Diagnostic Performance of Different Pleural Fluid Biomarkers in Tuberculous Pleurisy

Abstract

Due to the paucibacillary nature of tuberculous pleural effusion the diagnosis of pleural tuberculosis is challenging. This prospective study was undertaken to evaluate the diagnostic performance of ten different pleural fluid biomarkers in the differentiation between tuberculous and non-tuberculous pleural effusions. Two hundred and three patients with pleural effusion (117 men and 86 women, median age 65 years) were enrolled. Routine diagnostic work-up, including thoracentesis and pleural fluid analysis, was performed to determine the cause of pleural effusion. The following biomarkers were measured in pleural fluid: adenosine deaminase (ADA), interferon gamma (IFN-γ), interleukin 2 soluble receptor (IL-2sRα), sub-unit p40 of interleukin 12b (IL-12p40), interleukin 18 (IL-18), interleukin 23 (IL-23), IFN-γ induced protein 10 kDa (IP-10), Fas-ligand, human macrophage-derived chemokine (MDC) and tumor necrosis factor alfa (TNF-α). There were 44 (21.7%) patients with tuberculous pleural effusion, 88 (43.3%) patients with malignant pleural effusion, 35 (17.2%) with parapneumonic effusion/pleural empyema, 30 (14.8%) with pleural transudates, and 6 (3%) with miscellaneous underlying diseases. Pleural fluid IFN-γ was found the most accurate marker differentiating tuberculous from non-tuberculous pleural effusion, with sensitivity, specificity, PPV, NPV, and AUC 97%, 98%, 95.5%, 99.4%, and 0.99, respectively. Two other biomarkers (IP-10 and Fas ligand) also showed very high diagnostic accuracy with AUC≥0.95. AUC for ADA was 0.92. We conclude that IFN-γ, IP-10, and Fas-ligand in pleural fluid are highly accurate biomarkers differentiating tuberculous from non-tuberculous pleural effusion.

Development and Evaluation of the New Predictive Models in Tuberculous Pleuritis

“…IP-10, an interferon gamma induced 10 kDa protein, also known as CXCL-10, is a small particle chemokine that is produced and secreted by different cells (e.g., monocytes or neutrophils) in response to interferon or lipopolysaccharide stimulation (Guo et al 2014;Liu et al 2011). Our data on the diagnostic performance of IP-10, as compared with several other biomarkers of TPE, have been recently reported (Klimiuk et al 2015). Although some individual pleural fluid biomarkers demonstrate high diagnostic accuracy in the differentiation between TPE and non-TPE, there is still a room for predictive models that use not only pleural fluid biomarkers but also relatively simple and easily available clinical parameters.…”

“…Our previous studies have shown very high diagnostic accuracy of pleural fluid IFN-γ in diagnosing TPE. The sensitivity and specificity of pleural fluid IFN-γ ranged between 97-100 % and 98-99 % in those studies (Krenke et al 2008;Klimiuk et al 2015). We decided not to use this biomarker in our predictive models of TPE in the present study because we could easily predict that the combination of pleural fluid IFN-γ and other pleural fluid biomarkers would not significantly increase the very high diagnostic performance of IFN-γ itself.…”

“…Finally, statistical analysis was performed with predictive models development and testing. The current study is complimentary to a previously published paper on the diagnostic performance of an array of pleural fluid biomarkers in distinguishing between TPE and non-TPE (Klimiuk et al 2015). Both studies were conducted in the same population of patients with pleural effusion.…”

Advances in the diagnosis of tuberculous pleuritis

“…It increases the mycobactericidal activity of macrophages. Free, unstimulated interferon-Ƴ levels in pleural fluid, measured by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay, are valuable in the identification of TB effusions with sensitivity and specificity similar to or, in some studies, slightly better than ADA (35,36). In a meta-analysis of 22 studies, totaling 2,101 patients with pleural effusions (of whom 782 had TB), interferon-Ƴ measurements yielded 89% sensitivity, 97% specificity and area under the SROC curve of 0.99 for the diagnosis of TB (37).…”

Mycobacterium tuberculosisModulates the Metabolism of Alternatively Activated Macrophages to Promote Foam Cell Formation and Intracellular Survival

“…Importantly, we provide ex vivo evidence for the refractoriness of M(IL-4/IL-13) macrophages to become foamy by finding a negative correlation between the expression of CD209, a M(IL-4)-associated marker, and the numbers of LB-containing CD14 + cells isolated directly from the pleural cavity of TB patients, providing physiological relevance to our in vitro findings. Since tuberculous pleural effusions have, if any, very few bacilli content (35), we consider that the impact of potential in situ infection on the macrophage metabolic state, which may then lead M(IL-4) cells to become FM, might be very low. Additionally, while CD206 is also known to be induced by IL-4 and IL-13 (36), we did not find such an association between this marker and the numbers of FM.…”