Elsevier

Tuberculosis

Volume 92, Issue 3, May 2012, Pages 248-252
Tuberculosis

Diagnostics
CXCL12 as a biological marker for the diagnosis of tuberculous pleurisy

https://doi.org/10.1016/j.tube.2012.01.001Get rights and content

Summary

Although a chemokine CXCL12 is implicated in some infectious diseases, especially those in which T cell-mediated immunity plays critical roles, the relevance of CXCL12 to tuberculosis has never been elucidated. To determine the clinical efficacy of CXCL12 as a diagnostic marker for tuberculous (TB) pleurisy, we measured CXCL12 concentration in pleural fluid and serum from patients with various etiologies.

Of 60 patients with pleural fluid, the median age of TB patients was 52 which was significantly lower than 71 of non-TB patients (P < 0.01). CXCL12 level in TB effusion (4456 ± 1013 pg/mL, n = 15) was significantly higher than non-TB effusion (2851 ± 1229 pg/mL, n = 45) (P < 0.01). On the other hand, serum CXCL12 level showed no significant differences among TB pleurisy, non-TB pleurisy, and normal healthy subjects. The sensitivity and specificity of CXCL12 in pleural fluid for the diagnosis of TB pleurisy was 60.0% and 93.2% (cut-off value = 4600 pg/mL), respectively. Area under the receiver operating characteristic (ROC) curve (AUC) for CXCL12 was 0.84. As the source of CXCL12, pleural mesothelium, endothelium of pulmonary vessels, bronchial epithelium, multinucleated giant epithelioid cells, and macrophages were positive for CXCL12 staining.

Increased CXCL12 level in pleural fluid could be an informative diagnostic marker for differentiating TB pleurisy from other etiologies.

Introduction

Tuberculosis is histologically characterized by caseating granulomas that consist of predominant aggregation of macrophages and T lymphocytes.1 Macrophages further develop into multinucleated giant epithelioid cells. Lymphocytes, especially T helper 1 (Th1) cells, have to be recruited and accumulated to the inflammation foci from the systemic bloodstream as the first process to develop anti-tuberculosis immunity, however, the mechanism is not well understood.2

Chemokines are small cytokine-like peptides that direct various subsets of hematopoietic cells to specific anatomical sites by ligation with their cognate G-protein coupled receptors.3, 4 CXCL12, also known as stromal cell-derived factor-1α (SDF-1α), is a CXC chemokine that exhibits a variety of biological effects through its only known receptor CXCR4.5, 6, 7 CXCL12 not only has chemotactic activity for broad range of hematopoietic cell linage such as early B cell progenitors, B/T cell subpopulations, monocytes, megakaryocytes and CD34-positive stem cells,8, 9, 10, 11 but also plays critical roles in the development of neural cells, cerebellum, cardiac septum and mesenteric vasculature.12, 13, 14, 15 Moreover, CXCL12/CXCR4 axis has been recently shown to be important in migration and metastasis of solid tumors including lung cancer16 and associated with infectious diseases such as human immunodeficiency virus (HIV) infection6, 7, 17 and viral hepatitis.18

Tuberculous (TB) pleurisy is a frequent clinical manifestation of TB infection in the thorax. Adenosine deaminase (ADA) activity in pleural fluid is a well known useful diagnostic marker for TB effusion. Interferon (IFN)-γ level in pleural fluid is also proven to increase in TB pleurisy with a potentially equal or better diagnostic sensitivity and specificity compared with ADA.19, 20, 21, 22, 23, 24 Since the Th1 lymphocyte is known to play a central role in anti-tuberculosis immune response and CXCL12 is one of the most efficacious T lymphocyte chemoattractants,7 CXCL12 produced from inflammation foci probably triggers mobilization and accumulation of T lymphocytes into the intra-pleural space. However, the clinical significance of CXCL12 in TB pleurisy has never been elucidated thus far. Therefore, we measured CXCL12 concentration in serum and pleural fluid in patients with pleural effusion and evaluated the significance as diagnostic marker for TB pleurisy. We also compared CXCL12 with IFN-γ and ADA in terms of their diagnostic power to differentiate TB pleurisy from non-TB.

Section snippets

Patients and diagnosis criteria for pleurisy

The study protocol had been approved by the institutional ethical committee at National Hospital Organization Toneyama National Hospital (Osaka, Japan). Sixty patients with pleural effusion from any cause who had given written informed consent were enrolled in this study from 2003 to 2007. Their pleural effusions and sera were collected and stored at −80 °C until measurement. Five healthy volunteers also provided their sera as controls. Patients were classified into two subgroups according to

Patient profile with pleural effusion

The study group consisted of 38 men and 22 women. TB etiology was confirmed in 10 (16.7%) as “definite” and 5 (8.3%) as “clinical”, respectively. The rest of the 45 non-TB patients were with effusion secondary to lung carcinoma (50.0%) (n = 30; 23 non-small cell and 7 small cell histology), empyema (11.7%) (n = 7) and miscellaneous (13.3%) (n = 8; 3 cardiac failure, 2 rheumatoid arthritis, 3 idiopathic). The median age was 52 (ranging 21–80) in TB patients and 71 (ranging 33–86) in non-TB

Discussion

TB pleurisy generally affects younger people in countries with higher incidence of TB infection, whereas TB patients are getting older in industrial countries. The reason is presumed that majority is caused by reactivation in the latter countries while caused by primary infection in the former countries. Japan is still in the middle of both regarding TB incidence.27, 28 In our present study, 7 patients are of 20–30’s, who are considered to be infected primarily, and possibly account for the

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    S. Kohmo and T. Kijima contributed equally to this work.

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