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(Chest. 2003;124:978-983.)
© 2003 American College of Chest Physicians

Etiology and Pleural Fluid Characteristics of Large and Massive Effusions*

José Manuel Porcel, MD, FCCP and Manuel Vives, MD

* From the Department of Internal Medicine (Dr. Porcel), University Hospital Arnau de Vilanova, Lleida, Spain; and the Division of Internal Medicine (Dr. Vives), Clínica Recoletas, Albacete, Spain.

Correspondence to: José Manuel Porcel, MD, FCCP, Department of Internal Medicine, University Hospital Arnau de Vilanova, Alcalde Rovira Roure 80, 25198 Lleida, Spain; e-mail: jporcelp{at}medynet.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To report the etiology of large and massive pleural effusions, and to compare their biochemical fluid characteristics with those of smaller size, and between malignant and nonmalignant conditions.

Design: Retrospective chart review of all patients undergoing thoracentesis at an academic medical center in Lleida, Spain, during a 10-year period.

Patients: Posteroanterior chest radiographs were available in 766 patients during the study period. Large pleural effusions (ie, two thirds or more of the hemithorax without its complete obliteration) were identified in 70 patients (9%), and massive pleural effusions (ie, hemithorax was completely opacified) were identified in 93 patients (12%).

Results: A similar etiologic spectrum between large and massive pleural effusions was observed. The most frequent cause of these pleural effusions was malignancy (89 patients; 55%), followed by complicated parapneumonic or empyema (36 patients; 22%), and tuberculosis (19 patients; 12%). Compared with nonmalignant pleural effusions, patients with large or massive malignant pleural effusions were more likely to have pleural fluids with higher RBC counts (18.0 x 109 cells/L vs 2.7 x 109 cells/L, respectively; p < 0.001) and lower adenosine deaminase (ADA) activity (11.5 vs 31.5 U/L, respectively; p < 0.001), which were the two parameters that were selected by a stepwise logistic-regression model as independent predictors of malignancy. In addition, large/massive malignant pleural effusions showed higher median RBC counts (18.0 x 109 cells/L vs 4.3 x 109 cells/L, respectively; p < 0.001), higher lactate dehydrogenase levels (641 vs 409 U/L, respectively; p = 0.001), lower pH (7.39 vs 7.42, respectively; p = 0.006) content, but similar cytologic yield (63% vs 53%, respectively; p = 0.171) than smaller malignant pleural effusions.

Conclusions: The presence of a large or massive pleural effusion enables the clinician to narrow the differential diagnosis of pleurisy, since most effusions are secondary to malignancy or infections (either bacterial or mycobacterial). Bloody pleural fluid with low ADA content favors a malignant condition.

Key Words: adenosine deaminase • empyema • malignant effusion • massive effusion • pleural effusion • tuberculosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
When a pleural effusion is diagnosed in a patient, the need for a timely and systematic evaluation is indicated. The list of etiologies of pleural effusions is extensive, although sometimes they can be inferred from the clinical circumstances. Ascertaining the amount of pleural fluid, as documented by chest radiograph, can be helpful in arriving at a presumptive cause of the pleural effusion. Thus, there is a general agreement that malignancy is the most common cause of pleural effusions occupying the entire hemithorax.1 Surprisingly, we have identified only two series, one in the English language literature2 and the other in the Spanish language literature,3 that support this notion (from a MEDLINE search conducted among articles from 1966 to 2002, with the subject heading massive pleural effusion). In addition, the leading etiology of nonmalignant massive pleural effusions is in dispute.2 3 In the present study, we intended to evaluate the etiologic spectrum of large and massive pleural effusions in a series larger than those previously reported, as well as to compare the biochemical characteristics of pleural fluid among pleural effusions of different sizes. We next attempted to determine what factors from the pleural fluid analysis were predictive of malignancy in patients with large or massive pleural effusions.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We reviewed the medical charts of all patients who had undergone a diagnostic thoracentesis at the University Hospital Arnau de Vilanova (Lleida, Spain) from June 1992 to June 2002. Clinical, radiologic, and pleural fluid data were recorded. The size of the effusion was assessed on the posteroanterior radiograph by visually estimating the area of the hemithorax occupied by pleural fluid. Pleural effusions were deemed to be nonlarge (ie, slight or of moderate size) if they occupied less than two thirds of the hemithorax, large if they affected two thirds or more of the hemithorax without reaching its complete length, and massive if they opacified the entire hemithorax. Only the measurement of the predominant side was considered in patients with bilateral effusions. We examined the following pleural fluid analytes: RBC count; leukocyte count; percentage of neutrophils and lymphocytes; glucose level; protein level; lactate dehydrogenase (LDH) level; adenosine deaminase (ADA) level; pH; fluid/serum protein ratio; and fluid/serum LDH ratio.

The causes of pleural effusions were determined by well-established clinical criteria. Specifically, the criteria for pleural effusions of tuberculous origin were as follows: (1) positive results for Löwenstein cultures of pleural fluid, sputum, or pleural biopsy specimens; (2) the presence of a granuloma in a pleural biopsy specimen after excluding other causes of granulomatous pleuritis; or (3) an exudative lymphocytic effusion with an ADA level of > 40 U/L, along with a positive tuberculin skin test result and the exclusion of any other potential causes of pleurisy. A pleural effusion was categorized as malignant if pleural fluid cytology or pleural biopsy findings were positive for malignancy (ie, true malignant), or if the patient had a known cancer with no other explanation for the effusion (ie, paramalignant). The term complicated parapneumonic effusions (PPEs) referred to those non-purulent-appearing effusions that did not resolve without chest tube drainage, whereas empyema described the presence of pus within the pleural space. The terms transudate or exudate were based on the cause of the effusion rather than on the criteria of Light et al.4 Thus, the category transudates encompasses those effusions that were clearly due to congestive heart failure, cirrhosis, or nephrosis. Exudative effusions not associated with neoplasm, tuberculosis, or pneumonia were classified as other exudates.

Statistical Analysis
Results are reported as medians (quartiles). Comparisons between groups used the {chi}2 and Fisher exact tests for categoric variables, and the nonparametric Kruskal-Wallis and Mann-Whitney tests were used for continuous variables. The area under the receiver operating characteristic curve accurately compared the discriminative properties of pleural fluid analytes. Demographic and pleural fluid data that distinguished malignant from nonmalignant large/massive effusions in the bivariate analysis, were entered into a stepwise logistic regression model in order to identify independent predictors of malignancy. All statistical comparisons were two-sided and were carried out at the 0.05 significance level. Data were analyzed with a statistical software package (SPSS, version 10.0; SPSS, Inc; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 1,051 patients who were evaluated during the study period, 285 were excluded from the study because either the radiologic data were unavailable or only an anteroposterior radiograph obtained with the patients in the supine position was performed. In the remaining 766 patients, a posteroanterior upright chest radiograph was obtained for review. Among this study group, 231 patients had malignant effusions, 150 patients had PPEs (uncomplicated effusion, 52 patients; complicated pleural effusion or empyema, 98 patients), 113 patients had tuberculous effusions, 114 patients had transudative pleural effusions, and 158 patients had other exudative pleural effusions.

Seventy patients (9%) exhibited large pleural effusions, and 93 patients (12%) exhibited massive pleural effusions. Most of these pleural effusions were unilateral (159 of 163 pleural effusions; 98%). There were 100 men and 63 women, with a median age of 64 years (quartiles, 48 to 75 years). Their underlying diseases are shown in Table 1 . Somewhat more than a half of large or massive pleural effusions (89 of 163 pleural effusions; 55%) were related to malignancies. The group of patients with large/massive malignant pleural effusions as a whole encompassed 58 patients with true malignant effusions and 31 with paramalignant effusions. The following primary tumors were found: lung, 28 tumors; breast, 19 tumors; unknown, 10 tumors; gynecologic, 7 tumors; hematologic, 7 tumors; GI, 5 tumors; and miscellaneous, 13 tumors (mesothelioma, 4 tumors; head and neck, 4 tumors; kidney, 2 tumors; sarcoma, 1 tumor; thymoma, 1 tumor; and melanoma, 1 tumor). The second most common cause of large and massive effusions was PPEs, representing a fifth of the total number of etiologies (36 of 163 patients; 22%) and nearly half of nonmalignant etiologies (36 of 74 patients; 49%). Of note, all patients in this subgroup had complicated PPEs or empyema, whereas none of the 52 uncomplicated PPEs extended to two thirds or more of the hemithorax. The third most common cause was tuberculous pleurisy (19 of 163 patients; 12%), and a variety of miscellaneous causes completed the list, of which hepatic hydrothorax deserves mention.


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  		Table 1.. Etiology of Nonlarge, Large, and Massive Pleural Effusions in 766 Patients*

 
Overall, 38% of malignant effusions (89 of 231), 37% of complicated PPEs and empyema (36 of 98), 27% of hepatic hydrothoraces (4 of 15), and 17% of tuberculous effusions (19 of 113) affected two thirds or more of the hemithorax. These percentages changed to 27%, 23%, 7%, and 8%, respectively, if only a subgroup analysis of massive effusions was considered. Congestive heart failure (2 of 87 patients; 2%) among others, also may cause this condition.

There were significant differences between the groups of patients with large/massive and nonlarge effusions regarding the following pleural fluid parameters: RBC count; pH; glucose level; LDH level; pleural fluid/serum protein ratio; and pleural fluid/serum LDH ratio (Table 2 ). When the 89 patients having large or massive malignant effusions were compared to the remaining 142 patients in the malignant effusion population, the former had fluids with higher median levels of RBCs (18.0 x 109 cells/L vs 4.3 x 109 cells/L, respectively; p < 0.001), higher medial levels of LDH (641 U/L vs 409 U/L, respectively; p = 0.001), and lower pH (7.39 vs 7.42, respectively; p = 0.006), yet only the subgroup with massive effusions differed in terms of glucose fluid concentrations (5.55 mmol/L vs 6.27 mmol/L, respectively; p = 0.006). Similar results were obtained when only true malignant patients were considered for comparisons. However, the sensitivity of cytologic examination did not differ between the large/massive and nonlarge malignant pleural effusion groups (56 of 89 patients [63%] vs 74 of 140 patients [53%]; p = 0.171).


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  		Table 2.. Comparison of Demographics and Pleural Fluid Data Among Nonlarge, Large, and Massive Pleural Effusions*

 
On the other hand, the 36 patients with large or massive PPEs showed higher median leukocyte counts (13.38 x 109 cells/L vs 2.72 x 109 cells/L, respectively; p = 0.001), higher median LDH levels (2,438 U/L vs 996 U/L, respectively; p = 0.002), lower pH (6.97 vs 7.34, respectively; p < 0.001), and lower glucose levels (0.28 mmol/L vs 5.00 mmol/L, respectively; p = 0.001) than the 114 patients with PPEs of smaller size. Finally, the leukocyte count was significantly higher in the pleural fluid of the 94 patients whose tuberculous effusions occupied less than two thirds of the hemithorax (2.35 x 109 cells/L) than in that of patients with large or massive tuberculous pleurisy (0.92 x 109 cells/L; p = 0.001).

In comparison to the patients with nonmalignant etiologies, those with malignant pleural effusions who belonged to the large/massive group were older, and their pleural fluids exhibited significantly higher values of RBC, glucose, and pH, but lower leukocyte count, LDH level, ADA level, and pleural fluid/serum LDH ratio (Table 3 ). When these parameters entered a stepwise logistic regression analysis, a high RBC count and a low ADA level were selected as the most significant independent predictors of malignancy. Identical results were obtained if only a subgroup analysis of true malignant effusions had been performed.


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  		Table 3.. Comparison of Demographics and Pleural Fluid Data Between Patients With Malignant and Nonmalignant Effusions of Large/Massive Size*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, this is the largest study to address the causes of large and massive pleural effusions. In 1972, Maher and Berger2 reported on 46 patients with pleural effusions occupying the entire hemithorax, of whom 31 (67%) had malignant diseases and 15 (33%) had nonmalignant conditions. Later on, Pedro de Lelis et al3 reviewed 84 cases of massive pleural effusions, and recognized that most (60 effusions; 71%) were of neoplastic origin. Accordingly, we also found malignancy to be the leading cause of large and massive effusions in our population, accounting for 89 of 163 cases (55%). Although similar, this rate (59% if only the subgroup of patients with massive effusion was considered) appears to be somewhat less dramatic than those rates mentioned above.

The rate of massive PPEs was much lower in prior publications, in which only four patients (8.7%)2 and two patients (2.4%)3 were reported. Patient selection might explain this low incidence. In contrast, PPEs and empyema represented the main nonmalignant etiology (49%) and the second most common overall etiology (22%) in our series. The absence of patients with typical or noncomplicated PPEs extending into two thirds or more of the hemithorax supports the inclusion of large effusions as a risk of poor outcome in patients with PPEs that deserve drainage of the pleural space.5 Tuberculosis, which was barely encountered (two cases; 4%) as a cause of massive effusion in the American series,2 appeared as the leading etiology of the nonmalignant category (13 of 24, 54%) in the previous Spanish study,3 and as the third overall cause in our population. This is probably due to the still high incidence of tuberculosis in Spain. In fact, two series from Spain involving 642 and 1,000 consecutive patients, respectively, with pleural effusions found that tuberculosis was the most frequent etiology (25%)6 and the second most frequent etiology (15.5%).7 In keeping with the results of Valdés et al,8 nearly 20% of our tuberculous effusions affected two thirds or more of the hemithorax. On the other hand, what we can infer from the finding of an identical etiologic spectrum between large and massive effusions is that effusions of both sizes have the same clinical significance.

Massive pleural effusions occur occasionally as a complication of cirrhosis (hepatic hydrothorax),9 congestive heart failure,1 trauma,10 chronic pancreatitis,11 dialysis,12 connective tissue diseases and vasculitis,13 14 ovarian hyperstimulation syndrome,15 chylothorax,16 or subarachnoid pleural fistulas,17 among others. We were surprised by the observation of a 74-year-old woman with a recurrent pulmonary embolism, as demonstrated by helical CT scanning, that was associated with a massive pleural effusion. She had primary antiphospholipid antibody syndrome, with pleural malignancy being excluded after numerous laboratory and imaging studies over a period of 9 months. Of note, in a recent study,18 none of 60 patients with pleural effusions secondary to pulmonary embolism had effusions that occupied more than one half of the hemithorax.

Obviously, pleural fluid tests are a useful guideline when assessing the etiology of pleural effusions, regardless of their size. The differences in pleural fluid biochemical profiles among nonlarge, large, and massive effusions may in part mirror the relative contributions of diverse etiologies in each group. Overall, the examination of pleural fluid in large/massive pleural effusions revealed the presence of biological markers of both inflammation (ie, high LDH levels) and metabolic activity (ie, low pH and glucose content) compared with smaller pleural effusions, which may be in the genesis of an increased pleural fluid formation. In addition to pleural inflammation, increased vascular permeability and leakage play a key role in the development of exudative pleural effusions. Not surprisingly, malignant and empyema fluids, which represent the main causes of large/massive effusions, have been consistently found to contain high levels of vascular endothelial growth factor.19 The determination of whether the absolute concentrations of this factor and certain cytokines that drive hyperpermeability may affect the volume of pleural effusion awaits further investigation.

As one might anticipate,2 3 older age and hemorrhagic fluids were associated with malignancy. The differences in pleural fluid ADA levels between malignant and nonmalignant effusions probably reflect the high incidence of empyema and tuberculosis, which are two disease entities that tend to have a high pleural fluid ADA level, in the latter subgroup. Interestingly, effusion size did not influence the yield of fluid cytology, despite a supposedly greater tumor burden in the pleural space of malignant massive effusions, as reflected by their lower glucose fluid contents.

One possible criticism of the present study is that 27% of the 1,051 patients who underwent thoracentesis during the study time period were excluded. However, we do not think that this selection factor biased our results, because the etiologic distribution of the 766 patients who composed the studied sample strictly reflects the epidemiology of pleural effusions in our geographic region.7 20

In conclusion, the amount of pleural fluid may be of diagnostic yield in that malignancy is a strong consideration in the diagnosis of any massive bloody pleural effusion. However, a significant proportion of benign etiologies, namely, complicated PPEs and empyema, and tuberculosis should be kept in mind, although the first can be easily distinguished from pleural metastases by the clinical picture,1 and the second can be distinguished by the ADA fluid content when the results of cytologic studies are negative.21 22


   Footnotes
 
Abbreviations: ADA = adenosine deaminase; LDH = lactate dehydrogenase; PPE = parapneumonic effusion

Received for publication August 23, 2002. Accepted for publication March 21, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  2. Maher, GG, Berger, HW Massive pleural effusion: malignant and nonmalignant causes in 46 patients. Am Rev Respir Dis 1972;105,458-460[ISI][Medline]
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  9. Degawa, M, Hamasaki, K, Yano, K, et al Refractory hepatic hydrothorax treated with transjugular intrahepatic portosystemic shunt. J Gastroenterol 1999;34,28-31[CrossRef][ISI][Medline]
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  11. Muray, S, Porcel, JM, Rubio, M Tratamiento conservador de la fístula pancreatopleural sin seudoquiste [letter] Med Clin (Barc) 1999;112,48-49
  12. Rudnick, MR, Coyle, JF, Beck, LH, et al Acute massive hydrothorax complicating peritoneal dialysis, report of 2 cases and a review of the literature. Clin Nephrol 1979;12,38-44[Medline]
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