Diagnostic Value of Interleukin-1, Interleukin-6, and Tumor Necrosis Factor in Pleural Effusions* Nektaria Xirouchaki, MD; Nikolaos Tzanakis, MD; Demosthenes Bouros, MD, FCCP; Despina Kyriakou, MD; Nikolaos Karkavitsas, MD; Michalis Alexandrakis, MD; and Nikolaos M. Siafakas, MD, PhD, FCCP Study objectives: Interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- were measured in pleural fluid from 57 patients with pleural effusion in order to evaluate the diagnostic utility of these cytokines. We studied 20 patients with malignant pleural effusion, 11 patients with parapneumonic pleural effusion, 9 patients with tuberculous pleural effusion, and 17 patients with transudative pleural effusion. Cytokines were measured by radioimmunoassay. Setting: University tertiary hospital. Results: The mean values of the three cytokines measured in pleural fluid or in serum were significantly higher in patients with exudates than with transudates (p < 0.05). The ratio of IL-6 in pleural fluid to serum was significantly higher in exudates than in transudates (p < 0.05). The level of IL-6 in pleural fluid was significantly higher in tuberculous than malignant (p < 0.007) or parapneumonic pleural effusions (p < 0.04). No significant difference between the three types of exudates was found in pleural fluid levels of IL-1 or TNF-. Conclusions: Serum levels of IL-1, TNF-, and in particular IL-6 can distinguish exudates from transudates, while pleural fluid IL-6 levels could be useful as an additional marker in the differential diagnosis of tuberculous, malignant, and parapneumonic exudates. Finally, our results suggest that there is local cytokine production in exudative pleural effusions. (CHEST 2002; 121:815– 820) Key words: cytokines; exudates; malignant; parapneumonic; pleural disease; pleural fluid; transudates; tuberculous Abbreviations: IL = interleukin; TNF = tumor necrosis factor T he development of inflammation in the pleura results in an increased vascular permeability leading to pleural fluid accumulation. This pleural fluid is enriched in proteins, inflammatory cells, and mediators. 1,2 The management of pleural effusion is still a difficult clinical problem. 3 Although a variety of simple laboratory tests are in use, a number of cases remain undiagnosed or the “diagnosis” is based on clinical evidence alone. 2,4,5 This is especially true regarding the differentiation of exudates of various causes. 3,6 Cytokines are proteins with relatively low molec- ular weight that are secreted by cells in response to a variety of different stimuli and act as key mediators of the host response to various infectious, inflammatory, and immunologic challenges. 7–10 Cytokines are thought to exert their effects by binding to specific receptors on the surface of the cell, although cytokines may in some instances have direct membrane effects. 11 Cytokine-producing cells and cytokines have been reported in pleural effusions from patients with malignant diseases, tuberculosis, and empyema. 1,12–20 Interleukin (IL)-1 is an immunoregulatory cytokine with an essential role in T-cell activation. IL-1 is produced mainly by mononuclear phagocytes but also by many other types of cells in response to inflamma- tory stimuli. 12 It has a wide range of biological activities on many target cell types, including B cells, T cells, and monocytes. 10,21,22 It has been reported that IL-1 levels are increased in tuberculous pleural effusion 19 and in malignant pleural effusion after pleurodesis. 23 *From the Departments of Thoracic Medicine (Drs. Xirouchaki, Tzanakis, Bouros, and Siafakas), Hematology (Drs. Kyriakou and Alexandrakis), and Nuclear Medicine (Dr. Karkavitsas), Medical School, University of Crete, University General Hospital of Heraklion, Crete, Greece. Manuscript received December 12, 2000; revision accepted September 24, 2001. Correspondence to: Nikolaos M. Siafakas, MD, PhD, FCCP, Professor of Thoracic Medicine, Department of Thoracic Medi- cine, Medical School University of Crete, Heraklion, 71110, Crete, Greece; e-mail: siafak@ med.uoc.gr CHEST / 121 / 3 / MARCH, 2002 815