What is the best approach to diagnose and manage a patient with pleural effusion, considering various underlying causes such as heart failure, lung cancer, and other malignancies?

Diagnostic and Management Approach to Pleural Effusion

For any unilateral pleural effusion or bilateral effusion with normal heart size, perform diagnostic thoracentesis with ultrasound guidance to determine etiology, as this is the cornerstone of diagnosis and will direct all subsequent management. 1, 2

Initial Diagnostic Workup

When to Perform Thoracentesis

• Mandatory indications: Any new, unexplained unilateral pleural effusion requires thoracentesis 1, 2
• Bilateral effusions: Perform thoracentesis if heart size is normal on chest radiograph, suggesting non-cardiac etiology 1
• Ultrasound guidance is mandatory for all pleural interventions to reduce pneumothorax risk from 8.9% to 1.0% 1, 2

Essential Pleural Fluid Tests

Send fluid for the following analyses at every thoracentesis 1, 2:

• Cell count and differential
• Total protein and LDH (to apply Light's criteria)
• Glucose and pH (critical for parapneumonic effusions)
• Cytology (send 25-50 mL for optimal yield)
• Microbiological cultures (5-10 mL in aerobic and anaerobic blood culture bottles)
• Gross appearance and odor (must be documented)

Transudate vs. Exudate Classification

• Apply Light's criteria to distinguish transudate from exudate 2, 3
• Transudates: Direct therapy toward underlying heart failure or cirrhosis 3
• Exudates: Require extensive workup as pneumonia, cancer, tuberculosis, and pulmonary embolism account for most cases 3

Specific Clinical Scenarios

Suspected Malignant Effusion

Pleural fluid cytology has only 62% sensitivity; if negative but suspicion remains high, proceed directly to thoracoscopic or image-guided pleural biopsy rather than repeating cytology. 1

• Cytology sensitivity varies by tumor type: Lung cancer 67%, extrathoracic primaries 62%, mesothelioma 58% 1
• If first cytology is non-diagnostic, obtain a second sample to increase yield before proceeding to biopsy 1
• Medical thoracoscopy achieves 95% diagnostic sensitivity compared to 62% for cytology and 44% for closed pleural biopsy 1
• Blind (non-image-guided) pleural biopsies should never be performed 1
• Bronchoscopy has low diagnostic yield and should not be routine unless hemoptysis, atelectasis, or large effusion without mediastinal shift suggests endobronchial obstruction 1

Common malignant causes 4:

• Lung cancer (most common, 25-52% of malignant effusions)
• Breast cancer (3-27% of malignant effusions)
• Mesothelioma (particularly hemorrhagic effusions with asbestos exposure)
• Lymphoma (12-22% of malignant effusions)

Suspected Parapneumonic Effusion/Pleural Infection

For any parapneumonic effusion where diagnostic aspiration does not yield frank pus, perform immediate pH analysis. 1

• pH ≤7.2: High risk of complex parapneumonic effusion or empyema—insert intercostal drain immediately if safe volume accessible on ultrasound 1
• **pH >7.2 and <7.4**: Intermediate risk—if LDH >900 IU/L, consider drain insertion 1
• Send fluid in blood culture bottles (5-10 mL aerobic and anaerobic) for optimal microbiological yield 1
• RAPID scoring should be used to risk stratify patients and inform prognosis discussions 1

Suspected Tuberculous Effusion

In high prevalence populations, measure pleural fluid adenosine deaminase (ADA) and/or interferon-gamma, but always prioritize tissue sampling for culture and sensitivity. 1

• ADA testing: Can be used for diagnosis in high prevalence areas or as exclusion test in low prevalence populations 1
• Tuberculin skin test: Positive in approximately 70% of tuberculous pleurisy cases 1
• Tissue sampling remains the gold standard to obtain culture and sensitivity data for treatment guidance 1

Unilateral Effusion in Known Heart Failure

Use serum NT-proBNP (not pleural fluid NT-proBNP) combined with thoracic ultrasound to guide decision-making; if NT-proBNP <1500 μg/mL or clinical features suggest alternative diagnosis, perform thoracentesis. 1

Clinical features suggesting non-cardiac cause 1:

• Weight loss
• Chest pain
• Fevers
• Elevated white cell count or C-reactive protein
• CT evidence of malignant pleural disease or infection

If treating as heart failure 1:

• Optimize heart failure therapy and monitor clinical progress
• Reassess patient and effusion for improvement
• If no improvement, proceed to thoracentesis

Rheumatoid Arthritis-Associated Effusion

• Measure pleural fluid pH, glucose, and complement 1
• Rheumatoid arthritis is unlikely if glucose >1.6 mmol/L (29 mg/dL) 1

Systemic Lupus Erythematosus

• Do not measure pleural fluid ANA as it mirrors serum levels and is unhelpful 1
• Consider pleural fluid ANA only to support diagnosis of lupus pleuritis in appropriate clinical context 1
• LE cells in pleural fluid are diagnostic of SLE 1

Therapeutic Thoracentesis

Volume and Rate Considerations

Remove no more than 1.5 L at initial thoracentesis to prevent re-expansion pulmonary edema, draining at approximately 500 mL/hour if using continuous drainage. 4, 5

• Complete hemithorax opacification typically represents 2,000-2,500 mL of fluid 5
• Stop drainage immediately if patient develops chest tightness, persistent cough, or dyspnea 5
• Monitor pleural pressure if available to guide safe drainage volumes 2

Post-Drainage Assessment

• If symptoms improve: Confirms effusion as cause of dyspnea 2
• If symptoms persist: Investigate alternative causes including lymphangitic carcinomatosis, atelectasis, pulmonary embolism, or endobronchial obstruction 2
• Assess lung re-expansion on imaging to determine if lung is expandable 2

Management of Persistent Undiagnosed Effusion

In persistently undiagnosed effusions after cytology and pleural biopsy, reconsider pulmonary embolism and tuberculosis as these are treatable conditions that may be missed. 1

• Approximately 15% of effusions remain undiagnosed after repeated cytology and pleural biopsy 1
• After thoracoscopy, less than 10% remain undiagnosed compared to >20% with pleural fluid analysis and closed needle biopsy alone 1
• If thoracoscopy is not diagnostic, VATS or exploratory thoracotomy may be indicated 1

Common Pitfalls to Avoid

• Never skip thoracentesis in unilateral effusions assuming heart failure without confirmation, as 41% of acute decompensated heart failure patients have unilateral effusions 1
• Do not perform blind pleural biopsies—always use image guidance or thoracoscopy 1
• Avoid routine bronchoscopy in undiagnosed effusions unless specific indications present 1
• Do not rely solely on single cytology sample in suspected malignancy—sensitivity improves with second sample 1
• Never drain large effusions rapidly—re-expansion pulmonary edema risk increases significantly 4, 5