Lactology Foundation

Pleural Effusion

A pleural effusion is a collection of fluid abnormally present in the pleural space, usually resulting from excess fluid production and/or decreased lymphatic absorption. It is the most common manifestation of pleural disease, and its etiologies range in spectrum from cardiopulmonary disorders and/or systemic inflammatory conditions to malignancy. Approximately 1.5 million pleural effusions are diagnosed in the United States each year.

Anatomy
The pleural space (cavity) in a healthy patient is a potential space sandwiched between the parietal and visceral pleurae. The parietal pleura completely lines the inner chest wall surface of the thoracic cavity, inclusive of the bilateral medial mediastinum, the subcostal left and right diaphragmatic leaflets, and the innermost muscle surface of the ribs and associated musculature. The visceral pleura tightly envelops both lungs completely, folding into the interlobar fissures, meeting the parietal pleura at the hilar root of the lungs. The right and left pleural cavities are separated in healthy people by the anterior and posterior mediastinum.
Playing a vital role in respiration, the potential space of the pleural cavity in healthy patients joins the natural outward movement of the chest wall to that of the natural inward movement of the lungs via two mechanisms. First, the potential space's relative vacuum sustains the visceral and parietal pleurae's extreme adherence and is uninterrupted and not disrupted. Second, a diminutive volume of pleural fluid (calculated at 0.13 mL/kg of body weight under normal situations) serves as the lubricant to facilitate the normal physiological sliding motion of both pleural surfaces against each other during inspiration and expiration. This small volume of lubricating fluid is maintained via a delicate balance of hydrostatic and oncotic pressure and peripheral sulcal lymphatic drainage; disturbances in any of these mechanisms may lead to pathology and, possibly, manifest as a pleural effusion.

Etiology
The normal pleural space contains approximately 10 mL of fluid, representing the balance between (1) hydrostatic and oncotic forces in the visceral and parietal pleural capillaries and (2) persistent sulcal lymphatic drainage. Pleural effusions may result from disruption of this natural balance.
Presence of a pleural effusion heralds an underlying disease process that may be pulmonary or nonpulmonary in origin and, furthermore, that may be acute or chronic. Although the etiologic spectrum of pleural effusion can be extensive, most pleural effusions are caused by congestive heart failure, pneumonia, malignancy, or pulmonary embolism.

Deferent mechanisms may play a role in the formation of pleural effusion:
Iterated permeability of the pleural membranes (eg, inflammation, malignancy, pulmonary embolism)
• Reduction in intravascular oncotic pressure (eg, hypoalbuminemia due to nephrotic syndrome or cirrhosis)
• Increased capillary permeability or vascular disruption (eg, trauma, malignancy, inflammation, infection, pulmonary infarction, drug hypersensitivity, uremia, pancreatitis)
• Increased capillary hydrostatic pressure in the systemic and/or pulmonary circulation (eg, congestive heart failure, superior vena cava syndrome)
• Reduction of pressure in the pleural space (ie, due to an inability of the lung to fully expand during inspiration); this is known as "trapped lung" (eg, extensive atelectasis due to an obstructed bronchus or contraction from fibrosis leading to restrictive pulmonary physiology)
• Decreased lymphatic drainage or complete lymphatic vessel blockage, including thoracic duct obstruction or rupture (eg, malignancy, trauma)
• Increased peritoneal fluid with microperforated extravasation across the diaphragm via lymphatics or microstructural diaphragmatic defects (eg, hepatic hydrothorax, cirrhosis, peritoneal dialysis)
• Movement of fluid from pulmonary edema across the visceral pleura
• Persistent increase in pleural fluid oncotic pressure from an existing pleural effusion, causing further fluid accumulation
The net result of effusion formation is a flattening or inversion of the diaphragm, a mechanical dissociation of the visceral and parietal pleura, and an eventual restrictive ventilatory defect as measured by pulmonary function testing.
Pleural effusions are generally classified as transudates or exudates, based on the mechanism of fluid formation and pleural fluid chemistry. Transudates result from an imbalance of oncotic and hydrostatic pressures, whereas exudates are the result of inflammatory processes of the pleura and/or decreased lymphatic drainage. In some cases, it is not rare for pleural fluid to exhibit mixed characteristics of transudate and exudate.

Transudates
Transudates result from an imbalance in oncotic and hydrostatic pressures. Transudative effusions are usually ultrafiltrates of plasma squeezed out of the pleura as a result of an imbalance in hydrostatic and oncotic forces in the chest. However, other mechanisms of injury may include upward movement of fluid from the peritoneal cavity or, in iatrogenic cases, direct infusion into the pleural space from misplaced (or even migrated) central venous catheters or nasogastric feeding tubes.
Transudates are caused by a small, defined group of etiologies, including the following:
• Congestive heart failure
• Cirrhosis (hepatic hydrothorax)
• Atelectasis (may be due to occult malignancy or pulmonary embolism)
• Hypoalbuminemia
• Nephrotic syndrome
• Peritoneal dialysis
• Myxedema
• Constrictive pericarditis
• Urinothorax (usually due to obstructive uropathy)
• Cerebrospinal fluid (CSF) leaks to the pleura (in the setting of ventriculopleural shunting or of trauma/surgery to the thoracic spine)
Duropleural fistula (rare, but may be a complication of spinal cord surgery)
• Extravascular migration of central venous catheter
• Glycinothorax (rare complication of bladder irrigation with 1.5% glycine solution following urologic surgery)

Exudates
Produced by a variety of inflammatory conditions (and often requiring a more extensive evaluation and treatment strategy than transudates), exudative effusions develop from inflammation of the pleura or from decreased lymphatic drainage at pleural edges.
Mechanisms of exudative formation include pleural or parenchymal inflammation, impaired lymphatic drainage of the pleural space, transdiaphragmatic cephalad movement of inflammatory fluid from the peritoneal space, altered permeability of pleural membranes, and/or increased capillary wall permeability or vascular disruption. Pleural membranes are involved in the pathogenesis of the fluid formation. Of note, the permeability of pleural capillaries to proteins is increased in disease states with elevated protein content.
The more common causes of exudates include the following:
Parapneumonic causes
Malignancy (most commonly lung or breast cancer, lymphoma, and leukemia; less commonly ovarian carcinoma, stomach cancer, sarcomas, melanoma)[9]
Pulmonary embolism
Collagen-vascular conditions (rheumatoid arthritis, systemic lupus erythematosus)
Tuberculosis (TB)
Pancreatitis Trauma
Postcardiac injury syndrome Esophageal perforation Radiation pleuritis Sarcoidosis
Fungal infection Pancreatic pseudocyst Intra-abdominal abscess
Status post coronary artery bypass graft (CABG) surgery Pericardial disease
Meigs syndrome (benign pelvic neoplasm with associated ascites and pleural effusion)
Ovarian hyperstimulation syndrome
Drug-induced pleural disease (see Pneumotox.com for an extensive and searchable list of drugs that may cause pleural effusion)
Asbestos-related pleural disease
Yellow nail syndrome (yellow nails, lymphedema, pleural effusions)
Uremia
Trapped lung (localized pleural scarring with the formation of a fibrin peel prevents incomplete lung expansion, at times leading to pleural effusion)
Chylothorax (acute illness with elevated triglycerides in pleural fluid)
Pseudochylothorax (chronic condition with elevated cholesterol in pleural fluid) istula (ventriculopleural, biliopleural, gastropleural)

Epidemiology
Occurrence in the United States
Since pleural effusion is usually the manifestation of an underlying disease process, its precise incidence is difficult to determine. Nevertheless, the incidence in the United States is estimated to be at least 1.5 million cases annually.Most of these cases are caused by congestive heart failure, bacterial pneumonia, malignancy, and pulmonary embolism.
International occurrence
The estimated prevalence of pleural effusion is 320 cases per 100,000 people in industrialized countries, with a distribution of etiologies related to the prevalence of underlying diseases.
Sex-related demographics
Although certain etiologies have a sex predilection, the general understanding is that the incidence of pleural effusion is equal between the sexes. Nearly two thirds of malignant pleural effusions occur in women, in whom they are associated with breast and gynecologic malignancies.
Pleural effusion associated with systemic lupus erythematosus is specifically more common in women than in men. In the United States, the incidence of pleural effusion in the setting of malignant mesothelioma is higher in men, probably because of their higher occupational exposure to asbestos.
Pleural effusions associated with chronic pancreatitis are more common in men, with the majority of male cases having alcohol abuse as the impetus. Rheumatoid effusions also occur more commonly in males than in females.
Race- and age-related demographics
Since pleural effusion is usually the manifestation of an underlying disease process, racial differences most likely reflect racial variation in incidence of the causative disorder.
Pleural effusions usually occur in adults. However, they appear to be increasing in children, often in the setting of underlying pneumonia. Fetal pleural effusions have also been reported and under certain circumstances may be treated prior to delivery.
Prognosis
The prognosis in pleural effusion varies in accordance with the condition's underlying etiology. However, patients who seek medical care earlier in the course of their disease and those who obtain prompt diagnosis and treatment have a substantially lower rate of complications than do patients who do not.
Morbidity and mortality
Morbidity and mortality of pleural effusions are directly related to cause (and if applicable, staging) of the underlying disease at the time of presentation, as well as biochemical findings in the pleural fluid.
Morbidity and mortality rates in patients with pneumonia and pleural effusions are higher than those in patients with pneumonia alone. Parapneumonic effusions, when recognized and treated promptly, typically resolve without significant sequelae. However, untreated or inappropriately treated parapneumonic effusions may lead to empyema, constrictive fibrosis, and sepsis.
Development of a malignant pleural effusion is associated with a very poor prognosis, with median survival of 4 months and mean survival of less than 1 year. The most common associated malignancy in men is lung cancer. The most common associated malignancy in women is breast cancer. Median survival ranges from 3-12 months, depending on the malignancy. Effusions from cancers that are more responsive to chemotherapy, such as lymphoma or breast cancer, are more likely to be associated with prolonged survival, compared with those from lung cancer or mesothelioma.
Cellular and biochemical findings in the fluid may also be indicators of prognosis. For example, a lower pleural fluid pH is often associated with a higher tumor burden and a worse prognosis.

Presentation
History
A detailed medical history should be obtained from all patients presenting with a pleural effusion, as this may help to establish the etiology. For example, a history of chronic hepatitis or alcoholism with cirrhosis suggests hepatic hydrothorax or alcohol-induced pancreatitis with effusion. Recent trauma or surgery to the thoracic spine raises the possibility of a CSF leak. The patient should be asked about a history of cancer, even remote, as malignant pleural effusions can develop many years after initial diagnosis.
An occupational history should also be obtained, including potential asbestos exposure, which could predispose the patient to mesothelioma or benign asbestos-related pleural effusion. The patient should also be asked about medications they are taking.
The clinical manifestations of pleural effusion are variable and often related to the underlying disease process. The most commonly associated symptoms are progressive dyspnea, cough, and pleuritic chest pain.
Dyspnea
Dyspnea is the most common symptom associated with pleural effusion and is related more to distortion of the diaphragm and chest wall during respiration than to hypoxemia. In many patients, drainage of pleural fluid alleviates dyspnea despite limited alterations in gas exchange. Drainage of pleural fluid may also allow the underlying disease to be more easily recognized on repeat chest radiographs. Note that dyspnea may be caused by the condition producing the pleural effusion, such as underlying intrinsic lung or heart disease or obstructing endobronchial lesions rather than by the effusion itself.
Cough
Cough in patients with pleural effusion is often mild and nonproductive. More severe cough or the production of purulent or bloody sputum suggests an underlying pneumonia or endobronchial lesion.
Chest pain
The presence of chest pain, which results from pleural irritation, raises the likelihood of an exudative etiology, such as pleural infection, mesothelioma, or pulmonary infarction.
Pain may be mild or severe. It is typically described as sharp or stabbing and is exacerbated with deep inspiration. Pain may be localized to the chest wall or referred to the ipsilateral shoulder or upper abdomen due to diaphragmatic irritation. Pain may decrease in intensity as the pleural effusion increases in size and the inflamed pleural surfaces are no longer in contact with each other.
Extrapulmonary symptoms
Other symptoms in association with pleural effusions may suggest the underlying disease process. Increasing lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea may all occur with congestive heart failure.
Night sweats, fever, hemoptysis, and weight loss should suggest TB. Hemoptysis also raises the possibility of malignancy, other endotracheal or endobronchial pathology, or pulmonary infarction. An acute febrile episode, purulent sputum production, and pleuritic chest pain may occur in patients with an effusion associated with pneumonia.
Physical Examination
Physical findings in pleural effusion are variable and depend on the volume of the effusion. Typically, there are no clinical findings for effusions less than 300 mL. With effusions greater than 300 mL, chest wall/pulmonary findings may include the following:
Dullness to percussion, decreased tactile fremitus, and asymmetrical chest expansion, with diminished or delayed expansion on the side of the effusion: These are the most reliable physical findings of pleural effusion: /lediastinal shift away from the effusion: This finding is observed with effusions greater than 1000 mL. Displacement of ie trachea and mediastinum towards the side of the effusion is an important clue to obstruction of a lobar bronchus by an airway; bronchial lesion, which can be due to malignancy or, less commonly, to a nonmalignant cause, such as a foreign body obstruction.
• Diminished or inaudible breath sounds
• Egophony (known as "E-to-A" changes) at the most superior aspect of the pleural effusion
• Pleural friction rub
Other physical and extrapulmonary findings may suggest the underlying cause of the pleural effusion.
Peripheral edema, distended neck veins, and S3 gallop suggest congestive heart failure. Edema may also be a manifestation of nephrotic syndrome, pericardial disease, or, when combined with yellow nailbeds, the yellow nail syndrome.
Cutaneous changes and ascites suggest liver disease.
Lymphadenopathy or a palpable mass suggests malignancy.

Diagnostic Considerations Transudative pleural effusion
Considerations in the differential diagnosis of transudative pleural effusion include the following:
• Congestive heart failure (most common)
• Cirrhosis with hepatic hydrothorax
• Nephrotic syndrome
• Peritoneal dialysis/continuous ambulatory peritoneal dialysis
• Hypoproteinemia
• Glomerulonephritis
• Superior vena cava obstruction
• Fontan procedure
• Urinothorax
■ CSF leak to the pleural space
Exudative pleural effusion
Conditions to consider in the differential diagnosis of exudative pleural effusion include the following:
• Malignancy
• Pneumonia
• Tuberculosis
• Pulmonary embolism
• Fungal infection
• Pancreatic pseudocyst
• Intra-abdominal abscess
Post CABG surgery
Postcardiac injury syndrome
• Pericardial disease
• Meigs syndrome
• Ovarian hyperstimulation syndrome
• Rheumatoid pleuritis
• Lupus erythematosus
• Drug-induced pleural disease
• Asbestos pleural effusion
• Yellow nail syndrome
• Uremia
• Trapped lung
• Chylothorax
• Pseudochylothorax
• Acute respiratory distress syndrome
• Chronic pleural thickening
• Malignant mesothelioma
• Hypothyroidism
Additional causes of pleural effusion or mimics of pleural effusion are as follows:
• Congestive heart failure and pulmonary edema
• Diaphragmatic injuries
• Esophageal rupture and tears
• Hypothyroidism and myxedema coma
• Lung neoplasms
• Pancreatitis
• Q fever
• Rheumatoid arthritis

Workup
Approach Considerations
Thoracentesis should be performed for new and unexplained pleural effusions when sufficient fluid is present to allow a safe procedure. Observation of pleural effusion is reasonable when benign etiologies are likely, as in the setting of overt congestive heart failure, viral pleurisy, or recent thoracic or abdominal surgery.
Laboratory testing helps to distinguish pleural fluid transudates from exudates. However, certain types of exudative pleural effusions might be suspected simply by observing the gross characteristics of the fluid obtained during thoracentesis. Note the following:
• Frankly purulent fluid indicates an empyema • A putrid odor suggests an anaerobic empyema milky, opalescent fluid suggests a chylothorax, resulting most often from lymphatic obstruction by malignancy or oracic duct injury by trauma or surgical procedure
• Grossly bloody fluid may result from trauma, malignancy, post-pericardiotomy syndrome, or asbestos-related effusion and indicates the need for a spun hematocrit test of the sample. A pleural fluid hematocrit level of more than 50% of the peripheral hematocrit level defines a hemothorax, which often requires tube thoracostomy
• Black pleural fluid suggests a limited number of diseases, including infection with Aspergillus niger or Rizopus oryzae, malignant melanoma, non-small cell lung cancer or ruptured pancreatic pseudocyst, or charcoal-containing empyema

Normal pleural fluid
Normal pleural fluid has the following characteristics:
• Clear ultrafiltrate of plasma that originates from the parietal pleura
• A pH of 7.60-7.64
• Protein content of less than 2% (1-2 g/dL)
• Fewer than 1000 white blood cells (WBCs) per cubic millimeter
• Glucose content similar to that of plasma
• Lactate dehydrogenase (LDH) less than 50% of plasma

Distinguishing Transudates From Exudates
The initial diagnostic consideration is distinguishing transudates from exudates. Although a number of chemical tests have been proposed to differentiate pleural fluid transudates from exudates, the tests first proposed by Light et al have become the criterion standards.
The fluid is considered an exudate if any of the following are found:
• Ratio of pleural fluid to serum protein greater than 0.5
• Ratio of pleural fluid to serum LDH greater than 0.6
• Pleural fluid LDH greater than two thirds of the upper limits of normal serum value The fluid is considered a transudate if all of the above are absent.
These criteria require simultaneous measurement of pleural fluid and serum protein and LDH. However, a meta-analysis of 1448 patients suggested that the following combined pleural fluid measurements might have sensitivity and specificity comparable to the criteria from Light et al for distinguishing transudates from exudates:
• Pleural fluid LDH value greater than 0.45 of the upper limit of normal serum values
• Pleural fluid cholesterol level greater than 45 mg/dL
• Pleural fluid protein level greater than 2.9 g/dL
Clinical judgment is required when pleural fluid test results fall near the cutoff points.
The criteria from Light et al and these alternative criteria identify nearly all exudates correctly, but they misclassify approximately 20-25% of transudates as exudates, usually in patients on long-term diuretic therapy for congestive heart failure (because of the concentrating effect of diuresis on protein and LDH levels within the pleural space).
Using the criterion of serum minus pleural protein concentration level of less than 3.1 g/dL, rather than a serum/pleural fluid ratio of greater than 0.5, more correctly identifies exudates in these patients.
Although pleural fluid albumin is not typically measured, a gradient of serum albumin to pleural fluid albumin of less than 1.2 g/dL also identifies an exudate in such patients. Button, studies suggest that pleural fluid levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are elevated in s due to congestive heart failure. Moreover, elevated pleural NT-proBNP was demonstrated to out-perform fluid BNP as a marker of heart failure-related effusion.[33] Thus, at institutions where this test is available, high pleural levels of NT-proBNP (defined in different studies as >1300-4000 ng/L) may help to confirm heart failure as the cause of an otherwise idiopathic chronic effusion.
In a more recent systematic review, pleural fluid cholesterol greater than 55 mg/dL and pleural LDH greater than 200 U/L each had better positive and negative likelihood ratio for distinguishing exudates from transudates than did Light's criteria.

Pleural Fluid LDH, Glucose, and pH
Pleural fluid LDH
Pleural fluid LDH levels greater than 1000 IU/L suggest empyema, malignant effusion, rheumatoid effusion, or pleural paragonimiasis. Pleural fluid LDH levels are also increased in effusions from Pneumocystis jiroveci (formerly, P carinii) pneumonia. The diagnosis is suggested by a pleural fluid/serum LDH ratio of greater than 1, with a pleural fluid/serum protein ratio of less than 0.5.
Pleural fluid glucose and pH
In addition to the previously discussed tests, glucose and pleural fluid pH should be measured during the initial thoracentesis in most situations.
A low pleural glucose concentration (30-50 mg/dL) suggests malignant effusion, tuberculous pleuritis, esophageal rupture, or lupus pleuritis. A very low pleural glucose concentration (ie, < 30 mg/dL) further restricts diagnostic possibilities, to rheumatoid pleurisy or empyema.
Pleural fluid pH is highly correlated with pleural fluid glucose levels. A pleural fluid pH of less than 7.30 with a normal arterial blood pH level is caused by the same diagnoses as listed above for low pleural fluid glucose. However, for parapneumonic effusions, a low pleural fluid pH level is more predictive of complicated effusions (that require drainage) than is a low pleural fluid glucose level. In such cases, a pleural fluid pH of less than 7.1-7.2 indicates the need for urgent drainage of the effusion, while a pleural fluid pH of more than 7.3 suggests that the effusion may be managed with systemic antibiotics alone.
In malignant effusions, a pleural fluid pH of less than 7.3 has been associated in some reports with more extensive pleural involvement, higher yield on cytology, decreased success of pleurodesis, and shorter survival times.
Handle pleural fluid samples as carefully as arterial samples for pH measurements, with fluid collected in heparinized syringes and ideally transported on ice for measurement within six hours. However, studies have determined that when collected in heparinized syringes, pleural fluid pH does not change significantly even over several hours at room temperature. Consequently, if appropriately collected samples can be processed quickly, pH measurements should not be canceled simply because the sample was not transported on ice.

Pleural Fluid Cell Count Differential
If an exudate is suspected clinically or is confirmed by chemistry test results, send the pleural fluid for total and differential cell counts, Gram stain, culture, and cytology.
Pleural fluid lymphocytosis, with lymphocyte values ​​greater than 85% of the total nucleated cells, suggests TB, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, and chylothorax. Pleural lymphocyte values ​​of 50-70% of the nucleated cells suggest malignancy.
Pleural fluid eosinophilia (PFE), with eosinophil values ​​greater than 10% of nucleated cells, is seen in approximately 10% of pleural effusions and is not correlated with peripheral blood eosinophilia. PFE is most often caused by air or blood in the pleural space. Blood in the pleural space causing PFE may be the result of pulmonary embolism with infarction or benign asbestos pleural effusion. PFE may be associated with other nonmalignant diseases, including parasitic disease (especially paragonimiasis), fungal infection (coccidioidomycosis, cryptococcosis, histoplasmosis), and a variety of medications.
The presence of PFE does not exclude a malignant effusion, especially in patient populations with a high prevalence of malignancy. The presence of PFE makes tuberculous pleurisy unlikely and also makes the progression of a parapneumonic to an empyema unlikely.
lial cells are found in variable numbers in most effusions, but their presence at greater than 5% of total nucleated cells diagnosis of TB less likely. Markedly increased numbers of mesothelial cells, especially in bloody or eosinophilic.

Pleural Fluid Culture and Cytology
Cultures of infected pleural fluids yield positive results in approximately 60% of cases. This occurs even less often for anaerobic organisms. Diagnostic yields, particularly for anaerobic pathogens, may be increased by directly culturing pleural fluid into blood culture bottles.
Malignancy is suspected in patients with known cancer or with lymphocytic, exudative effusions, especially when bloody. Direct tumor involvement of the pleura is diagnosed most easily by performing pleural fluid cytology.
Heparinized samples (1 mL of 1:1000 heparin per 50 mL of pleural fluid) should be submitted for analysis if the pleural fluid is bloody and they should be refrigerated if samples will not be processed within one hour.
The reported diagnostic yields in cytology vary from 60-90%, depending on the extent of pleural involvement and the type of primary malignancy. Cytology findings are positive in 58% of effusions related to mesothelioma.
The sensitivity of cytology is not highly related to the volume of pleural fluid tested. Sending more than 50-60 mL of pleural fluid for cytology does not increase the yield of direct cytospin analysis, and volumes of approximately 150 mL are sufficient when both cytospin and cell block preparations are analyzed.
Tumor markers, such as carcinoembryonic antigen, Leu-1, and mucin, are suggestive of malignant effusions (especially adenocarcinoma) when pleural fluid values ​​are very high. However, because of low sensitivity, they are not helpful if the values ​​are normal or only modestly increased.
Tuberculous pleuritis
Suspect tuberculous pleuritis in patients with a history of exposure or a positive PPD finding and in patients with lymphocytic exudative effusions, especially if less than 5% mesothelial cells are detected on differential cell counts.
Because most tuberculous pleural effusions probably result from a hypersensitivity reaction to the Mycobacterium rather than from microbial invasion of the pleura, acid-fast bacillus stains of pleural fluid are rarely diagnostic (< 10% of cases). Pleural fluid cultures grow M tuberculosis in less than 65% of cases.
In contrast, the combination of histology and culture of pleural tissue obtained by pleural biopsy increases the diagnostic yield for TB to 90%.
Adenosine deaminase (ADA) activity of greater than 43 U/mL in pleural fluid supports the diagnosis of tuberculous pleuritis. However, the test has a sensitivity of only 78%. Therefore, pleural ADA values ​​of less than 43-50 U/mL do not exclude the diagnosis of TB pleuritis.
Interferon-gamma concentrations of greater than 140 pg/mL in pleural fluid also support the diagnosis of tuberculous pleuritis. Unfortunately, this test is not routinely available.
Additional Laboratory Tests
Additional specialized tests are warranted when specific etiologies are suspected. Measure pleural fluid amylase levels if a pancreatic origin or ruptured esophagus is suspected or if a unilateral, left-sided pleural effusion remains undiagnosed after initial testing. Of note, increased pleural fluid amylase can also be seen with malignancy. An additional assay of amylase isoenzymes can help distinguish a pancreatic source (diagnosed by elevated pleural fluid pancreatic isoenzymes) from other etiologies.
Measure triglyceride and cholesterol levels in milky pleural fluids when chylothorax or pseudochylothorax is suspected.
Consider immunologic studies, including pleural fluid antinuclear antibody and rheumatoid factor, when collagen-vascular diseases are suspected.

Scanning and Ultrasonography
A study involving 41 consecutive patients with hepatic hydrothorax indicated that hepatic hydrothorax virtually always presents with ascites that can be revealed by ultrasonography or computed tomography (CT) scanning. Point of care bedside ultrasonography has become the standard of care in many facilities. Also see Pleural Effusion Imaging.
Chest CT scanning with contrast should be performed in all patients with an undiagnosed pleural effusion, if it has not previously been performed, to detect thickened pleura or signs of invasion of underlying or adjacent structures. The two diagnostic imperatives in this situation are pulmonary embolism and tuberculous pleuritis. In both cases, the pleural effusion is a harbinger of potential future morbidity. In contrast, a short delay in diagnosing metastatic malignancy to the pleural space has less impact on future clinical outcomes. CT angiography should be ordered if pulmonary embolism is strongly suggested. Also see Pleural Effusion Imaging.

Chest Radiography
Effusions of more than 175 mL are usually apparent as blunting of the costophrenic angle on upright posteroanterior chest radiographs. On supine chest radiographs, which are commonly used in the intensive care setting, moderate to large pleural effusions may appear as a homogeneous increase in density spread over the lower lung fields. Apparent elevation of the hemidiaphragm, lateral displacement of the dome of the diaphragm, or increased distance between the apparent left hemidiaphragm and the gastric air bubble suggests subpulmonic effusions.
Bilateral pleural effusions with loss of bilateral costophrenic sulci (meniscus sign). Anteroposterior, upright chest radiograph.
Lateral decubitus films more reliably detect smaller pleural effusions. Layering of an effusion on lateral decubitus films defines a freely flowing effusion and, if the layering fluid is 1 cm thick, indicates an effusion of greater than 200 mL that is amenable to thoracentesis. Failure of an effusion to layer on lateral decubitus films indicates the presence of loculated pleural fluid or some other etiology causing the increased pleural density. Note that decubitus films are almost never performed in those institutions with bedside ultrasonography.
Left lateral decubitus film displaying freely layering left-sided pleural effusion.

Idiopathic Exudative Effusions
Despite evaluations with repeated diagnostic thoracenteses, approximately 20% of exudative effusions remain undiagnosed. Clues to the diagnosis that may have been overlooked include (1) occupational exposure to asbestos 10-20 years earlier, which may suggest benign asbestos effusion; (2) medication exposure to nitrofurantoin, amiodarone, or medications associated with a drug-induced lupus syndrome; and (3) hepatic hydrothorax unrecognized in a patient with minimal or undetectable ascites.
Among patients with undiagnosed pleural effusions after the primary evaluation, those who meet all 6 of the following clinical parameters are predicted to have a benign course, and no further evaluation is necessary:
• Patients are clinically stable
• Patients do not have weight loss
• The results of the purified protein derivative (PPD) test, used in detecting tuberculous pleural effusion, are negative and the pleural adenosine deaminase (ADA) value, also used in diagnosing tuberculous pleural effusion, is less than 43 U/mL
• The patient does not have a fever
• The pleural fluid differential blood cell count has less than 95% lymphocytes
• The effusion occupies less than 50% of the hemithorax
For other patients with undiagnosed exudative effusions, approximately 20% have a specific etiology determined, including malignancy. For such patients, weigh the benefits and risks of pursuing a diagnostic strategy that will involve using progressively more invasive procedures, given the low likelihood of finding a curable etiology. Note the following:
• Bronchoscopy - Consider only if a patient has parenchymal abnormalities or hemoptysis
• Surgical approaches to the diagnosis of pleural effusions - Includes video-assisted thoracoscopy (pleuroscopy) and open thoracotomy, allows direct visualization and biopsy of the pleura for diagnosis of exudative effusions, which reveals an etiology in 92% of effusions that remain undiagnosed after a medical evaluation, with an operative mortality of less than 0.5%
• Medical thoracoscopy - Where available, may be diagnostic and therapeutic; complete drainage of the effusion and talc sclerosis can be performed at the time of the procedure
Note that in most medical centers, surgical exploration using thoracoscopy or thoracotomy entails the risks of general anesthesia and is probably warranted only in patients who are symptomatic and anxious for a (potentially incurable) diagnosis.