PEDIATRICS/ORIGINAL RESEARCH

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1 PEDIATRICS/ORIGINAL RESEARCH Comparison of the Test Characteristics of Procalcitonin to C-Reactive Protein and Leukocytosis for the Detection of Serious Bacterial Infections in Children Presenting With Fever Without Source: A Systematic Review and Meta-analysis Chia-Hung Yo, MD, Pei-Shan Hsieh, BPH, Si-Huei Lee, MD, Jiunn-Yih Wu, MD, Shy-Shin Chang, MD, Kuang-Chau Tasi, MD, MSc, Chien-Chang Lee, MD, MSc From the Department of Emergency Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan (Yo, Tsai); the Department of Rehabilitation and Physical Medicine, Taipei Veteran General Hospital, Taipei, Taiwan (S-H Lee); the Department of Family Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan (Chang); the Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (Chang); the Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan (Wu); and the Department of Emergency Medicine, National Taiwan University Hospital Yunlin Branch, Douliou, Taiwan (Hsieh, C-C Lee). Study objective: We determine the usefulness of the procalcitonin for early identification of young children at risk for severe bacterial infection among those presenting with fever without source. Methods: The design was a systematic review and meta-analysis of diagnostic studies. Data sources were searches of MEDLINE and EMBASE in April Included were diagnostic studies that evaluated the diagnostic value of procalcitonin alone or compared with other laboratory markers, such as C-reactive protein or leukocyte count, to detect severe bacterial infection in children with fever without source who were aged between 7 days and 36 months. Results: Eight studies were included (1,883 patients) for procalcitonin analysis, 6 (1,265 patients) for C-reactive protein analysis, and 7 (1,649 patients) for leukocyte analysis. The markers differed in their ability to predict serious bacterial infection: procalcitonin (odds ratio [OR] 10.6; 95% confidence interval [CI] 6.9 to 16.0), C- reactive protein (OR 9.83; 95% CI 7.05 to 13.7), and leukocytosis (OR 4.26; 95% CI 3.22 to 5.63). The randomeffect model was used for procalcitonin analysis because heterogeneity across studies existed. Overall sensitivity was 0.83 (95% CI 0.70 to 0.91) for procalcitonin, 0.74 (95% CI 0.65 to 0.82) for C-reactive protein, and 0.58 (95% CI 0.49 to 0.67) for leukocyte count. Overall specificity was 0.69 (95% CI 0.59 to 0.85) for procalcitonin, 0.76 (95% CI 0.70 to 0.81) for C-reactive protein, and 0.73 (95% CI 0.67 to 0.77) for leukocyte count. Conclusion: Procalcitonin performs better than leukocyte count and C-reactive protein for detecting serious bacterial infection among children with fever without source. Considering the poor pooled positive likelihood ratio and acceptable pooled negative likelihood ratio, procalcitonin is better for ruling out serious bacterial infection than for ruling it in. Existing studies do not define how best to combine procalcitonin with other clinical information. [Ann Emerg Med. 2012;60: ] Please see page 592 for the Editor s Capsule Summary of this article. A feedback survey is available with each research article published on the Web at A podcast for this article is available at /$-see front matter Copyright 2012 by the American College of Emergency Physicians. SEE EDITORIAL, P INTRODUCTION Fever is a common reason for pediatric visits to the emergency department (ED). Although the majority of patients have minor bacterial or viral infections, it is important to recognize those having serious bacterial infections to provide appropriate care with antibiotics and early hospitalization. 1,2 After history-taking and physical examination, it is estimated that 20% of febrile infants and young children receive a diagnosis of fever without an apparent source of infection. 3 Of these, about 20% may have severe bacterial infection, such as lobar pneumonia, bacteremia, bacterial meningitis, Volume 60, NO. 5 : November 2012 Annals of Emergency Medicine 591

2 Tests for Sources of Serious Bacterial Infections in Children Editor s Capsule Summary What is already known on this topic Only a small subset of febrile children younger than 3 years has a serious bacterial infection, but we lack accurate markers to identify that subset. What question this study addressed A meta-analysis included studies of children younger than 3 years with fever without source. Eight studies with 1,887 cases evaluated procalcitonin as a marker of serious bacterial infection, including bacteremia, pneumonia, and urinary tract infection. What this study adds to our knowledge Procalcitonin performed better than leukocytosis or C-reactive protein at identifying serious bacterial infection, with sensitivity 83% and specificity 69%. How this is relevant to clinical practice Procalcitonin may have some utility in identifying serious bacterial infection, but it is not clear how many of these infections could be identified with other tests such as chest radiograph or urinalysis, or how procalcitonin should be combined with other clinical information. pyelonephritis, or urinary tract infection After the introduction of an effective Hib and PCV7 vaccine, the rate of severe bacterial infection decreased dramatically, with occult bacteremia rates now ranging from 0.02% to 0.7%. 20 However, given the serious outcomes of missed diagnoses, this is still a great diagnostic challenge for clinicians. The risk is greatest among infants and children younger than 36 months, making proper diagnosis and management paramount. For decades, investigators have attempted to find clinical or laboratory markers that can accurately differentiate severe bacterial infection from localized or viral infections in young children with fever without source ; unfortunately, no single, ideal marker has been identified. 7,10,12,13,29-39 The WBC count is routinely recommended as an initial screening marker in children with fever without source. C- reactive protein has been thought to be a more sensitive and specific biomarker than leukocyte count 40,41 ; in addition, procalcitonin, the prohormone of calcitonin, has been shown to distinguish bacterial from viral infections and to correlate well with clinical severity. 4-13,39,42,43 In healthy individuals, circulating levels of procalcitonin are generally very low but can increase by hundreds- to thousands-fold within 4 to 6 hours in response to systemic bacterial infection. During the last decade, numerous studies have evaluated the accuracy of procalcitonin as a marker of severe bacterial infection in children with fever Yo et al without source, and most compared it with C-reactive protein or leukocyte count. The purpose of this study was to quantitatively summarize, by means of a meta-analysis, all existing evidence in the literature from such reports. MATERIALS AND METHODS We adhered to the methods and procedures of the Cochrane Collaboration 44 and the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines 45 for reporting systematic reviews. We performed a comprehensive search of the MEDLINE, EMBASE, and Cochrane databases for pertinent studies published since inception to April Procalcitonin has not yet been listed as a Medical Subject Headings term, so for our initial search, we used procalcitonin as the text word, and we did not set any language restriction. We identified additional references by crosschecking bibliographies of retrieved full-text articles. Study Design We included studies that met all of the following criteria: (1) age range between 7 days and 36 months; (2) evaluation of procalcitonin alone or compared with other laboratory markers, such as C-reactive protein or leukocyte count, to detect severe bacterial infection in children with fever without source; and (3) sufficient data to construct a 2 2 contingency table. We excluded studies having significant overlap (more than 50%) of study patients with the selected studies. Two authors (C.-H.Y. and P.- S.H.) independently assessed all titles and abstracts to determine that inclusion criteria were satisfied. Full-text articles were retrieved if either of the reviewers considered the abstract potentially suitable. The 2 reviewing authors then independently assessed the full text of the retrieved studies for their suitability for inclusion. Discrepancies were resolved by having an additional reviewer (C.-C.L.) assess the full article, and then consensus was reached about inclusion in the meta-analysis. The 2 original reviewers independently extracted data from each study selected. Extracted data comprised the following: overall study characteristics (including the first author, country, language, and date of publication), patient characteristics (including age range and percentage of male patients), quantitative data required for construction of a 2 2 table (including number of participants, sensitivity, specificity, and case number), information about the procalcitonin test (including cutoff levels, quantitative or semiquantitative nature of the test), study settings, and outcomes. The quality of the selected studies was determined using Quality Assessment of Diagnostic Accuracy Studies criteria (Table 1). 46 We consistently used data having the highest sensitivity and performed a sensitivity analysis in which we used the data with the lowest sensitivity instead of the data with the highest sensitivity. Two studies did not report full data required for inclusion in our metaanalysis, and, unfortunately, we did not receive a response from the corresponding authors to our requests. Data Collection and Processing and Primary Data Analysis We used the bivariate random-effects model for diagnostic meta-analysis to obtain weighted overall estimates of the 592 Annals of Emergency Medicine Volume 60, NO. 5 : November 2012

3 Yo et al Tests for Sources of Serious Bacterial Infections in Children Table 1. Quality assessment of diagnostic accuracy studies criteria for included studies. Study ID Spect Select Ref Time Period Vfull Vbias Indep Index Test Testdesc Refdesc Blintest Blinref Clin Indeterm Withdraw Lacour, 2001 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Galetto-Lacour, 2003 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Thayyil, 2005 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Unclear Yes Andreola, 2007 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Guen, 2007 Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Maniaci, 2008 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Unclear Olaciregui, 2009 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes Manzano, 2010 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Unclear Spect, Representative spectrum of patients; Select, selection criteria clearly described; Ref, adequate reference standard; Time Period, short time period between reference and index test; Vfull, all patient verified by reference standards; Vbias, same reference standard used; Indep Index Test, reference independent of index test; Testdesc, adequate index test description; Refdesc, adequate reference test; Blintest, blinding for index test; Blinref, blinding for reference test; Clin, clinical data available; Indeterm, uninterpretable test result reports; Withdraw, withdraw explained. sensitivity and specificity of procalcitonin as a marker for severe bacterial infection in children with fever without source. The bivariate approach assumes a bivariate distribution for the logittransformed sensitivity and specificity. In addition to accounting for study size, the bivariate model estimates and adjusts for the negative correlation between sensitivity and specificity of the index test that may arise from the use of different thresholds in different studies. A further advantage of the bivariate model is that it uses a random-effects approach for sensitivity and specificity, which allows for any heterogeneity beyond chance resulting from clinical and methodological differences between and among studies. A summary receiver operating characteristic curve was constructed as a way to summarize the true- and false-positive rates of the different diagnostic criteria. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio, as well as their corresponding 95% confidence intervals (CIs), were calculated on the basis of the binominal distributions of the true positives and true negatives. We also performed the more conventional diagnostic odds ratio meta-analysis. Unadjusted data were used exclusively in all meta-analyses. Summary diagnostic odds ratios were estimated by random- (DerSimonian-Laird) or fixed-effects models, depending on whether I 2 was greater than 50%. We used a linear regression of log odds ratios on inverse roots of effective sample sizes as a test for funnel plot asymmetry in diagnostic meta-analyses. A nonzero slope coefficient is suggestive of significant small-study bias (P.10). To formally quantify the extent of between-study variation (heterogeneity), we calculated the I 2 statistics. Statistically significant heterogeneity was considered present at I 2 greater than 50%. Sources of heterogeneity then were examined by Galbraith plots and metaregression. We defined a priori the following clinical and design characteristics of a study as potentially relevant covariates: cutoff value, study setting, and age range of the study patients. We performed an exploratory analysis by testing the covariates one at a time in the meta-regression model. Statistical analyses were conducted with Stata (version 10.0; StataCorp, College Station, Figure 1. Flow chart of study identification and inclusion. TX), notably, the midas and metandi commands. All statistical tests were 2-sided, and statistical significance was defined as P.05. RESULTS Our search yielded 1,856 citations, 181 of which were retrieved for full-text review. Of these, 173 articles were excluded, mainly because related exposure or outcomes were not studied or reported (Figure 1). A total of 8 citations were selected for our meta-analysis, 6 citations of which included analysis of C-reactive protein levels and 7 citations for leukocyte Volume 60, NO. 5 : November 2012 Annals of Emergency Medicine 593

4 Tests for Sources of Serious Bacterial Infections in Children Yo et al Table 2. Summary of the characteristics of the included studies. Author, Year, Country Age Range Study Design No. of Participants Prevalence, % Biomarker Tested Lacour, 2001, Switzerland 4 7 days to 36 mo Prospective, observational PCT, CRP, WBC, IL-6, IL-1Ra Galetto-Lacour, 2003, Switzerland 5 7 days to 36 mo Prospective, observational PCT, CRP, WBC, IL-6 Thayyil, 2005, England 6 7 days to 36 mo Prospective, observational PCT, CRP, WBC Andreola, 2007, Italy 7 7 days to 36 mo Prospective, observational PCT, CRP, WBC Guen, 2007, France 8 7 days to 36 mo Prospective, observational PCT, CRP, WBC Maniaci, 2008, USA 9 3 mo Prospective, observational PCT, WBC Olaciregui, 2009, Spain 10 3 mo Prospective, observational PCT-Q, CRP, WBC Manzano, 2010, Canada 11 1 to 36 mo Randomized controlled trial PCT, WBC PCT, Procalcitonin; CRP, C-reactive protein; IL, interleukin; UTI, urinary tract infection. Table 3. Summary of subgroup analysis of the included studies by different study characteristics. Variables Number of Studies Sensitivity (95% CI) Specificity (95% CI) AUROC (95% CI) Procalcitonin Overall analysis ( ) 0.69 ( ) 0.84 ( ) Age 36 mo 4-8, ( ) 0.72 ( ) 0.84 ( ) Cutoff 0.5 ng/ml 5-7,10, ( ) 0.72 ( ) 0.82 ( ) ED setting 4,5,7, ( ) 0.69 ( ) 0.85 ( ) CRP Overall analysis 4-8, ( ) 0.76 ( ) 0.81 ( ) Cutoff 40 mg/l 4,5,7, ( ) 0.76 ( ) 0.81 ( ) Age 36 mo ( ) 0.75 ( ) 0.81 ( ) ED setting 4,5,7, ( ) 0.80 ( ) 0.84 ( ) Leukocyte count Overall analysis 4-8,10, ( ) 0.73 ( ) 0.70 ( ) Cutoff 15,000/mm 3(4-6,8,10,11) ( ) 0.72 ( ) 0.68 ( ) Age 36 mo 4-8, ( ) 0.71 ( ) 0.70 ( ) ED setting 4,5,7,10, ( ) 0.76 ( ) 0.77 ( ) OR, Odds ratio. counts. In total, we included 1,883 patients tested for procalcitonin, 1,265 patients tested for C-reactive protein, and 1,649 patients tested for leukocyte counts. The prevalence of severe bacterial infection in each group was 340 of 1,883 (18.1%), 248 of 1,265 (19.6%), and 310 of 1,649 (18.8%), respectively. We evaluated the quality of included studies using Quality Assessment of Diagnostic Accuracy Studies criteria. The 2 reviewers (C.-H.Y., P.-S.H.) agreed 86% of the time (14 items); the 2 items on which the 2 reviewers disagreed were resolved by a consensus meeting with the 3 coauthors (C.-H.Y., P.-S.H., and C.-C.L.). All studies were prospective, enrolled consecutive outpatients presenting with fever without source, and had an independent reference examination for severe bacterial infection outcome (Table 2). Among the possible sources of bias, about 80% of the studies did not indicate whether physicians were blinded to the index tests when making a final diagnosis of severe bacterial infection. Several studies did not explicitly explain withdrawals, define an acceptable delay between tests, or report uninterpretable results. A small proportion of studies did not adequately describe reference standards or reference tests. No evidence of publication bias was found (Table 3). Characteristics of Study Subjects Table 2 lists study and population characteristics of all 8 patient populations. Most enrolled patients were aged between 7 days and 36 months (Table 2). Patients were treated exclusively in the ED setting in 6 of the 8 studies, and Annals of Emergency Medicine Volume 60, NO. 5 : November 2012

5 Yo et al Tests for Sources of Serious Bacterial Infections in Children Table 2. Continued. Cutoff, PCT, ng/ml; CRP, mg/l; WBC, /mm 3 PCT 0.9, CRP 40, WBC 15,000 PCT 0.5, CRP 40, WBC 15,000 PCT 0.5, CRP 50, WBC 15,000 PCT 0.5; CRP 40, 80; WBC 10,000 PCT 2; CRP 40, 80; WBC 15,000 PCT 0.12, WBC: NA PCT 0.5, CRP 30, WBC 15,000 PCT 0.5, WBC 15,000 Outcomes Patient Setting PCT Sensitivity, Specificity, % CRP Sensitivity, Specificity, % WBC Sensitivity, Specificity, % Bacteremia, pyelonephritis lobar pneumonia, meningitis osteoarthritis ED 92.9, , , 77.1 Bacteremia, pyelonephritis lobar pneumonia, ED 93.1, , , 74.3 meningitis osteoarthritis, deep abscess Bacterial pneumonia, bacterial meningitis, Pediatric unit 87.5, , , 53.1 septicemia/occult bacteremia, pyelonephritis Bacteremia, pyelonephritis, lobar pneumonia, ED 73.4, , , 75.4 bacterial meningitis, bone or joint infections sepsis Occult bacteremia Pediatric unit 57.1, , , 65.9 UTI, bacteremia bacterial meningitis bacterial gastroenteritis bacterial pneumonia ED 96.7, 25.5 NA NA UTI, bacteremia, cellulitis, sepsis, bacterial ED 63.4, , , 78.6 gastroenteritis, pneumonia UTI, pneumonia occult bacteremia, bacterial ED 77.4, 64.0 NA 71.0, 75.1 meningitis, neutropenia ED, emergency department; UTI, urinary tract infection. Table 3. Continued. Positive Likelihood Ratio Negative Likelihood Ratio Diagnostic OR (95% CI) I 2 (95% CI) Publication Bias (Egger s Test P Value) 2.69 ( ) 0.25 ( ) 10.6 ( ) 30.2 (0 68.9) ( ) 0.25 ( ) 9.25 ( ) 47.6 ( ) ( ) 0.31 ( ) 9.38 ( ) 30.9 (0 73.5) ( ) 0.23 ( ) 10.1 ( ) 48.8 (0 79.7) ( ) 0.34 ( ) 9.83 ( ) 45.5 (0 78.4) ( ) 0.35 ( ) 9.49 ( ) 66.0 ( ) ( ) 0.35 ( ) 9.17 ( ) 56.0 (0 83.7) ( ) 0.31 ( ) 11.1 ( ) 0 ( ) ( ) 0.58 ( ) 4.26 ( ) 41.5 ( ) ( ) 0.54 ( ) 5.05 ( ) 33.5 ( ) ( ) 0.58 ( ) 4.04 ( ) 58.8 (0 84.7) ( ) 0.53 ( ) 4.53 ( ) 41.4 ( ).556 included pediatric inpatients. The prevalence of severe bacterial infection in these 8 studies ranged from 3.2% to 29.2%, with a median of 18.1%. Procalcitonin has the best diagnostic accuracy to detect severe bacterial infection among children with fever without source, followed by leukocyte count and C-reactive protein. According to the bivariate model, procalcitonin has greater sensitivity than C-reactive protein or leukocyte count (overall 0.83 [95% CI 0.70 to 0.91], 0.74 [95% CI 0.65 to 0.82], and 0.58 [95% CI 0.49 to 0.67], respectively), and the 3 markers have roughly comparable specificity (overall 0.69 [0.59 to 0.85], 0.76 [0.70 to 0.81], and 0.73 [0.67 to 0.77], respectively) (Table 3). The summary receiver operating characteristic curves of the 3 markers are presented in Figure 2. For studies examining procalcitonin, the study heterogeneity appears to be more dichotomous than a gradation. Three studies 4,5,9 showed strong sensitivity and the rest showed unacceptably poor sensitivity (Figure 2A). Most studies were performed exclusively in the ED environment. The diagnostic odds ratios for procalcitonin, C- reactive protein, and leukocyte count were 10.6 (6.9 to 16.0), 9.83 (7.05 to 13.7), and 4.26 (3.22 to 5.63), respectively (Figure 3). The positive likelihood ratios for procalcitonin, C- reactive protein, and leukocyte count were 2.69 (1.87 to 3.87), 3.10 (2.48 to 3.87), and 2.11 (1.63 to 2.74), respectively. The negative likelihood ratios for procalcitonin, C-reactive protein, and leukocyte count were 0.25 (0.15 to 0.40), 0.34 (0.25 to 0.46), and 0.58 (0.46 to 0.73), respectively. The degree of Volume 60, NO. 5 : November 2012 Annals of Emergency Medicine 595

6 Tests for Sources of Serious Bacterial Infections in Children Yo et al Figure 2. Plot of sensitivity and specificity for studies using procalcitonin (PCT) (A), C-reactive protein (B), or leukocyte count (C) for the detection of serious bacterial infection (SBI) among children with fever without source (FWS), together with the summary receiver operating characteristic curve (solid line) and the bivariate summary estimate (solid square), together with the corresponding 95% confidence ellipse (inner dashed line) and 95% prediction ellipse (outer dotted line). The symbol size for each study is proportional to the study size. The 95% CIs were determined on the basis of the assumption that the 2 variables follow a bivariate normal distribution. The 95% prediction region is based on independent variables, which gives a range of values around which an additional observation of the dependent variable can be expected to be located. consistency was calculated by I 2. The I 2 values for procalcitonin, C-reactive protein, and leukocyte count were 30.2 (95% CI 0 to 68.9), 45.5 (95% CI 0 to 78.4), and 41.5 (95% CI 0 to 75.39), respectively (Table 3). We did not observe a substantial degree of inconsistency in studies included for the meta-analyses for procalcitonin (I %), C-reactive protein (I %), or leukocyte count (I %). We performed subgroup analysis by restricting studies with similar cutoff value, study settings, or 596 Annals of Emergency Medicine Volume 60, NO. 5 : November 2012

7 Yo et al Tests for Sources of Serious Bacterial Infections in Children aged 36 months or younger revealed mildly decreased sensitivity (from 0.83 to 0.82) and moderate improvement in specificity (from 0.69 to 0.72). No significant evidence of potential publication bias was observed by Egger s test for asymmetry of the funnel plot (Table 3). Exploratory meta-regression analysis did not find that any prespecified covariate significantly changed the effect estimate. LIMITATIONS Several limitations must be considered when interpreting the findings of this meta-analysis. By pooling studies dealing with a variety of sample types, clinical settings, and study populations, we may have introduced heterogeneity. Hence, the results of this meta-analysis are applicable mainly to febrile children with fever without source who present to the ED. We conducted multiple comparisons for meta-analysis or subgroup analysis, but the number of studies was too small to protect from type I errors. Not all included studies used the same commercial kit to test for procalcitonin and C-reactive protein, but all were of the immunometric assay type, so the values obtained were assumed to be comparable. Given the imperfect sensitivity and specificity of the procalcitonin test, we do not recommend prescribing empirical antibiotics simply on the basis of the biomarker test results. Instead, we recommend developing an algorithm similar to that developed by Philipp et al for adult pneumonia patients, which interprets gray-zone procalcitonin results (eg, 0.25 to 0.5 ng/ml) in the context of clinical findings. 51 At present, there is no formal cost-effectiveness analysis based on US data. However, an analysis from the United Kingdom shows that procalcitonin incurs an additional cost of 45 to 125 (US $70 to $200) in the treatment course of pneumonia, which is small relative to the overall costs of pneumonia treatment. Moreover, the cost should be weighed against the potential adverse effects of antibiotics and emerging antibiotics resistance. 52 Figure 3. Forest plot of diagnostic odds ratio for studies using PCT (A), C-reactive protein (B), or leukocyte count (C) to detect SBI among children with fever without source. age distribution but did not find significant heterogeneity improvement (Table 3). We used Galbraith plots to determine sources of heterogeneity. The Galbraith plot did not reveal any significant outlying study. The subgroup analysis on patients DISCUSSION The prevalence of severe bacterial infection in children with fever without source who are younger than 3 years is approximately 20% Differentiating the majority of patients who will have a benign course from those who have serious infections poses a great challenge to front-line clinicians. Missed diagnoses may cause delayed administration of antibiotics, potentially having long-term effects on morbidity and mortality. Procalcitonin is a biomarker that has been shown to differentiate bacterial from nonbacterial infection and which correlates well with clinical severity. Several studies have shown that procalcitonin can be used to detect severe bacterial infection in children with fever without source Our study was designed to assess the diagnostic accuracy of the procalcitonin test for detecting severe bacterial infection among pediatric patients presenting with fever without source and to compare it with the more conventional C-reactive protein test and leukocyte count. Our meta-analysis, which included 8 Volume 60, NO. 5 : November 2012 Annals of Emergency Medicine 597

8 Tests for Sources of Serious Bacterial Infections in Children studies comprising a total of 1,883 patients, demonstrated the superior discriminative capability of procalcitonin over conventional laboratory markers, as revealed by area under the summary receiver operating characteristic curve data of 0.84 (95% CI 0.80 to 0.87) for procalcitonin, 0.81 (95% CI 0.78 to 0.84) for C-reactive protein, and 0.70 (95% CI 0.65 to 0.74) for leukocyte count. The diagnostic odds ratio for procalcitonin (10.6; 95% CI 6.9 to 16.0) was also superior to that of C- reactive protein (9.83; 95% CI 7.05 to 13.7) and leukocyte count (4.26; 95% CI 3.22 to 5.63). The positive likelihood ratios for procalcitonin, C-reactive protein, and leukocyte count were 2.69 (95% CI 1.87 to 3.87), 3.10 (95% CI 2.48 to 3.87), and 2.11 (95% CI 1.63 to 2.74), respectively. The negative likelihood ratios for procalcitonin, C-reactive protein, and leukocyte count were 0.25 (95% CI 0.15 to 0.40), 0.34 (95% CI 0.25 to 0.46), and 0.58 (95% CI 0.46 to 0.73), respectively. Procalcitonin outperforms C-reactive protein and leukocyte count in sensitivity rather than specificity, making it a better rule-out diagnostic tool. In a typical ED setting, where prevalence of severe bacterial infection is approximately 20% for febrile children younger than 3 years, the posttest to test probabilities after a positive test result are therefore 40%, 44%, and 35% for procalcitonin, C-reactive protein, and leukocyte count, respectively; those after a negative test are 6%, 8%, and 13%, respectively. The overall positive likelihood ratio (2.69; 95% CI 1.87 to 3.87) for the procalcitonin test was not sufficiently high to be used as a reliable rule-in tool for the diagnosis of severe bacterial infection. For example, in a population with a 20% prevalence (pretest probability) of severe bacterial infection, a positive likelihood ratio of 2.69 translates into a positive predictive value (posttest probability) of 40%. In other words, approximately 2 in 5 patients with positive procalcitonin test results can be expected to have either clinically or microbiologically confirmed severe bacterial infection. The diagnostic value of procalcitonin to rule out severe bacterial infection in children with fever without source performed as well as its rule-in value. In the same population with a 20% prevalence of severe bacterial infection, a negative likelihood ratio of 0.25 translates into a negative predictive value of 94%. In other words, only 1 in 20 patients with negative procalcitonin results will have either clinically or microbiologically confirmed severe bacterial infection. However, given the huge social and medical costs associated with missed severe bacterial infection diagnoses, we recommend the procalcitonin test not be used as a stand-alone test. Several clinical trials show that an algorithm integrating clinical information and procalcitonin results or repeated procalcitonin measurements in clinically suspected cases may further reduce the false-negative rate. Results of studies examining procalcitonin appears to be dichotomous. Three studies 4,5,9 showed strong sensitivity, whereas the rest showed unacceptably poor sensitivity (Figure 2A). However, the Galbraith plot analysis did not show any of the 3 studies to be a significant outlier. The high sensitivity of the study by Maniaci Yo et al et al 9 may be due to the use of a low cutoff value (0.12 ng/ml), whereas the high sensitivity for the other 2 studies 4,5 may well be ascribed to the high prevalence of case patients (22% and 29%, respectively) in the study population. C-reactive protein is an acute-phase protein released by the liver in response to systemic inflammation of infectious or noninfectious cause. 47 Likewise, leukocytosis has long been recognized as a nonspecific marker of systemic infection, tissue damage, or stress events. In contrast, procalcitonin responds specifically to systemic infection, particularly bacterial infection. 48 However, we did not find greater specificity for procalcitonin compared with C-reactive protein. A probable explanation may be the confounding presence in this special group of patients of the relatively few having noninfectious causes for fever without source. Our analysis revealed that procalcitonin outperforms C-reactive protein and leukocyte count mainly in sensitivity. We thought this may be explained by the kinetics of serum levels of procalcitonin and C-reactive protein. In response to systemic infection, procalcitonin is rapidly released from all tissues of the body and peaks as early as 12 to 24 hours after onset, 49 whereas C-reactive protein level increases slowly during the first 12 hours, peaking 48 to 72 hours after infection onset. 47 Unlike adult patients, febrile children, especially febrile infants, are usually brought to the ED within the first few hours of fever onset, which may further reduce the sensitivity of the C-reactive protein test for this group of patients. Although it seems the relatively low sensitivity of serum C-reactive protein for predicting severe bacterial infection may severely limit its value in clinical practice, recent studies have shown that C-reactive protein has an interdependent diagnostic value with the procalcitonin test and that the combination of the procalcitonin test and urine dipstick test provides better accuracy than any single test used alone. 12,50 One study included in our meta-analysis used bacteremia as the only definition of severe bacterial infection, 8 but the others used a broader definition, including bacterial isolation from sterile body fluids or clinical and radiologic criteria highly suggestive of invasive bacterial infection. 4-7,9-13,42 Therefore, our study confirms the usefulness of biomarkers in recognizing all potentially invasive bacterial processes, even in the absence of bacteremia. Variability in the ages of evaluated patients was noted in the included studies. A child s age is important because neonates are more vulnerable to bacterial pathogens and different age groups are susceptible to different pathogenic spectra. This can affect the diagnostic accuracy of the reference standard test. Most of the studies we analyzed included children aged 3 to 36 months as one group, although this age grouping is thought to be arbitrary. Two studies included children younger than 3 months, 9,10 probably because the widely recognized Rochester and Philadelphia criteria emphasize that febrile infants younger than 90 days belong to a specific age group for diagnostic and treatment purposes. Sensitivity analysis and meta-regression did not reveal significant effect modification by 598 Annals of Emergency Medicine Volume 60, NO. 5 : November 2012

9 Yo et al different age ranges. Therefore, it was assumed that the populations of all studies were homogeneous. In summary, our study found that, compared with conventional leukocyte counts and C-reactive protein level, procalcitonin performs better for detecting serious bacterial infection among children with fever without source. Considering the poor pooled positive likelihood ratio and acceptable pooled negative likelihood ratio, procalcitonin is better for ruling out serious bacterial infection than for ruling it in. Existing studies do not define how best to combine the diagnostic value of procalcitonin with other clinical information to improve overall diagnostic accuracy. Supervising editor: Gregory J. Moran, MD Author contributions: C-HY, J-YW, and C-CL were responsible for study concept and design. C-HY, P-SH, S-HL, S-SC, K-CT, and C-CL were responsible for acquisition of data. C-HY, P-SH, S-HL, J-YW, and C-CL were responsible for analysis and interpretation of data. C-HY and C-CL were responsible for drafting the article. K-CT and C-CL were responsible for critical revision of the article for important intellectual content. C-HY, P-SH, and C-CL were responsible for statistical analysis. C-CL takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see The authors have stated that no such relationships exist. Publication dates: Received for publication November 2, Revisions received March 9, 2012, and May 14, Accepted for publication May 17, Available online August 22, Address for correspondence: Chien-Chang Lee, MD, MSc, umealinkoping@yahoo.com.tw. REFERENCES 1. Baraff LJ. Management of infants and young children with fever without source. Pediatr Ann. 2008;37: Baraff LJ. 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Economic Report: Procalcitonin to Differentiate Bacterial Lower Respiratory Infections From Non-bacterial Causes. Centre for Evidence-based Purchasing, London: NHS; Did you know? Podcasts are available for almost every article in Annals. Visit to find out more. 600 Annals of Emergency Medicine Volume 60, NO. 5 : November 2012