What are the likely etiologies and recommended work‑up for an exudative pleural effusion that is lymphocyte‑predominant with a leukocyte count of approximately 230 cells per microliter?

Lymphocytic Exudative Pleural Effusion with Low Cell Count: Diagnostic Approach

The most critical priority is to systematically exclude tuberculosis and malignancy, as these are the two dominant causes of lymphocyte-predominant exudative effusions, even with a relatively low total leukocyte count of 230 cells/μL. 1

Primary Differential Diagnosis

The lymphocytic predominance (assuming >50% lymphocytes) in an exudative effusion creates a narrow but critical differential:

• Tuberculosis – This is the most common infectious cause of lymphocyte-rich exudative effusions and must be ruled out first, accounting for approximately 12% of massive pleural effusions but occurring across all effusion sizes 2, 1

• Malignancy – Malignant disease accounts for 42–77% of all exudative pleural effusions, with lymphocytic predominance seen in 49.6% of malignant effusions 2, 3

  • Lung carcinoma causes approximately one-third of all malignant pleural effusions 2
  • Lymphoma (Hodgkin's and non-Hodgkin's) represents ~10% of malignant effusions and characteristically produces lymphocyte-rich exudates 2
  • Breast carcinoma is the second most frequent malignancy with lymphocyte-predominant effusions 2
  • Mesothelioma must be considered, especially with asbestos exposure history 2, 1

• Post-transplant effusions – Late effusions (>15 days post-transplant) are typically exudative and lymphocyte-predominant 4

Critical Initial Workup

Essential Pleural Fluid Analyses

Core biochemical tests (if not already obtained):

• Protein, LDH, pH, and glucose levels are mandatory 2
• pH <7.20 with glucose <60 mg/dL would indicate complicated parapneumonic effusion requiring immediate drainage, even with lymphocytic predominance 4, 1
• pH <7.30 in malignant effusions predicts poor survival (median 2.1 vs 9.8 months) 1

Microbiologic evaluation:

• Acid-fast bacilli (AFB) staining and mycobacterial culture are critical for tuberculosis diagnosis, though sensitivity is limited 1
• Gram stain and bacterial culture to exclude parapneumonic effusion 1
• Consider sending pleural fluid in anaerobic blood culture bottles to improve yield 4

Tuberculosis-specific markers:

• Adenosine deaminase (ADA) >35–45 U/L with >50% lymphocytes strongly suggests tuberculous pleuritis 2
• This combination has high diagnostic accuracy and can justify empirical anti-tuberculous therapy in the appropriate clinical setting 2

Cytology:

• Cytology with cytospin preparation has 49–91% sensitivity for malignancy overall but only 31–55% sensitivity for lymphoma 2, 1
• Mesothelioma has particularly poor cytology sensitivity (≤30%) 1
• If initial cytology is negative but malignancy is suspected, do not rely on a single sample—only 60% of malignant effusions are diagnosed by initial cytology 1

Imaging Studies

Contrast-enhanced CT chest (with fluid present):

• Better visualizes pleural abnormalities and identifies optimal biopsy sites 1, 5
• Findings favoring tuberculosis: circumferential pleural thickening >1 cm, mediastinal surface involvement, nodularity, but no chest-wall invasion 2
• Findings suggesting malignancy: circumferential pleural thickening with mediastinal involvement, chest-wall invasion, diaphragmatic or parietal pleural nodularity 2

Thoracic ultrasound:

• Tuberculous effusions show highly complex internal septations, differing from typical malignant effusions 2

Algorithmic Approach to Tissue Diagnosis

Given the low sensitivity of cytology for lymphoma and mesothelioma, pleural biopsy is essential when malignancy remains suspected after negative cytology 1:

1. Medical thoracoscopy is considered superior to cytology alone, particularly for lymphoma (chromosome analysis sensitivity ~85%) 1

   • Thoracoscopy is the gold standard for diagnosis in pleural disease and recommended as the final diagnostic step for unexplained exudative effusion 4
   • Sensitivity for tuberculosis with pleural biopsy: 69–97% 2

2. Ultrasound-guided closed pleural biopsy is an alternative with comparable diagnostic yield (90% vs 94.7% for thoracoscopy), shorter procedure duration, shorter hospital stay, and fewer complications 6

3. CT-guided biopsy when thoracoscopy is not available or patient is unfit 5

Critical Pitfalls to Avoid

• Do not assume tuberculosis based solely on lymphocyte predominance—up to 10% of tuberculous effusions are neutrophil-predominant 1
• Do not overlook lymphoma—non-Hodgkin's lymphoma commonly causes direct pleural infiltration with lymphocytic effusions; flow cytometry for clonality improves diagnosis 1
• Do not delay drainage if pH <7.2, even with lymphocytic predominance, as this indicates complicated effusion requiring immediate drainage 1
• Do not miss mesothelioma—obtain thorough occupational history including asbestos exposure 2
• Malignancy can coexist with pleural infection in ~5% of patients—follow-up imaging for up to 2 years is advised when clinical concern persists 2

Additional Diagnostic Considerations

When tuberculosis and malignancy remain undiagnosed:

• Re-evaluate for pulmonary embolism, which can cause lymphocyte-predominant exudative effusions 2
• Consider nonspecific pleuritis (NSP)—found in up to 40% of thoracoscopic pleural biopsies, but 8% eventually prove to be malignant (most commonly mesothelioma) 4
• Use ancillary histological techniques: homozygous deletion of CDKN2A by FISH (100% specificity for mesothelioma) and loss of BAP1 expression on immunohistochemistry 4

Clinical context matters:

• A positive tuberculin skin test accompanying an exudative, lymphocyte-predominant effusion can justify empirical anti-tuberculous therapy in the appropriate clinical setting 2
• In lymphocyte-predominant effusions with ≥80% lymphocytes, the most frequent etiologies are tuberculosis (35.1%) and malignancy (23.3%) 3, 7