What are the differential diagnoses for pleural effusion?

Differential Diagnoses for Pleural Effusion

Pleural effusions are classified into transudates and exudates, with the most common causes being congestive heart failure (29%), malignancy (26%), pneumonia (16%), tuberculosis (6%), post-surgical complications (4%), pericardial diseases (4%), and cirrhosis (3%). 1

Initial Classification Framework

The differential diagnosis hinges on distinguishing transudative from exudative effusions using Light's criteria 1:

• Exudate if ANY of the following:

  • Pleural fluid protein/serum protein ratio >0.5 2
  • Pleural fluid LDH/serum LDH ratio >0.6 2
  • Pleural fluid LDH >2/3 upper limit of normal for serum 2

• Transudate: None of the above criteria met 1

Modified Light's criteria using pleural fluid LDH >0.66 of upper laboratory limits provides better discrimination. 1

Transudative Effusions (Systemic Factors)

Primary Causes:

• Congestive heart failure: Accounts for approximately 80% of all transudative effusions and 29% of total pleural effusions 3, 4. Bilateral effusions occur in 59% of heart failure cases, while 41% present unilaterally (right-sided more common than left) 3

• Hepatic cirrhosis with ascites: Represents approximately 10% of transudative effusions 3. Fluid moves directly from peritoneal cavity through diaphragmatic pores 2

• End-stage renal failure: Prevalence of 24.7% among patients with end-stage renal disease 3

• Nephrotic syndrome: Due to decreased oncotic pressure 1

Clinical pitfall: 25-30% of cardiac and hepatic transudates are misclassified as exudates by Light's criteria, particularly in diuretic-treated patients. Use serum-effusion albumin gradient >1.2 g/dL to reclassify as transudate when heart failure is suspected. 3, 4

Exudative Effusions (Local Pleural/Pulmonary Factors)

Infectious Causes:

• Parapneumonic effusions/empyema: Approximately 40% of pneumonia patients develop pleural effusion 2. Turbid fluid that clears after centrifugation indicates cell debris and empyema 1

• Tuberculosis: Accounts for 6% of all pleural effusions 1. Characterized by lymphocytic exudate with ADA >40-47 U/L (sensitivity 97.1%, specificity 92.9% at 41.5 U/L cutoff) 5. Acid-fast bacillus stains positive in only 10-20% of cases 5

• HIV-related effusions: Primary causes are Kaposi's sarcoma (33%), parapneumonic effusions (28%), tuberculosis, Pneumocystis carinii pneumonia (10%), and lymphoma (7%) 5, 4

Malignant Causes:

• Lung cancer: Most common cause of malignant pleural effusion 4, 6

• Breast cancer: Second most common malignant cause 4

• Lymphomas and leukemias: Third leading malignancy group 2

• Mesothelioma: Critical to minimize needle incisions as 40% become invaded by tumor 1

Grossly bloody pleural fluid (haematocrit >50% of peripheral blood) suggests: malignancy, pulmonary embolus with infarction, trauma, benign asbestos pleural effusions, or post-cardiac injury syndrome 1

Thromboembolic:

• Pulmonary embolism: Approximately 75% present with pleuritic pain; effusions typically occupy <1/3 hemithorax with dyspnea disproportionate to effusion size 1. Pleural fluid tests are unhelpful for diagnosis—maintain high clinical suspicion 1

Inflammatory/Autoimmune:

• Rheumatoid arthritis: Produces lowest glucose concentrations (<1.6 mmol/l) along with empyema 1. Can present bilaterally 3

• Systemic lupus erythematosus: Causes exudative effusions; ANA tests in pleural fluid are not useful as they reflect serum levels 4

• Collagen vascular diseases: Associated with pH <7.2 1

Other Exudative Causes:

• Esophageal rupture: Presents with pH <7.2, low glucose, and elevated amylase 1

• Acute pancreatitis: Elevated pleural fluid amylase; isoenzyme analysis differentiates from malignancy or esophageal rupture 1

• Drug-induced: Multiple medications cause exudative effusions (see British National Formulary or pneumotox.com for comprehensive list) 1

• Post-cardiac surgery: Accounts for 4% of effusions 1

Key Diagnostic Markers by Etiology

Low pH (<7.2) with normal blood pH:

Empyema, rheumatoid arthritis, esophageal rupture, malignancy 1

Low glucose (<3.3 mmol/l):

Empyema, rheumatoid disease, lupus, tuberculosis, malignancy, esophageal rupture 1

Elevated amylase:

Pancreatitis, esophageal rupture, malignancy (use isoenzyme analysis) 1

Lymphocytic predominance:

Tuberculosis (though not exclusive), malignancy 5

Critical caveat: In persistent undiagnosed pleural effusions, always reconsider tuberculosis and pulmonary embolism as they are treatable disorders frequently missed 5