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Articles

Procalcitonin as a diagnostic marker for sepsis: a systematic
review and meta-analysis
Christina Wacker, Anna Prkno, Frank M Brunkhorst*, Peter Schlattmann*

Summary
Lancet Infect Dis 2013; Background Procalcitonin is a promising marker for identification of bacterial infections. We assessed the accuracy
13: 426–35 and clinical value of procalcitonin for diagnosis of sepsis in critically ill patients.
Published Online
February 1, 2013
Methods We searched Medline, Embase, ISI Web of Knowledge, the Cochrane Library, Scopus, BioMed Central, and
http://dx.doi.org/10.1016/
S1473-3099(12)70323-7 Science Direct, from inception to Feb 21, 2012, and reference lists of identified primary studies. We included articles
See Comment page 382
written in English, German, or French that investigated procalcitonin for differentiation of septic patients—those
*Contributed equally
with sepsis, severe sepsis, or septic shock—from those with a systemic inflammatory response syndrome of non-
infectious origin. Studies of healthy people, patients without probable infection, and children younger than 28 days
Department of Medical
Statistics, Computer Sciences were excluded. Two independent investigators extracted patient and study characteristics; discrepancies were resolved
and Documentation by consensus. We calculated individual and pooled sensitivities and specificities. We used I² to test heterogeneity and
(C Wacker Cand Med, investigated the source of heterogeneity by metaregression.
A Prkno Cand Med,
Prof P Schlattmann PhD), and
Department of Findings Our search returned 3487 reports, of which 30 fulfilled the inclusion criteria, accounting for 3244 patients.
Anaesthesiology and Intensive Bivariate analysis yielded a mean sensitivity of 0·77 (95% CI 0·72–0·81) and specificity of 0·79 (95% CI 0·74–0·84).
Care Medicine The area under the receiver operating characteristic curve was 0·85 (95% CI 0·81–0·88). The studies had
(Prof F M Brunkhorst MD),
Centre for Sepsis Control and
substantial heterogeneity (I²=96%, 95% CI 94–99). None of the subgroups investigated—population, admission
Care, Jena University Hospital, category, assay used, severity of disease, and description and masking of the reference standard—could account
Jena, Germany for the heterogeneity.
Correspondence to:
Prof Peter Schlattmann, Interpretation Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients. Nevertheless,
Department of Medical Statistics,
the results of the test must be interpreted carefully in the context of medical history, physical examination, and
Computer Sciences and
Documentation, Centre for microbiological assessment.
Sepsis Control and Care, Jena
University Hospital, Funding Ministry of Education and Research, the Deutsche Forschungsgemeinschaft, Thuringian Ministry for
Bachstraße 18, 07743 Jena,
Germany
Education, Science and Culture, the Thuringian Foundation for Technology, Innovation and Research, and the
peter.schlattmann@mti.uni- German Sepsis Society.
jena.de
Introduction Several humoral and cellular systems are activated
Worldwide, sepsis and its sequelae are still a common during sepsis, with a subsequent release of various
cause of acute illness and death in patients with molecules that mediate the host response to infection.
community-acquired and nosocomial infections.1,2 The Several potential bloodstream biomarkers have been
American College of Chest Physicians and the Society investigated for their ability to diagnose sepsis, estimate
of Critical Care Medicine Consensus Conference its severity, and provide a prognosis. The 116-aminoacid
(Northbrook, IL, USA; August, 1991) defined sepsis as polypeptide procalcitonin had been termed the “the
systemic inflammatory response caused by infection.3 champion so far” for identification of bacterial infections8
However, no gold standard exists for proof of infection. because it has several advantages over other potential
Bacteraemia is identified in only about 30% of patients biomarkers—ie, wide biological range, short time of
with sepsis, depending on previous antibiotic treat- induction after bacterial stimulus, and long half-life.9
ment.4,5 Furthermore, early clinical signs of sepsis, such However, only two meta-analyses have investigated the
as fever, tachycardia, and leucocytosis, are non-specific accuracy of procalcitonin for the diagnosis of sepsis, with
and overlap with signs of systemic inflammatory re- conflicting results.10,11 Both were limited by selected
sponse syndromes of non-infectious origin, especially populations, did not include a heterogeneous patient
in patients who have undergone surgery. Other signs, population, and, most importantly, were biased by the
such as arterial hypotension, thrombocytopenia, or choice of a gold standard for the definition of sepsis.
increased lactate concentrations suggest, too late for Additionally, new studies of procalcitonin have been
life-saving treatment, progression to organ dysfunction. done since the publication of the meta-analyses and our
Thus, delay in diagnosis and treatment of sepsis in- understanding of procalcitonin is still developing.
creases mortality, prolongs length of hospital stay, and We did a meta-analysis to investigate the ability
increases costs,6,7 highlighting the need for early and of procalcitonin to differentiate between sepsis and
reliable diagnostic biomarkers for sepsis. systemic inflammatory response syndromes of

426 www.thelancet.com/infection Vol 13 May 2013

thelancet. Methods admission category (surgical or medical). false negatives. expert opinions. setting (emergency department. 166 full-text reviews We only included publications written in English. 30 studies included in meta-analysis including the quality assessment from the retrieved studies. and 93 reference group or control group did not correspond to editorials were excluded. Studies checklist. Articles non-infectious origin in critically ill patients and address The extracted data were general and detailed the heterogeneity of patients and the affect of individual methodology characteristics. needed. and true negatives in patients with sepsis and patients with sepsis from those who have a systemic systemic inflammatory response syndrome. Animal experiments. the studies had to provide sufficient 2280 not relevant* information to construct the 2×2 contingency table—ie. the study was excluded. 2012. we also quality scoring is difficult and should not be included in used the search terms “NOT (review OR letter OR meta-analyses. or intensive care unit). Embase (via OvidSP). ISI Web of Knowledge. 136 did not meet the selection criteria correspondences. or French.15 we included only item 9 (description of editorial OR “animal experiment” OR “meeting abstract” the reference standard) and item 11 (diagnostic review OR “proceeding paper” OR “poster presentation” OR bias) of the 14 individual quality-related items as “meta-analysis” OR “case report”)”. severity of Search strategy and selection criteria illness (sepsis. and details We systematically searched Medline (via PubMed). the presence of infection had to be microbiologically confirmed or at least clinically suspected because of one or more 3321 excluded on the basis of title or abstract characteristics: white blood cells in a normally sterile 64 animal experiments 76 case reports body fluid. stratified by inflammatory response syndrome without infection. if agreement could not be reached. German. reference standard for sepsis. Scopus. and children younger than 28 days. 3 language other than English. If no response was received after sending a Our medical subject heading terms (for Medline). We contacted the Direct for studies that assessed the accuracy of pro.13 We tailored the guidelines for scoring drome” OR SIRS)”. diagnostic accuracy of procalcitonin as a marker for sepsis. German. population (adults or children). www. and Science and false positives and negatives. reminder. or French 2 age younger than 28 days Procedures Two investigators (CW.12 3487 articles retrieved from databases In accordance with these definitions. poster presentations. searched the reference list of each primary study identified and of previous systematic reviews. and Scopus. To reduce the number of results. We searched the covariates in a bivariate random-effects model to test databases between inception and Feb 21. patients without probable 1 no well defined reference standard according to guidelines 37 no 2×2 contingency table could be made infection. We used the numbers to calculate sensitivity and To be eligible. 316 meeting abstracts. we used an exact binomial definitions established by the American College of Chest rendition16 of the bivariate mixed-effects regression Physicians and Society of Critical Care Medicine Consensus Conference3 or the German Sepsis Society. *Did not investigate the resolved by referral to a third investigator (FMB). ascending cholangitis). case reports. We also excluded all studies our definitions that involved healthy people. characteristics of the study covariates. BioMed Central. or correspondence Furthermore. general ward. false posi- procalcitonin for differentiation between critically ill tives. studies had to have a well defined specificity and a corresponding CI.com/infection Vol 13 May 2013 427 . of the procalcitonin assays and cutoffs used. radiographic evidence of 145 commentaries and letters pneumonia in association with production of purulent 21 meta-analyses 382 reviews sputum. which included the use of To synthesise data. perforated viscus. We also them as possible sources of variation and bias. Discrepancies were resolved in a consensus Figure 1: Study selection meeting or. study. reviews. the Each investigator also recorded the number of true Cochrane Library. they were Some studies were excluded for more than one reason.14 Because overall searches in Science Direct. and syndrome associated with a high risk of 37 editorials infection (eg. and text (for others) were We assessed the methodological quality of the studies “(procalcitonin OR PCT) AND (sepsis OR “bacterial with the Quality Assessment of Diagnostic Accuracy infection” OR “systemic inflammatory response syn. Embase. corresponding authors if further information was calcitonin for the diagnosis of sepsis. for each item of the checklist to our review. AP) independently extracted data. false and true positives and negatives were provided. Statistical analysis Studies were included if they assessed the accuracy of We tabulated true positives. or septic shock). severe sepsis. EMTREE terms (for Embase).

the between-study variation. severe sepsis. but geneity among studies was recorded.com/infection Vol 13 May 2013 . curve for procalcitonin with summary operating points for analysis of treatment trials. 16 8 23 4 0·80 0·74 surgical and septic shock (0·56–0·94) (0·55–0·88) Gaini32 2006 Adult Medical HW PCT-Kryptor 1 93 80% Sepsis. 53 5 37 19 0·74 0·88 surgical and septic shock (0·62–0·83) (0·74–0·96) Meynaar41 2011 Adult Medical and ICU PCT-Kryptor 2 76 42% Sepsis.19. 56 9 10 18 0·76 0·53 and septic shock (0·64–0·85) (0·29–0·76) Gibot33 2004 Adult Medical ICU PCT-LIA 0·6 76 62% Sepsis.21 diagnostic odds ratios. 21 2 13 13 0·62 0·87 surgical and septic shock (0·44–0·78) (0·60–0·98) Clec’h29 2006 Adult Medical ICU PCT-Kryptor 1 76 47% Septic shock 29 2 38 7 0·81 0·95 (0·64–0·92) (0·83–0·99) Clec’h29 2006 Adult Surgical ICU PCT-Kryptor 9·7 67 46% Septic shock 28 9 27 3 0·90 0·75 (0·74–0·98) (0·58–0·88) Dorizzi30 2006 Adult Medical and ICU PCT-LIA 1 83 61% Sepsis.18 for meta. 42 6 26 9 0·82 0·81 surgical and septic shock (0·69–0·92) (0·64–0·93) Du31 2003 Adult Medical and ICU PCT-LIA 1·6 51 39% Sepsis.thelancet. covariates such as population or admission category. specificity. severe sepsis.20 This model does not transform confidence contour ellipsoid (two-dimensional CI). and respective variances between the two investigators for assessment of metho- to construct a hierarchical summary receiver operating dological quality. and ratio and did a regression test of asymmetry. To and the covariance between them. 58 4 14 2 0·97 0·78 surgical and septic shock (0·88–1·00) (0·52–0·94) Hsu36 2011 Adult Medical ICU PCT-Kryptor 2·2 66 83% Severe sepsis and 31 0 11 24 0·56 1·00 septic shock (0·42–0·70) (0·72–1·00) Ivancevic37 2008 Adult Surgical ·· PCT-LIA 1·1 63 65% No information 34 5 17 7 0·83 0·77 (0·68–0·93) (0·55–0·92) Jimeno38 2004 Adult Medical ·· PCT-LIA 0·5 104 39% No information 17 5 58 24 0·41 0·92 (0·26–0·58) (0·82–0·97) Kofoed39 2007 Adult Medical HW and PCT-Kryptor 0·25 151 64% No information 77 23 32 19 0·80 0·58 ED (0·71–0·88) (0·44–0·71) Latour-Perez40 2010 Adult Medical and ICU PCT-Q 0·5 114 63% Sepsis. We back-transformed investigate publication bias. 39 9 20 8 0·83 0·69 and septic shock (0·69–0·92) (0·49–0·85) Groselj-Grenc34 2009 Paediatric Medical and PICU PCT-LIA 0·28 36 67% Sepsis. we estimated mean logit sensitivity combine results from multiple studies with attention to and specificity with their standard error and 95% CIs. the potential source preserves the two-dimensional nature of the data taking of heterogeneity was investigated by metaregression. 20 3 9 4 0·83 0·75 surgical and septic shock (0·63–0·95) (0·43–0·95) Harbarth35 2001 Adult Medical and ICU PCT-LIA 1·1 78 77% Sepsis. severe sepsis. severe sepsis. severe sepsis. into account any correlation between the two. modified for synthesis of sensitivity and specificity on the curves and a 95% diagnostic test data. If hetero- into a single indicator of diagnostic accuracy. We then used the derived logit We calculated κ statistics to assess the agreement estimates of sensitivity. severe sepsis. Articles model developed by van Houwelingen17. We used study-specific between-study variability in logit sensitivity and specificity. severe sepsis. we constructed effective these quantities to the original receiver operating curve sample size funnel plots versus the log diagnostic odds scale to obtain summary sensitivity. 31 9 35 1 0·97 0·80 surgical and septic shock (0·84–1·00) (0·65–0·90) (Continues on next page) 428 www. specificity. 73 45 170 49 0·60 0·79 and septic shock (0·51–0·69) (0·73–0·84) Arkader26 2006 Paediatric Medical and PICU PCT-LIA 2 28 50% No information 12 0 14 2 0·86 1·00 surgical (0·57–0·98) (0·77–1·00) Bell27 2003 Adult Medical and ICU PCT-LIA 15·75 83 75% No information 47 2 19 15 0·76 (0·63– 0·90 surgical 0·86) (0·70–0·99) Castelli28 2004 Adult Medical and ICU PCT-LIA 1·2 49 69% Sepsis. Study-level covariates can be used in metaregression to Based on this model. Year Population Admission Setting Procalcitonin Cutoff n Prevalence Severity TP FP TN FN Sensitivity Specificity category assay (ng/ (%) (95% CI) (95% CI) mL) Ahmadinejad24 2009 Adult Medical and ED PCT-Q 0·5 120 59% No information 63 11 38 8 0·89 0·78 surgical (0·79–0·95) (0·63–0·88) Al-Nawas25 1996 Adult Medical ·· PCT-LIA 0·5 337 36% Sepsis. severe sepsis. severe sepsis. severe sepsis. pairs of sensitivity and specificity of individual studies We calculated I² to assess heterogeneity.

for the bivariate summary receiver operating curve 3244 critically ill patients were included in the analysis. severe sepsis. lung.11. TP=true positive. PICU=paediatric intensive care unit. Only four studies writing of the report. systemic inflammatory response syndrome of non- Graphs were produced with the MIDAS module and the infectious origin. or septic module for STATA. 17 2 17 13 0·57 0·89 surgical and septic shock (0·37–0·75) (0·67–0·99) Ruiz-Alvarez45 2009 Adult Medical and ICU PCT-Kryptor 0·32 103 76% Sepsis. We used Proc of whom 1863 (57%) had sepsis and 1381 (43%) had GLIMMIX in SAS (version 9. severe sepsis. eg. shock). Articles Year Population Admission Setting Procalcitonin Cutoff n Prevalence Severity TP FP TN FN Sensitivity Specificity category assay (ng/ (%) (95% CI) (95% CI) mL) (Continued from previous page) Naeini42 2006 Adult Medical and ·· PCT-Q 0·5 50 50% Sepsis. whereas access to all the data in the study and had final 27 investigated adult patients (table). The the reference lists of the identified articles and previous appendix shows assay characteristics. 55 2 8 20 0·73 0·80 surgical and septic shock (0·62–0·83) (0·44–0·97) Wanner53 2000 Adult Surgical ED and PCT-LIA 1·5 133 34% No information 34 20 68 11 0·76 0·77 ICU (0·60–0·87) (0·67–0·86) All assays made by BRAHMSGmbH (Hennigsdorf. severe sepsis. HW=hospital ward. The prevalence of sepsis among studies ranged data collection. Search of procalcitonin assay for diagnosis of sepsis (table). data interpretation. abdomen.23 did not identify any more dological quality of the included studies according to relevant articles. Our database search retrieved 3487 articles. After Most studies were done in intensive care units. the study was divided Most studies (17 of 30) used a quantitative manual into two parts. 65 9 16 13 0·83 0·64 surgical and septic shock (0·73–0·91) (0·43–0·82) Sakr46 2008 Adult Surgical ICU PCT-LIA 2 327 36% Sepsis. leaving (20 of 30) were done in Europe (table). 499 (42%) had sepsis. severe sepsis. we excluded 3321. four reviewing the titles and abstracts. Table: Study characteristics We used the MIDAS module22 for STATA (version 12) The table shows the main study characteristics. 234 (20%) had severe sepsis. 19 2 21 8 0·70 0·91 surgical and septic shock (0·50–0·86) (0·72–0·99) Tugrul52 2002 Adult Medical and ICU PCT-LIA 1·31 85 88% Sepsis. urinary tract—varied. TN=true negative.thelancet. 21 of 30 studies reported classification Quality Assessment of Diagnostic Accuracy Studies of severity of illness (sepsis. See Online for appendix systematic reviews10.3) to do the metaregression. severe sepsis. The corresponding author had full were done in a paediatric setting. data analysis. The sponsor of the study had no role in study design.com/infection Vol 13 May 2013 429 . of them in a paediatric intensive care unit. Sites of infection— responsibility for the decision to submit for publication. Of 1173 patients. and most After a full text review we excluded a further 136. thus we analysed 31 datasets. The source of infection (community-acquired or Results nosocomial) also differed between studies. 82 92 116 37 0·69 0·56 and septic shock (0·60–0·77) (0·49–0·63) Selberg47 2000 Adult Medical ICU PCT-LIA 3·3 33 67% Sepsis and severe 19 5 6 3 0·86 0·55 sepsis (0·65–0·97) (0·23–0·83) Simon48 2008 Paediatric Medical and PICU PCT-LIA 2·5 64 39% No information 17 10 29 8 0·68 0·74 surgical (0·46–0·85) (0·58–0·87) Suprin49 2000 Adult Medical ICU PCT-LIA 2 95 79% Sepsis. severe sepsis. IQR 0·5–2·0). medical and surgical patients. bloodstream. FN=false negative. and 440 (38%) had septic Role of the funding source shock. Because in one study procalcitonin concentration differed substantially be- investigators reported diagnostic accuracy separately for tween studies (median 1·1 ng/mL. ED=emergency department. FP=false positive. severe sepsis. The cutoff for 30 studies for inclusion (figure 1). or between 34% and 88% (mean 60%). severe sepsis. 22 1 24 3 0·88 0·96 surgical and septic shock (0·69–0·97) (0·80–1·00) Oshita43 2010 Adult ·· ·· PCT-Q 0·5 168 67% No information 76 11 45 36 0·68 0·80 (0·58–0·76) (0·68–0·90) Pavcnik-Arnol44 2007 Paediatric Medical and PICU PCT-Kryptor 5·79 49 61% Sepsis. severe sepsis. the Quality Assessment of Diagnostic Accuracy Studies www. 49 6 14 26 0·65 0·70 and septic shock (0·53–0·76) (0·46–0·88) Tsalik50 2011 Adult ·· ED PCT-Kryptor 0·1 336 74% Sepsis. 168 33 56 79 0·68 0·63 and septic shock (0·62–0·74) (0·52–0·73) Tsangaris51 2009 Adult Medical and ICU PCT-Kryptor 1 50 54% Sepsis. analysis and to calculate κ statistics. Germany). ICU=intensive care unit. the metho.

appendix). we did items.43–45. but all studies fulfilled at least four items.com/infection Vol 13 May 2013 . the summary receiver operating characteristic curve Pooled sensitivity was 0·77 (95% CI 0·72–0·81) and (0·83 [95% CI 0·80–0·86] vs 0·79 [0·75–0·83]. 22 studies metaregression analyses.thelancet. 5 (partial verification bias). We also compared adult with paediatric Sensitivity (95% CI) Specificity (95% CI) Wanner and colleagues (2000)53 0·76 (0·60–0·87) 0·77 (0·67–0·86) Tugrul and colleagues (2002)52 0·73 (0·62–0·83) 0·80 (0·44–0·97) Tsangaris and colleagues (2009)51 0·70 (0·50–0·86) 0·91 (0·72–0·99) Tsalik and colleagues (2011)50 0·68 (0·62–0·74) 0·63 (0·52–0·73) Suprin and colleagues (2000)49 0·65 (0·53–0·76) 0·70 (0·46–0·88) Simon and colleagues (2008)48 0·68 (0·46–0·85) 0·74 (0·58–0·87) Selberg and colleagues (2000)47 0·86 (0·65–0·97) 0·55 (0·23–0·83) Sakr and colleagues (2008)46 0·69 (0·60–0·77) 0·56 (0·49–0·63) Ruiz-Alvares and colleagues (2009)45 0·83 (0·73–0·91) 0·64 (0·43–0·82) Pavcnik-Arnol and colleagues (2007)44 0·57 (0·37–0·75) 0·89 (0·67–0·99) Oshita and colleagues (2010)43 0·68 (0·58–0·76) 0·80 (0·68–0·90) Naeini and colleagues (2006)42 0·88 (0·69–0·97) 0·96 (0·80–1·00) Meynaar and colleagues (2011)41 0·97 (0·84–1·00) 0·80 (0·65–0·90) Latour-Perez and colleagues (2010)40 0·74 (0·62–0·83) 0·88 (0·74–0·96) Kofoed and colleagues (2007)39 0·80 (0·71–0·88) 0·58 (0·44–0·71) Jimeno and colleagues (2004)38 0·41 (0·26–0·58) 0·92 (0·82–0·97) Ivancevic and colleagues (2008)37 0·83 (0·68–0·93) 0·77 (0·55–0·92) Hsu and colleagues (2011)36 0·56 (0·42–0·70) 1·00 (0·72–1·00) Harbath and colleagues (2001)35 0·97 (0·88–1·00) 0·78 (0·52–0·94) Groselj-Grenc and colleagues (2009)34 0·83 (0·63–0·95) 0·75 (0·43–0·95) Gibot and colleagues (2004)33 0·83 (0·69–0·92) 0·69 (0·49–0·85) Gaini and colleagues (2006)32 0·76 (0·64–0·85) 0·53 (0·29–0·76) Du and colleagues (2003)31 0·80 (0·56–0·94) 0·74 (0·55–0·88) Dorizzi and colleagues (2006)30 0·82 (0·96–0·92) 0·81 (0·64–0·93) Clec’h and colleagues (2006. figure 2).39. We obtained data 6 (differential verification bias). The and uninterpretable results (item 13) were poor (appendix).24. for significance). degrees of 0·3 0·4 0·5 0·6 0·7 0·8 0·9 1·0 freedom=30·00. and 14 (withdrawals) were from 13 studies (nine provided data for medical patients fulfilled by all studies. The proportion of heterogeneity was 0·59 (p<0·0001). diagnostic accuracy in surgical patients was higher than We identified publication bias by Deeks’ regression test of that in medical patients as measured by the area under asymmetry (t=4·12. Overall. p<0·0005. figure 3). not tested pooled specificity was 0·79 (95% CI 0·74–0·84. Reports of test review bias (item 10) and four provided data for surgical patients). We omitted item 12 of the curve was 0·85 (95% CI 0·81–0·88. the methodological quality probably caused by different cutoffs was small (0·05). We recorded no interpret the test results. Articles checklist. medical)29 0·81 (0·64–0·92) 0·95 (0·83–0·99) Castelli and colleagues (2004)28 0·62 (0·44–0·78) 0·87 (0·60–0·98) Bell and colleagues (2003)27 0·76 (0·63–0·86) 0·90 (0·70–0·99) Arkader and colleagues (2006)26 0·86 (0·57–0·98) 1·00 (0·77–1·00) Al-Nawas and colleagues (1996)25 0·60 (0·51–0·69) 0·79 (0·73–0·84) Ahmadinejad and colleagues (2009)24 0·89 (0·79–0·95) 0·78 (0·63–0·88) Combined 0·77 (0·72–0·81) 0·79 (0·74–0·84) Q=135·21. To was moderate. Substantial checklist (clinical data) because the index test is fully heterogeneity exists among the studies (overall I² for automated and no further clinical data are needed to bivariate model 96%. 95% CI 94–99). surgical)29 0·90 (0·74–0·98) 0·75 (0·58–0·88) Clec’h and colleagues (2006. None of the studies fulfilled all of the identify the source of heterogeneity. p=0·00 Sensitivity I2=77·81 (70·34–85·28) Specificity I2=78·06 (70·69–85·42) Figure 2: Sensitivity and specificity of procalcitonin assay for diagnosis of sepsis 430 www. (73%) met at least 50% of the items. degrees of Q=136·71. p=0·00 0·2 0·3 0·4 0·5 0·6 0·7 0·8 0·9 1·0 freedom=30·00. and The area under the receiver operating characteristic how the items were assessed.47–52 To compare medical with surgical patients we did a Items 3 (reference standard). evidence of a threshold effect (tested with the STATA The inter-rater reliability for assessment of quality items MIDAS module).26–28.13 how the studies scored on each item. stratified bivariate regression analysis.30–36.41.

interleukin 6 concentrations. First. Second. Therefore. no conclusion can be drawn for patients other than surgical. studies were excluded that had sites of value of procalcitonin for tumour necrosis factor α and infection typical in sepsis. 95% confidence contour In a meta-analysis from 2007. 1·0 0·5 0 Tang and colleagues10 concluded that procalcitonin is Specificity not able to discriminate between sepsis and systemic Figure 3: Summary receiver operating characteristic curve inflammatory response syndrome.11 were excluded from our systematic review clinical spectrum.64–69 Furthermore.11 Sensitivity In a meta-analysis from 2006. with different sites of infection. not tested 1·0 for significance). four studies curve was 0·78 (95% CI 0·73–83). Use of a more homogenous population would definitions for the target condition or included patients solve this difficulty. methodological quality. they included studies effects regression model. two meta-analyses have investigated the diagnostic accuracy of procalcitonin in critically ill patients. Furthermore. with conflicting results. accuracy of procalcitonin was low. which might cause underestimation of none of the study characteristics were responsible for the diagnostic accuracy. Uzzan and colleagues11 reported that the summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein for identification of sepsis. several ways—eg. the meta-analysis of Tang and col- concentration. response syndrome and thus were not in accordance so observational studies are biased by the choice of www. that assessed patients who did not have systemic Our meta-analysis has several limitations. further unrecorded differences be- not have systemic inflammatory response syndrome in tween the studies probably contribute to the hetero- the control group. 0·5 Area under the curve 0·85 (95% CI 0·81–0·88) lished between April. data analysis. a reliable test of infection is still absent. 2004.76 is associated with an increase in procalcitonin Furthermore. but would cause selection bias. The diagnostic Also shows 95% confidence contour and 95% prediction contour. their had insufficient information to construct the findings were heavily biased because of their selection 2 × 2 contingency table. and November. Third. or Summary receiver operating characteristic curve other study-specific covariates. studies that investigated the diagnostic capacity of Thus.70–73 One investigated the predictive criteria. majority of this heterogeneity.1 exclusion of patients with septic shock leagues10 has substantial shortcomings in its quantitative could reduce the overall estimate of diagnostic accuracy. including 18 studies 95% prediction contour 0 published between April. such as abdominal sepsis. Thus. the investigators restricted the population to surgery or trauma patients. who had infection without systemic inflammatory Second. patients’ analyses10. Because progression of sepsis to septic shock infection after cardiac surgery. Analysis of the other covariates yielded no significant results (data not shown). studies that assessed measurements in several patients75 and one study the ability of procalcitonin to diagnose septic shock were investigated the prognostic value of procalcitonin for excluded. admission category. including studies pub. However. and October. Articles patients (0·85 [0·82–0·88] vs 0·85 [0·81–0·88]. we inflammatory response syndrome or who were not detected substantial heterogeneity between studies but critically ill.54–66 and seven did not provide clear geneity. Thus. the heterogeneity could not be explained by metaregression analysis.77 First. 1996.com/infection Vol 13 May 2013 431 . we used the bivariate mixed- sepsis and to septic shock. we included all eligible specificity into a single measure of diagnostic accuracy. 23 studies included in the previous meta. To retain the procalcitonin in the continuum from sepsis to severe two-dimensional character.74 Another did multiple pancreatitis. mean sensitivity and specificity were both 71% (95% 67–76) and the area under the summary receiver operator characteristic with our selection criteria. 1996. Discussion Procalcitonin can differentiate effectively between sepsis and systemic inflammatory response syndrome of non- infectious origin. The studies differ in Accordingly. important information is missing.thelancet.10. and procalcitonin because 13 included healthy controls or patients who did assay used. or meningitis. Previously. However. the researchers did not assess the heterogeneity of patients Individual studies Summary operating point from different settings. It summarised pairs of sensitivity and To prevent systematic bias. 2005.54.

We only included studies Some had a cutoff that led to the most favourable results that had a well defined reference standard for sepsis. we do not know definitively whether all specificity at different thresholds. However.13 ill patients without bacterial infection should be identified correctly. but most accuracy. the post-test probability for a 99·5 0·5 positive test result is 48% (figure 4). critically Assessment of Diagnostic Accuracy Studies checklist. patient’s medical condition. the Fourth. Likewise a negative 99·7 0·3 likelihood ratio of 0·29 reduces the post-test probability 99·8 0·2 to 7% for a negative test result. In our study. Articles gold standard. Thus. In recent 3 1000 97 years. could cause interobserver variability. these likelihood 99·9 0·1 ratios are calculated from dichotomised data. First. for whom 50 diagnostic decision making is of upmost importance. which might have of standardisation of clinical and radiological findings affected our findings. Second. To minimise resultant the cost of specificity or vice versa. 1 99 The most important feature of a biomarker is its 2 Likelihood ratio 98 potential to change clinical decision making. to prevent the development of antibiotic Accuracy checklist78 and also consider using the Quality resistance. for diagnostic accuracy. The absence of a clinical Pretest probability (%) 30 5 70 40 2 60 threshold effect suggests that a cutoff of between 50 1 50 1·0 and 2·0 ng/mL is helpful for discrimination of 0·5 60 40 patients with sepsis from other inflammatory conditions. Finally. investigators should examine the validity 0·2 99·8 of procalcitonin in a selected group of patients to find a 0·3 99·7 rational cutoff. 20 20 10 80 The median cutoff of the studies included was Post-test probability (%) 1·1 ng/mL (IQR 0·5–2·0).79 Our meta-analysis provides important 10 100 90 information for critically ill patients. we only included studies written about 30% of patients with sepsis. to ascertain diagnostic value in 0·5 99·5 everyday clinical practice. bacteraemia occurs in only relevant articles. which could lead to The cutoffs that separated patients who had sepsis false-negative or false-positive judgments about the from those who did not varied greatly between studies. investigators leading to denial of treatment could be fatal in sepsis. Given a 99·3 0·7 pretest probability of 20%. English. and increased side-effects and costs. To solve this problem. The difficulty is that patients with infection were identified as such. The values Third.6 should use the Standards for Reporting of Diagnostic However. depending on lists of primary studies. the established cutoff has to be 0·7 99·3 validated in a diagnostic controlled trial. a rational threshold is needed. absence in German. we looked again for did not provide much detailed information about how further studies by searching the databases and reference infection was proved. All included can lead to an overestimation of overall diagnostic studies fulfilled this requirement (appendix). which confirmed or at least clinically suspected. both 95 5 0·002 likelihood ratio and post-test probability were moderate 97 0·001 3 (figure 4).5 Additionally. cutoffs between 0·1 and 0·5 ng/mL have been 5 500 95 calculated in patients with lower respiratory tract 7 200 93 infections. 70 0·2 30 in accordance with recommendations. the cutoffs were not subsequently validated. Others gave sensitivity and Nevertheless. A positive likelihood ratio of 4 implies that a 98 2 person with disease is four-times more likely to have a 99 1 positive test result than is a healthy person. but could not identify additional previous antibiotic treatment. especially with regard to uninterpretable results other. Figure 4: Fagan nomogram of the procalcitonin test for diagnosis of sepsis The disadvantage of making data dichotomous is that 432 www.thelancet.4. To change the cutoff means changing sensitivity at and test review bias (appendix). We recommend different phases in testing diagnostic 0·1 Positive likelihood ratio 99·9 Negative likelihood ratio accuracy. The result of the procalcitonin test is either positive or negative. According to our inclusion criteria. implementation of some studies was reported of diagnostic accuracy are correlated negatively with each poorly.com/infection Vol 13 May 2013 . False-negative results bias and to ensure more homogeneity. Nevertheless. we detected publication bias. Studies with presence of infection had to be microbiologically desirable results are more likely to be published.80 0·1 80 0·05 20 Likelihood ratios and post-test probabilities are also 0·02 relevant for clinicians. or French. They provide information about 90 0·01 10 the likelihood that a patient with a positive or negative 93 0·005 7 test actually has sepsis or not.

J Clin Epidemiol 2005. a tool for the quality assessment the course of disease is advisable. Eslick GD. study. the Deutsche Forschungsgemeinschaft (Schl 3-1). Nix D. 5: 19. Harbord R. Rutjes AW. 3 Bone RC. Bossuyt PM. J Clin Epidemiol 2006. and the of diagnostic test accuracy was assessed. Macaskill P. Gauvin F. J Antimicrob Chemother 2008. BMC Med Res Methodol 2006. and interpreted data. German Sepsis Society. 79: 1605–08. 1: 331–33. 26 Arkader R. and gave administrative. but rather it must be interpreted in 13 Whiting P. likelihood ratios based on multiple cutoffs. 17 Van Houwelingen HC. about the reliability of the test. Conflicts of interest Zwinderman AH. and associated costs of care. Miller E. 29: 1303–10. Saint-Louis P. outcome. The epidemiology of procalcitonin and C-reactive protein levels as markers of bacterial sepsis in the United States from 1979 through 2000. Prevention. A bivariate technical. microbiological BMC Med Res Methodol 2003. 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Procalcitonin: a marker of Sepsis Project Working Group. et al. procalcitonin is a helpful marker for of the S2k Guidelines of the German Sepsis Society (DSG) and the German Interdisciplinary Association for Intensive and diagnosis of sepsis in critically ill patients. Advanced methods in revised the report. and follow-up care of sepsis. 34: 1996–2003. To provide more precise information response syndrome. et al. Nicolas P. N Engl J Med infection: a systematic review and meta-analysis. 9 Dandona P. Perret GY.35. Science and Culture (ProExcellence. Shah PM. Glas AS. Byth K. Serum 2 Martin GS. sepsis. et al. Reitsma JB. Innovation and Research. First revision In conclusion. Weswood ME. 31: 629–36. Crit Care Med 2001. Bivariate analysis of sensitivity and specificity We declare that we have no conflicts of interest. Eur J Med Res 1996.40.23. The work was supported by the German Centre for Sepsis Control & Care. 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