Combined Biomarkers and Their Serum-to-Pleural Fluid Ratios for Differentiating Multiple Types of Pleural Effusion: A Single-Centered Study

Abstract

Background: Pleural effusion is a common clinical manifestation arising from diverse etiologies, including tuberculosis, malignancy, parapneumonic infection, and connective tissue disorders. Accurate differentiation between these types is essential for timely and targeted treatment but remains challenging due to overlapping clinical, radiological, and biochemical features. Conventional diagnostic methods, including microbiological assays and cytology, have limited sensitivity, while invasive procedures, although more accurate, are not always feasible. Biomarker-based approaches have emerged as promising noninvasive tools, but most studies have evaluated them in isolation rather than as combined diagnostic strategies. Objective: This study aimed to evaluate the diagnostic performance of a combined panel of serum and pleural fluid biomarkers and their ratios in distinguishing between tuberculous, malignant, complicated parapneumonic, uncomplicated parapneumonic, and connective tissue disease–related pleural effusions. Methods: A cross-sectional study was conducted over six months at Ayub Teaching Hospital, Abbottabad, involving 163 patients with confirmed pleural effusion. Serum and pleural fluid samples were analyzed for adenosine deaminase (ADA), lactate dehydrogenase (LDH), C-reactive protein (CRP), total protein, glucose, albumin, white blood cell count, pH, and pleural fluid–to–serum ratios. Statistical analysis included the Kruskal–Wallis H-test, Mann–Whitney U test with Bonferroni correction, and receiver operating characteristic (ROC) curve analysis. Results: Tuberculous effusion was most common (79.8%), followed by malignant (12.3%), complicated parapneumonic (4.3%), uncomplicated parapneumonic (2.5%), and connective tissue disease–related (1.2%). Pleural fluid ADA was significantly higher in tuberculous effusion (median 73.9 U/L, p < 0.00001), whereas LDH and CRP were markedly elevated in malignant and complicated parapneumonic effusions (median LDH > 1300 U/L, CRP > 11.0 mg/dL). PF/serum ADA and LDH ratios further improved discriminatory accuracy, and pH < 7.20 strongly indicated complicated parapneumonic effusion. Combined biomarker analysis demonstrated superior diagnostic performance (AUC up to 0.94) compared to individual markers. Conclusion: A multi-biomarker approach integrating ADA, LDH, CRP, pH, and pleural fluid–to–serum ratios significantly improves the etiological classification of pleural effusion. This strategy enhances diagnostic accuracy, reduces the need for invasive procedures, and supports timely, targeted management.