Integrated semi-targeted metabolomics analysis reveals distinct metabolic dysregulation in pleural effusion caused by tuberculosis and malignancy

Tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) are the 2 most frequent causes of exudative pleural effusions (PEs). However, the clinical differentiation is challenging.Metabolic signatures in pleural effusion from 156 patients were profiled. An integrated semi-targeted metabolomics platform was incorporated for high throughput metabolite identification and quantitation. In this platform, orbitrap based mass spectrometry with data dependent MS/MS acquisition was applied in the analysis. In-house database containing ~1000MS/MS spectra were established and "MetaInt" was developed for metabolite alignment.Using this strategy, lower levels of amino acids, citric acid cycle intermediates and free fatty acids accompanied with elevated acyl-carnitines and bile acids were observed, demonstrating increased energy expenditure caused by TPE. Kynurenine pathway from tryptophan was significantly enhanced in TPE. The ratio of tryptophan/kynurenine exhibited decent performance in differentiating TPE from MPE with sensitivity of 92.7% and specificity of 86.1%. After two further independent validations, it turns out that the ratio of tryptophan/kynurenine can be applied confidently as a potential biomarker together with adenosine deaminase (ADA) for clinical diagnosis of TPE.Conclusively, the integrated in-house platform for high throughput semi-targeted metabolomics analysis reliably identified great potential of tryptophan/kynurenine ratio as a novel diagnostic biomarker to distinguish pleural effusion caused by tuberculosis and malignancy.