The distinction between transudates and exudates

Transcription

1 Journal of Biomedical Science (2005) 12: DOI /s The distinction between transudates and exudates Ugur Gonlugur 1, * & Tanseli Efeoglu Gonlugur 2 1 Department of Chest Diseases, Cumhuriyet University Medical School, 58140, Sivas, Turkey; 2 Department of Chest Diseases, Sivas State Hospital, Sivas, Turkey Received 1 June 2005; accepted in revised form 25 July 2005 Ó 2005 National Science Council, Taipei Key words: pleural effusions, biochemical criteria, exudates, transudates, thoracentesis Summary The first step in the diagnosis of pleural effusions is the distinction between exudates and transudates. The aim of this study was to evaluate the usefulness of various parameters for the differentiation of pleural exudates and transudates. We recorded clinical characteristics, final diagnoses, and measured pleural fluid and serum levels of albumin, protein, LDH, cholesterol, and bilirubin of 381 consecutive patients with pleural effusion. Seventy-one (23%) pleural effusions were transudates and 236 were exudates. As a single criterion, the pleural fluid to serum albumin ratio >0.5 was the most accurate parameter (88.4%). An albumin gradient of 12 g/l had an accuracy of 75% in the whole population but it detected 96% of transudative effusions in patients treated with diuretics. Light s criteria and abbreviated Light s criteria had similar accuracies, 87.8% vs. 88.2%, respectively. In conclusions, different alternatives can be used instead of Light s criteria. Introduction Light s criteria [1] are the standard for differentiating transudative and exudative processes but the main disadvantage of Light s criteria is the misclassification of transudates as exudates [2 6]. In trying to improve specificity, a number of alternative criteria have been proposed, including the pleural fluid cholesterol [2, 3], the serum-effusion albumin gradient [4], and combined pleural fluid cholesterol and LDH [7]. The purpose of this study was to compare the efficiency of the various biochemical parameters, and to identify an optimum marker combination for differentiating exudates from transudates. Methods We retrospectively studied 381 consecutive patients admitted to Cumhuriyet University Hospital who *To whom correspondence should be addressed. Fax: ; gonlugur@e-kolay.net underwent a diagnostic thoracentesis over a 10- year period. Detailed clinical and laboratory data were extracted from medical records, including biochemical parameters of paired specimens of blood and pleural fluid. Because of retrospective nature of the study, the aetiology of pleural effusions was established with clinical diagnostic criteria decided prior to the start data collection. The diagnosis of the disease causing the effusion was considered to be confirmed when the following conditions were met: 1. Congestive heart failure (CHF) was diagnosed when the presence of enlarged heart with clinical or echocardiographic evidence of cardiac dysfunction, and one or more of the following alterations: pulmonary venous congestion on radiography, peripheral oedema, tachycardia, or ventricular gallop. Patients suspected of having malignancy, respiratory infections, pulmonary embolism, or persistence of the effusion after adequate

2 986 treatment of the cardiac insufficiency, were excluded. 2. Chronic renal failure was diagnosed when raised urea and creatinine levels in the presence of clinical evidence of fluid overload (e.g., pulmonary or peripheral oedema) and an absence of malignancy or respiratory infections. 3. Tuberculous pleurisy was diagnosed by identifying bacilli in pleural fluid or biopsy specimen cultures or by the presence of caseous granulomas in pleural biopsy tissue. 4. Parapneumonic effusion was diagnosed when the presence of clinically and radiologically confirmed pneumonia with no direct or indirect evidence of bacterial invasion of the effusion. 5. Empyema was identified by the presence of pneumonia with one or more of the following indicators of bacterial invasion of the effusion: pus, bacteria in Gram s stain smear or culture, and ph under 7.0 or progressively decreasing to under Malignant mesothelioma was diagnosed by using a panel composed of antibodies directed against calretinin, EMA, thrombomodulin, HBME-1, CD15, B72.3, and CEA on histological/cytological specimens of the pleura. 7. Secondary pleural tumour was diagnosed by detection of malignant cells at cytological examination or in a biopsy specimen. 8. Pulmonary embolism was diagnosed if there was a high-probability ventilation-perfusion scan and strong clinical suspicion. 9. Other exudates were defined by effusions that were clearly caused by Dressler s syndrome, collagen vascular disease, or pancreatitis. In all cases, there was an absence of malignancy, respiratory infections, and disease causing transudates. Effusions associated with CHF and chronic renal failure were classified as transudates and the rest were classified as exudates. The patients who had combined diseases such as CHF and pneumonia were not included in the study. Only the results of the first thoracentesis were considered. Biochemical parameters were determined using a multichannel analyser (SYNCHRON LX20). Total protein levels were measured by the modified biuret method. Albumin levels were measured using bromcresol green by spectrophotometric method. Lactate dehydrogenase (LDH) levels were measured using a kinetic UV optimised standard method (the upper normal limit for serum is defined at 460 IU/l). Total cholesterol concentration was determined by an enzymatic spectrophotometric method (cholesterol esterase and cholesterol oxidase). The concentration of total bilirubin was determined by measurement of azobilirubin after reaction with diazotised sulfanilic acid and addition of an accelerator. The usefulness of each biochemical parameter for identifying exudates was evaluated using Bayesian methods to measure the following: sensitivity, TP/TP+FN; specificity, TN/TN+FP; accuracy, TP+TN/TP+TN+FP+FN where TP is the number of true positive diagnoses, TN the number of true negative diagnoses, FP the number of false positive diagnoses, and FN the number of false negative diagnoses. Receiver-operating characteristics (ROC) curves were generated for each of the eight individual tests using SPSS for Windows (Ver.10.0, Chicago, IL). The area under curve (AUC) was the primary test function used to compare the diagnostic accuracies of individual tests. The optimum cut-off level was determined by selecting points of test values that provided the greatest sum of sensitivity and specificity. Results Three hundred and eighty-one patients with pleural effusions were evaluated; 74 patients were excluded from the study. This included two patients with the diagnosis of a traumatic haemothorax, four patients having pleural effusion secondary to pulmonary embolism [7, 8], and a further 68 patients whose effusions did not meet the above-determined criteria. The probable diagnoses for these patients were probable TB, 34 patients; postoperative effusion, 2 patients; paramalignant effusion, 32 patients (these patients were known with malignancies, but no malignant cells were shown in the pleural cavity). The remaining 307 patients (80.5%) consisted of 119 women and 188 men. Considering the aetiology of the effusions as the gold standard for the classification of pleural fluid [5, 7], 71 pleural fluid samples (23%) were labelled as transudates

3 987 and 236 were labelled as exudates. Among the 71 patients with transudates, 27 were women and 44 were men, with an average of 62 (range 28 80). Among the 236 patients with exudates, 92 were women and 144 were men, with an average of 52 (range 15 85). The causes of the 307 effusions are shown in Table 1. According to the criteria of Light et al. [1], an exudate is defined as fulfilling one or more of the following: (I) pleural fluid/serum protein ratio greater than 0.5, or (II) a pleural fluid/serum LDH ratio greater than 0.6, or (III) a pleural fluid LDH concentration greater than 307 IU/l (the cut-off value of pleural fluid LDH is two-thirds of the upper normal limit for the serum LDH). Light s criteria are systematically used in our hospital for the evaluation of all pleural effusions, as an implicit protocol. Using these criteria, 37 of 302 were misclassified (accuracy 87.8%). Nine patients with exudates and 28 patients with transudates were misclassified (sensitivity 96.2%, specificity 58.8%). Joseph and colleagues suggested that 82% of the upper limit of the normal serum LDH level should be used to differentiate between exudates and transudates for estimating the fluid LDH level [9]. Using 377 IU/l as a cut-off point for separating exudates from transudates, 226 of 295 patients were correctly classified (accuracy 76.6%). Fiftyeight patients with exudates and 11 patients with transudates falsely classified (sensitivity 74.7%, specificity 83.3%). In the study of Heffner et al., it has been proposed a cut-off point of 45% of the upper limit of the normal serum LDH level [10]. Using 207 IU/l as a cut-off point for separating exudates from transudates, 255 of 295 patients were correctly classified (accuracy 86.4%). Sixteen Table 1. Causes of pleural effusions. Aetiology n (%) Transudates Congestive heart failure 62 (20%) Chronic renal failure 9 (3%) Exudates Tuberculosis 26 (9%) Parapneumonic 44 (14%) Empyema 31 (10%) Malignant mesothelioma 67 (22%) Secondary pleural tumour 57 (19%) Collagen vascular disease 7 (2%) Dressler s syndrome 4 (1%) patients with exudates and 24 patients with transudates falsely classified (sensitivity 93.0%, specificity 63.6%). Using a cut-off point of 60 mg/dl [2, 3] for pleural fluid cholesterol concentration, 108 of 145 effusions were correctly classified (accuracy 74.5%). In contrast, Heffner et al. proposed a cut-off point of 45 mg/dl instead of higher values [10]. Using this cut-off level, 119 of 145 effusions were correctly classified (accuracy 82.1%). On the other hand, using a dividing line of 0.3 for the pleural fluid/serum cholesterol [3], 103 of 121 effusions were correctly classified (accuracy 85.1%). Using a dividing line of >0.6 for the ratio of pleural fluid bilirubin to serum bilirubin [10], 116 of 138 pleural fluid samples were correctly classified (accuracy 84.1%). Based on the work done by Roth et al. [4], a cut-off value of 12 g/l was used; an exudate having a gradient 12 g/l and a transudate having a gradient >12 g/l. By this method, 213 patients were correctly classified (accuracy 74.7%). Additionally, we also researched the efficiency of the parameter of the pleural fluid/serum albumin for the differentiation of exudates from transudates (Table 2). The ROC analysis that we performed demonstrated no differences among any of the test (Table 2). Tables 3 and 4 show the accuracy, sensitivity, and specificity of individual/multiple criteria. In a patient who had diuresed and the fluid seemed as exudates according to Light s criteria, a cut-off value of 12 g/dl for the serumeffusion albumin gradient showed the best accuracy (Table 5). Discussion Studies that report the diagnostic value of pleural tests vary considerably in case mix, study design, and the statistical analyses employed. Meisel et al. [6] investigated the pleural fluid/serum bilirubin ratio and yielded a sensitivity and specificity of 96% and 83%, respectively. In the study by Burgess et al. [5], a sensitivity and specificity of 81% and 61%, respectively, were obtained. In the current study, these rates were 90% and 61%. Using a cut-off value of 0.3 for the pleural fluid/ serum cholesterol ratio yielded an accuracy, sensitivity, and specificity of 85%, 86%, and 81%, respectively, in our study. In the study by

4 988 Table 2. Area under ROC curve (AUC) for the various test criteria. Parameters AUC Std. error 95% CI Optimum cut-off level Fluid/serum protein >0.48 Fluid/serum albumin >0.51 Fluid LDH concentration >236 IU/l Fluid/serum LDH >0.56 Fluid cholesterol >36.5 mg/dl Fluid/serum cholesterol >0.23 Fluid/serum bilirubin >0.61 Serum-effusion albumin gradient <1.25 Table 3. The diagnostic values of biochemical tests in the separation of exudates from transudates (PF: Pleural fluid). Parameter No of patients Accuracy (95% CI) Sensitivity (95% CI) Specificity (95% CI) Light s criteria % ( ) 96.2% ( ) 58.8% ( ) PF/serum protein > % ( ) 88.3% ( ) 81.5% ( ) PF LDH concentration >307 IU/l % ( ) 81.7% ( ) 77.3% ( ) PF LDH concentration >377 IU/l % ( ) 74.7% ( ) 83.3% ( ) PF LDH concentration >207 IU/l % ( ) 93.0% ( ) 63.6% ( ) PF/serum LDH > % ( ) 89.9% ( ) 79.4% ( ) PF cholesterol concentration >60 mg/dl % ( ) 70.5% ( ) 95.7% ( ) PF cholesterol concentration >45 mg/dl % ( ) 79.5% ( ) 95.7% ( ) PF cholesterol/serum cholesterol % ( ) 86.0% ( ) 81.0% ( ) PF bilirubin/serum bilirubin > % ( ) 90.0% ( ) 60.7% ( ) Serum-effusion albumin gradient 12 g/l % ( ) 69.4% ( ) 92.4% ( ) Serum-effusion albumin gradient 13 g/l % ( ) 76.7% ( ) 90.9% ( ) PF/serum albumin > % ( ) 90.9% ( ) 80.3% ( ) PF/serum albumin > % ( ) 81.7% ( ) 92.4% ( ) Burgess et al. [5], these rates were 86%, 92%, and 71%, respectively. The sensitivity and specificity for cholesterol level were found as 100% and 95%, respectively in the study of Hamm et al. [3]. For a cut-off level of 60 mg/dl, these rates were 72% and 85% in one study [11], and 71% and 96%, respectively, in our study. This parameter had the lowest diagnostic accuracy of studied individual tests. The pleural fluid to serum albumin ratio has been reported to be inferior to serum-effusion albumin gradient in the diagnostic separation of transudates and exudates [4]. For pleural fluid to serum albumin ratio >0.5, Joseph et al. found a 71% sensitivity and 89% specificity although they noted that pleural fluid LDH concentration was a superior test compared to two above parameters [12]. In contrast, we found that the pleural fluid to serum albumin ratio >0.5 was the most accurate parameter. Pleural fluid LDH concentration showed a better accuracy when using the cut-off value of >0.45 of the upper limits of the laboratory s normal LDH as suggested by Heffner et al. [10]. Our results showed that this approach was more effective than the cut-off value of >0.67 of the upper limits. The application of the alternative cut-off values suggested by Heffner et al. [10] increased the efficiency of pleural fluid LDH and cholesterol concentration. Costa et al. concluded that pleural fluid cholesterol plus pleural fluid LDH are able to separate pleural exudates from transudates with a sensitivity of 99% and a specificity of 98% [7]. These figures were better than those of Light s criteria with the added advantages of avoiding the necessity of a concomitant venipuncture and a cheaper cost. However, Table 4 showed that the combination of these two parameters showed a similar

5 989 Table 4. Combination test results of biochemical parameters (PF: Pleural fluid). Parameters No of patients Accuracy (95% CI) Sensitivity (95% CI) Specificity (95% CI) Light s criteria % ( ) 96.2% ( ) 58.8% ( ) PF LDH concentration >307 IU/l or PF/serum protein > % ( ) 95.3% ( ) 62.5% ( ) PF/serum LDH >0.6 or PF/serum protein > % ( ) 95.7% ( ) 67.2% ( ) PF LDH concentration >307 IU/l or PF/serum albumin > % ( ) 97.0% ( ) 63.1% ( ) PF LDH concentration >307 IU/l or PF/serum albumin > % ( ) 94.4% ( ) 75.4% ( ) PF LDH concentration >207 IU/l or PF cholesterol concentration >45 mg/dl % ( ) 97.8% ( ) 42.9% ( ) PF LDH concentration >207 IU/l or Serum-effusion albumin gradient 13 g/l % ( ) 95.2% ( ) 68.7% ( ) PF LDH concentration >207 IU/l or PF/serum albumin > % ( ) 97.0% ( ) 63.1% ( ) PF LDH concentration >207 IU/l and PF/serum albumin > % ( ) 74.4% ( ) 94.0% ( ) PF/serum LDH >0.6 and PF/serum albumin > % ( ) 83.4% ( ) 88.1% ( ) Table 5. Percent of transudates correctly classified in patients receiving diuretics who are thought to have a transudate by clinical criteria but the fluid is identified as exudate by Light s criteria. Parameter No of patients tested Serum-effusion albumin gradient >12 g/l Serum-effusion albumin gradient >13 g/l Serum-effusion albumin gradient >14 g/l Serum-effusion total protein gradient >29 g/l Serum-effusion total protein gradient >30 g/l PF cholesterol concentration >60 mg/dl PF cholesterol concentration >45 mg/dl PF/serum albumin > PF/serum albumin > % Correctly classified performance as Light s criteria. On the other hand, Heffner et al. [10] noted the high degree of correlation between LDH and the LDH ratio and found little loss of sensitivity by excluding one or the other. They suggested that abbreviated Light s criteria (i.e., eliminate either the pleural fluid LDH or fluid/serum LDH ratio) could be used instead of classical Light s criteria. The albumin gradient has been considered a more accurate parameter than Light s criteria to separate transudates from exudates in patients receiving diuretics [4, 5]. Its use has been recommended for patients who are thought to have a transudative process by clinical criteria but whose pleural fluid is identified as exudative by Light s criteria. Our results confirmed that, in such conditions, serum-effusion albumin gradient >12 g/l should be preferred for demonstrating real transudates. Because diuresis causes water to leave the pleural space faster than protein and LDH, concentrations and concentration ratios of a wide range of constituents raised in pleural liquid [13]. As a result, many transudates would have been misclassified as exudates using Light s criteria. Although Romero-Candeira et al. reported the increase in the pleural concentration of albumin

6 990 were similar to those of total protein [13], we found that the albumin gradient was a better parameter than the total protein gradient in patients with effusions who were diuresed. To explain better performance of the albumin gradient, Burgess et al. [5] suggested that diuresis increases the clearance of albumin more than the clearance of total protein in pleural fluid. We excluded 19.5% of patients from the study. The exclusion of these effusions probably results in an inflation of the test performance. These exclusions represent a major limitation of retrospective designs in evaluating test performance. Conclusions Because of high sensitivity in identifying exudates, Light s criteria have become the standard method for making this distinction. However, Table 4 showed that it is possible to use the different alternatives. On the other hand, pleural fluid/ serum LDH ratio or pleural fluid LDH concentration could be removed from Light s criteria without affecting diagnostic accuracy. Our results showed that any particular test or test combination had superior diagnostic accuracy. A single parameter such as pleural fluid/serum albumin ratio greater than 0.5, can show similar accuracy as Light s criteria. We propose to use of two parameters (the cutoff value for pleural fluid LDH concentration of >0.45 of the upper limits of the laboratory s normal LDH and pleural fluid to serum albumin ratio >0.5). Ninety-seven percent of our exudates had one of these two conditions. If a pleural fluid met both conditions, the probability of exudate was 94%. Acknowledgements The authors would like to thank Dr. Ahmet Aker for carrying out the pleural fluid biochemical analyses and Ziynet Cinar for the statistical analyses. Cumhuriyet University research and ethics committee approved the study (No: /2). References 1. Light R.W., MacGregor M.I., Luchsinger P.C. and Ball W.C., Pleural effusions: the diagnostic separation of transudates and exudates. Ann. Intern. Med. 77: , Valdes L., Pose A., Suarez J. et al., Cholesterol: a useful parameter for distinguishing between pleural exudates and transudates. Chest 99: , Hamm H., Brohan U., Bohmer R. and Missmahl H.P., Cholesterol in pleural effusions: a diagnostic aid. Chest 92: , Roth B.J., O Meara T.F. and Cragun W.H., The serumeffusion albumin gradient in the evaluation of pleural effusions. Chest 98: , Burgess L.J., Maritz F.J. and Taljaard J.J.F., Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates. Chest 107: , Meisel S., Shamiss A., Thaler M., Nussinovitch N. and Rosenthal T., Pleural fluid to serum bilirubin concentration ratio for the separation of transudates from exudates. Chest 98: , Costa M., Quiroga T. and Cruz E., Measurement of pleural fluid cholesterol and lactate dehydrogenase: a simple and accurate set of indicators for separating exudates from transudates. Chest 108: , Sahn S.A., The pleura: state of the art. Am. Rev. Respir. Dis. 138: , Joseph J., Badrinath P., Basran G.S. and Sahn S.A., Is the pleural fluid transudates or exudate? A revisit of the diagnostic criteria. Thorax 56: , Heffner J.E., Brown L.K. and Barbieri C.A., Diagnostic value of tests that discriminate between exudative and transudative pleural effusions. Chest 111: , Romero S., Candela A., Martin C., Hernandez L., Trigo C. and Gil J., Evaluation of different criteria for the separation of pleural transudates. Chest 104: , Joseph J., Badrinath P., Basran G.S. and Sahn S.A., Is albumin gradient or fluid to serum albumin ratio better than the pleural fluid lactate dehydrogenase in the diagnostic of separation of pleural effusion? BMC Pulmonary Med. 2: Romero-Candeira S., Fernandez C., Martin C., Sanchez- Paya J. and Hernandez L., Influence of diuretics on the concentration of proteins and other components of pleural transudates in patients with heart failure. Am. J. Med. 110: , 2001.