What is lymphocytic pleural fluid and what are its differential diagnoses?

Lymphocytic Pleural Fluid: Definition and Differential Diagnosis

Definition

Lymphocytic pleural fluid is defined as a pleural effusion with greater than 50% lymphocytes on differential cell count, though some authorities use a threshold of ≥15% lymphocytes to indicate lymphocytosis. 1

• Normal pleural fluid contains predominantly mesothelial cells, macrophages, and lymphocytes in small numbers 1
• A lymphocyte differential count ≥25% suggests granulomatous lung disease, while ≥50% is particularly suggestive of specific etiologies 1
• Lymphocyte counts ≥80% narrow the differential diagnosis significantly 2, 3

Differential Diagnosis

Most Common Causes

Tuberculosis and malignancy are the two most important diagnoses to consider in lymphocytic pleural effusions, as they account for the majority of cases and have significant implications for morbidity and mortality. 4, 2

Tuberculous Pleuritis

• Tuberculosis accounts for approximately 6% of all pleural effusions and should always be considered in undiagnosed cases 4
• Lymphocytes predominate overwhelmingly (>80%) in 29 of 31 (94%) verified tuberculous effusions 2
• The median lymphocyte percentage in tuberculous effusions is 88% 3
• High pleural fluid C-reactive protein levels (≥50 mg/L) have 95% specificity for tuberculosis in lymphocytic effusions, while low levels (<30 mg/L) have 95% sensitivity for excluding the disease 5
• Pleural fluid eosinophilia (>10%) was not present in any patient with proven tuberculosis, making this finding useful for excluding TB 2
• Pleural fluid smears for acid-fast bacilli are only positive in 10-20% of cases, with culture positive in only 25-50%; adding pleural biopsy histology and culture improves diagnostic sensitivity to approximately 90% 4

Malignant Pleural Effusions

• Malignancy causes lymphocytic predominance (>80%) in 18 of 24 (75%) malignant effusions 2
• The median lymphocyte percentage in malignant effusions is approximately 50% 3
• Pleural fluid typically shows a predominance of either lymphocytes or other mononuclear cells 1
• Lymphoma-associated malignant pleural effusions can mimic tuberculous effusions with lymphocytic exudate and high adenosine deaminase (ADA) levels, making differentiation challenging 6
• Absence of fever and serum LDH >460 U/L (sensitivity 76%, specificity 81%) help distinguish lymphoma from tuberculosis 6
• Pleural fluid eosinophilia (>10%) occurred in only 1 of 24 malignant effusions (malignant mesothelioma) 2

Other Important Causes

Systemic Lupus Erythematosus

• SLE causes pleural disease in up to 50% of patients during their illness course 4
• The presence of LE cells in pleural fluid is diagnostic 4

Rheumatoid Arthritis

• Affects the pleura in approximately 5% of patients, more common in men 4
• Pleural fluid glucose below 60 mg/dL strongly suggests rheumatoid etiology 4
• Lymphocytic predominance can occur but is significantly less than in tuberculous effusions (p<0.005) 2

Cardiac Failure

• Lymphocytic predominance occurs in 44.4% of heart failure effusions 3
• These are typically transudates, though 25-30% may be misclassified as exudates 4

Uncomplicated Parapneumonic Effusions

• Lymphocytic predominance occurs in 29.2% of uncomplicated parapneumonic effusions 3
• These effusions have significantly lower lymphocyte percentages than tuberculous effusions (p<0.001) 2

Less Common Causes

Hypersensitivity Pneumonitis (when pleural involvement occurs)

• Nonfibrotic HP shows median BAL lymphocyte count of 46% (range 20-80%) 1
• Fibrotic HP shows lower median BAL lymphocyte count of 19% (range 11-41%) 1
• BAL lymphocyte percentage >50% is particularly suggestive of HP or cellular NSIP 1

Chylothorax

• Appears milky and remains so after centrifugation, unlike empyema which clears 4
• Can present with lymphocytic predominance 4

Uremic Pleuritis

• Occurs in approximately 24.7% of patients with end-stage renal failure 4
• Typically presents as a transudate with low pH 4

Diagnostic Approach Algorithm

When confronted with a lymphocytic pleural effusion, follow this systematic approach:

1. Determine if exudate or transudate - If transudate, consider cardiac failure, cirrhosis, or uremic pleuritis 4

2. If exudate with lymphocyte count >50%:

   • Measure pleural fluid C-reactive protein: ≥50 mg/L strongly suggests tuberculosis (95% specificity) 5
   • Check for pleural fluid eosinophilia: >10% eosinophils essentially excludes tuberculosis 2
   • Measure serum LDH: >460 U/L suggests lymphoma over tuberculosis 6
   • Assess for fever: absence favors lymphoma over tuberculosis 6

3. If lymphocyte count ≥80%:

   • Tuberculosis (35.1% of cases) and malignancy (23.3% of cases) are most likely 3
   • Pursue acid-fast bacilli smears, mycobacterial culture, and consider pleural biopsy for tuberculosis 4
   • Send cytology (repeat if initial negative) and consider pleural biopsy for malignancy 4

4. If diagnosis remains unclear after initial workup:

   • Reconsider pulmonary embolism and tuberculosis as they are amenable to specific treatment 4
   • Consider empirical antituberculous therapy if tuberculin skin test positive with exudative lymphocytic effusion 4
   • Approximately 15% of pleural effusions remain undiagnosed despite repeated cytology and pleural biopsy, with many ultimately proving malignant 4

Critical Pitfalls to Avoid

• Do not exclude tuberculosis based solely on the presence of mesothelial cells (>5%) - 12% of tuberculous effusions have this finding 3
• Do not exclude parapneumonic effusion based on lymphocytic predominance - 29.2% of uncomplicated parapneumonic effusions are lymphocyte-predominant 3
• Do not exclude malignancy based on lymphocyte count ≥80% - 23.3% of malignant effusions have this finding 3
• Do not rely on ADA levels alone to distinguish tuberculosis from lymphoma - lymphoma can also present with high ADA levels 6
• Neutrophil-predominant pleural tuberculosis exists (9.5% of cases) and should not be excluded based on cell differential alone 7