could lead to early beta lactam therapy. and only a moderate correlation with ESR (r= 0. CRP.

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AC    . PCT is a reliable predictor for response to beta-lactam therapy in pediatric CAP.ACCEPTED MANUSCRIPT Highlights CE P TE D MA NU SC R IP T PCT has been proposed for detecting community-acquired pneumonia in children. There is no consensus in the use of PCT in pediatric CAP severity assessment.