Eosinophilic Pleural Effusions
Eosinophilic pleural effusions, defined as a pleural effusion that contains at least 10% eosinophils, may be caused by almost every condition that can cause pleural disease. Eosinophilic pleural effusion occurs most commonly during conditions associated with the presence of blood or air in the pleural space, infections, and malignancy. Drug-induced pleural effusions, pleural effusions accompanying pulmonary embolism, and benign asbestos pleural effusions are also among the common causes of eosinophilic pleural effusion. No etiology is found in as many as one third of patients. Because studies evaluating different diagnostic approaches with eosinophilic pleural effusions are lacking, the authors suggest that certain noninvasive and invasive diagnostic tools must be used based on the patient's clinical characteristics.
Eosinophilic pleural effusion (EPE), first described by Harmsen in 1894, is defined as a pleural effusion that contains at least 10% eosinophils. EPEs account for 5 to 16% of exudative pleural effusions and can be a manifestation of a great variety of diseases ( Table 1). Most of the information about EPE comes from small series and cases reports. A considerable proportion of these patients (343 cases of EPE reported in the English literature until 1983) has been summarized previously by Adelman et al.. Since then, most of the information comes from four studies, which include 146 patients with EPE. Noticeably, most studies have not taken into consideration whether pleural fluid eosinophilia was found on the first or subsequent thoracenteses. Because thoracentesis itself is a cause of pleural fluid eosinophilia, some of the reported cases of EPE may have been attributed falsely to other etiologies when in fact they were the result of thoracentesis. The extent of this misclassification is unknown.
The presence of air or blood in the pleural space is responsible for many EPEs. Adelman et al. reported that pneumothorax was the cause of EPE in 12.5% of 343 patients. Sadikot et al. showed that blood is an important factor causing postthoracic surgery EPE. They reported that pleural effusions occurring within the first month after coronary artery bypass grafting are often bloody and eosinophilic (median eosinophils, 38.5%), whereas the postcoronary artery bypass grafting pleural effusions occurring later are usually nonbloody and do not contain eosinophils. Because air and blood frequently coexist in the pleural space (surgical procedures, thoracentesis, chest trauma), it is often difficult to determine which of the two are responsible for the EPE. For this reason we included these two etiologic factors in the same category ( Table 1 ). Air/blood was the most common cause of EPE in the studies by Adelman et al. (29%) and Spriggs and Boddington (64%). Other series reported that 16 to 39% of EPEs were the result of blood/air in the pleural space.
However, pleural blood or air does not always cause EPE. Among 250 patients with pleural fluid red blood cell counts ≥100,000/mm at our institution, only 51 (20%) had pleural fluid eosinophilia. Thoracentesis is thought to be a very common cause of EPE because of the introduction of blood or air into the pleural space. However, Rubins and Rubins reported that only 3 of 130 patients (2.9%) with non-EPE who underwent a second thoracentesis and 4 of 36 (11.1%) of those who underwent repeated thoracenteses within 2 to 12 weeks had higher numbers of pleural fluid eosinophils in subsequent thoracenteses.
Infection resulting from bacteria, mycobacteria, parasites, fungi, and viruses may cause EPE. When present, eosinophils appear late during the course of parapneumonic effusions (a month or more), even after the resolution of the pneumonia. This is the reason why some authors have called these EPEs "postpneumonic". Parapneumonic effusions represented 9% and 33% of EPE in two recent series. Tuberculous pleural effusions very rarely contain high numbers of eosinophils. Adelman et al. reported an EPE prevalence of 1.3% among 700 tuberculous pleural effusions. Tuberculosis was the etiology in only 4% of their 343 EPEs. However, a study from Scandinavia showed the prevalence of EPE was 5.7% among 141 patients with tuberculous pleuritis. Another study from the same center reported that 18% of 78 EPEs were of tuberculous origin. More recently, tuberculosis was reported to be the cause of EPE in 15.6% of 45 patients from Spain. The Spanish, but not the Scandinavian, group indicated that only pleural fluids from the first thoracentesis were studied. We suggest that tuberculous pleuritis, although associated rarely with pleural fluid eosinophilia, should still be considered as a possible cause of EPE in populations with a high prevalence of tuberculosis.
Coccidioidomycosis, histoplasmosis, and cryptococcosis have been reported to cause EPE, typically with concomitant parenchymal disease. Among parasites that cause EPE, the most frequent is Paragonimus spp., which is endemic in eastern and southeastern Asia but can be also found in Africa, South America, and even North America. Other parasitic diseases associated with EPE are sparganosis, toxocariasis, cutaneous myasis, loiasis, strongyloidiasis, echinococcosis,Dracunculus medinensis infection, lymphatic filariasis, ascariasis, and amebiasis. Viruses have been also thought to cause EPE. The diagnosis of viral pleuritis was made clinically and we are not aware of a report with laboratory proof of the viral origin of an EPE.
The relationship between EPE and malignancy is controversial. The frequency of malignant etiology among EPEs has varied between 6% and 40% in different studies. In our hospital, 15 of 172 cases of EPE (8.7%) found since 1997 were malignant. Interestingly, when five major EPE series were tabulated, malignancy was the most common diagnosis when idiopathic cases and cases resulting from air/blood were excluded ( Table 2 ). The prevalence of EPE among malignant pleural effusions has varied between 2.3% and 11.6%. Notable support against the association between EPE and malignancy came from Adelman et al., who concluded that the presence of pleural fluid eosinophilia decreases the likelihood that a pleural effusion is malignant. The belief that the presence of pleural fluid eosinophilia denotes a benign underlying disorder was challenged by three more recent studies that included 1058 patients in total (111 with EPE). According to these studies malignancy was as prevalent among EPE as non-EPE. Overall, 27% of the patients with EPE and 29.8% of those with non-EPE had malignant pleural effusion. When patients with obviously benign pleural fluid (transudates and effusions after pleural traumatic injury) were excluded, malignancy was the cause in 25 of 79 EPEs (31.6%) and 282 of 660 non-EPEs (42.7%). Eosinophilic malignant pleural effusions are not necessarily hemorrhagic. In our institution, 8 of the 59 malignant pleural effusions (13.6%) with red blood cell counts more than 10,000 cells/mm and 3 of the 13 (23%) with red blood cell counts more than 100,000 cells/mm were eosinophilic. The pleural fluid red blood cell count was lower than 10,000 cells/mm in seven malignant EPEs. In view of this fact, we suggest that a malignant etiology should be considered in all patients with undiagnosed EPEs.
Benign pleural effusions develop in patients exposed to asbestos with a mean latency of 30 years (range, 1-58 years) after the first exposure, and 25 to 50% of these effusions are eosinophilic. Adelman et al. reported that 4% of EPEs were benign asbestos pleural effusions. Pulmonary embolism is accompanied by pleural effusions in 30 to 50% of the cases, and as much as 18% of them are eosinophilic. In the series by Spriggs and Boddington, 12 of 127 (9.5%) pleural effusions with more than 20% eosinophils were the result of pulmonary embolism. Pulmonary embolism was recognized as the etiologic factor in only 4% of 343 EPEs summarized by Adelman et al. and in 3.4% of 147 EPEs from the four studies conducted more recently. To our knowledge, 10 drugs have been associated with the development of an EPE ( Table 3). Valproic has also been considered as a cause of EPE although, in our opinion, the pleural effusion described in the relevant case report was most likely a postpneumonic effusion.
Finally, it should be noted that no diagnosis is ever established in many cases with EPE. In the series of Adelman et al., one third of the patients with EPE remained undiagnosed, and they were called "idiopathic." In the 147 patients with EPE reported in the four more recent series, the percentage of idiopathic pleural effusions was 15.6%. The similarity of the clinical features and course of the patients with idiopathic EPE with those with benign asbestos pleural effusion and the fact that the diagnosis of the second is difficult and frequently overlooked, led some authors to speculate that a respectable proportion of patients with idiopathic EPE have benign asbestos pleural effusion. We think that pleural effusions resulting from pulmonary emboli are also underdiagnosed. Because pulmonary embolism is a very common disease with an associated pleural effusion in 30 to 50%, of which approximately 20% are eosinophilic, it is reasonable to argue that some of the "idiopathic" EPEs are the result of occult pulmonary emboli. Viral infection, another common and difficult-to-diagnose cause of pleural effusion, may also be the cause of some cases of "idiopathic" EPE.
Introduction
Eosinophilic pleural effusions, defined as a pleural effusion that contains at least 10% eosinophils, may be caused by almost every condition that can cause pleural disease. Eosinophilic pleural effusion occurs most commonly during conditions associated with the presence of blood or air in the pleural space, infections, and malignancy. Drug-induced pleural effusions, pleural effusions accompanying pulmonary embolism, and benign asbestos pleural effusions are also among the common causes of eosinophilic pleural effusion. No etiology is found in as many as one third of patients. Because studies evaluating different diagnostic approaches with eosinophilic pleural effusions are lacking, the authors suggest that certain noninvasive and invasive diagnostic tools must be used based on the patient's clinical characteristics.
Definition and Etiology
Eosinophilic pleural effusion (EPE), first described by Harmsen in 1894, is defined as a pleural effusion that contains at least 10% eosinophils. EPEs account for 5 to 16% of exudative pleural effusions and can be a manifestation of a great variety of diseases ( Table 1). Most of the information about EPE comes from small series and cases reports. A considerable proportion of these patients (343 cases of EPE reported in the English literature until 1983) has been summarized previously by Adelman et al.. Since then, most of the information comes from four studies, which include 146 patients with EPE. Noticeably, most studies have not taken into consideration whether pleural fluid eosinophilia was found on the first or subsequent thoracenteses. Because thoracentesis itself is a cause of pleural fluid eosinophilia, some of the reported cases of EPE may have been attributed falsely to other etiologies when in fact they were the result of thoracentesis. The extent of this misclassification is unknown.
The presence of air or blood in the pleural space is responsible for many EPEs. Adelman et al. reported that pneumothorax was the cause of EPE in 12.5% of 343 patients. Sadikot et al. showed that blood is an important factor causing postthoracic surgery EPE. They reported that pleural effusions occurring within the first month after coronary artery bypass grafting are often bloody and eosinophilic (median eosinophils, 38.5%), whereas the postcoronary artery bypass grafting pleural effusions occurring later are usually nonbloody and do not contain eosinophils. Because air and blood frequently coexist in the pleural space (surgical procedures, thoracentesis, chest trauma), it is often difficult to determine which of the two are responsible for the EPE. For this reason we included these two etiologic factors in the same category ( Table 1 ). Air/blood was the most common cause of EPE in the studies by Adelman et al. (29%) and Spriggs and Boddington (64%). Other series reported that 16 to 39% of EPEs were the result of blood/air in the pleural space.
However, pleural blood or air does not always cause EPE. Among 250 patients with pleural fluid red blood cell counts ≥100,000/mm at our institution, only 51 (20%) had pleural fluid eosinophilia. Thoracentesis is thought to be a very common cause of EPE because of the introduction of blood or air into the pleural space. However, Rubins and Rubins reported that only 3 of 130 patients (2.9%) with non-EPE who underwent a second thoracentesis and 4 of 36 (11.1%) of those who underwent repeated thoracenteses within 2 to 12 weeks had higher numbers of pleural fluid eosinophils in subsequent thoracenteses.
Infection resulting from bacteria, mycobacteria, parasites, fungi, and viruses may cause EPE. When present, eosinophils appear late during the course of parapneumonic effusions (a month or more), even after the resolution of the pneumonia. This is the reason why some authors have called these EPEs "postpneumonic". Parapneumonic effusions represented 9% and 33% of EPE in two recent series. Tuberculous pleural effusions very rarely contain high numbers of eosinophils. Adelman et al. reported an EPE prevalence of 1.3% among 700 tuberculous pleural effusions. Tuberculosis was the etiology in only 4% of their 343 EPEs. However, a study from Scandinavia showed the prevalence of EPE was 5.7% among 141 patients with tuberculous pleuritis. Another study from the same center reported that 18% of 78 EPEs were of tuberculous origin. More recently, tuberculosis was reported to be the cause of EPE in 15.6% of 45 patients from Spain. The Spanish, but not the Scandinavian, group indicated that only pleural fluids from the first thoracentesis were studied. We suggest that tuberculous pleuritis, although associated rarely with pleural fluid eosinophilia, should still be considered as a possible cause of EPE in populations with a high prevalence of tuberculosis.
Coccidioidomycosis, histoplasmosis, and cryptococcosis have been reported to cause EPE, typically with concomitant parenchymal disease. Among parasites that cause EPE, the most frequent is Paragonimus spp., which is endemic in eastern and southeastern Asia but can be also found in Africa, South America, and even North America. Other parasitic diseases associated with EPE are sparganosis, toxocariasis, cutaneous myasis, loiasis, strongyloidiasis, echinococcosis,Dracunculus medinensis infection, lymphatic filariasis, ascariasis, and amebiasis. Viruses have been also thought to cause EPE. The diagnosis of viral pleuritis was made clinically and we are not aware of a report with laboratory proof of the viral origin of an EPE.
The relationship between EPE and malignancy is controversial. The frequency of malignant etiology among EPEs has varied between 6% and 40% in different studies. In our hospital, 15 of 172 cases of EPE (8.7%) found since 1997 were malignant. Interestingly, when five major EPE series were tabulated, malignancy was the most common diagnosis when idiopathic cases and cases resulting from air/blood were excluded ( Table 2 ). The prevalence of EPE among malignant pleural effusions has varied between 2.3% and 11.6%. Notable support against the association between EPE and malignancy came from Adelman et al., who concluded that the presence of pleural fluid eosinophilia decreases the likelihood that a pleural effusion is malignant. The belief that the presence of pleural fluid eosinophilia denotes a benign underlying disorder was challenged by three more recent studies that included 1058 patients in total (111 with EPE). According to these studies malignancy was as prevalent among EPE as non-EPE. Overall, 27% of the patients with EPE and 29.8% of those with non-EPE had malignant pleural effusion. When patients with obviously benign pleural fluid (transudates and effusions after pleural traumatic injury) were excluded, malignancy was the cause in 25 of 79 EPEs (31.6%) and 282 of 660 non-EPEs (42.7%). Eosinophilic malignant pleural effusions are not necessarily hemorrhagic. In our institution, 8 of the 59 malignant pleural effusions (13.6%) with red blood cell counts more than 10,000 cells/mm and 3 of the 13 (23%) with red blood cell counts more than 100,000 cells/mm were eosinophilic. The pleural fluid red blood cell count was lower than 10,000 cells/mm in seven malignant EPEs. In view of this fact, we suggest that a malignant etiology should be considered in all patients with undiagnosed EPEs.
Benign pleural effusions develop in patients exposed to asbestos with a mean latency of 30 years (range, 1-58 years) after the first exposure, and 25 to 50% of these effusions are eosinophilic. Adelman et al. reported that 4% of EPEs were benign asbestos pleural effusions. Pulmonary embolism is accompanied by pleural effusions in 30 to 50% of the cases, and as much as 18% of them are eosinophilic. In the series by Spriggs and Boddington, 12 of 127 (9.5%) pleural effusions with more than 20% eosinophils were the result of pulmonary embolism. Pulmonary embolism was recognized as the etiologic factor in only 4% of 343 EPEs summarized by Adelman et al. and in 3.4% of 147 EPEs from the four studies conducted more recently. To our knowledge, 10 drugs have been associated with the development of an EPE ( Table 3). Valproic has also been considered as a cause of EPE although, in our opinion, the pleural effusion described in the relevant case report was most likely a postpneumonic effusion.
Finally, it should be noted that no diagnosis is ever established in many cases with EPE. In the series of Adelman et al., one third of the patients with EPE remained undiagnosed, and they were called "idiopathic." In the 147 patients with EPE reported in the four more recent series, the percentage of idiopathic pleural effusions was 15.6%. The similarity of the clinical features and course of the patients with idiopathic EPE with those with benign asbestos pleural effusion and the fact that the diagnosis of the second is difficult and frequently overlooked, led some authors to speculate that a respectable proportion of patients with idiopathic EPE have benign asbestos pleural effusion. We think that pleural effusions resulting from pulmonary emboli are also underdiagnosed. Because pulmonary embolism is a very common disease with an associated pleural effusion in 30 to 50%, of which approximately 20% are eosinophilic, it is reasonable to argue that some of the "idiopathic" EPEs are the result of occult pulmonary emboli. Viral infection, another common and difficult-to-diagnose cause of pleural effusion, may also be the cause of some cases of "idiopathic" EPE.
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