Is an elevated adenosine deaminase (ADA) level in pleural fluid suggestive of tuberculous pleurisy?

Elevated Adenosine Deaminase (ADA) in Pleural Fluid is Highly Suggestive of Tuberculous Pleurisy

Pleural fluid adenosine deaminase (ADA) levels >40 U/L are highly suggestive of tuberculous pleurisy, with a sensitivity of 88-91% and specificity of 85-93%, making it a valuable diagnostic marker for tuberculosis in pleural effusions. 1, 2

Diagnostic Value of ADA in Pleural Fluid

ADA Testing in Pleural Fluid

• The American Thoracic Society/Infectious Diseases Society of America suggests measuring ADA levels in pleural fluid from patients with suspected pleural TB (conditional recommendation, low-quality evidence) 1
• ADA levels provide supportive evidence that must be interpreted within the entire clinical context 1
• Meta-analyses have demonstrated that ADA has excellent diagnostic performance for tuberculous pleural effusions:
  • Sensitivity: 88-91%
  • Specificity: 85-93% 2

Diagnostic Thresholds

• ADA levels >40-55 U/L are highly suggestive of tuberculous pleurisy 2
• ADA levels <16.8 U/L make tuberculous effusion highly unlikely (nearly 100% negative predictive value) 2
• In some studies, using a threshold of 52.4 U/L yields:
  • Sensitivity: 93.7%
  • Specificity: 88.7%
  • Positive predictive value: 85.5%
  • Negative predictive value: 95.2% 3

Improving Diagnostic Accuracy

ADA Isoenzymes

• ADA2 isoenzyme (with a cutoff of >40.6 U/L) has superior diagnostic performance compared to total ADA:
  • Sensitivity: 97.2%
  • Specificity: 94.2% 3

Combined Markers

• Combining ADA with lymphocyte/neutrophil ratio ≥0.75 significantly improves specificity:
  • Sensitivity: 88%
  • Specificity: 95%
  • Diagnostic efficiency: 92% 4

Diagnostic Flowchart for High ADA Pleural Effusions

A validated diagnostic flowchart for patients with pleural fluid ADA ≥40 U/L incorporates three key factors 5:

1. Pleural fluid LDH <825 IU/L
2. Absence of neutrophil predominance or cell degeneration
3. Pleural fluid ADA/total protein ratio ≥14

This flowchart has demonstrated:

• Diagnostic accuracy: 77.7-80.9%
• Sensitivity: 78.8-86.2%
• Specificity: 75.7-82.6% 6, 5

Important Caveats and Limitations

False Positives

• ADA levels can also be elevated in:
  • Empyema and other pleural infections
  • Rheumatoid pleurisy
  • Some malignancies (especially lymphomas)
  • Nontuberculous mycobacterial infections 1, 6

False Negatives

• ADA levels may not be elevated in:
  • Patients with HIV and tuberculosis 1, 2
  • Elderly patients (significantly lower ADA levels compared to younger patients) 7
  • Current smokers (4.8 times more likely to have low ADA levels in TB pleurisy) 7

Complementary Testing

• Smears for acid-fast bacilli are only positive in 10-20% of tuberculous effusions 1
• Pleural fluid culture is only 25-50% positive for TB 1
• Adding pleural biopsy histology and culture improves the diagnostic rate to about 90% 1
• Interferon-gamma (IFN-γ) testing has excellent performance:
  • Sensitivity: 89%
  • Specificity: 97% 1, 2

Clinical Application

In areas with high TB prevalence, an elevated ADA level strongly suggests tuberculous pleurisy. In low prevalence areas, ADA is more valuable as an exclusion test, with normal levels making TB highly unlikely. The diagnostic accuracy can be further improved by considering additional factors such as lymphocyte/neutrophil ratio, pleural fluid LDH levels, and ADA/total protein ratio.

When interpreting ADA results, clinicians should be aware of potential false positives and false negatives, particularly in elderly patients, smokers, and those with HIV infection.