What conditions can cause false positive elevations of Adenosine Deaminase (ADA) levels?

False Positive Elevations of Adenosine Deaminase (ADA)

ADA levels can be falsely elevated in empyema, malignant lymphoma, rheumatoid pleurisy, and certain malignancies, with empyema and lymphoma capable of producing extremely high values that exceed typical tuberculous thresholds. 1, 2

Primary Causes of False Positive ADA Elevation

Empyema (Bacterial Pleural Infection)

• Empyema is the most critical diagnostic pitfall, as it can elevate ADA above typical tuberculous thresholds (>40-47 U/L) 1
• Parapneumonic effusions account for more than 40% of cases with elevated ADA, and empyematous effusions represent half of cases exceeding the tuberculosis cutoff 3
• Extremely high ADA activity (>250 U/L) should specifically raise suspicion of empyema or lymphoma 3
• Neutrophil-rich tuberculous effusions (111.6 U/L) actually have higher ADA levels than lymphocyte-rich tuberculous effusions (62.4 U/L), making differentiation from bacterial empyema more challenging 3

Malignant Lymphoma

• Lymphoma, particularly diffuse large B cell lymphoma (DLBCL), can produce markedly elevated ADA levels 4
• Three out of four patients with elevated ADA without tuberculosis in one series had lymphoma 5
• ADA elevation >250 U/L should raise suspicion of malignancy, especially when associated with markedly elevated LDH levels 4
• Lymphomatous effusions represent approximately half of all cases exceeding the tuberculosis cutoff 3

Other Malignancies

• Malignant pleural effusions can elevate ADA, though typically to lower levels (median 54.1 U/L) than tuberculosis 6
• Neoplastic effusions accounted for 12 cases with ADA >47 U/L in one series, with 8 of these having a 2'-deoxyadenosine deaminase/ADA ratio <0.49 7
• The British Thoracic Society explicitly warns that ADA levels are raised in malignancy 1

Rheumatoid Pleurisy

• Autoimmune diseases, particularly rheumatoid pleurisy, can produce elevated ADA (median 48.5 U/L) 6
• The British Thoracic Society specifically identifies rheumatoid pleurisy as a cause of elevated ADA 1, 2

Distinguishing True from False Positives

Key Discriminatory Features for Empyema

• Perform bench centrifugation: empyema leaves a clear supernatant as cell debris separates, while tuberculous effusions remain milky 1
• Check pleural fluid glucose: purulent effusions with positive cultures have significantly lower glucose (47.3 ± 25.3 mg/dL) versus non-infectious effusions (102.5 ± 35.6 mg/dL) 1
• Assess neutrophil predominance: bacterial effusions have the highest neutrophil proportions (69 ± 23%), while tuberculous effusions show lymphocyte predominance 1
• Neutrophil predominance or cell degeneration, WBC ≥9200/µL, or CRP ≥12 mg/dL help diagnose pleural infection 6

Key Discriminatory Features for Malignancy

• Pleural fluid amylase ≥75 U/L and ADA/total protein ratio <14 help diagnose malignant pleural effusion 6
• High serum LDH helps diagnose malignant lymphoma 6
• Pleural fluid LDH <825 IU/L is beneficial for diagnosing tuberculosis over other causes 6

ADA Isoenzyme Analysis

• The 2'-deoxyadenosine deaminase/ADA activity ratio <0.49 differentiates tuberculous effusions from empyemas and parapneumonic effusions, but fails to discriminate well between tuberculous and neoplastic effusions 7
• ADA-2 >40 U/L combined with total ADA >47 U/L and 2'-deoxyadenosine deaminase/ADA ratio <0.49 achieved 100% sensitivity and 97% specificity for tuberculosis 7

Critical Clinical Pitfalls

• Never make a presumptive tuberculosis diagnosis based solely on elevated ADA without microbiologic or histologic confirmation 4
• The American College of Chest Physicians emphasizes that ADA cannot definitively distinguish between tuberculous and bacterial empyema 1
• In low tuberculosis prevalence areas (e.g., 1% prevalence), the positive predictive value of ADA may be as low as 7%, despite a negative predictive value of 99.9% 3
• ADA provides supportive evidence only and must be interpreted in the entire clinical context, not as a definitive diagnosis 8, 9