The pleural cavity contains a relatively small amount of fluid—approximately 10 mL on each side.¹ Pleural fluid volume is maintained by a balance between fluid production and removal, and changes in the rates of either can potentially result in the presence of excess fluid, traditionally known as a pleural effusion.

The classic work of Light et al in 1972 demonstrated that 99% of pleural effusions could be classified into two general categories: transudative or exudative (See Light's criteria in the "Diagnosis" section).² A basic difference is that transudates, in general, reflect a systemic perturbation, whereas exudates usually signify underlying local (pleuro-pulmonary) disease.

The accumulation of pleural fluid can usually be explained by one or more of the following factors:

1. Increased pleural fluid formation:

1. Elevation of hydrostatic pressure (eg, congestive heart failure)
2. Decreased colloid osmotic pressure (eg, cirrhosis, nephrotic syndrome)
3. Increased capillary permeability (eg, infection, neoplasm)
4. Passage of fluid through openings in diaphragm (eg, cirrhosis with ascites)
5. Reduction of pleural space pressures (eg, atelectasis)

2. Decreased pleural fluid absorption:

1. Lymphatic obstruction
2. Elevation of systemic venous pressures resulting in impaired lymphatic drainage [eg, superior vena cava (SVC) syndrome]

The presence of fluid in the normally negative-pressure environment of the pleural space has a number of consequences for respiratory physiology. Pleural effusions produce a restrictive ventilatory defect and also decrease the total lung capacity, functional residual capacity, and forced vital capacity.³ They may cause ventilation-perfusion mismatches and, when large enough, compromise cardiac output.

The differential diagnosis of pleural effusions is briefly summarized in Tables 1 and 2.

Many patients are asymptomatic upon the discovery of a pleural effusion. When present, symptoms are usually due to the underlying disease process. Pleuritic chest pain indicates inflammation of the parietal pleura (since the visceral pleura is not innervated and thus not sensitive to pain). Other symptoms include dry, nonproductive cough and dyspnea. Physical examination findings that may reveal the presence of an effusion are reduced tactile fremitus, dull or flat note on percussion, and diminished/absent breath sounds on auscultation. It is also important to note the presence of other clues that may point to the cause of the effusion (eg, signs of heart failure, breast masses, etc).

Imaging Studies:

Chest Radiography
The posteroanterior and lateral chest radiographs are still the most important initial tools in the diagnosis of a pleural effusion (Figure 1). Free pleural fluid gravitates to the more dependent portions of the space; thus, most fluid collects around the inferior surface of the lung posteriorly, spilling out laterally and anteriorly as the amounts increase. About 50 mL of fluid is needed to be visible on the lateral radiograph as a meniscus posteriorly, and when more than 500 mL is present, the meniscus usually obscures the entire hemidiaphragm.⁴ The lateral decubitus films help in differentiating free fluid from loculated fluid (that which is confined by fibrous pleural adhesions).

Ultrasound
Ultrasound is useful both as a diagnostic tool and as an aid in performing thoracentesis. Its major advantage over conventional radiography is its ability to differentiate between solid and liquid components and thus assist in identifying pleural fluid loculations. It is also valuable in detecting subpulmonic or subphrenic pathology.

Computed Tomography ( See Figure 2)
Cross-sectional imagery helps distinguish anatomic compartments more clearly (eg, the pleural space from lung parenchyma). This modality is useful as well in distinguishing empyema (split pleura sign) from lung abscess, in detecting pleural masses, and in outlining loculated fluid collections.⁵

Laboratory Studies:

Criteria of Light et al
Ideally, the work-up of a pleural effusion should begin with a diagnostic thoracentesis followed by classification of the pleural fluid into either a transudate or an exudate. In 1972, Light and coworkers developed the currently accepted benchmark in classifying pleural fluid:²

• Pleural fluid protein/serum protein ratio greater than 0.5
• Pleural fluid lactate dehydrogenase (LDH)/serum LDH ratio greater than 0.6
• Pleural fluid LDH greater than two-thirds the upper limit of normal for serum LDH (a cut-off value of 200 IU/L was used previously)

Pleural fluid is classified as an exudate if it meets any one of the aforementioned criteria. Conversely, if all three characteristics are not met, then the fluid is classified as a transudate. Following these guidelines, the original study of Light et al² had a diagnostic sensitivity of 99% and specificity of 98% for an exudate. In more recent years, as noted by Tarn and Lapworth,⁶ a number of studies used modifications to Light's criteria but had poorer diagnostic accuracy.

Additional Markers

• Cholesterol
  Although the reason is unclear, cholesterol concentration is higher in exudates than transudates. Various studies have looked at the utility of cholesterol measurements alone, as a fluid/serum ratio, or in combination with LDH, with cut-offs ranging from 45 to 60 mg/dL. Currently, pleural fluid cholesterol measurements, on their own, probably reduce misclassifications but cannot be used as a substitute to measurements of protein and LDH.
  
  
• Serum-pleural Fluid Albumin Gradient
  One of the limitations of the Light et al criteria is that they may label some patients with transudates as having exudative effusions (eg, patients with heart failure who undergo diuretic treatment). Roth et al used the serum-effusion albumin gradient (serum albumin concentration minus effusion albumin concentration) with a cut-off of 12 g/L (exudates if below that level, transudates if above), and obtained a specificity of 100% as compared with 72% with Light's criteria.⁷ However, use of this marker alone may result in misclassification of many exudates as well.
  
  
• Glucose
  Very low glucose levels (less than 25 mg/100 mL), though not pathognomonic, are seen in a few diseases. Rheumatoid arthritis, tuberculosis, empyema, and tumors/malignancy with extensive involvement of the pleura are most commonly associated with very low glucose levels.
  
  
• Amylase
  Elevated pleural fluid amylase is seen with pancreatitis and esophageal rupture, and in approximately 10% of malignant effusions.
  
  
• pH
  Normal pleural fluid pH has been estimated to be around 7.64. Good et al noted that a pH below 7.30 suggests the presence of an inflammatory or infiltrative process.⁸ These may include parapneumonic effusions, empyema, malignancy, connective tissue diseases, tuberculosis, and esophageal rupture. Urinothorax is peculiar in that it is the only cause of a low pH transudative effusion. According to the current American College of Chest Physicians (ACCP) consensus statement on the treatment of parapneumonic effusions,⁹ pH is the preferred pleural fluid chemistry test (determined using a blood gas analyzer) for classifying the category of a parapneumonic effusion for subsequent management (See Therapy and Outcomes Section, Table 3).
  
  
• Adenosine Deaminase
  Adenosine deaminase (ADA) levels tend to be higher in tuberculous pleural effusions than in other exudates. A level above 70 U/L is highly suggestive of tuberculous pleuritis, whereas a level below 40 U/L virtually rules out this diagnosis. Other pleural diseases where high ADA levels may be seen are rheumatoid pleuritis and empyema.¹⁰

Other Diagnostic Modalities:

Pleural Biopsy
The use of a needle (Abrams' needle) to obtain specimens from the parietal pleura has become less frequent with the increasing availability of improved serum markers and thoracoscopy. At present, a needle biopsy of the pleura is used mainly to diagnose tuberculous pleuritis when other markers (eg, ADA) are negative.

Thoracoscopy
Invasive techniques for the diagnosis of pleural effusions have gained more popularity with the advent of video-assisted technology. Thoracoscopy offers the advantages of visual evaluation of the pleura, direct tissue sampling, and therapeutic intervention (eg, dissecting loculations and pleurodesis). Medical thoracoscopy (performed by pulmonologists under conscious sedation) and video-assisted thoracoscopic surgery, or VATS (performed by surgeons under general anesthesia) is currently indicated for the diagnosis of pleural effusions that have remained undiagnosed despite previous, less-invasive tests (eg, thoracentesis).

THERAPY AND OUTCOMES

Therapeutic Thoracentesis:

Drainage of a pleural effusion is indicated in the following situations:

• In complicated parapneumonic effusions or empyema (See Table 3)
• Symptomatic relief of dyspnea
• Need for evaluation of underlying lung parenchyma

The current guidelines proposed by the ACCP for the treatment of parapneumonic effusions⁹ categorize the risk for poor outcome as well as the need for drainage of the effusion based on the pleural space anatomy, pleural fluid bacteriology (culture and Gram's stain), and pleural fluid chemistry (pH).

herapeutic thoracentesis may be repeated if indicated; however, more definitive therapy (eg, pleural "sclerosis"; see below) is usually needed to treat recurrent, symptomatic pleural effusions. At any one time, no more than 1 L to 1.5 L of fluid should be removed (unless pleural space pressure is monitored) to avoid re-expansion pulmonary edema and post-thoracentesis shock. The use of supplemental oxygen is probably of benefit as well, since post-thoracentesis decreases in arterial oxygenation have also been reported, the magnitude and duration of which roughly correlate with the amount of fluid removed.

Pleural Sclerosis and Fibrinolytics:

The use of a "sclerosing" agent to produce a chemical serositis and subsequent fibrosis of the pleura is indicated in recurrent, symptomatic malignant effusions. Agents such as talc, doxycycline, bleomycin, and quinacrine have been used. It is essential that all fluid be initially drained and that there is full expansion of the underlying lung (usually via a tube thoracostomy) before proceeding with sclerosis. Failure of treatment is usually due to the inability to approximate the pleural surfaces during administration of the agent. With proper technique, however, doxycycline sclerosis has been reported to be 80% to 90% effective.

More recently, randomized, controlled trials have shown that the use of fibrinolytics (urokinase or streptokinase instilled via a tube thoracostomy) improved fluid drainage and chest radiograph findings significantly, and was an effective method for managing parapneumonic effusions.^11,12

Surgical Therapy:

The inadequacy of conventional drainage strategies has led the ACCP consensus panel to recommend video-assisted thoracoscopic surgery (VATS) and thoracotomy as acceptable approaches to managing patients with complicated pleural effusions. Parietal pleurectomy and decortication of the visceral pleura are definitive procedures with excellent response rates. "Angelillo Mackinlay" and colleagues¹³ compared outcomes of patients who underwent VATS or thoracotomy (with or without rib resection) for management of parapneumonic effusions, and concluded that clinical outcomes were comparable but VATS offered advantages in postoperative care. Despite these advanced techniques, it is important to remember that morbidity and mortality rates remain high, and that the patient's general medical condition, expected long-term prognosis, and baseline lung function should be considered before proceeding with surgery.

Pleural Effusions in Specific Diseases:

Collagen-vascular Diseases
The pleura is involved in a majority of patients with systemic lupus erythematosus (SLE) at some time during the course of their disease. These pleural effusions are usually small and bilateral, and the most common symptom is chest pain. Previous studies have shown that the finding of LE cells and high antinuclear antibody titers in pleural fluid have a high specificity but are not particularly sensitive in diagnosing this condition. Therefore, routine use of these tests is not presently recommended. SLE effusions are usually responsive to corticosteroids. Pleural effusions occur less commonly in patients with rheumatoid arthritis and, in contrast to SLE effusions, they occur more commonly in men. A striking characteristic of rheumatoid effusions is their low glucose level (less than 25 mg/dL). The measurement of rheumatoid factor in pleural fluid is also not useful, since this may be elevated in other inflammatory states. In contrast to SLE, there is little evidence that corticosteroids are beneficial in treating rheumatoid pleurisy, probably because the natural history of this disease is much more variable.

Malignancy
The pleura is involved in neoplastic disease more commonly through metastasis than through primary tumors. Lung and breast cancer are the leading causes of metastatic disease to the pleura. Other less common causes are hematologic (eg, lymphoma and leukemia), ovarian, and gastrointestinal tumors. Cytologic examination of the pleural fluid is positive in more than 50% of cases with pleural involvement. The use of tumor markers (eg, carcinoembryonic antigen (CEA) in establishing the diagnosis is not specific enough to be recommended routinely. Immunocytometry has been used to establish the diagnosis of lymphomas and has been helpful in cases of idiopathic effusions where conventional techniques were nondiagnostic.¹⁴

Chylothorax
Leakage of chyle from a disruption of the thoracic duct leads to a chylothorax. Common causes of this condition are listed in Table 4. Although the grossly appearing "milky" fluid usually indicates the diagnosis, the best way to ascertain this diagnosis is by measuring pleural fluid triglyceride levels (Figure 3). A triglyceride level above 110 mg/dL confirms the diagnosis, whereas a level below 40 mg/dL excludes the diagnosis. The finding of chylomicrons in the effusion (using electrophoresis) also establishes the diagnosis. Treatment of a chylous effusion is aimed at preventing the complications of malnutrition due to the continuous loss of protein, fat, and electrolytes. Conservative measures include shifting to a medium-chain triglyceride diet to minimize the accumulation of fluid and total parenteral nutrition. Definitive treatment modalities include thoracic duct ligation or pleuroperitoneal shunt implantation. Pleurodesis is not very effective due to the anti-inflammatory characteristics of chyle.

Hemothorax
Whenever the gross appearance of pleural fluid is bloody, a hematocrit level should be determined. Hemothorax is considered present when the pleural fluid hematocrit is greater than 50% of the peripheral blood hematocrit. Hemothorax most commonly results from chest trauma. Nontraumatic hemothorax, although uncommon, must alert the clinician to the possibility of malignancy or pulmonary embolism. Treatment of this condition requires immediate chest tube thoracostomy, and if bleeding persists (more than 200 mL drainage per hour), subsequent thoracotomy.

Post-coronary Artery Bypass Graft
Approximately one-half of patients who undergo coronary artery bypass grafting develop pleural effusions. The precise pathophysiology of this postoperative occurrence is unclear, but is probably related to pleural trauma during surgery or bleeding into the pleural space. Light et al¹⁵ divided these large effusions into two categories: those that occur within 30 days of surgery and those that occur after. Within 30 days of surgery, the fluid is bloody, eosinophilic, and easily resolvable with drainage (thoracentesis). After 30 days, the fluid is clear-yellow and predominantly lymphocytic, but these effusions are difficult to manage because they frequently recur. In either case, it is easy to distinguish these effusions from those caused by congestive heart failure, since the former are usually exudative.

Other Pleural Diseases:

Pneumothorax
Air between the lung and chest wall (in the pleural space) is termed a "pneumothorax" (Figure 4).Table 5 lists the classification of pneumothoraces. Common causes of pneumothoraces include trauma, iatrogenic factors (eg, thoracentesis, mechanical ventilation), chronic obstructive pulmonary disease, infection, and malignancy.

The incidence of primary spontaneous pneumothorax is higher in men less than 40 years old, and the relative risk rises with heavier smoking. Secondary spontaneous pneumothorax is a more serious condition, since it further compromises an already abnormal lung function. Most secondary spontaneous pneumothoraces are related to chronic obstructive pulmonary disease or infection (eg, Pneumocystis carinii). Trauma-related pneumothorax can result either in an open (to the atmosphere) pneumothorax or a closed (tension) pneumothorax, in which intrapleural pressures frequently exceed atmospheric pressures. Table 6 summarizes the currently adopted guidelines by the ACCP for the treatment of spontaneous pneumothorax.¹⁶ Traumatic pneumothorax usually requires the placement of a tube thoracostomy until the air leak resolves. The ACCP consensus statement also recommends surgical intervention (thoracoscopy with bullectomy and a procedure to produce pleural symphysis) in preventing the recurrence of secondary pneumothoraces.¹⁶

Asbestos-related Pleural Disease
The spectrum of pleural diseases with asbestos exposure ranges from the classic pleural plaques to effusions and malignancy. Pleural plaques are fibrous lesions found mostly on the parietal pleura after more than 20 years of exposure. They are considered "markers" of clinically relevant asbestos exposure and may occur without any evidence of asbestos-related lung disease;¹⁷ furthermore, they are not considered to be premalignant lesions. Small, benign effusions are common and are often the earliest manifestations (within the first 20 years) of exposure, and the pathologic findings are nonspecific. Upon examination of the pleural fluid, however, the presence of mesothelial cells with atypical features makes it difficult to distinguish these benign effusions from effusions due to mesothelioma. Therefore, benign asbestos pleural effusions are exudates that can represent a diagnostic problem when other signs of asbestos exposure have not yet manifested.

Wagner and associates recognized the association of mesothelioma and asbestos in 1960.¹⁸ Most patients are middle-aged and have a significant history of asbestos exposure. The diagnosis is often suggested by the history of cough and pleuritic chest pain as well as findings of elevated hyaluronic acid levels in pleural fluid, and chest CT results. The diagnosis is confirmed by tissue biopsy through thoracoscopy or thoracotomy. The prognosis of patients with mesotheliomas is generally poor (less than 1-year survival after diagnosis), and the management involves multimodality therapy.

AIDS-related Pleural Disease
The immunologic impairment in AIDS leads to a variety of infectious and neoplastic processes. Infectious complications include the development of bacterial parapneumonic effusions and empyema. In developing countries, tuberculous involvement of the pleura is common. P carinii, although a common cause of pneumonia in patients with AIDS, is rarely a cause of pleural effusions. However, P carinii has been associated with pneumothorax in this patient population, so much so that the development of an unexplained spontaneous pneumothorax in a person infected with human immunodeficiency virus should prompt a search for P carinii infection.¹⁹ Pleural effusions can also occur with Kaposi's sarcoma and non-Hodgkin's lymphoma, and responses to treatment for these disease entities have been poor.

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