Adenosine deaminase in pleural effusion: Bridging diagnosis and the pathophysiology of inflammation

Table 1 Global research gaps addressed by Maranhão et al[3]

Gap	Study contribution
Lack of standardized cutoffs	Derived a P-ADA cutoff (≥ 9.00 U/L) using rigorous statistical validation in a Brazilian cohort
Ethnic/regional variability	First Latin American study to address population-specific thresholds for P-ADA
Pathophysiological insights	Linked elevated P-ADA to ADA2 isoform activity in macrophages and lymphocytes during inflammation
Multi-center validation	Highlighted the need for global multicenter trials

P-ADA: Pleural adenosine deaminase.

Table 2 Methodology workflow

Step	Content	Key details
Study design	Retrospective cohort study	Data collected from March 2015 to December 2019 at two hospitals in Rio de Janeiro, Brazil. Total patients: 157 (124 exudates, 33 transudates)
Inclusion criteria	Confirmed diagnosis of pleural effusion (exudates/transudates)	Exudates: n = 124 (79%); Transudates: n = 33 (21%)
Exclusion criteria	Absolute contraindications, hemolyzed PF, chronic renal failure, jaundice, unknown etiology, immunosuppressive medication use	Final cohort: 157 patients (after exclusions)
Sample size calculation	Based on MedCalc software (AUC > 0.50, α = 0.05, β = 0.20)	Required: 57 patients (19 exudates, 38 transudates); Actual: 157 patients
P-ADA assay	Kinetic method (Diazyme ADA kit)	Linear range: 0–200 U/L; Reference value: < 15 U/L (healthy adults)
Statistical analysis	ROC curve, Youden index, DeLong test, Hosmer–Lemeshow goodness-of-fit	AUC = 0.8107 (95%CI: 0.7174–0.8754), P < 0.0001

AUC: Area under the curve; P-ADA: Pleural adenosine deaminase; ROC: Receiver operating characteristic; PF: Pleural fluids.

Table 3 Comparison of traditional markers and pleural adenosine deaminase for pleural effusion diagnosis

Marker/method	Pros	Cons
Light’s criteria	Standardized, non-invasive	Low specificity for inflammation etiology (e.g., cannot distinguish TB from cancer)
LDH	Sensitive for identifying exudates	Not specific to inflammation; influenced by tissue necrosis
Protein level	Used in Light’s criteria	Less discriminatory than P-ADA for differentiating inflammatory vs transudative effusions
P-ADA ≥ 9.00 U/L	High specificity and sensitivity for inflammation. Non-invasive and cost-effective	Requires validation across diverse populations. Lacks global consensus on cutoffs

LDH: lactate dehydrogenase; P-ADA: Pleural adenosine deaminase; TB: Tuberculosis.

Table 4 Key questions for future research

Research question	Potential impact
How does P-ADA correlate with disease severity?	Improves prognostic stratification
Can P-ADA differentiate between specific etiologies (e.g., TB vs cancer)?	Enhances more targeted and effective treatment plans
What is the role of ADA in resolving inflammation?	Identifies new therapeutic targets for inflammatory conditions
How does P-ADA interact with other biomarkers (e.g., IL-6, ADA1)?	Strengthens multimodal diagnostics
Are there genetic variations affecting P-ADA levels?	Explains population-specific differences in cutoffs

TB: Tuberculosis; P-ADA: Pleural adenosine deaminase; IL-6: Interleukin 6; ADA1: Adenosine deaminase 1.