What is the cause of raised pleural fluid adenosine deaminase (ADA) levels?

Causes of Elevated Pleural Fluid Adenosine Deaminase (ADA)

Elevated pleural fluid ADA is most commonly associated with tuberculous pleural effusion, but can also be found in empyema, parapneumonic effusions, rheumatoid pleurisy, and certain malignancies, particularly lymphoma. 1, 2

Primary Causes of Elevated Pleural Fluid ADA

Tuberculous Pleural Effusion

• Pleural fluid ADA has high sensitivity (91%) and specificity (88%) for diagnosing tuberculous pleurisy, especially in high TB prevalence regions 2
• ADA levels in tuberculous effusions are typically significantly higher (median 83.1 U/L) than in most other conditions 3
• The diagnostic threshold for TB is typically >40-47 U/L in lymphocytic exudates 4
• ADA elevation in TB is primarily due to an increase in ADA-2 isoenzyme, originating from monocytes and macrophages 5

Non-Tuberculous Causes

• Empyema and Parapneumonic Effusions:

  • ADA can be markedly elevated in empyema, sometimes reaching levels similar to those seen in TB 1, 3
  • Neutrophil predominance, WBC count ≥9200/μL, or CRP levels ≥12 mg/dL help distinguish these from TB 3

• Rheumatoid Pleurisy:

  • Can present with elevated ADA levels 1, 2
  • Usually accompanied by low glucose levels (<1.6 mmol/L) in pleural fluid 1

• Malignancies:

  • Certain malignancies, particularly lymphomas, can present with high ADA levels 3, 5
  • Malignant pleural effusions typically have lower ADA levels (median 54.1 U/L) than TB 3
  • Pleural fluid amylase ≥75 U/L and ADA/total protein ratio <14 help identify malignant causes 3

• Autoimmune Diseases:

  • Can occasionally cause elevated ADA (median 48.5 U/L), though typically lower than in TB 3
  • High eosinophil count in both serum and pleural fluid may suggest autoimmune etiology 3

Diagnostic Considerations

Differential Diagnosis Algorithm

• When encountering elevated pleural fluid ADA:
  1. Consider TB first, especially with ADA >40 U/L and lymphocytic predominance 4
  2. Rule out empyema if neutrophil predominance, cell degeneration, or high inflammatory markers are present 3
  3. Consider malignancy if pleural fluid ADA/total protein ratio <14 3
  4. Evaluate for rheumatoid arthritis if pleural glucose is low (<1.6 mmol/L) 1

Important Caveats

• ADA may not be elevated in HIV patients with TB, creating potential false negatives 1, 2
• The utility of ADA for TB diagnosis is reduced in low TB prevalence regions due to lower positive predictive value 2, 4
• Pleural fluid LDH <825 IU/L with elevated ADA is more suggestive of TB than other causes 3

Clinical Application

• In high TB prevalence regions, ADA >47 U/L has reported sensitivity of 100% and specificity of 91% for TB diagnosis 5
• In young patients (≤35 years) from high TB prevalence areas, ADA >47 U/L is highly predictive of TB 6
• Combining ADA with other markers (ADA-2 >40 U/L and 2'-deoxyadenosine deaminase/ADA ratio <0.49) can improve diagnostic accuracy to 98% 5
• Interferon-gamma measurement in pleural fluid can complement ADA testing with even higher sensitivity (89%) and specificity (97%) for TB diagnosis 1, 2