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(Chest. 2005;128:3291-3297.)
© 2005 American College of Chest Physicians

Increased Oxidative Stress in Exudative Pleural Effusions*

A New Marker for the Differentiation Between Exudates and Transudates?

Evangelia Papageorgiou, MD; Konstantinos Kostikas, PhD; Theodoros Kiropoulos, BSc; Eleni Karetsi, MD; Georgios Mpatavanis, MD and Konstantinos I. Gourgoulianis, PhD

* From the Department of Respiratory Medicine, University of Thessaly, University Hospital of Larissa, Greece.

Correspondence to: Konstantinos Kostikas, Department of Respiratory Medicine, University of Thessaly, University Hospital of Larissa, 41110 Mezourlo, Larissa, Greece; e-mail: ktk{at}otenet.gr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Oxidative stress has been associated with various respiratory disorders. We tested the hypothesis that exudates would present higher levels of oxidative stress compared to transudates, expressing the increased local oxidative burst in the former.

Design: Prospective, cross-sectional study.

Patients or participants: One hundred six consecutive patients who had undergone thoracentesis were studied. Ninety patients with a final diagnosis of pleural effusion were further analyzed.

Setting: The respiratory department and a clinical laboratory of a tertiary hospital.

Interventions: Subjects underwent diagnostic thoracentesis, and standard biochemical parameters (ie, total protein, lactate dehydrogenase, and albumin levels) were measured in pleural fluid and serum. Oxidative stress levels were assessed with a commercially available method (d-ROMs test; Diacron; Grosseto, Italy) that uses conventional Carratelli units (UCarr). In 14 patients, duplicate measurements of oxidative stress and a second thoracentesis were performed on the following day for the assessment of the repeatability of measurements. Receiver operating characteristic (ROC) analysis was performed in order to determine the optimal cutoff level for the differentiation between exudates and transudates.

Measurements and results: Oxidative stress levels were higher in exudates compared to transudates (mean [± SD] stress level, 274 ± 72 vs 126 ± 34 UCarr, respectively; p < 0.0001). No significant differences were found among the levels of oxidative stress in exudative effusions of different etiologies. The area under the ROC curve was 0.992 (95% confidence interval, 0.945 to 0.997), and the method provided high sensitivity (96.8%), high specificity (96.3%), and high accuracy (96.7%) for the diagnosis of exudates at a cutoff level for oxidative stress of 186 UCarr. Consecutive measurements of oxidative stress in the same samples and on fluid from two different thoracenteses performed on 2 consecutive days presented excellent repeatability.

Conclusions: Oxidative stress levels are higher in exudative pleural effusions compared to transudative effusions, probably due to reactive oxygen species produced in the former.

Key Words: exudates • hydroperoxides • oxidative stress • pleural effusion • transudates


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The lung represents unique tissue in both its exposure to higher oxygen tensions and its high concentration of antioxidants.1 The imbalance between oxidants and antioxidants is referred to as oxidative stress and has been associated with various respiratory disorders. Increased oxidative stress participates in the pathogenesis of both airways and parenchymal lung diseases. Asthma, COPD, and bronchiectasis have been associated with inflammation and increased levels of oxidative stress.234 Inflammatory cells generate free radicals in patients with interstitial lung diseases such as pulmonary fibrosis and sarcoidosis.56 Increased oxidant burden has also been found in patients with pleural effusions due to lung cancer (LCa)7 and obstructive sleep apnea.8 Furthermore, free radicals are closely associated with diseases such as cystic fibrosis, primary pulmonary hypertension, and bronchopulmonary dysplasia.91011

Various markers of oxidative stress, including hydrogen peroxide and 8-isoprostane, have been reported to be increased in the lung. Such markers have been determined in various biological samples, as in blood,1213 sputum,14 BAL fluid,15 and exhaled breath condensate1617 collected from patients with lung diseases. These samples express either local or systemic levels of oxidative stress. The pleural cavity is a closed space that is segregated from the rest of the respiratory system but interacts with the lung in different disease processes. However, the local production of free radicals and the role of oxidative stress in the pathogenesis of pleural effusions have not been extensively studied.

Pleural effusions are often a diagnostic dilemma for the physician as the differential diagnosis is wide. The first step in the evaluation of pleural effusions is the distinction between exudates and transudates. The criteria described by Light et al18 have become a standard method for this separation because of their high sensitivity in identifying exudates. The main disadvantage appears to be the misclassification of transudates as exudates.19 More recent studies have proposed other methods for the differentiation of exudates and transudates.202122

The aim of the present study was to evaluate the levels of oxidative stress in the pleural fluid of patients with pleural effusions of various etiologies. We tested the hypothesis that exudates would present higher levels of oxidative stress compared to transudates, expressing the increased local oxidative burst in the former. We also examined whether oxidative stress could serve as an independent marker for the differentiation between exudative and transudative pleural effusions. Finally, we validated the method we used for the assessment of oxidative stress by testing the repeatability of the measurements on the same samples and on samples taken from the same subjects on 2 consecutive days.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
This study was performed on patients who were hospitalized in the Respiratory Medicine Department of the Medical School of the University of Thessaly in Larissa between May and December 2004. During this time, 106 consecutive patients who had undergone diagnostic thoracentesis for pleural effusions were studied. Sixteen of these patients were excluded from this study if either, despite extensive evaluation, the cause of the pleural effusion was indeterminate, or more than one plausible cause of the pleural effusions was present. The study protocol was approved by the local ethics committee, and all subjects gave their written informed consent.

Sample Collection and Analysis
Pleural fluid and blood samples were collected from all patients on the day of their hospital admission. All samples were immediately analyzed using standard commercially available methods for the following biochemical parameters: glucose; total protein lactate dehydrogenase (LDH); and albumin. Aliquots of the pleural fluid samples were additionally used for the determination of the levels of oxidative stress.

Diagnostic Criteria for Pleural Effusions
The determination of the etiology of the pleural effusions was based on the clinical presentation, the results of appropriate diagnostic tests, and the response to treatment for each patient. Accordingly, effusions were classified into the following groups, which were defined by predetermined criteria:

  1. Effusions secondary to LCa were diagnosed by the demonstration of malignant cells on cytologic examination or in a biopsy specimen or histologically proven primary lung malignancy with the exclusion of any other cause of pleural effusion.
  2. The diagnosis of tuberculous effusions was based either on the presence of positive stain or culture for Mycobacterium tuberculosis (TB) in the pleural fluid, sputum, or pleural biopsy specimen; or in the presence of typical caseating granulomas on a pleural biopsy specimen. When a pleural biopsy was not performed, we considered patients to have tuberculous pleurisy if they met the following criteria: (1) adenosine deaminase levels in pleural fluid of > 40 U/L23; (2) the exclusion of any other cause of pleural effusion; and (3) the response to antituberculous therapy.
  3. Other malignant pleural effusions (OCas) were clearly secondary to ovarian malignancy, breast malignancy, renal cell carcinoma, and non-Hodgkin lymphoma in patients in whom other causes for the development of pleural effusions had been excluded.
  4. Infectious (parapneumonic) effusions were identified by the presence of pulmonary infections associated with acute febrile illness, pulmonary infiltrates, purulent sputum, and the response to antibiotic treatment; identification of the organism in the pleural fluid; or the presence of empyema, which was associated with a finding of franc pus in the pleural cavity. None of these patients presented any radiologic signs of loculation at the time of the thoracentesis.
  5. Other exudates included effusions that were attributed to rheumatoid arthritis, eosinophilic pleural effusions, and posttraumatic effusions.
  6. The diagnosis of congestive heart failure (CHF) was based on the findings of an enlarged heart and/or pulmonary venous congestion on a chest radiograph, evidence of left ventricular systolic or diastolic dysfunction on echocardiography, peripheral edema, and/or response to treatment for CHF.
  7. Renal failure was diagnosed by increased levels of urea and creatinine in the presence of fluid overload and by the exclusion of other causes for the development of pleural effusions.
  8. Other causes of transudative pleural effusions included the following: nephrotic syndrome diagnosed in patients with proteinuria, edema, and hypoalbuminemia; liver cirrhosis diagnosed by liver biopsy in the presence of ascites; and other causes of hypoalbuminemia, which was defined by a serum albumin level of < 30 g/L in the absence of proteinuria and histologically proven liver cirrhosis. In all of these cases, all other causes for the development of pleural effusions were excluded.

Pleural effusions secondary to diseases that directly involve pleural surfaces were considered to be exudates, and the rest were considered to be transudates. Using this classification, exudative effusions in this study included malignancy, TB, infective conditions, rheumatoid arthritis, posttraumatic and eosinophilic effusions; transudative effusions included CHF, renal failure, and hypoalbuminemia. The classification of the effusions as exudative and transudative was made by two experienced clinicians (K.K. and K.I.G.) who were not aware of the measurements of oxidative stress in the pleural fluid. The characterization of effusions as exudates was further validated using the criteria of Light et al,18 as follows: pleural fluid protein/serum protein ratio of > 0.5; pleural fluid LDH/serum LDH ratio of > 0.6; and pleural fluid LDH level more than two thirds of the upper limit of the normal value for serum. In four of the transudates that were due to CHF in patients receiving long-term therapy with diuretics and presented a pleural fluid protein/serum protein ratio of > 0.5, the serum-effusion albumin gradient (ie, serum albumin concentration – pleural fluid albumin concentration) was also calculated.21 In these cases, this gradient was > 1.2, indicating the transudative nature of these effusions.

Assessment of Levels of Oxidative Stress
Pleural fluid samples were analyzed immediately after their collection by an investigator (T.K.) who was not aware of the clinical features of the patients or the results of the other parameters. A commercially available method was used for the assessment of the levels of oxidative stress in the pleural fluid (d-ROMs test; Diacron; Grosseto, Italy), as has been previously described for blood samples.2425 This is a spectrophotometric method that assesses overall oxidative stress by measuring the total level of hydroperoxides, given that hydroperoxides are intermediate oxidative products of lipids, peptides, and amino acids. Briefly, immediately after the thoracentesis the pleural fluid is centrifuged and 20 µL of pleural fluid are diluted in 1 mL of acetate-buffered solution (pH, 4.8). Hydroperoxide groups react with the transition metal ions liberated from the proteins in the acidic medium, and are converted to alkoxyl and peroxyl radicals according to the Fenton reaction.26 These newly formed radicals, the quantities of which are directly proportional to those of the peroxides present in pleural fluid, are trapped chemically with 20 µL of chromogen (N,N-diethparaphenyldiamine), leading to the formation of the radical cation of this chromogen. The purple color resulting from this reaction over time was monitored in a spectrophotometer ({lambda}16; Perkin Elmer; Norwalk, CT) at 505 nm. The results of this method are expressed in conventional units (Carratelli units [UCarr]); 1 UCarr corresponds to 0.8 mg/L H2O2.

Repeatability
The repeatability of the measurements of hydroperoxides with the test for oxidative stress in pleural effusions was checked in pleural fluid samples that had been obtained from two serial thoracenteses performed on 2 consecutive days in a total of 14 patients, including the following: (1) four patients with malignant pleural effusions due to LCa; (2) four patients with malignant pleural effusions from other causes; (3) two patients with tuberculous effusions; and (4) four patients with transudative pleural effusions. All 14 patients were in stable condition between the two thoracenteses. A further analysis consisted of two serial measurements on the initial (from the first day) samples, in order to assess the repeatability of the method on the same samples.

Statistical Analysis
Data are presented as the mean ± SD, unless otherwise mentioned. Comparisons of levels of oxidative stress between two different groups were compared using unpaired t tests, as the data were normally distributed. Comparisons between more than two groups were performed with one-way analysis of variance. The normality of distribution was checked with a Shapiro-Wilks test. Correlations between oxidative stress levels and other parameters were checked with the Pearson correlation coefficient. For the evaluation of the repeatability of the measurements of oxidative stress in pleural effusions we have used the method described by Bland and Altman.27 A p value of < 0.05 was considered to be statistically significant.

For the evaluation of oxidative stress as a marker for the differentiation between exudates and transudates, a receiver operating characteristic (ROC) curve was generated by plotting the sensitivity against 1-specificity, and the area under the curve with 95% confidence intervals was calculated. For the optimum cutoff point provided by the ROC analysis, the following parameters were assessed: sensitivity = TP/(TP + FN); specificity = TN/(TN + FP); positive predictive value = TP/(TP + FP); negative predictive value = TN/(TN + FN); and accuracy = (TP + TN)/(TP + TN + FP + FN). TP is the number of true-positive diagnoses (ie, number of exudates correctly diagnosed), TN is the number of true-negative diagnoses (ie, number of transudates correctly diagnosed), FP is the number of false-positive diagnoses, and FN is the number of false-negative diagnoses. Because exudates and transudates are complementary terms, we have used the above terminology referring to exudates.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic characteristics and the pleural fluid characteristics of the 90 patients who were studied are presented in Table 1 . The causes of the transudative and exudative effusions are presented in Table 2 .


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  		Table 1. Demographic Characteristics and Pleural Fluid Measurements*

 

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  		Table 2. Etiology of Pleural Effusions (n = 90)

 
The mean oxidative stress levels were higher in exudates compared to transudates (274 ± 72 vs 126 ± 34 UCarr, respectively; p < 0.0001). Similar differences were noticed for each of the subgroups of patients with exudative pleural effusions compared to those with transudative effusions (transudative effusions, 126 ± 34 UCarr; LCa, 279 ± 68 UCarr; other malignancies, 266 ± 67; tuberculous pleuritis, 272 ± 52; other causes, 268 ± 93 UCarr; p < 0.0001 for each pair) [Fig 1 ]. No significant differences were found between the levels of oxidative stress in the subgroups of patients with exudative pleural effusions (p = 0.33). Accordingly, no significant differences were found between the levels of oxidative stress in the subgroups of patients with transudative pleural effusions (p = 0.42).



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  		Figure 1. Oxidative stress levels in the pleural fluid of patients with transudative pleural effusions (TrPE) [n = 28; {circ}] and exudative pleural effusions (ExPE) [n = 62 {blacktriangleup}]; LCas, n = 22 ({blacktriangledown}); OCas, n = 18 ({diamondsuit}); TB, n = 8 (•); and other malignancies, n = 14 ({blacksquare}). The levels of oxidative stress are expressed in UCarr. Each symbol represents one individual. Horizontal bars represent mean values. See text for details.

 
Determination of the Optimum Cutoff Value for the Differentiation Between Exudates and Transudates
The ROC analysis provided the curve presented in Fig 2 . The area under the ROC curve was 0.992 (95% confidence interval, 0.945 to 0.997), suggesting the high sensitivity and specificity of the method. The optimum cutoff point for the differentiation between exudates and transudates was selected as the level of oxidative stress with the greatest sum of sensitivity and specificity. That is the point closest to the top left-hand corner on the ROC curve. This point corresponds to a level of oxidative stress of > 186 UCarr. This cutoff point provides a sensitivity of 96.8%, a specificity of 96.3%, a positive predictive value of 98.4%, a negative predictive value of 92.9%, and an accuracy of 96.7% for the diagnosis of exudates.



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  		Figure 2. ROC curve of pleural fluid values of oxidative stress. The optimum cutoff level for the differentiation between exudates and transudates was determined as the point that provides the greatest sum of sensitivity and specificity, in this case a level of > 186 UCarr.

 
Application of the Method in Transudates After Diuretics
Four of our patients with diagnosed CHF who had already been receiving diuretics prior to undergoing thoracentesis presented with effusions that should have been characterized as exudates by the criteria of Light et al.18 In these patients, the serum albumin/pleural fluid albumin ratio was > 1.2, indicating the transudative nature of these effusions. In all of these patients, the levels of oxidative stress were also suggestive of transudative effusions (mean, 126 ± 34 UCarr; range, 69 to 148 UCarr).

Repeatability of Oxidative Stress Measurements
The measurements of oxidative stress in the pleural fluid in two different thoracenteses performed on 2 consecutive days presented excellent repeatability. The mean oxidative stress levels on days 1 and 2 were 229 ± 95 and 228 ± 93 UCarr, respectively. The correlation between oxidative stress measurements on 2 consecutive days was statistically significant (r = 0.99; p < 0.0001). The mean (± 2 SDs) difference with limits of agreement was 0.43 ± 13.09, and all values were well within the limits of agreement in the Bland-Altman plot (Fig 3 , top, A).



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  		Figure 3. Top, A: assessment of repeatability of oxidative stress measurements in pleural effusions on 2 consecutive days in 14 subjects, presented in Bland-Altman plots (differences against mean values). Bottom, B: assessment of repeatability of two serial oxidative stress measurements made in the same (first day) samples taken from the 14 subjects, presented in Bland-Altman plots. The levels of oxidative stress in both plots are expressed in UCarr. Dotted lines represent the mean difference value and the limits of agreement (± 2 SDs).

 
Further analysis of two serial measurements on the initial (first-day) samples showed again excellent repeatability. The mean oxidative stress levels on measurements 1 and 2 were 229 ± 94 and 229 ± 93 UCarr, respectively. The correlation between the two consecutive measurements of oxidative stress was statistically significant (r = 0.99; p < 0.0001). The mean (± 2 SDs) difference with limits of agreement was –0.50 ± 5.69, and all values were well within the limits of agreement in the Bland-Altman plot (Fig 3, bottom, B).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this prospective study, we have shown that exudative pleural effusions present increased levels of oxidative stress compared to transudative effusions. No significant differences in the levels of oxidative stress were found among the subgroups of patients with exudative effusions due to different etiologies. The method that we used proved to be repeatable in the same samples and in samples taken from two serial thoracenteses performed on 2 consecutive days. The levels of oxidative stress measured with this assay may serve as good markers for the differentiation of exudates and transudates.

To the best of our knowledge, this is the first study to investigate the levels of oxidative stress in pleural effusions in humans. The increased levels of oxidative stress in exudates probably represent the increased local production of free radicals. The origin of this local oxidative burst is related to the nature of each disease entity. However, the local production of oxidants in the pleural cavity has not been extensively studied. There is in vitro evidence in animal models that reactive oxygen and nitrogen species may be implicated in the pathogenesis of asbestos-related pleural effusions.28 In the diseases studied in our patients, there is little evidence in the literature regarding the local production of oxidative stress. Oxidants have been shown to play an important role in carcinogenesis, serving not only as tumor initiators but also as tumor promoters and regulators of gene expression.29 This has been shown both in LCa and in other malignancies. TB has been associated with increased levels of several markers of oxidative stress and decreased antioxidant capacity.30 Mesothelial cells are responsible for the release of oxidants in pleural space infections.31 All of the above-mentioned disease processes may contribute to the increased oxidative stress production when the pleural cavity is involved. Transudative pleural effusions, on the contrary, are not related to local pleural pathology, but are produced by an imbalance between the hydrostatic and oncotic pressures, which does not lead to the formation of reactive oxygen species. This may be a plausible explanation for the increased oxidative stress levels in exudates compared to transudates.

In this study, we assessed the overall oxidative stress indirectly by measuring the level of total hydroperoxides in pleural fluid by a commercially available method (d-ROMs test; Diacron). This method has not been previously assessed in pleural fluid, although it has been validated before in blood samples.25 In blood samples, it has been shown that the method presents both an acceptable stability and an acceptable margin of error.32 In pleural effusions, hydroperoxides proved to be detectable in all of the samples of our study, and their concentration was significantly higher in exudative pleural effusions compared to transudative pleural effusions. Furthermore, the measurement of overall oxidative stress was highly repeatable on measurements on the same samples and on samples taken from the same subjects on 2 consecutive days, thus indicating that the results may be safely interpreted in each patient. An important disadvantage of this assay, though, is the fact that it did not prove to be a good marker for the differentiation between exudates of different etiologies, once no difference was noticed in the levels of oxidative stress in different disease entities. A possible explanation for this finding may be the fact that the method provides a measurement of overall oxidative stress, not being able to illuminate subtle differences between different disease processes. Further studies on the validation of more specific markers of oxidative stress might be useful in this regard.

The separation between exudative and transudative pleural effusions in our study was based on clinical presumption, after a thorough investigation of each patient, compared with the evaluation using the criteria of Light et al.18 Any patients with diagnostic uncertainty were excluded from further evaluation. In this group of well-characterized pleural effusions, the measurement of oxidative stress proved to be an excellent marker for the differentiation between exudates and transudates. The method provided high sensitivity (96.8%), specificity (96.3%), and accuracy (96.7%) for the characterization of an effusion as an exudate, when a cutoff level of oxidative stress of > 186 UCarr, which was provided by the ROC analysis, was used. These results were superior to the results provided using the criteria of Light et al,18 and were comparable to those using other criteria from the literature.3334 This, again, may be attributed to the different pathophysiology behind the production of exudates and transudates, which results in low levels of locally produced reactive oxygen species in the latter.

Furthermore, with the application of the criteria of Light et al,18 15 to 30% of transudates in the literature are misclassified as exudates, and most cases of misclassifications occur in patients receiving diuretic therapy.35 In the present study, four of our patients with transudative effusions who are receiving long-term diuretic therapy (4 of 28 patients; 14%) would have been misclassified as having exudative effusions according to the criteria of Light et al.18 To overcome this limitation, the use of alternative criteria, such as the serum-effusion albumin gradient, has been recommended.21 These criteria provided the correct classification of these effusions as exudates in all four patients mentioned. Additionally, all four patients were treated with more aggressive diuresis with good responses. Interestingly, the levels of oxidative stress in all four of these patients were well into the transudative range. This finding suggests that the measurement of oxidative stress may be useful for the differentiation between transudates and exudates even in such marginal effusions. However, the small number of cases in our study does not provide strong evidence for such an assumption, and further studies are needed in this regard.

In conclusion, in this study we have reported that the levels of oxidative stress are higher in exudative pleural effusions compared to transudative pleural effusions, probably due to the reactive oxygen species produced in the former. Oxidative stress levels were assessed with a rapid commercially available method that was highly repeatable in the patients studied, and may serve as a marker for the differentiation between exudates and transudates in clinical practice.


   Footnotes
 
Abbreviations: CHF = congestive heart failure; FN = false-negative; FP = false-positive; LCa = pleural effusions due to lung cancer; LDH = lactate dehydrogenase; OCa = other malignant pleural effusions; ROC = receiver operating characteristic; TB = tuberculosis; TN = true-negative; TP = true-positive; UCarr = Carratelli units

Received for publication March 9, 2005. Accepted for publication May 10, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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