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(Chest. 2004;125:987-989.)
© 2004 American College of Chest Physicians

Comparison of Six Biological Markers for the Diagnosis of Tuberculous Pleuritis*

Akio Hiraki, MD, PhD; Keisuke Aoe, MD, PhD; Ryosuke Eda, MD, PhD; Tadashi Maeda, MD, PhD; Tomoyuki Murakami, MD, PhD; Kazuro Sugi, MD, PhD and Hiroyasu Takeyama, MD, PhD

* From the Departments of Respiratory Medicine (Drs. Hiraki, Aoe, Eda, Maeda, and Takeyama) and Clinical Research (Drs. Murakami and Sugi), National Sanyo Hospital, Respiratory Disease Center, Yamaguchi, Japan.

Correspondence to: Keisuke Aoe, MD, PhD, Department of Respiratory Medicine and Clinical Research, National Sanyo Hospital, Respiratory Disease Center, 685 Higashi-kiwa, Ube, Yamaguchi 755-0241, Japan; e-mail: keisukeaoe{at}mtf.biglobe.ne.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Study objective: We sought a marker to differentiate tuberculous pleural effusions from nontuberculous pleural effusions, which otherwise can be difficult.

Patients: We studied 55 patients with pleural effusions, 20 (36%) with tuberculous pleuritis and 35 (64%) with a nontuberculous etiology.

Measurement and results: Pleural fluid levels of adenosine deaminase, interferon (INF)-{gamma}, interleukin (IL)-12p40, IL-18, immunosuppressive acidic protein, and soluble IL-2 receptors were measured and were subjected to receiver operating characteristic analysis. INF-{gamma} had the greatest sensitivity and specificity for tuberculous pleuritis among the six biological markers studied.

Conclusion: The determination of INF-{gamma} levels in pleural fluid is the most informative in the diagnosis of tuberculous effusion.

Key Words: cytokine • diagnosis • pleural fluid • tuberculous pleuritis


   Introduction
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 Abstract
 Introduction
Materials and Methods
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Worldwide, tuberculosis (TB) is the single most frequent cause of death by an infectious agent and also is a major cause of pleural effusion.1 The diagnosis of tuberculous pleuritis should be considered in any patient with an exudative pleural effusion. However, it is sometimes difficult to establish the diagnosis using only conventional methods. A reliable clinical marker permitting the rapid and accurate diagnosis of tuberculous pleuritis is greatly needed.

A variety of biological markers have been proposed to facilitate the diagnosis of tuberculous pleuritis, including increased pleural fluid concentrations of adenosine deaminase (ADA), interferon (INF)-{gamma}, interleukin (IL)-12p40, IL-18, immunosuppressive acidic protein (IAP), and soluble IL-2 receptors (sIL-2Rs).2 3

Previous reports2 3 have suggested that these biological markers are useful for the diagnosis of tuberculous pleuritis. However, which of these six markers is most useful for the diagnosis of tuberculous pleuritis has not been determined. To determine the marker with the greatest diagnostic significance, we performed receiver operating characteristic (ROC) analysis on these six markers.


   Materials and Methods
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 Abstract
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 Materials and Methods
Results and Discussion
 References
 
Patients
Fifty-five inpatients with pleural effusions who were admitted to National Sanyo Hospital between April 2000 and September 2001 were studied. Clinical signs and symptoms, demographic data, and radiologic results were recorded. The clinical features of these patients are summarized in Table 1 . The study group included 42 men and 13 women, with a mean age of 64 years. Twenty patients (36%) had tuberculous pleuritis, and 35 patients (64%) had an effusion due to a nontuberculous etiology.


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  		Table 1.. Patient Characteristics

 
Diagnosis of Tuberculous, Malignant, and Miscellaneous Pleural Effusions
Tuberculous effusions were diagnosed when any of the following criteria were met: TB isolated from pleural fluid or pleural tissue; granulomas in the pleural tissue showing staining for acid-fast bacilli; granulomas in pleural tissue that did not stain for acid-fast bacilli, but which responded to antituberculous treatment; or a sputum culture positive for TB. Malignant pleural effusions were diagnosed either by pleural fluid cytology or biopsy specimen histology. Miscellaneous pleural effusions were those not linked to either TB or malignant disease.

Sample Collection and Determination of ADA, INF-{gamma}, IL-12, IL-18, IAP, and sIL-2R Levels
Each sample of pleural fluid was collected in a syringe during thoracentesis, which was performed with written informed consent, and was centrifuged at 2,000 revolutions per minute for 10 min. The supernatant was frozen at -80°C until assayed for markers. ADA and IAP activity were measured by autoanalyzer using commercially available kits. IL-18, INF-{gamma}, and sIL-2R was measured using commercially available enzyme-linked immunosorbent assay kits. IL-12p40 was measured using commercially available quantitative sandwich enzyme immunoassay kits.

Statistical Analysis
To compare the performances of markers, ROC curves were constructed.4


   Results and Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Making a differential diagnosis between tuberculous and nontuberculous pleural effusions is a critical clinical problem, and conventional methods have proven to be inadequate. The direct examination of pleural fluid by Ziehl-Neelsen staining has quite low sensitivity. Although a culture is more sensitive, several weeks are required to grow Mycobacterium tuberculosis. The sensitivity of pleural biopsy reportedly is higher than that of thoracentesis both by culture and histology. However, a biopsy requires greater expertise and is more invasive, and the examination of a biopsy specimen is subject to sampling error.5

Pleural levels of a number of biological markers have been proposed as aids in the diagnosis of tuberculous pleuritis, including those of ADA, INF-{gamma}, IL-12p40, IL-18, IAP, and sIL-2R, the levels of which are all significantly higher in tuberculous pleural effusions than in nontuberculous pleural effusions.2 3 However, the sensitivities of these markers have never been compared directly.

As shown in Figure 1 , ROC analysis demonstrated that INF-{gamma} is the most sensitive and specific indicator of tuberculous pleuritis among these six biological markers (area under the curve [AUC], 1.000). The next most sensitive was sIL-2R (AUC, 0.990), followed by ADA (AUC, 0.958), IL-18 (AUC, 0.949), IAP (AUC, 0.926), and IL-12p40 (AUC, 0.866). INF-{gamma} is produced by T lymphocytes in response to stimulation by specific antigens or nonspecific antigens, and is capable of modifying the response of other cells to the immune system.6 INF-{gamma} is known to activate macrophages so that they increase their bactericidal capacity against M tuberculosis. Therefore, INF-{gamma} levels in pleural fluid may reflect the stimulation of T lymphocytes by tuberculous antigens.



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  		Figure 1.. ROC analysis. Pleural fluid INF-{gamma} concentrations are more useful for distinguishing tuberculous pleuritis compared with ADA, INF-{gamma}, IL-12p40, IL-18, IAP, and sIL-2Rs.

 
In conclusion, INF-{gamma} is the most sensitive and specific biological marker of tuberculous pleuritis among the six reported. The measurement of the INF-{gamma} levels at the onset of pleural effusion may facilitate the early diagnosis of tuberculous pleuritis. INF-{gamma} should be measured routinely in patients who are strongly suspected of having TB, despite its relatively high cost compared with ADA assays. Further studies comparing these biological markers with polymerase chain reaction methods for detecting the DNA of M tuberculosis in pleural fluid are needed.


   Acknowledgements
 
We wish to thank Drs. M. Moriyama, H. Kohara, K. Makihata, K. Takao, and K. Murakami for kindly providing clinical samples and offering critical comments.


   Footnotes
 
Abbreviations: ADA = adenosine deaminase; AUC = area under the curve; IAP = immunosuppressive acidic protein; IL = interleukin; INF = interferon; ROC = receiver operating characteristic; sIL-2R = soluble interleukin-2 receptors; TB = tuberculosis

Received for publication June 10, 2003. Accepted for publication October 20, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Raviglione, MC, Luelmo, F (1996) Update on the global epidemiology of tuberculosis. Curr Issues Public Health 2,192-197[Medline]
  2. Aoe, K, Hiraki, A, Murakami, T, et al Diagnostic significance of interferon-{gamma} in tuberculous pleural effusions. Chest 2003;123,740-744[Abstract/Free Full Text]
  3. Hiraki, A, Aoe, K, Matsuo, K, et al Simultaneous measurement of T-helper 1 cytokines in tuberculous pleural effusion. Int J Tuberc Lung Dis 2003;7,1172-1177[ISI][Medline]
  4. Metz, CE Basic principles of ROC analysis. Semin Nucl Med 1978;8,283-298[ISI][Medline]
  5. Barbas, CS, Cukier, A, de Varvalho, CR, et al The relationship between pleural fluid findings and development of pleural thickening in patients with pleural tuberculosis. Chest 1991;100,1264-1267[Abstract/Free Full Text]
  6. Green, JA, Cooperband, SR, Kibrick, S Immune specific induction of interferon production in cultures of human blood lymphocytes. Science 1969;164,1415-1417[Abstract/Free Full Text]



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