Pleural Effusion Due to Pulmonary Embolization
INCIDENCE
It is estimated that at least 800,000 persons have a pulmonary embolic event each year in this country (3). The incidence of pulmonary embolus increased 50% between 1998 and 2005 (3). Because pleural effusions occur in 30% to 50% of patients with pulmonary emboli (4,5,6), 240,000 to 400,000 pleural effusions secondary to pulmonary emboli should occur annually. Therefore, one should expect to see more cases of pleural effusions secondary to pulmonary embolization than due to bronchogenic carcinoma. Nevertheless, in most large series, pulmonary embolization accounts for less than 5% of the pleural effusions. There are two explanations for this discrepancy. First, individuals interested in pleural effusion do not see many of the patients that have pleural effusions due to pulmonary emboli as the effusions are small and a thoracentesis is not performed (7). Second, the diagnosis of pulmonary embolus is frequently not considered in patients with undiagnosed pleural effusions. Indeed, in an epidemiologic study from the Czech Republic, pulmonary embolism was the fourth leading cause of pleural effusion (8).
It is likely that pulmonary embolism is responsible for a substantial fraction of undiagnosed pleural effusions. Gunnels (9) followed 27 patients with exudative pleural effusions in whom no diagnosis was established after an initial workup, including pleural biopsy. Of the 19 patients who did not have malignant disease, 2 subsequently died, and both had pulmonary emboli at autopsy. One wonders how many of the remaining 17 patients might have had pulmonary emboli if this diagnosis had been considered. Along the same lines, Storey et al. (10) reported on a series of 133 patients with pleural effusions in which only 3 were due to pulmonary emboli, but causes were not determined in 25 patients. Because these authors do not mention any evaluation of their patients for pulmonary emboli, one wonders how many of the 25 patients would have been switched from the undetermined category to the pulmonary embolus category if the possibility of pulmonary embolus had been explored.
PATHOPHYSIOLOGIC MECHANISMS
The primary mechanism by which pulmonary emboli produce pleural effusion is by increasing the permeability of the capillaries in the lung. The interstitial fluid that results from this increased permeability traverses the visceral pleura and leads to the accumulation of pleural fluid. In the experimental situation, it has been shown that more than 20% of the fluid formed in the lung with increased permeability pulmonary edema is cleared through the pleural space (11). It is probable that ischemia of the capillaries in the visceral pleura plays at most a minor role because these capillaries are supplied by the bronchial circulation (12). Leckie and Tothill (13) have demonstrated that patients with a pleural effusion secondary to pulmonary emboli have a large amount of protein entering and leaving the pleural space. The main factor responsible for the increased permeability of the pulmonary
capillaries is probably the release of inflammatory mediators from the platelet-rich thrombi. It is possible that vascular endothelial growth factor (VEGF) may play a role in the formation of pleural fluid in at least some patients. Indeed a very high pleural fluid VEGF level was reported in one patient with pulmonary embolism (14). The release of such mediators can increase the permeability of the capillaries in either the visceral pleura or the lung. Ischemia of the pulmonary capillaries distal to the embolus may also contribute to the increased permeability.
capillaries is probably the release of inflammatory mediators from the platelet-rich thrombi. It is possible that vascular endothelial growth factor (VEGF) may play a role in the formation of pleural fluid in at least some patients. Indeed a very high pleural fluid VEGF level was reported in one patient with pulmonary embolism (14). The release of such mediators can increase the permeability of the capillaries in either the visceral pleura or the lung. Ischemia of the pulmonary capillaries distal to the embolus may also contribute to the increased permeability.
CLINICAL MANIFESTATIONS
Symptoms and Signs
There are three symptom complexes associated with pulmonary emboli: (a) pleuritic pain or hemoptysis, (b) isolated dyspnea, and (c) circulatory collapse. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, 56% of the 119 patients with pleuritic chest pain or hemoptysis had pleural effusion, 26% of the 31 with isolated dyspnea had pleural effusion, and none of the 5 with circulatory collapse had pleural effusion (15). More than 75% of patients with pleural effusions secondary to pulmonary emboli have pleuritic chest pain (16), which is almost invariably on the side of the effusion (4). Indeed, the presence of pleuritic chest pain in a patient with pleural effusion is suggestive of pulmonary embolus. In one series, pulmonary emboli were present in 12 of 22 patients (55%) younger than the age of 40 who presented as outpatients with pleural effusion and pleuritic chest pain (17). Dyspnea, also present in more than 70% of patients (16,18), is usually out of proportion to the size of the pleural effusion. Cough and apprehension are present in approximately 50% of patients (16,18). Approximately 50% of these patients are febrile (18) but less than 10% have temperatures above 38.5°C (16,18). Approximately 15% have hemoptysis (16). Most patients have a respiratory rate above 20 per minute, and a heart rate above 100 per minute occurs in approximately 40% (7, 15). In the PIOPED study, 113 of 117 patients (97%) with no preexisting cardiac or pulmonary disease had dyspnea or tachypnea or pleuritic chest pain (16).
Chest Radiograph
When a pleural effusion is secondary to pulmonary emboli, an associated parenchymal infiltrate may or may not be present. In one series of 62 patients with pleural effusions secondary to pulmonary embolism, 28 (45%) had no associated infiltrate (4), but in another series of 20 patients, only 1 (5%) did not have an associated infiltrate (19). In a third series of 10 patients with pulmonary emboli and bilateral pleural effusions, only 3 (30%) had parenchymal infiltrates (20). Infiltrates are usually in the lower lobes, are pleural based, and are convex toward the hilum. Patients with an embolic occlusion of segmental pulmonary arteries are more likely to have infiltrates than those with an embolic occlusion of the central arteries (19).
The pleural effusions secondary to pulmonary emboli are small, with the mean size equal to approximately 15% of the hemithorax (4). In the PIOPED study, 48 of the 56 effusions (86%) were manifest only as blunting of the costophrenic angle and in no patient did the pleural effusion occupy more than one third of a hemithorax (7,16). In a second series of 73 patients (7), effusions occupied less than a third of the hemithorax in 66 (90%), occupied 50% of the hemithorax in 3 (4%), and occupied more than two thirds the hemithorax in 4 (6%). If parenchymal infiltrates are present, the pleural effusions are larger. In one series, the pleural effusion occupied greater than 15% of the hemithorax in 74% of the patients with parenchymal infiltrates but in only 21% of those without parenchymal infiltrates (4). The pleural effusions are usually unilateral, but about 15% to 35% are bilateral (7, 21). The pleural effusions with pulmonary emboli may be loculated, particularly if the diagnosis has been delayed for more than 10 days (7,22). There is not a close relationship between the sidedness of the pleural effusion and that of the pulmonary embolus (7). In one study of 93 patients (7), the pulmonary embolus was unilateral in 61 and the pleural effusion was ipsilateral in 38, on the contralateral side in 7, and bilateral in 16.
Pleural Fluid Findings
In patients with pulmonary emboli, analysis of the pleural fluid is not helpful in establishing the diagnosis because the pleural fluid associated with pulmonary emboli can vary widely. Nevertheless, a thoracentesis should be performed in patients suspected of having pulmonary emboli to exclude other causes of pleural effusion such as tuberculosis, malignant disease, or pneumonia with a parapneumonic effusion.
Although in the past it has been stated that the pleural effusion with pulmonary embolus may be a transudate or an exudate, it appears that almost all
pleural effusions secondary to pulmonary emboli are exudates (7,23). Romero et al. (23) reported that the pleural fluid was an exudate in 60 of 60 pleural fluids secondary to pulmonary embolus. The pleural fluid is not always blood tinged or bloody. In the series of Romero et al. (23), the pleural fluid red blood cell (RBC) count was above 100,000/mm3 in 11 patients (18%), was between 10,000 and 100,000/mm3 in 29 patients (48%), and was below 10,000/mm3 in 20 patients (33%). The differential white blood cell (WBC) count may reveal predominantly polymorphonuclear leukocytes or lymphocytes (23,24). Spriggs and Boddington (25) have reported that pleural effusions secondary to pulmonary emboli frequently have large numbers of mesothelial cells or eosinophils.
pleural effusions secondary to pulmonary emboli are exudates (7,23). Romero et al. (23) reported that the pleural fluid was an exudate in 60 of 60 pleural fluids secondary to pulmonary embolus. The pleural fluid is not always blood tinged or bloody. In the series of Romero et al. (23), the pleural fluid red blood cell (RBC) count was above 100,000/mm3 in 11 patients (18%), was between 10,000 and 100,000/mm3 in 29 patients (48%), and was below 10,000/mm3 in 20 patients (33%). The differential white blood cell (WBC) count may reveal predominantly polymorphonuclear leukocytes or lymphocytes (23,24). Spriggs and Boddington (25) have reported that pleural effusions secondary to pulmonary emboli frequently have large numbers of mesothelial cells or eosinophils.
CLINICAL PROBABILITY OF PULMONARY EMBOLUS
There have been several analyses developed to assess the clinical probability of pulmonary embolus. The most well known until recently were those reported in 2001 by Wells et al. (26) and in the same year by Wicki et al. (27). There were significant problems with both. The Geneva score (27) required a blood gas on room air for its calculation, whereas with the score of Wells (26), much weight is given to whether the physician thinks that pulmonary embolism is the most likely diagnosis.
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