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

Abstract

This editorial underscores the importance of Maranhão et al’s study, which investigates pleural adenosine deaminase (P-ADA) as a biomarker for inflammatory pleural effusions. Despite advances in imaging, distinguishing between inflammatory and non-inflammatory causes of pleural effusion remains a diagnostic challenge. The authors conducted a rigorous retrospective cohort analysis of 157 patients (124 with inflammatory exudates and 33 with non-inflammatory transudates), establishing a robust cutoff value of P-ADA ≥ 9.00 U/L for diagnosing inflammatory diseases using receiver operating characteristic curve analysis and internal statistical calibration. This is the first study to define a standardized P-ADA threshold in a Brazilian cohort, addressing previous inconsistencies in cutoff values. Furthermore, the authors delved into the pathophysiological mechanisms underlying elevated P-ADA, linking it to purinergic signaling pathways and immune cell activation, particularly emphasizing the role of ADA2 isoforms in macrophages and lymphocytes. Their findings support P-ADA as a non-invasive, cost-effective biomarker for early diagnosis, treatment stratification, and minimizing the need for invasive procedures such as thoracentesis. This has particular relevance in resource-limited settings, where streamlined diagnostics can reduce healthcare costs and improve patient outcomes. Future studies must prioritize global validation, explore the integration of adenosine deaminase with additional biomarkers (e.g., interleukin 6, C-reactive protein), and support the development of point-of-care technologies.

Key Words: Pleural effusion; Pleural adenosine deaminase; Inflammatory; Pathophysiological; Diagnosis

Core Tip: Maranhão et al introduce a standardized pleural adenosine deaminase (P-ADA) cutoff (≥ 9.00 U/L) for diagnosing inflammatory pleural effusions, validated via rigorous statistical analysis in a Brazilian cohort. This addresses inconsistencies in international reference values and links P-ADA to purinergic signaling and ADA2 isoform activation in macrophages and lymphocytes. The study emphasizes P-ADA’s clinical utility as a non-invasive, cost-effective biomarker to reduce the need for invasive procedures (e.g., thoracentesis) and improve diagnostic accuracy in resource-limited settings. Its integration into clinical workflows could streamline management, reduce healthcare costs, and enable early treatment stratification, pending multicenter validation for broader global application.

INTRODUCTION

Pleural effusion, a prevalent clinical presentation of various inflammatory and non-inflammatory conditions, poses considerable diagnostic challenges in clinical practice. Although imaging techniques such as chest radiography and ultrasonography can identify effusions, determining their etiology—such as tuberculosis, malignancy, or congestive heart failure—requires invasive procedures such as thoracentesis. This has spurred growing interest in non-invasive, cost-effective biomarkers, particularly for differentiating between exudates (inflammatory) and transudates (non-inflammatory).

Adenosine deaminase (ADA), an enzyme involved in purine metabolism and immune regulation, has emerged as a promising biomarker for pleural effusions. Previous studies have linked elevated P-ADA levels to tuberculous pleurisy and other inflammatory conditions[1,2]. However, conflicting cutoff values and limited validation in diverse settings have hindered its widespread adoption.

The study by Maranhão et al[3] addresses these gaps through a rigorous retrospective cohort analysis of 157 patients (Table 1). Using the receiver operating characteristic curve analysis and the Youden index, the authors established an optimal P-ADA cutoff of ≥ 9.00 U/L, further validated via bootstrapping and internal calibration. Multivariable logistic regression confirmed the independent predictive value of P-ADA after adjusting for potential confounders. Table 2 clarifies the methodology, and supplementary materials include extended statistical data. The proposed cutoff demonstrated strong diagnostic performance (AUC = 0.8107), with high sensitivity (77.69%) and specificity (68.75%). Notably, this is the first Brazilian and global study to derive a standardized P-ADA reference value using strict statistical criteria, underscoring its novelty and potential for clinical implementation.

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.

CURRENT DIAGNOSTIC CHALLENGES

Current guidelines rely on Light’s criteria—based on protein and lactate dehydrogenase (LDH) levels—to differentiate exudates from transudates[4]. However, these markers exhibit limited specificity for identifying the underlying cause of the severity of inflammation, such as differentiating tuberculosis from malignancy. As a result, invasive procedures such as thoracentesis remain necessary, contributing to diagnostic delays and increased healthcare costs, particularly in resource-limited settings. Furthermore, commonly used biomarkers such as interleukin-6, C-reactive protein, and LDH show considerable overlap across conditions and lack sufficient diagnostic precision when used individually, underscoring the need for multi-marker panels to improve diagnostic accuracy.

Overreliance on imaging and invasive procedures not only increases healthcare costs but also delays definitive treatment. In low-resource settings, such challenges are further exacerbated, making accessible and affordable biomarkers critical for facilitating early diagnosis and guiding timely management.

ROLE OF ADA IN PLEURAL INFLAMMATION

ADA plays a critical role in regulating purinergic signaling—a cell communication system using molecules such as ATP and adenosine—and modulating immune responses, highlighting its value as a biomarker. By influencing these pathways, ADA helps shape inflammatory and immune reactions, making it a meaningful indicator of disease states. Inflammatory mediators (e.g., cytokines) upregulate ADA activity, with ADA2 isoforms predominantly expressed in macrophages and lymphocytes. Elevated P-ADA levels reflect increased leukocyte infiltration and tissue damage, hallmarks of inflammatory diseases such as tuberculosis and parapneumonic effusions.

The study by Maranhão et al[3] reinforces the clinical utility of P-ADA by demonstrating its superiority over traditional markers. The proposed cutoff value of 9.00 U/L effectively distinguishes between inflammatory and non-inflammatory effusions, with minimal overlap observed in common etiologies such as adenocarcinoma and lymphoma.

CLINICAL IMPLICATIONS OF THE STUDY

Implementing a standardized P-ADA cutoff significantly enhances the diagnostic accuracy for pleural effusion compared to conventional approaches (Table 3).

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.

Early diagnosis

Rapid identification of pleural effusion etiology using P-ADA reduces reliance on repeated thoracentesis, a critical advantage in resource-limited settings where access to advanced diagnostic tools is limited. This approach minimizes patient exposure to invasive procedures, thereby lowering discomfort and the risk of complications such as infection and pneumothorax.

Treatment stratification

Patients with P-ADA levels ≥ 9.00 U/L are more likely to benefit from anti-inflammatory therapies (e.g., corticosteroids) or prompt referral to tuberculosis-specialized centers. This facilitates personalized treatment strategies, improving outcomes by aligning clinical interventions with specific underlying causes (e.g., tuberculous vs. malignant).

Cost reduction

As a non-invasive biomarker, P-ADA testing reduces the need for procedural costs associated with imaging, biopsies, or prolonged hospital stays. Early diagnosis and targeted treatment may lower long-term healthcare expenditure by preventing disease progression.

LIMITATIONS AND FUTURE DIRECTIONS

The integration of P-ADA into multimodal biomarker panels, alongside markers such as interleukin-6 and C-reactive protein, can significantly enhance diagnostic accuracy for pleural effusions. Understanding the role of ADA in pleural inflammation will advance our knowledge of disease pathogenesis. With ongoing advancements in point-of-care technologies, rapid and cost-effective P-ADA assays hold promise for widespread implementation in primary care and low-resource settings. Initiatives to harmonize P-ADA cutoff values across regions are essential to ensure consistency in global clinical practice. Furthermore, investigating the mechanisms underlying the elevation of P-ADA in inflammatory conditions raises several crucial questions (Table 4), which could potentially pave the way for the discovery of novel therapeutic targets.

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.

The study acknowledges several limitations, including its reliance on retrospective data, potential selection bias in case recruitment, and the absence of longitudinal follow-up. The lack of comparison with P-ADA cutoff values from other studies and populations represents a significant gap. To enhance the robustness and generalizability of their findings, the authors could consider several avenues for future research. Collaborating with international cohorts would enable validation of the proposed P-ADA cutoff across diverse geographic and demographic groups, including Asian and European populations. Such cross-regional and cross-racial comparisons would be invaluable in establishing a more universally applicable diagnostic threshold. Additionally, investigating the underlying factors that might influence P-ADA expression, such as genetic, environmental, and epidemiological variables, could provide valuable insights into the variability of P-ADA levels across different populations. By addressing these limitations, the authors would not only strengthen their current work but also further solidify the role of P-ADA as a reliable biomarker in pleural inflammatory diseases.

CONCLUSION

The study by Maranhão et al[3] represents a paradigm shift in the diagnostics of pleural effusion. By establishing a validated, statistically sound P-ADA cutoff, the authors offer a practical tool to streamline clinical workflows and improve patient outcomes. As we continue to unravel the complexities of pleural inflammation, P-ADA stands as a beacon of progress—a biomarker that bridges bench-to-bedside innovation and underscores the power of precision medicine in respiratory care.