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Diagnostic evaluation of a pleural effusion in adults
John E Heffner, MD
Steven A Sahn, MD
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.2 is current through April 2007; this topic was last changed on May*01,*2007. The next version of UpToDate (15.3) will be released in October 2007.
INTRODUCTION*—*Determining the cause of a pleural effusion is greatly facilitated by analysis of the pleural fluid. Thoracentesis is a simple bedside procedure that permits fluid to be rapidly sampled, visualized, examined microscopically, and quantified. A systematic approach to analysis of the fluid in conjunction with the clinical presentation should allow the clinician to diagnose the cause of an effusion in about 75 percent of patients at the first encounter [1]: A definitive diagnosis, provided by the finding of malignant cells or specific organisms in the pleural fluid, can be established in approximately 25 percent of patients. A presumptive diagnosis, based on the pre-thoracentesis clinical impression, can be substantiated by pleural fluid analysis in an additional 50 percent of patients.
Even with a nondiagnostic thoracentesis, pleural fluid analysis can be useful in excluding other possible causes, such as infection. Thus, clinical decision-making information can be gained from pleural fluid analysis in over 90 percent of patients [1].
An approach to pleural fluid analysis will be presented here. Pleural imaging, the technique of thoracentesis, and an approach to undiagnosed pleural effusions are discussed separately. (See "Imaging of pleural effusions in adults" and see "Diagnostic thoracentesis" and see "The undiagnosed pleural effusion").
INDICATIONS FOR THORACENTESIS*—*The indication for diagnostic thoracentesis is the new finding of a pleural effusion. Observation, in lieu of diagnostic thoracentesis, may be warranted in uncomplicated congestive heart failure and viral pleurisy. In the former setting, the clinical diagnosis is usually secure; in the latter, there is typically a small amount of fluid. However, if the clinical situation is atypical or does not progress as anticipated, thoracentesis should be performed [2].
Only a select number of diagnoses can be established definitively by thoracentesis. These include malignancy, empyema, tuberculous pleurisy, fungal infection of the pleural space, lupus pleuritis, chylothorax, urinothorax, esophageal rupture, hemothorax, peritoneal dialysis, and extravascular migration of a central venous catheter (show table 1) [3].
PLEURAL FLUID ANALYSIS
Gross appearance*—*Initial diagnostic clues can be obtained by gross inspection of pleural fluid as it is being aspirated from the patient's chest [3]. Observations that are helpful for diagnosis are listed (show table 2).
Characterization*—*The pleural fluid is next characterized as either a transudate or an exudate.
**Transudates*—*Transudates are largely due to imbalances in hydrostatic and oncotic pressures in the chest. However, they can also result from movement of fluid from the peritoneal or retroperitoneal spaces, or from iatrogenic causes, such as crystalloid infusion into a central venous catheter that has migrated [2]. Nevertheless, transudates have a limited number of diagnostic possibilities that can usually be discerned from the patient's clinical presentation (show table 3).
**Exudates*—*In contrast, exudative effusions present more of a diagnostic challenge. Disease in virtually any organ can cause exudative pleural effusions by a variety of mechanisms, including infection, malignancy, immunologic responses, lymphatic abnormalities, noninfectious inflammation, iatrogenic causes, and movement of fluid from below the diaphragm (show table 4) [2].
Exudates result primarily from pleural and lung inflammation (resulting in a capillary protein leak) or from impaired lymphatic drainage of the pleural space (resulting in decreased removal of protein from the pleural space) [2]. Exudates can also result from movement of fluid from the peritoneal space, as seen with acute or chronic pancreatitis, chylous ascites, and peritoneal carcinomatosis. (See "Mechanisms of pleural liquid accumulation in disease").
**Diagnostic criteria*—*Light's criteria is a traditional method of separating transudates and exudates that measures serum and pleural fluid protein and LDH. If at least one of the following three criteria is present, the fluid is defined as an exudate [4]: Pleural fluid protein/serum protein ratio greater than 0.5. Pleural fluid LDH/serum LDH ratio greater than 0.6. Pleural fluid LDH greater than two thirds the upper limits of the laboratory's normal serum LDH.
The combination of the three criteria has a higher sensitivity, but a lower specificity, than each individual criterion. This is an inherent consequence of combining two or more tests into a diagnostic rule when only one test must be fulfilled to define a positive result. The tradeoff is appropriate for screening pleural fluid because it is important that exudates not be missed, since they can have important prognostic implications.
Light's criteria have been criticized for including both the pleural fluid LDH/serum LDH ratio and the pleural fluid LDH because they are highly correlated [5]. An abbreviated version of Light's criteria has similar diagnostic accuracy and has been recommended for clinical use [5,6].
Alternative diagnostic criteria also exist. A meta-analysis of eight studies (1448 patients) examined pleural fluid tests and found that several tests identified exudates with accuracy similar to those used in Light's criteria, but did not require concurrent measurement of serum protein or LDH [5]. Proposed two-criteria and three-criteria diagnostic rules — which require one criterion to be met to define an exudate — include: Two-test rule
******-**Pleural fluid cholesterol greater than 45 mg/dL
******- Pleural fluid LDH greater than two-thirds the upper limit of the laboratory's normal serum LDH Three-test rule
******-**Pleural fluid protein greater than 2.9 mg/dL
******-**Pleural fluid cholesterol greater than 45 mg/dL
******- Pleural fluid LDH greater than two-thirds the upper limit of the laboratory's normal serum LDH
All available tests commonly misclassify pleural fluid as exudates or transudates when values are near the cutoff points. Thus, clinical judgment is required when evaluating patients with borderline test results [7].
Chemical analysis*—*The measurement of pleural fluid protein and LDH, glucose, pH, and amylase can provide useful information.
**Protein*—*Most transudates have absolute total protein concentrations below 3.0 g/dL, although acute diuresis in congestive heart failure can elevate protein levels into the exudative range [8-10]. However, such patients have a pleural fluid to serum albumin gradient greater than 1.2 gm/dL, which correctly categorizes their effusions as transudates. Tuberculous pleural effusions virtually always have total protein concentrations above 4.0 g/dL [4]. When pleural fluid protein concentrations are in the 7.0 to 8.0 g/dL range, Waldenstrom's macroglobulinemia and multiple myeloma should be considered [11,12].
**LDH*—*Several specific disease associations have been noted with pleural fluid protein and LDH levels: Pleural fluid LDH levels above 1000 IU/L (with upper limit of normal for serum of 200 IU/L) are characteristically found in empyema [13], rheumatoid pleurisy [14], and pleural paragonimiasis [15], and are sometimes observed with malignancy. Pleural fluid secondary to Pneumocystis jiroveci pneumonia has the characteristic finding of a pleural fluid/serum LDH ratio greater than 1.0 and a pleural fluid/serum protein ratio of less than 0.5 [16]. Urinothorax is another cause of elevated pleural fluid LDH associated with low pleural fluid protein levels [17].
**Glucose*—*A low pleural fluid glucose concentration (less than 60 mg/dL (3.33 mmol/liter), or a pleural fluid/serum glucose ratio less than 0.5) narrows the differential diagnosis of the exudate to the following possibilities [18]: Rheumatoid pleurisy Complicated parapneumonic effusion or empyema Malignant effusion Tuberculous pleurisy Lupus pleuritis Esophageal rupture
All transudates and all other exudates have pleural fluid glucose concentration similar to that of blood glucose.
The mechanism responsible for a low pleural fluid glucose depends upon the underlying disease. Specific examples include: Decreased transport of glucose from blood to pleural fluid with rheumatoid pleurisy [19,20] or malignancy [21]. Increased utilization of glucose by constituents of pleural fluid, such as neutrophils, bacteria (empyema), and malignant cells [22].
The lowest glucose concentrations are found in rheumatoid pleurisy and empyema, with glucose being undetectable in some cases. In comparison, when the glucose concentration is low in tuberculous pleurisy, lupus pleuritis, and malignancy, it usually falls into the range of 30 to 50 mg/dL (1.66 to 2.78 mmol/liter) [18].
**pH*—*Pleural fluid pH should always be measured in a blood gas machine rather than with a pH meter or pH indicator paper, as the latter will result in inaccurate measurements [23]. A pleural fluid pH below 7.30 with a normal arterial blood pH is found with the same diagnoses associated with low pleural fluid glucose concentrations [24]. The pH of normal pleural fluid is approximately 7.60, due to a bicarbonate gradient between pleural fluid and blood [25]. Thus, a pH below 7.30 represents a substantial accumulation of hydrogen ions. Transudates generally have a pleural fluid pH in the 7.40 to 7.55 range, while the majority of exudates range from 7.30 to 7.45 [24].
The mechanisms responsible for pleural fluid acidosis (pH <7.30) include; Increased acid production by pleural fluid cells and bacteria (empyema) [22,26]. Decreased hydrogen ion efflux from the pleural space, due to pleuritis, tumor, or pleural fibrosis. Specific examples include malignancy [21], rheumatoid pleurisy [19,20], and tuberculous pleurisy.
A low pleural fluid pH has diagnostic, prognostic, and therapeutic implications for patients with parapneumonic and malignant effusions [27]. Patients with a low pleural fluid pH malignant effusion have a high initial positive yield on pleural fluid cytology. They also tend to have a shorter survival and poorer response to chemical pleurodesis than those with a pH >7.30, although the strength of these associations do not provide prognostic value for individual patients [28-30].
Clinicians should not use the pleural fluid pH as the sole criterion for the decision to recommend pleurodesis. A parapneumonic effusion with a low pleural fluid pH (7.15) indicates a high likelihood of necessity for pleural space drainage (show figure 1) [31,32]. (See "Pathogenesis and management of parapneumonic effusions and empyema in adults").
**Amylase*—*The finding of an amylase-rich pleural effusion, defined as either a pleural fluid amylase greater than the upper limits of normal for serum amylase or a pleural fluid to serum amylase ratio greater than 1.0, narrows the differential diagnosis of an exudative effusion to the following major possibilities [2]: Acute pancreatitis Chronic pancreatic pleural effusion Esophageal rupture Malignancy
Other rare causes of an amylase-rich pleural effusion include pneumonia, ruptured ectopic pregnancy, hydronephrosis, and cirrhosis [33]. Pancreatic disease is associated with pancreatic isoenzymes, while malignancy and esophageal rupture are characterized by a predominance of salivary isoenzymes [33].
**Other*—*Several studies have demonstrated that N-terminal pro-brain natriuretic peptide (NT-proBNP) is elevated in the pleural fluid of patients who have congestive heart failure and a pleural effusion [34-36]. However, numerous issues need to be addressed before routine measurement of pleural fluid NT-proBNP can be suggested. Prospective studies are needed to compare pleural fluid NT-proBNP in patients with cardiac pleural effusions versus patients with chronic congestive heart failure who have pleural effusions due to other causes. In addition, it must be determined whether pleural fluid NT-proBNP has greater diagnostic value than standard measurement of plasma NT-proBNP. It is possible that this diagnostic test may prove useful for diagnosing a cardiac pleural effusion in patients whose pleural fluid appears exudative (eg, due to diuresis).
Nucleated cells*—*The total pleural fluid nucleated cell count is virtually never diagnostic. There are, however, some settings in which the count may be helpful: Counts above 50,000/µL are usually found only in complicated parapneumonic effusions, including empyema. Exudative effusions from bacterial pneumonia, acute pancreatitis, and lupus pleuritis usually have total nucleated cell counts above 10,000/µL [2,37]. Chronic exudates, typified by tuberculous pleurisy and malignancy, typically have nucleated cell counts below 5000/µL [2,37].
The timing of thoracentesis in relation to the acute pleural injury determines the predominant cell type. The early cellular response to pleural injury is neutrophilic. As the time from the acute insult lengthens, the effusion develops a mononuclear predominance if the pleural injury is not ongoing [2].
**Lymphocytosis*—*Pleural fluid lymphocytosis, particularly with lymphocyte counts representing 85 to 95 percent of the total nucleated cells, suggests tuberculous pleurisy, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, or chylothorax [2,3,38]. Carcinomatous pleural effusions will be lymphocyte-predominant in over one-half of cases; however, the percentage of lymphocytes is usually between 50 and 70 percent [38]. (See "Tuberculous pleural effusions in non-HIV infected patients", and see "Diagnosis and management of chylothorax and chyliform effusions").
**Eosinophilia*—*Pleural fluid eosinophilia (defined by pleural fluid eosinophils representing more than 10 percent of the total nucleated cells) usually suggests a benign, self-limited disease, and is commonly associated with air or blood in the pleural space [39,40]. However, two studies have noted that malignancy is as prevalent in eosinophilic as noneosinophilic pleural effusions [41,42]. The differential diagnosis of pleural fluid eosinophilia includes [39,40]: Pneumothorax Hemothorax Pulmonary infarction Benign asbestos pleural effusion Parasitic disease Fungal infection (coccidioidomycosis, cryptococcosis, histoplasmosis) Drugs Malignancy (carcinoma, lymphoma)
Pleural fluid eosinophilia appears to be rare with tuberculous pleurisy on the initial thoracentesis [39,40]. (See "Pleural fluid eosinophilia").
**Mesothelial cells*—*Mesothelial cells are found in small numbers in normal pleural fluid, are prominent in transudative pleural effusions, and are variable in exudative effusions. The major clinical significance of mesothelial cells in exudates is that tuberculosis is unlikely if there are more than five percent mesothelial cells [38,40,43,44].
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