What are the causes of pleural effusion in patients with a history of cancer, heart failure, or autoimmune diseases?

Causes of Pleural Effusion

The most common causes of pleural effusion are heart failure (29%), malignancy (26%), pneumonia (16%), tuberculosis (6%), post-surgery (4%), pericardial diseases (4%), and cirrhosis (3%), with the specific etiology varying significantly based on patient comorbidities including cancer, heart failure, and autoimmune diseases. 1

Transudative Causes

Heart failure is the dominant cause of transudative effusions, accounting for more than 80% of all transudates. 1, 2 This is particularly relevant in patients with known cardiac disease, where bilateral effusions are typical. 3

• Liver cirrhosis accounts for approximately 10% of transudates, typically occurring in patients who also have ascites, with fluid moving directly from the peritoneal cavity through diaphragmatic pores. 1, 4
• End-stage renal failure causes pleural effusions in 24.7% of patients, usually due to fluid overload, heart failure, or uremic pleuritis. 1, 5
• Other transudative causes include hypoalbuminemia, nephrotic syndrome, and atelectasis. 1

Critical Diagnostic Point for Transudates

A common pitfall is the misclassification of cardiac and hepatic transudates as exudates, which occurs in 25-30% of cases when using Light's criteria alone. 1, 5, 2 When heart failure is suspected but Light's criteria suggest an exudate, a serum-effusion albumin gradient >1.2 g/dL can reclassify the effusion as a transudate. 1 Additionally, NT-proBNP levels >1500 μg/mL in serum or pleural fluid can accurately diagnose heart failure as the cause. 1, 2

Exudative Causes in Cancer Patients

Malignancy is a leading cause of exudative effusions, with lung cancer being the most common neoplasm causing pleural effusion, followed by breast cancer. 1, 2, 3

• Lymphomas account for approximately 10% of malignant effusions. 1
• Dyspnea is the predominant symptom in more than half of patients with malignant effusions, resulting from decreased chest wall compliance, mediastinal shifting, decreased ipsilateral lung volume, and reflex stimulation. 1
• Hemoptysis in the presence of pleural effusion is highly suggestive of bronchogenic carcinoma. 1
• Dull, aching chest pain localized to the side of effusion is typical, especially with mesothelioma. 1

Malignancy-Specific Diagnostic Approach

Therapeutic thoracentesis should be performed in virtually all dyspneic patients to determine effect on breathlessness and rate of recurrence. 1 If dyspnea is not relieved by thoracentesis, investigate lymphangitic carcinomatosis, atelectasis, thromboembolism, or tumor embolism. 1

Exudative Causes in Patients with Autoimmune Diseases

Rheumatoid Arthritis

Rheumatoid arthritis causes pleural involvement in 5% of patients, with pleural effusions being more common in men despite the disease generally affecting more women. 6, 1, 5

• Suspected cases should have pleural fluid pH, glucose, and complement measured. 6
• Rheumatoid arthritis is unlikely to be the cause if the glucose level in the fluid is above 1.6 mmol/L (29 mg/dL). 6
• Pleural fluid can be serous, turbid, yellow-green, milky, or hemorrhagic. 6, 5

Systemic Lupus Erythematosus

Up to 50% of patients with SLE will have pleural disease at some time during the course of their disease. 6, 1, 5

• The presence of LE cells in pleural fluid is diagnostic of SLE. 6, 5
• The pleural fluid ANA level should NOT be measured as it mirrors serum levels and is therefore unhelpful. 6, 2 This is a critical pitfall to avoid, as 10% of non-SLE effusions (including malignancy) can be ANA positive. 6

Infectious Causes

Parapneumonic Effusions

Parapneumonic effusions are the most common cause of exudative effusions, occurring in approximately 40% of hospitalized pneumonia cases. 1, 3, 4

• Pleural fluid pH should be performed in every case of suspected parapneumonic effusion. 6
• A pH level less than 7.2 is indicative of complicated parapneumonic effusion and warrants prompt consultation for catheter or chest tube drainage, possible tissue plasminogen activator/deoxyribonuclease therapy, or thoracoscopy. 3
• Chest tubes should be inserted if the pleural fluid is gross pus, if the Gram stain is positive, if the glucose level is below 40 mg/dL, or if the pH is less than 7.00. 4

Tuberculosis

Tuberculosis accounts for approximately 6% of pleural effusions and should always be reconsidered in undiagnosed cases as it is amenable to specific treatment. 1, 5

• A positive tuberculin skin test (positive in about 70% of tuberculous pleurisy) combined with an exudative pleural effusion containing predominantly lymphocytes is sufficient to justify empirical antituberculous therapy. 6, 5, 2
• Pleural fluid smears for acid-fast bacilli are only positive in 10-20% of cases, with culture positive in only 25-50%. 5
• Pleural fluid adenosine deaminase (ADA) has a sensitivity of 0.91 and specificity of 0.88 for diagnosing tuberculous pleural effusion. 6

Vascular Causes

Pulmonary embolism is associated with pleural effusions in up to 40% of cases, with 80% being exudates and 80% being bloodstained. 1, 5

• There are no specific pleural fluid characteristics that distinguish PE-related effusions, so diagnosis should be pursued on clinical grounds with a high index of suspicion. 1
• Imaging for embolism should be undertaken if clinical suspicion exists. 1
• Symptoms of PE (acute dyspnea, pleuritic pain, hemoptysis) may overshadow effusion symptoms. 1

Special Populations

HIV Patients

In patients with HIV infection, the three leading causes of pleural effusion are Kaposi's sarcoma (33%), parapneumonic effusions (28%), and tuberculosis (14%). 6, 2

• Pneumocystis carinii pneumonia accounts for 10% and lymphoma for 7% of effusions in HIV patients. 6

Post-Asbestos Exposure

Benign asbestos pleural effusion typically occurs within the first two decades after asbestos exposure, with prevalence related to exposure dose and shorter latency than other asbestos-related disorders. 6, 5

• The effusion is usually small, asymptomatic, and has a propensity to be hemorrhagic. 6, 5
• The effusion may resolve within 6 months, leaving behind residual diffuse pleural thickening. 6, 5

Approach to Persistent Undiagnosed Effusions

In persistently undiagnosed effusions, pulmonary embolism and tuberculosis should be reconsidered since these disorders are amenable to specific treatment. 6, 1, 5

• Approximately 15% of pleural effusions remain undiagnosed despite repeated cytology and pleural biopsy, with many ultimately proving malignant with continued observation. 1, 5
• If the first pleural fluid cytology specimen is non-diagnostic, a second sample should be taken to increase the diagnostic yield. 6
• Thoracoscopy may be considered if malignancy is suspected after routine tests have failed. 1

Key Diagnostic Pitfalls to Avoid

• Diagnostic bronchoscopy is NOT indicated in the assessment of an undiagnosed effusion unless the patient has hemoptysis or features suggestive of bronchial obstruction. 6, 1
• Do not assume relief of dyspnea will occur with drainage—therapeutic thoracentesis should be performed first to assess symptom improvement. 1
• Serum biomarkers should not currently be used to diagnose secondary pleural malignancy, pleural infection, or autoimmune pleuritis. 6