The exposure to asbestos is definitely associated with the occurrence of benign exudative pleural effusions.

Pleural effusions are common after lung transplantation. Normally, 80% of the fluid that enters the interstitial spaces of the lungs is cleared from the lung through the lymphatics, whereas 20% is cleared through the pleural space (see Chapter 2). In the patient with a lung transplant, however, the lymphatics are transected, and, accordingly, almost all the fluid that enters the lung exits through the pleural space. The continuity of the lymphatics is restored within 2 to 4 weeks of lung transplantation (9).

Pleural effusions are usually not evident in the immediate posttransplant period because the patients have chest tubes. The amount of fluid that drains through the chest tube may be very large, particularly if the patient has the reperfusion syndrome. In one patient with a severe reperfusion syndrome, the chest tube drained more than 600 mL/hour (10). Prolonged chest tube drainage is necessary in many patients. In one series of 100 patients, the mean time for chest tube drainage was 19.3 days with a range of 5 to 52 days (11). Most patients do not have large amounts of chest tube drainage. Judson et al. (12) performed serial analyses on the chest tube drainage
from seven patients who had undergone lung transplantation. They reported that the mean output from the chest tube fell from 400 mL/day on day 1 to 200 mL/day on day 4 and that these mean outputs were similar to those seen in patients undergoing coronary artery bypass or other cardiothoracic surgeries (12). The pleural fluid on day 1 is a bloody neutrophilpredominant exudate, and on day 7 is still bloody with a mean protein of 2 g/dL and a mean lactate dehydrogenase (LDH) level of more than twice the upper limit of normal. Over the same time, the mean WBC decreased from 10,600 to 637 cells/mm³ and neutrophils decreased from 90% to 49% (12). Teixeira et al. (13) performed serial measurements of IL-1β, IL-6, IL-8, and VEGF in the pleural fluid of 20 patients who had undergone lung transplantation. They found that the levels of all four cytokines were much higher in the pleural fluid than in the serum and were highest at 6 hours after the transplantation (13). With time the levels of these cytokines tended to gradually decrease (13).

Pleural abnormalities are common on imaging studies of the chest posttransplantation. Ferrer et al. (11) reported that on thoracic computed tomography (CT) at 3 months posttransplantation, 34 of 58 patients (59%) had a pleural effusion whereas at 12 months posttransplantation 4 of 50 patients (8%) had a pleural effusion. Most patients (62%) at 3 months and (96%) at 12 months posttransplantation had pleural thickening (11).

It appears that some patients may develop a benign effusion 2 to 6 weeks posttransplantation. Shitrit et al. (14) reported that 10 of 35 patients (29%) developed more than a minimal pleural effusion between 2 and 12 weeks posttransplantation. Two of these patients had a parapneumonic effusion and one had rejection, but there was no explanation for the effusion in the other seven patients (14). A thoracentesis was performed in all the patients. In each instance, the pleural fluid was a lymphocyte-predominant exudate (13). Most did not recur after thoracentesis (14). It is likely that these effusions have a pathogenesis similar to those that occur after coronary artery bypass graft surgery (see Chapter 19).

It appears that patients who develop complications after their lung transplantation are likely to have a pleural effusion. In one series in children, radiologic findings were correlated with histopathologic diagnoses in 62 instances (15): pleural effusions occurred with 14 of 19 (74%) episodes of acute rejection, 7 of 8 (88%) instances of chronic rejection, 6 of 11 (55%) episodes of infection, 3 of 4 (75%) instances with lymphoproliferative diseases, and 15 of 20 (75%) episodes in which the histopathology was nonspecific. The high prevalence of effusion with the different entities after transplantation is probably due to the fact that a larger percentage of interstitial fluid exits through the pleural space in the patient after lung transplantation. The pleural effusion that accompanies acute lung rejection is a lymphocyte-predominant exudative pleural effusion (16).

After lung transplantation, patients are at risk of developing empyema. In one series of 392 patients from the University of Pittsburgh, empyema developed in 14 patients (3.6%) at a mean time of 46 days after transplantation (17). Four of the 14 patients (29%) died from complications of pneumonia or sepsis, or both (17). In a more recent study (18) from the Duke University, pleural infection occurred in 27% of 455 lung transplant recipients within 90 days of transplantation. Pleural infection in this study was defined as a positive bacterial, fungal, or viral culture or a pleural fluid WBC greater than 20,000 (18). Fungal pathogens accounted for more than 60% of the infections and Candida albicans was the predominant organism found (18).

The omental flap used to prevent dehiscence of the bronchial anastomosis may result in a pseudoeffusion on the chest radiograph. The omentum with its blood supply is introduced into the chest cavity through a small incision in the diaphragm. It is particularly likely to mimic an effusion on a supine radiograph (19).

The management of the patient with a pleural effusion post-lung transplantation is dependent upon the size of the effusion and the symptoms of the patient. If the effusion occupies more than 25% of the hemithorax, a thoracentesis should be performed immediately in an attempt to ascertain the etiology of the effusion. A therapeutic thoracentesis is recommended because if the patient has the typical post-lung transplant pleural effusion, this procedure is likely to be curative (14). The other main considerations are pleural infection, chylothorax, congestive heart failure, and rejection of the lung. If the effusion recurs after the therapeutic thoracentesis, consideration should be given to small-bore catheter drainage (20). If the effusion is very small, it can probably be ignored as these effusions are very common (11). If the effusion occupies less than 25% of the hemithorax but represents more than just blunting of the costophrenic angle, a diagnostic thoracentesis should be performed if the patient is complaining of shortness of breath or if the patient is not feeling up to par. It is important to remember that these patients
are immunosuppressed and accordingly are more likely to have infections. Moreover, patients with pleural infections may not be febrile because of the immunosuppression.

Pleural effusions can occur on occasion as a complication after bone marrow transplantation. Adam et al. (21) reviewed 860 patients who underwent bone marrow transplantation between 1998 and 2006 at Wayne State University and reported that pleural effusions occurred in 64 (7.4%). Malignancy was responsible for nine effusions while four patients had parapneumonic effusions or empyema (21). Diagnoses were not established in the remaining patients (21). Seber et al. (22) reviewed the medical records of 1,905 patients who received bone marrow transplants between 1974 and 1993 at the University of Minnesota. They found seven patients who had unexplained multiple effusions involving two or more of the pleural, pericardial, or peritoneal cavities. The pleura was involved in all patients. All of these cases of polyserositis occurred in recipients of allogeneic transplants. The pleural fluid was characterized by a WBC count below 1,000 cells/mm³ and a protein level below 3.0 g/dL. Because all patients had concomitant severe graft versus host disease, the effusions were also attributed to the same disease (22).

The lungs for some lung transplantations are being obtained from living donors. In one series of 62 living donors, 4 patients (6.4%) had a pleural effusion requiring drainage with a pigtail catheter and 2 additional patients (3.2%) had a loculated pleural effusion (23). In a second report (24), 2 of 21 donors (9.5%) had to be readmitted to the hospital for the development of a pleural effusion.

The livers for some liver transplantations are also being obtained from living donors. Pleural effusions may occur in the living donor partial hepatectomy. In one large series of 386 donors, pleural effusion occurred in 9 (2.3%) (25). Five of these patients received a drainage catheter that remained in place for a median of 5 weeks (25). In a second study (26) of 112 living donors, a CT scan was obtained on day 7 which revealed pleural effusion in 75% which were bilateral in 55% and right sided in 45%. Three patients developed a right-sided empyema and an additional five patients developed a pleural effusion requiring a thoracentesis (26).

The yellow nail syndrome consists of the triad of deformed yellow nails, lymphedema, and pleural effusions. Until 1986, only 97 patients had been reported with this syndrome (27). In one series, 89% of the reported cases had yellow nails, and these were the presenting manifestation in 37%. Lymphedema of various degrees was encountered in 80% of the reported cases and was the initial manifestation in 34%. Pleural effusions were found in 36% of all cases (27). The three separate entities may become manifest at widely varying times. For example, one patient developed lymphedema in childhood, chronic nail changes at age 78, and a pleural effusion in her ninth decade (28). An occasional patient with the yellow nail syndrome also has a pericardial effusion (29,30) or chylous ascites (30). In a series (31) of 41 patients from the Mayo Clinic, other chronic respiratory manifestations were present including bronchiectasis (44%), chronic sinusitis (41%), and recurrent pneumonia (22%). In this series, the median age at diagnosis was 61 years (31). There appears to be a relationship between rheumatoid arthritis and the yellow nail syndrome. Since 1979, 10 patients have been reported who had both the yellow nail syndrome and rheumatoid arthritis (32). Lastly, a recent report (33) demonstrated that the yellow nail syndrome could be associated with either common variable immunodeficiency or the specific antibody deficiency syndrome.

The basic abnormality in this syndrome appears to be hypoplasia of the lymphatic vessels. Lymphangiograms of the lower extremity demonstrate hypoplasia of at least some lymphatic vessels in most patients with the syndrome (28). Emerson (34) has postulated that pleural effusions may develop when a lower respiratory tract infection or pleural inflammation damages previously adequate but impaired lymphatic vessels. Subsequently, the lymphatic drainage of the pleural space is insufficient to maintain a fluidfree pleural space. In one report, biopsy of the parietal pleura revealed abnormally dilated lymphatics, neogenesis of lymphatic channels, and edematous tissues in some areas, suggesting some deficit in lymphatic drainage (35). However, the albumin turnover in the pleural fluid is not greatly decreased in patients with this syndrome (36). There has been one report (37) of the familial occurrence of the yellow nail syndrome.
In this report, the mother, three of four of her children, and her grandmother had the yellow nail syndrome (37).

With this syndrome, the nails are yellow, thickened, and smooth and may show transverse ridging (38). They are excessively curved from side to side, and the actual color is pale yellow to greenish. Onycholysis (separation of nail from bed) is frequently present, and nail growth is slow (38).

The pleural effusions are bilateral in approximately 50% of patients and vary in size from small to massive (38). Once pleural effusions have occurred with this syndrome, they persist and recur rapidly after a thoracentesis (28). The pleural fluid is usually a clear yellow exudate with a normal glucose level and predominantly lymphocytes in the pleural fluid differential WBC (28,34,38). The pleural fluid LDH tends to be low relative to the pleural fluid protein level. In one series (31), 5 of 16 patients (31%) had a chylothorax. The pleural biopsy reveals fibrosis, nonspecific inflammation, or lymphocytic cellular infiltrates, none of which is diagnostic of the disease (39).

The diagnosis is made when a patient has a chronic pleural effusion in conjunction with yellow nails or lymphedema. No specific treatment exists for the syndrome, but if the effusion is large and produces dyspnea, pleurodesis with a tetracycline derivative or thoracoscopy with pleural abrasion should be considered (31,35,38,40). One patient with pleural effusion secondary to the yellow nail syndrome has been treated successfully with a pleuroperitoneal shunt (41).

In sheep, elevation of the pressure in the superior vena cava leads to the accumulation of pleural fluid. Allen et al. (42) demonstrated that once the pressure in the superior vena cava was elevated above 15 mm Hg, pleural fluid accumulated. The higher the pressure in the superior vena cava, the greater the rate of fluid accumulation. The fluid was transudative in that the ratio of the pleural fluid to serum protein was less than 0:5. These workers attributed the pleural fluid formation to either lymph leakage out of the lymphatics that pass through the chest or obstruction of lung or chest lymphatics with subsequent leakage of interstitial fluid into the pleural space.

Ligation of the superior vena cava also leads to the formation of pleural fluid in dogs. Blalock et al. (43) ligated the superior vena cava of dogs and reported that within a few days of the procedure, bloody, nonchylous pleural effusions developed almost universally. Subsequently chylous effusions developed in about half the animals between 4 and 25 days after the ligation. An increase in the intravascular hydrostatic pressure in the external jugular vein above 10 cm H₂O correlated with the development of both chylous and bloody effusions in these animals (43).

In the clinical situation, pleural effusions are very common with superior vena caval obstruction. Rice et al. (44) reviewed the chest radiographs of 67 patients with the diagnosis of the superior vena caval syndrome at a tertiary referral hospital. They reported that the incidence of pleural effusions was 70% in the 43 cases due to malignancy and was 58% in the 24 cases with benign etiologies (44). The location of the effusions was 23% unilateral on the left, 39% unilateral on the right, and 39% bilateral (44). Most of the effusions occupied less than 25% of the hemithorax (44). The pleural fluid was analyzed in 22 of the patients and was found either to be an exudate or a chylothorax in each instance (44). The etiology of the effusions in the patient with malignancy could well have been the malignancy itself, and one would expect these effusions to be exudative. Only five of the effusions with benign etiologies were sampled and of these, two were exudates, two chylous, and one reported as “bloody.” It is not clear why the effusions secondary to the benign processes are exudative.

In neonates, superior vena caval thrombosis is also associated with the development of bilateral pleural effusions. Dhande et al. (45) reported a series of five babies who developed superior vena caval obstruction as a complication of the use of central venous catheters. The effusions occurred 7 to 19 days after the initial placement or change of a central venous catheter. All the infants required repeated thoracenteses to remove pleural fluid that accumulated at a rate of up to 200 mL/kg/day. The fluid was a clear transudate (protein level 1.2-2.2 g/dL) but became chylous when feedings were given. These workers attributed the pleural fluid accumulation to obstruction of thoracic lymph flow into the venous system. The incidence of superior vena caval thrombosis in infants who receive central venous catheters for total parenteral nutrition is approximately 10% (46). Approximately 3% of neonates who undergo neonatal cardiac surgery will develop the superior vena caval syndrome, and approximately half of these will develop a chylothorax (47). Fibrinolytic therapy is sometimes useful in treating the venous thrombosis, particularly if it is started within a few days of the development of the syndrome (47).

Sarcoidosis is occasionally complicated by a pleural effusion (48,49,50,51). The incidence of pleural effusion with sarcoidosis is probably approximately 1% to 2% (48,50,52), although it has been reported to be as high as 7% (48). Patients with sarcoid pleural effusion usually have extensive parenchymal sarcoidosis and frequently also have extrathoracic sarcoidosis (48). The symptoms of pleural involvement with sarcoidosis are variable; many patients have no symptoms (48), although an equal number of them have pleuritic chest pain or dyspnea.