What is the next step in managing a 37-year-old patient with persistent pleurisy, normal complete blood count (CBC), comprehensive metabolic panel (CMP), and negative screenings for human immunodeficiency virus (HIV), hepatitis, and tuberculosis, and unremarkable chest x-ray and computed tomography (CT) lung findings?

Workup for Persistent Pleurisy with Normal Initial Testing

In a 37-year-old with persistent pleurisy and unremarkable initial workup, you should strongly consider pulmonary embolism as the next diagnostic priority, followed by thoracoscopy if malignancy remains a concern after routine tests fail. 1, 2

Immediate Diagnostic Considerations

Pulmonary Embolism Evaluation

• Pulmonary embolism must be reconsidered and actively pursued since it is amenable to specific treatment and can present with pleurisy despite normal chest imaging 1, 2
• PE-associated pleural effusions occur in up to 40% of PE cases, and 80% are bloodstained, though effusions may be small or absent 2
• No specific pleural fluid characteristics distinguish PE-related effusions, so diagnosis should be pursued on clinical grounds with high index of suspicion 2
• Proceed directly to CT pulmonary angiography or ventilation/perfusion scanning if clinical suspicion exists, as imaging for embolism should be undertaken even when chest CT appears normal 1, 2

Reconsider Tuberculosis

• Despite negative initial TB screening, tuberculosis should be reconsidered as it is specifically treatable 1, 2
• A tuberculin skin test is positive in approximately 70% of patients with tuberculous pleurisy 1
• If you observe an exudative pleural effusion with predominantly lymphocytes plus a positive tuberculin skin test, this combination is sufficient to justify empirical antituberculous therapy 1
• Pleural fluid adenosine deaminase (ADA) levels and interferon-gamma are highly useful diagnostic tests—elevation of either in lymphocytic pleural effusions is virtually diagnostic of tuberculous pleurisy 3, 4

Advanced Diagnostic Approach

Thoracentesis and Pleural Fluid Analysis

• Perform diagnostic thoracentesis if any pleural effusion is present, even if small, as this is essential for distinguishing transudate from exudate 2, 5
• Light's criteria should be applied to classify the effusion, with protein and LDH measurements 2, 5
• Obtain pleural fluid for: cell count with differential, bacterial and mycobacterial cultures, cytology, ADA, and consider interferon-gamma 1, 5, 3
• If the first pleural fluid cytology is non-diagnostic, a second sample should be taken to increase diagnostic yield 1

Imaging Refinement

• Contrast-enhanced CT of chest, abdomen, and pelvis should be performed to evaluate for lymphadenopathy, visceral masses, splenomegaly, or occult malignancy 1
• Ultrasound can identify small loculated collections and guide further drainage procedures 5
• PET-CT may be considered if malignancy is suspected, though be aware that inflammatory conditions and infections can cause false positives 1

When Diagnosis Remains Elusive

Pleural Biopsy

• Closed pleural biopsy should be performed if initial thoracentesis is non-diagnostic, with specimens placed in both saline (for culture) and formalin (for histology) 1
• Pleural biopsy has particular value for diagnosing tuberculosis and malignancy 1, 5

Thoracoscopy

• If malignancy remains suspected after routine tests fail, thoracoscopy is the advised next step 1, 2
• Thoracoscopy provides direct visualization and targeted biopsy capability 1
• Approximately 15% of pleural effusions remain undiagnosed despite repeated cytology and pleural biopsy, with many ultimately proving malignant with continued observation 2

Critical Pitfalls to Avoid

• Do not perform bronchoscopy unless the patient has hemoptysis or features suggestive of bronchial obstruction—it is not indicated in the routine assessment of undiagnosed pleurisy 1
• Do not assume normal chest imaging excludes PE; the case example in the guidelines showed a patient with normal initial CT who later had confirmed bilateral pulmonary emboli 1
• Do not dismiss the possibility of malignancy in a young patient—lung cancer and lymphoma can present with pleurisy even at this age 2
• Avoid relying solely on negative TB screening tests; consider ADA and interferon-gamma levels in pleural fluid for more sensitive TB detection 3, 4

Timeline for Escalation

• If persistent sepsis or symptoms continue despite initial workup, reassess within 5-8 days and consider more invasive diagnostic procedures 6
• Ensure adequate nutritional support throughout the diagnostic process, as poor nutrition is associated with worse outcomes 6