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Virtually all patients with a newly discovered pleural effusion should undergo thoracentesis to aid in diagnosis and management. The routine pleural fluid (PF) evaluation usually includes the following: cell count and differential; tests for protein, LDH, glucose, adenosine deaminase, cytology and, if infection is a concern, pH and bacterial and mycobacterial cultures. Distinguishing transudates from exudates with Light's criteria is a pragmatic first step. If the effusion is an exudate, various PF tests have proven diagnostic utility: adenosine deaminase levels >35 IU/L usually indicate tuberculosis in lymphocyte-predominant PF; pH < 7.2 or glucose less than 60 mg/dL allow the clinician to identify complicated parapneumonic effusions; and conventional cytology may reveal malignant cells in 60% of the patients with malignant effusions. A number of optional PF tests may complement the diagnostic approach to an undiagnosed pleural effusion. For example, natriuretic peptide assays significantly improve the accuracy of a diagnosis of cardiac pleural effusion, whereas PF mesothelin levels greater than 20 nmol/L are highly suggestive of mesothelioma. [ABSTRACT FROM AUTHOR]