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Diagnostic accuracy of pleural fluid NT-pro-BNP for pleural effusions of cardiac origin: a systematic… Janda, Surinder; Swiston, John Nov 20, 2010

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RESEARCH ARTICLE Open AccessDiagnostic accuracy of pleural fluid NT-pro-BNPfor pleural effusions of cardiac origin: a systematicreview and meta-analysisSurinder Janda, John Swiston*AbstractBackground: Several studies have been published in the literature on the diagnostic accuracy of NT-pro-BNP forpleural effusions from heart failure in the last decade. The purpose of our study was to perform a systematicreview and meta-analysis on the diagnostic accuracy of pleural fluid NT-pro-BNP for pleural effusions of cardiacorigin.Methods: MEDLINE, EMBASE, PapersFirst, and the Cochrane collaboration and the Cochrane Register of controlledtrials were searched. All searches were inclusive as of March 2010. Studies were only included if the absolutenumber of true-positive, false-negative, true-negative, and false-positive observations were available, and the“reference standards” were described clearly. Two investigators independently reviewed articles and extracted data.Quality was assessed with the Quality Assessment for Diagnostic Accuracy Studies (QUADAS). The bivariate modelfor diagnostic meta-analysis was used to obtain a pooled sensitivity and a pooled specificity.Results: Ten studies (total number of patients 1120) were included in the meta-analysis. The average pleural fluidNT-pro-BNP level in effusions of cardiac origin was 6140 pg/mL. The pooled sensitivity and specificity of all studiescombined was 94% (95% CI: 90-97) and 94% (95% CI: 89-97) respectively. The pooled positive likelihood ratio was15.2 (95% CI: 8.1-28.7) and the pooled negative likelihood ratio was 0.06 (95% CI: 0.03-0.11). The area under theROC curve was 0.98 (95% CI: 0.96-0.99) and the diagnostic odds ratio was 246 (95% CI: 81-745).Conclusions: Pleural fluid NT-pro-BNP is a very useful biomarker with high diagnostic accuracy for distinguishingpleural effusions of cardiac origin.BackgroundPleural effusions arising from heart failure are usuallydiscriminated from other causes based on clinical criteriain association with biochemical analysis, particularly thediscrimination of transudates versus exudates, most com-monly using Light’s criteria [1]. The sensitivity of Light’scriteria for identifying exudative pleural effusions is veryhigh (98%)[2], however the criteria’s ability to excludetransudative effusions is low[3]. As a result, heart failureassociated pleural effusions can be misclassified as exu-dates using Light’s criteria, particularly after diureticshave been used. One study showed that 28% (5 of 18)patients with pleural effusions from congestive heartfailure (CHF) were misclassified as exudative effusionsusing Light’s criteria[4]. A diagnostic dilemma oftenarises when CHF-associated pleural effusions are misclas-sified as exudates which can then lead to the use of moreexpensive and sometimes invasive tests to diagnose theetiology of the effusion. A non-invasive and inexpensivestrategy to discriminate pleural effusions of a cardiac ori-gin would be beneficial in such circumstances.Serum brain natriuretic peptide (BNP) or the amino-terminal fragment N-terminal pro-brain natriureticpeptide (NT-pro-BNP) have an established role in thediagnosis, management, and prognosis of patients withCHF[5]. BNP, also known as B-type natriuretic peptide,is a 32 amino acid polypeptide secreted by the ventriclesof the heart in response to excessive stretching of cardi-omyocytes[6]. BNP is co-secreted along with a 76 aminoacid polypeptide, NT-pro-BNP, which is biologically* Correspondence: swiston@interchange.ubc.caDivision of Respiratory Medicine, The University of British Columbia,Vancouver, BC, CanadaJanda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58© 2010 Janda and Swiston; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.inactive[7]. The half-life of BNP is approximately 20minutes whereas of NT-pro-BNP is 1-2 hours[8]. BNPbinds to atrial natriuretic factor receptors leading to adecrease in systemic vascular resistance and centralvenous pressure, and an increase in natriuresis[6].Several studies have been published in the literatureon the diagnostic accuracy of NT-pro-BNP for pleuraleffusions from heart failure. The purpose of our studywas to perform a systematic review and meta-analysison the diagnostic accuracy of pleural fluid NT-pro-BNPfor pleural effusions of cardiac origin.MethodsThe systematic review and meta-analysis was performedaccording to the recently published recommendationsand checklist of the PRISMA statement[9].Searches were conducted on MEDLINE (inception-March2010); EMBASE (inception-March 2010), PapersFirst (incep-tion-March 2010), and the Cochrane collaboration and theCochrane Register of controlled trials for relevant studies.The following key terms were used: ‘pleural fluid’ or ‘pleuraleffusion’ AND ‘brain natriuretic peptide’ or ‘B-type natriure-tic peptide’ or ‘BNP’, ‘pro-BNP’ or ‘NT-pro-BNP’ or ‘amino-terminal pro-BNP’ or ‘congestive heart failure’ or ‘heart fail-ure’ or ‘CHF’. All searches were limited to ‘humans’. Weidentified additional studies by searching the bibliographiesof retrieved articles. Two independent reviewers (SJ and JS)performed the literature search. Studies relevant to the diag-nostic value of NT-pro-BNP for pleural effusions of cardiacorigin were included if the following criteria were met:pleural fluid NT-pro-BNP was used for diagnosing pleuraleffusions of cardiac origin; and a 2 × 2 contingency tablecould be formulated from the available data. Studies thatused BNP or other biomarkers were excluded.All studies that appeared to fit the inclusion criteriawere identified for full review by two reviewers (SJ andJS). Each reviewer independently selected studies forinclusion in the review. Disagreement between the twoextracting authors was resolved by consensus.The methodological quality of the selected studies wasgraded independently by two reviewers (SJ and JS) withthe Quality Assessment of Diagnostic Accuracy Studies(QUADAS) tool, a validated tool for the quality assess-ment of diagnostic accuracy studies[10]. We performedcomponent analysis using the QUADAS tool which wasdepicted as a proportional bar graph for each of the 14individual criteria. Disagreement between the twoextracting authors was resolved by consensus.The following variables were extracted from eachstudy: publication year; country of origin of study; studydesign; patient demographics and co-morbidities;NT-pro-BNP assay type; numbers of true-positive, false-negative, true-negative, and false-positive observations;correlation statistic between pleural fluid and serumNT-pro-BNP if available; and the reference standardused.We used the bivariate model for diagnostic meta-analysis to obtain an overall sensitivity and an overallspecificity[11]. Instead of using the diagnostic oddsratio, as used in conventional diagnostic meta-analysis[12], the bivariate model uses pairs of sensitivity andspecificity as the starting point of the analysis. In addi-tion to accounting for study size, the bivariate modelestimates and incorporates the negative correlation thatmay arise between the sensitivity and specificity of theindex test within studies as a result of differences in testthreshold between studies. The bivariate model uses arandom effects approach for both sensitivity and specifi-city, which allows for heterogeneity beyond chance as aresult of clinical and methodological differences betweenstudies. The pooled estimates of sensitivity and specifi-city were used to calculate the average positive andnegative likelihood ratios. Publication bias through smallstudy effects was assessed with a regression test on thediagnostic odds ratio[13].A receiver operating characteristic graph, with they-axis representing the index test’s sensitivity (true posi-tive rate) and the x-axis representing 1-specificity (falsenegative rate), was used to plot the individual and sum-mary points of sensitivity and specificity. Furthermore,around the pooled estimates, we also plotted a 95% con-fidence region and a 95% prediction region to illustratethe precision with which the pooled values were esti-mated (confidence ellipse of a mean) and to show theamount of between study variation (prediction ellipse;the likely range of values for a new study). We usedStata intercooled version 10.1 (StataCorp, College Sta-tion, Texas), in particular the midas and metandi com-mands, for all statistical analyses[14,15].ResultsOur search yielded 128 citations of which 117 wereexcluded for various reasons based on the title andabstract (Figure 1). Eleven were then retrieved for fulltext review of which three were excluded because BNPinstead of NT-pro-BNP was used as the biomarker (Fig-ure 1). Ten studies were included in the final analysis[16-25]. One study, by Seyhan et al[22], was initiallypublished online and then was retracted by the editorsof the journal. The reason for retraction was due to aviolation of the journal’s Information for Authors. There-fore, only the abstract was available for data extractionand a quality assessment was not possible.The studies were published from 2004 to 2010. Themajority of the studies (7/9)[16-19,22-24] were done inEurope whereas two were done in North America[20,25]and one in Asia[21]. All studies except for two (Porcelet el[23] and Long et al[25]) were of prospective designJanda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 2 of 11(Table 1). Furthermore, all studies except for two (Liaoet al[20] and Long et al[25]) used an electrochemicalluminescence immunoassay (ELCIA) performed on theElecsys 2010 analyzer (Roche) to measure levels of NT-pro-BNP whereas Liao et al[20] and Long et al[25] usedan enzyme-linked immunosorbent assay (ELISA) (Table1). A total of 1120 patients/pleural effusions wereincluded in this analysis (429 of cardiac origin and 691of non-cardiac origin). The control group (non-cardiacpleural effusions) consisted of mainly malignant pleuraleffusions and infections (Table 1).As there is no gold standard for effusions of cardiacorigin, clinical criteria was used as the reference stan-dard. All studies used some combination of the follow-ing criteria: history, physical exam, chest x-ray,electrocardiogram, echocardiogram, and response toFigure 1 Flow chart of the studies included in the meta-analysis.Table 1 Characteristics of the studies included in the meta-analysis.Study Year Country Design Assay Type Reference Standard Control Group†Tomcsanyi et al [16] 2004 Hungary PC ECLIA(1)‡ Clinical Criteria*a, b, c, e57% M; 14% I; 29% OPorcel et al [17] 2004 Spain PC ECLIA(1) Clinical Criteria*a, b, c, d, e, fNRKolditz et al [18] 2006 Germany PC ECLIA(1) Clinical Criteria*a, b, c, e, f59% M; 21% I; 30% OPorcel et al [19] 2007 Spain PC ECLIA(1) Clinical Criteria*a, b, c, d, e, f48% M; 20% I; 32% OLiao et al [20] 2008 USA PC ELISA Clinical Criteria*a, c, e25% M; 0% I; 75% OHan et al [21] 2008 Korea PC ECLIA(1) Clinical Criteria*a, b, e, f24% M; 66% I; 10% OSeyhan et al [22] 2009 Turkey PC ECLIA Clinical Criteria*N/AN/APorcel et al [23] 2009 Spain RC ECLIA(2) Clinical Criteria*a, b, c, e, f44% M; 29% I; 27% OBayram et al [24] 2009 Turkey PC ECLIA(1) Clinical Criteria*a, b, c, e, f23% M; 31% I; 46% OLong et al [25] 2010 USA RC ELISA Clinical Criteria*a, b, c, e25% M; 25% I; 25% O* = heart failure diagnosis based on (a) history, or (b) physical exam, or (c) chest x-ray, or (d) electrocardiogram, or (e) echocardiogram, or (f) response todiuretics; † = non-cardiac effusions; ‡ = generation of assay (one or two); ECLIA = electrochemical luminescence immunoassay; ELISA = enzyme-linkedimmunosorbent assay; I = infectious effusion; M = malignant effusion; N/A = not available; NR = not recorded; O = other causes (i.e. connective tissue disease,pleuritis, post-CABG, hepatic hydrothorax, pulmonary embolism, etc); PC = prospective cohort; RC = retrospective cohort;Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 3 of 11diuretics. Of the studies[18-20,23,25] that reported NewYork Heart Classification for the patients with effusionsof cardiac origin, all patients were either class III or IV.Overall, the quality of the reported studies was good(Figure 2). Five studies[16,19,20,23,25] maybe subject tospectrum bias as their method of recruitment of patientsconsisted of recruiting a target group (patients withpleural effusions of cardiac origin) and a control group(patients with pleural effusions of non-cardiac origin)rather than applying the index and reference test to anunselected patient population with pleural effusions.Most studies may be subject to review bias as it wasunclear in eight studies whether the investigators whoused the reference test (clinical criteria) were blinded tothe results of the NT-pro-BNP assay and six studies[16,18,20,21,24,25] did not state whether the laboratorypersonnel performing the index test (NT-pro-BNPassay) were blinded to the clinical diagnosis.The average NT-pro-BNP level for nine of the ten studieswas 6140 pg/mL in pleural effusions of cardiac origin (thisvalue was not available for one study[22]). Of the five stu-dies[16,18,19,21,24] that analyzed both serum and pleuralfluid NT-pro-BNP levels, all five studies showed high corre-lation between these two parameters (Table 2). Table 2 alsoshows that the percentage of cardiac effusions misclassifiedas exudates by Light’s criteria was relatively modest (range7%-36%) within various studies. However, when these mis-classified effusions from Light’s criteria were analyzed byNT-pro-BNP levels, the absolute number of misclassifiedeffusions was significantly reduced (Table 2).The pooled sensitivity and specificity of all studiescombined was 94% (95% CI: 90-97) and 94% (95% CI:89-97) respectively (Figure 3). The pooled positive likeli-hood ratio was 15.2 (95% CI: 8.1-28.7) and the poolednegative likelihood ratio was 0.06 (95% CI: 0.03-0.11).The area under the ROC curve was 0.98 (95% CI: 0.96-0.99) and the diagnostic odds ratio was 246 (95% CI:81-745). Figure 4 shows the summary receiver operatingcharacteristic graph with 95% confidence region and95% prediction region for NT-pro-BNP.The between study variability (i.e. heterogeneity)beyond what could be expected by sampling error wasmoderate with an I2 of 40% (p = 0.09) for the sensitivityresults and high with an I2 of 84% (p < 0.01) for theFigure 2 Proportion of all 14 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool criteria that were fulfilled for seven ofeight studies included in the meta-analysis.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 4 of 11specificity results. The bivariate model analysis revealsthat this heterogeneity is completely (100%) explainedby threshold effect. Analysis of small study effects,potentially a result of publication bias, yielded no signifi-cant evidence for such effects with a p value of 0.26 anda funnel plot that was fairly symmetrical (Figure 5).Figure 6 illustrates the post-test probabilities based onvarious pre-test probabilities using a Fagan nomogram.Discussion and ConclusionPleural effusions are relatively common in medical prac-tice. It is estimated that the annual incidence of pleuraleffusions in the United States (US) is 1.5 million cases[26]. The most common cause of pleural effusions isCHF with an estimated incidence of 500,000 cases inthe US per year[2]. Identifying the underlying etiologyof pleural effusions requires a combination of strategiesincluding clinical history, pleural fluid analysis, andpotentially more invasive procedures such as pleural tis-sue biopsy. Clinical history is very important in the diag-nosis of pleural effusions from a cardiac origin.However, alone, it does not appear to be very accurate.Romero-Candeira et al[27] studied 64 patients withtransudative pleural effusions of which 44 were due toCHF and showed that in 40% of cases initial clinical his-tory failed to correctly classify the effusion. Pleural fluidanalysis using Light’s criteria is better than clinicalhistory for diagnosing pleural effusions of cardiac originhowever these criteria misclassify transudates as exuda-tive effusions approximately 25% of the time, mainlyrelated to the use of diuretics[2]. Misclassification oftransudates to exudates can lead to inappropriate man-agement or potentially more invasive diagnostic investi-gations resulting in increased morbidity and health carecosts. As a result, tests with higher diagnostic accuracymay prove beneficial in terms of reducing morbidity andimproving cost-efficiency for diagnosing pleural effu-sions of cardiac origin.In the last decade several studies have been reportedassessing the diagnostic utility of pleural fluid NT-pro-BNP in pleural effusions of cardiac origin. To summar-ize these studies, we conducted a systematic review andmeta-analysis. We included ten studies, of which sevenwere from Europe, with a total of 1120 patients and/orpleural effusions. We showed that the pooled sensitivityand specificity were identical (94% [95% CI: 90-97] and94% [95% CI: 89-97]) with a diagnostic odds ratio of246 (95% CI: 81-745). When the study by Seyhan et al[22], which was retracted from the literature, wasexcluded from the analysis, the sensitivity, specificity,and diagnostic odds ratio remained the same within95% confidence intervals.The quality of the studies was generally good overall.The main limitations of the studies were the possibilityTable 2 Diagnostic accuracy variables of the studies included in the meta-analysis.Study No.Pts/PesTP FN TN FP Se Sp NT-pro-BNPThreshold*AverageNT-pro-BNP†Misclassification CorrelationStatistic∏Light’s‡ NT-pro-BNP§Tomcsanyi et al[16]28 14 0 14 0 100% 100% ≥ 599¶ 8236 1/14(7%)0/1 R2 = 0.95p < 0.0001Porcel et al[17] 117 40 4 68 5 91% 93% ≥ 1500 6931 10/35(29%)2/10 NRKolditz et al[18] 93 23 2 63 5 92% 93% ≥ 4000 10427 9/25(36%)0/9 S = 0.96p < 0.001Porcel et al[19] 93 49 4 35 5 92% 87% ≥ 1500 6106 8/53(15%)2/8 S = 0.96p < 0.001Liao et al[20] 40 10 0 29 1 100% 97% ≥ 2220 5390 NR NR NRHan et al[21] 240 81 1 156 2 99% 99% ≥ 1714 3310 28/82(34%)1/28 R2 = 0.93p < 0.001Seyhan et al[22] 115 47 4 61 3 92% 95% ≥ 1092 N/A 17/51(33%)N/A N/APorcel et al[23] 181 84 6 81 10 93% 89% ≥ 1500 6203 20/90(22%)4/20 NRBayram et al[24] 133 48 3 78 4 94% 95% ≥ 925 4468 19/51(37%)0/19 R2 = 0.91p < 0.001Long et al[25] 80 16 4 44 16 80% 73% ≥ 2000 4189 NR NR NR* = pleural fluid NT-pro-BNP threshold in pg/mL; † = average pleural fluid NT-pro-BNP in CHF effusions in pg/mL; ‡ = misclassification of CHF effusions asexudates by Light’s criteria; § = misclassification of the CHF effusions already misclassified by Light’s criteria now misclassified by NT-pro-BNP; ∏ = correlationbetween serum and pleural fluid NT-pro-BNP levels; ¶ = threshold from 599 to 1457 pg/mL resulted in 100% sensitivity and specificity; N/A = not availablebecause only abstract available for data extraction; No. = number; NR = not recorded; Pes = pleural effusions; Pts = patients; R2 = Pearson coefficient ofcorrelation; S = Spearman’s coefficient of rank correlation; Se = sensitivity; Sp = specificity.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 5 of 11of spectrum bias, review bias, and population bias. Spec-trum bias refers to distortions in a diagnostic test’s per-formance caused by a distortion in the study population.Testing is not done across a population with theexpected distribution of disease severity, but rather lim-ited subsets[28]. In our meta-analysis, five studies[16,19,20,23,25] acquired their study population byselecting CHF patients and patients with pleural effu-sions of non-cardiac origin (control group). The pre-sence of spectrum bias can lead to an overestimation ofthe sensitivity and specificity of the test[28]. Review biasrefers to a situation where persons interpreting theindex test have knowledge of the reference standard orvice versa, when persons interpreting the reference stan-dard have knowledge of the index test[29]. In our meta-analysis, it was very unclear whether this did or did notoccur because the majority of the studies did not reportwhether blinding during testing was done. Again, thismay have lead to an overestimation of the diagnosticperformance of the test. Finally, population bias refersto the generalizability of the diagnostic test to a widerpopulation[30]. The studies included in our meta-analysis had poor reporting of any co-morbid conditionswithin the CHF-associated pleural effusion group thuspotentially limiting generalizability. Furthermore, a thor-acentesis in patients with a high pre-test probability fora cardiac origin of the pleural effusion with low prob-ability for other causes would not usually be indicatedin most clinical scenarios thus further limiting the gen-eralizability of these results.Heterogeneity was moderate for the sensitivity resultsand high for the specificity results (Figure 3). In thesummary receiver operating characteristic graph (Figure4), all but three of the ten ‘sensitivity - (1-specificity)’combinations of the individual studies lie on or near thesummary receiver operating characteristic curve. Thisindicates that studies with a higher sensitivity havelower specificity and vice versa. This pattern is com-monly attributed to differences in the threshold level fortest positivity used in different studies[12]. As a result,the heterogeneity between the studies could well beexplained by threshold level differences between the stu-dies which ranged from 599 to 4000 pg/mL. Anotherpotential cause for the heterogeneity may be due to thevarious types of clinical criteria used for the referencestandard (Table 1) as there is no gold standard for theFigure 3 Forrest plot of the sensitivity and specificity of each individual study, pooled sensitivity and specificity, and I2 statistic forheterogeneity.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 6 of 11diagnosis of pleural effusions from a cardiac origin. Themost objective criteria for heart failure is echocardiogra-phy and all studies except for Seyhan et al[22] used thisparameter and of those studies, the majority definedCHF as an ejection fraction ≤ 40%. Furthermore, of thestudies that reported New York Heart Class, the CHF-associated pleural effusion patients were of New YorkHeart Class (NYHC) III or IV. The control groupamong the various studies differed and potentially couldhave contributed to the heterogeneity of the results aswell. Malignant pleural effusions and parapneumoniceffusions were the main groups that comprised the con-trol groups but some studies did have other causes as amajority of the control group such as connective tissuedisease, pleuritis, post-CABG, hepatic hydrothorax, andpulmonary embolism. Finally, eight of the ten studiesused electrochemical luminescence immunoassay(ECLIA) for measuring NT-pro-BNP (8 studies genera-tion one, one study generation two, one study unknowngeneration) while two studies used ELISA which mayhave added to the heterogeneity of results as well.ECLIA uses a non-competitive immunoassay that pro-duces luminescence via an electrochemical reaction andcompared to ELISA, is faster and more precise[31]. TheELISA kit from Biomedica has been compared to theECLIA kit from Roche Diagnostics revealing significantdisparity of results between the two types of assays[31].The Roche Diagnostics assay (ECLIA) has dual antibo-dies targeting two different areas of the NT-pro-BNPmolecule whereas the Biomedica assay (ELISA) only hasa single antibody targeting one region. This may resultin better recognition of NT-pro-BNP and hence betterdiagnostic accuracy for the Roche Diagnostics assay.Furthermore, the cut-off values for serum NT-pro-BNPare 10 fold higher using the Biomedica assay (ELISA)compared to the Roche Diagnostics assay (ECLIA)[31]which may have also added to the heterogeneity of theresults.The correlation between pleural fluid and serum levelsof NT-pro-BNP are high as shown by five studies[16,18,19,21,24] in our meta-analysis (Table 2). Thissuggests that thoracentesis could potentially be avoidedFigure 4 Summary receiver operating characteristic graph with 95% confidence region and 95% prediction region for NT-pro-BNP.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 7 of 11in patients with a clinical suspicion of CHF, elevatedNT-pro-BNP, and no suspicion for a co-existing causeof the pleural effusion.Most institutions use BNP to diagnose CHF. Three stu-dies[23,25,32] have examined the diagnostic accuracy ofBNP for pleural effusions of cardiac origin. The firststudy[32] of 57 patients showed a sensitivity of 97% and aspecificity of 89% for plasma BNP. The second study byPorcel et al[23] (181 patients), showed a sensitivity of74% and specificity of 92% for pleural fluid BNP and alsoshowed that the area under the curve (AUC) for NT-pro-BNP was higher than for pleural fluid BNP, 0.96 (95% CI:0.94-0.99) vs 0.90 (95% CI: 0.86-0.95) respectively. Corre-lation between pleural fluid NT-pro-BNP levels and BNPlevels was good, r = 0.78 (p < 0.001). The conclusionfrom this study was to use NT-pro-BNP rather than BNPfor diagnosing pleural effusions of cardiac origin becauseof the diagnostic superiority of NT-pro-BNP versus BNP,greater in-vitro stability of NT-pro-BNP compared withBNP, and longer half-life of NT-pro-BNP (1-2 hours)compared with BNP (20 minutes). The last study byLong et al[25] (80 patients) showed that the AUC forNT-pro-BNP was greater than for pleural fluid BNP, 0.84(95% CI: 0.72-0.95) vs 0.70 (95% CI: 0.57-0.83). Correla-tion between pleural fluid NT-pro-BNP and BNP levelswas also good but less impressive, r = 0.57 (p < 0.001),and only explained 32% of the variance in NT-pro-BNP.The conclusion from this study was that NT-pro-BNPwas a more stable molecule after sample processing andcould be maintained for a greater duration in an in vitrosetting compared to BNP and furthermore because of thehigher diagnostic accuracy of NT-pro-BNP, NT-pro-BNPshould be used over BNP to distinguish pleural effusionsof cardiac origin in select patient populations.It is difficult to suggest a threshold level for pleuralfluid NT-pro-BNP since the studies used varying thresh-old levels. The average pleural fluid NT-pro-BNP levelin the studies was 6140 pg/mL. Six of the studies[16,17,19,21,23,24] used a threshold level between 1457to 1714 pg/mL (sensitivity and specificity for a thresholdlevel of 1457 pg/mL by ROC analysis in the study byBayram et al[24] was 84% and 98%, respectively). Thepooled sensitivity and specificity of these six studies is95% (95% CI: 91-98) and 95% (95% CI: 89-98),Figure 5 Deeks’ funnel plot asymmetry test for publication bias.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 8 of 11respectively, with a diagnostic odds ratio of 370 (95% CI:101-1351). As a result, a threshold level of approxi-mately ≥ 1500 pg/mL provides very good diagnosticaccuracy for pleural fluid NT-pro-BNP.The utility of NT-pro-BNP for the diagnosis of pleuraleffusions of cardiac origin can be applied to several clinicalsituations. First, if the pre-test probability of a pleural effu-sion due to heart failure is high and alternative diagnosesare less likely, then a thoracentesis can be avoided and anelevated serum NT-pro-BNP level will be diagnostic for acardiac origin of the pleural effusion. Second, if the pre-test probability of a pleural effusion due to heart failure islow or alternative diagnoses are considered in addition toheart failure, then a thoracentesis should be performedand if the pleural fluid NT-pro-BNP level is high then thiswould be diagnostic of heart failure as one potential causefor the pleural effusion. Furthermore, in undiagnosedpleural effusions, for example when Light’s criteria mis-classify transudative CHF effusions as exudates and thepre-test probability is equivocal for CHF, a high pleuralfluid NT-pro-BNP would also be diagnostic.The results of our meta-analysis are corroborated byanother meta-analysis done by Zhou et al[33]. Theyincluded eight studies and found that the sensitivity andFigure 6 Fagan’s nomogram for NT-pro-BNP illustrating post-test probability with a fixed pre-test probability of 20% for a pleuraleffusion of cardiac origin.Janda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 9 of 11specificity for NT-pro-BNP for pleural effusions of car-diac origin was 95% (95% CI: 92-97) and 94% (95% CI:92-96), respectively, with a diagnostic odds ratio of 214(95% CI: 123-374). Based on their meta-analysis, Zhouet al[33] concluded that pleural fluid NT-pro-BNP hashigh diagnostic accuracy for differentiating cardiac fromnon-cardiac conditions in patients presenting withpleural effusions.In summary, misclassification of pleural effusions ofcardiac origin can lead to increased morbidity fromfurther invasive testing and increased health care costs.Clinical history and pleural fluid analysis with Light’scriteria may not have sufficient diagnostic accuracy todiagnose these effusions in certain clinical circum-stances. Although there is some heterogeneity withinthis analysis, we conclude that where the diagnosis ofpleural effusion of cardiac origin is under contempla-tion, pleural fluid NT-pro-BNP is a useful biomarkerwith high diagnostic accuracy.AbbreviationsBNP: brain natriuretic peptide; CHF: congestive heart failure; ELCIA:electrochemical luminescence immunoassay; ELISA: enzyme-linkedimmunosorbent assay; HSROC: hierarchical summary receiver operatingcharacteristic; NT-pro-BNP: N-terminal pro-brain natriuretic peptide; QUADAS:quality assessment of diagnostic accuracy studies; US: United States.Authors’ contributionsBoth SJ and JS conducted the literature search independently. Both SJ andJS analyzed the studies to be included independently. SJ retrieved thearticles. Both SJ and JS extracted the information independently. SJconducted the statistical analysis with confirmation by JS. SJ wrote themanuscript draft. Both SJ and JS read and approved the final manuscript.AcknowledgementsJS is a recipient of an In it for Life Scientist award from the VancouverCoastal Health Research Institute and the Vancouver General HospitalFoundation.Competing interestsDr. Janda and Dr. Swiston have no competing interests.Received: 29 August 2010 Accepted: 20 November 2010Published: 20 November 2010References1. Light RW, Macgregor MI, Luchsinger PC, Ball WC Jr: Pleural effusions: thediagnostic separation of transudates and exudates. Ann Intern Med 1972,77(4):507-513.2. Light RW: Clinical practice. Pleural effusion. N Engl J Med 2002,346(25):1971-1977.3. Romero S, Candela A, Martin C, Hernandez L, Trigo C, Gil J: Evaluation ofdifferent criteria for the separation of pleural transudates from exudates.Chest 1993, 104(2):399-404.4. Roth BJ, O’Meara TF, Cragun WH: The serum-effusion albumin gradient inthe evaluation of pleural effusions. Chest 1990, 98(3):546-549.5. 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Heart 96(15):1207-1211.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/10/58/prepubdoi:10.1186/1471-2466-10-58Cite this article as: Janda and Swiston: Diagnostic accuracy of pleuralfluid NT-pro-BNP for pleural effusions of cardiac origin: a systematicreview and meta-analysis. BMC Pulmonary Medicine 2010 10:58.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitJanda and Swiston BMC Pulmonary Medicine 2010, 10:58http://www.biomedcentral.com/1471-2466/10/58Page 11 of 11


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