Sequential Pleural Fluid and Serum Biomarker Measurements in Patients Undergoing Medical Thoracoscopy for Persistently Undiagnosed Pleural Effusion: A Pilot Study from a TB-Endemic Tertiary Centre

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Pleural effusion remains diagnostically challenging when standard thoracentesis does not establish an aetiology. This pilot analysis described sequential biomarker measurements in patients proceeding to medical thoracoscopy and explored their associations and discrimination across final diagnostic classifications. Prospectively collected data from a single-centre tertiary referral cohort were analysed. Pleural-fluid adenosine deaminase (ADA) and serum complement components 3 and 4 (C3 and C4) were obtained on day 1, whereas pleural-fluid cancer antigen 125 (CA125) and lactate dehydrogenase (LDH) were obtained at the day 7/thoracoscopy evaluation. Final classifications were based on a composite reference standard integrating thoracoscopy, histopathology, microbiology, cytology, imaging, and clinical follow-up. Analyses were exploratory. Amongst 75 patients, 6 (8.0%) were classified as tuberculous pleural effusion (TB-PE), 33 (44.0%) as malignant pleural effusion (MPE) and 36 (48.0%) as other non-tuberculous, non-malignant pleural effusions. ADA differed across groups (Kruskal–Wallis P = 0.002; Benjamini–Hochberg q = 0.010) and showed exploratory discrimination for TB-PE (area under the curve [AUC] 0.934; bootstrap 95% confidence interval [CI] 0.855–0.995). At the conventional ≥ 40 U/L threshold, sensitivity was 83.3%, specificity 93.4%, positive predictive value (PPV) 55.6%, negative predictive value (NPV) 98.3%, positive likelihood ratio (LR+) 12.7, and negative likelihood ratio (LR−) 0.18. CA125, LDH, C3 and C4 did not show significant omnibus group differences after reanalysis. In a post hoc sensitivity analysis excluding 26 patients retained as non-specific pleuritis (n = 49), ADA remained significantly different across groups (P = 0.004; q = 0.022). In this selected thoracoscopy cohort, day 1 pleural-fluid ADA showed the clearest exploratory signal, including after exclusion of non-specific pleuritis, but estimates were based on only six TB-PE cases and do not establish stand-alone utility or a role in avoiding thoracoscopy. The remaining biomarkers showed no robust aetiology-specific signal. ClinicalTrials.gov NCT06159179. Pleural effusion is a build-up of fluid around the lungs. Doctors usually begin by removing some of the fluid with a needle, called thoracentesis, and testing it to look for the cause. If the cause remains uncertain, medical thoracoscopy may be used to inspect the pleural surfaces inside the chest and obtain tissue samples. Biomarkers are substances measured in blood or body fluid that may provide information about disease. This study included 75 adults whose pleural effusions remained unresolved after sequential evaluation and who underwent thoracoscopy. The final classification was tuberculosis in 6 patients, cancer in 33 and another non-tuberculous, non-malignant finding, including non-specific pleuritis, in 36. Pleural-fluid adenosine deaminase (ADA) and serum complement components 3 and 4 (C3 and C4) were measured earlier in the pathway, whereas pleural-fluid cancer antigen 125 (CA125) and lactate dehydrogenase (LDH) were measured later at the day 7/thoracoscopy evaluation; therefore, they were not assessed as one simultaneous combined test. Pleural-fluid ADA was higher in the six patients ultimately classified as having tuberculous pleural effusion, although five of these six already had ADA ≥ 40 U/L on day 1. CA125 was numerically highest in the tuberculosis group rather than the cancer group, and CA125 and LDH did not reliably separate malignant from non-malignant effusions in this cohort. The study was small and did not determine whether biomarker testing could safely replace, avoid or delay thoracoscopy. Larger studies are needed before these findings can guide clinical decisions.