Background: The determination of cytokine concentrations in serum and bronchoalveolar lavage fluid (BALF) may contribute to the diagnosis of tuberculosis (TB) since cytokines have been ascribed an important role in TB pathogenesis. Objective: To assess the diagnostic accuracy of TNF-α, IFN-γ and IL-2 levels in serum and BALF of smear-negative pulmonary TB patients. Method: BALF was obtained from the affected lobe in patients with smear-negative TB or other pulmonary diseases (OPD), and from the right middle lobe in healthy controls. ELISA and a nephelometric method were used to detect cytokine and albumin levels. Results: TNF-α levels in BALF were significantly elevated in the TB group (n = 15) compared with the OPD patients (n = 40) and controls (n = 17; p < 0.001). Although these three cytokines correlated well with each other in BALF (p < 0.0001, and r ≧ 0.7, respectively), BALF IL-2 and IFN-γ levels were not significantly different among the groups (p > 0.05). BALF TNF-α or IFN-γ levels were significantly higher in patients with cavitary disease (n = 11) versus those without (n = 61; p < 0.05). However, no significant difference was found between cavitary (n = 7) and non-cavitary TB in cytokine levels (p > 0.05). Neither gender nor smoking status showed any statistical differences in cytokines in the groups (p > 0.05). Sensitivity and specificity of BALF TNF-α were found to be 73 and 76%, respectively. The positive and negative predictive values for BALF TNF-α were 44 and 91%, respectively. Conclusion: In cases of smear-negative TB, BALF TNF-α can be a useful tool to identify healthy subjects rather than smear-negative TB patients.

1.
Fishman JA: Mycobacterial infections; in Fishman AP, Elias JA, Fishman JA, Grippi MA, Kaiser LR, Senior RM (eds): Fishman’s Manual of Pulmonary Diseases and Disorders, ed 3. New York, McGraw-Hill, 2002, pp 763–819.
2.
Flynn JL, Chan J: Immunology of tuberculosis. Annu Rev Immunol 2001;19:93–129.
3.
Sahiratmadja E, Alisjahbana B, de Boer T, Adnan I, Maya A, Danusantoso H, Nelwan RH, Marzuki S, van der Meer JW, van Crevel R, van de Vosse E, Ottenhoff TH: Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment. Infect Immun 2007;75:820–829.
4.
Belli F, Capra A, Moraiti A, Rossi S, Rossi P: Cytokines assay in peripheral blood and bronchoalveolar lavage in the diagnosis and staging of pulmonary granulomatous diseases. Int J Immunopathol Pharmacol 2000;13:61–67.
5.
Somoskovi A, Zissel G, Zipfel PF, Ziegenhagen MW, Klaucke J, Haas H, Schlaak M, Muller-Quernheim J: Different cytokine patterns correlate with extension of disease in pulmonary tuberculosis. Eur Cytokine Netw 1999;10:135–142.
6.
Tsao TC, Huang CC, Chiou WK, Yang PY, Hsieh MJ, Tsao KC: Levels of interferon-gamma and interleukin-2-receptor-alpha for bronchoalveolar lavage fluid and serum were correlated with clinical grade and treatment of pulmonary tuberculosis. Int J Tuberc Lung Dis 2002;6:720–727.
7.
Vankayalapati R, Wizel B, Weis SE, Klucar P, Shams H, Samten B, Barnes PF: Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced cytokine production in patients with tuberculosis. Clin Infect Dis 2003;36:24–28.
8.
Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD, Britton WJ: Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504–3511.
9.
Dlugovitzky D, Torres-Morales A, Rateni L, Farroni MA, Largacha C, Molteni O, Bottasso O: Circulating profile of Th1 and Th2 cytokines in tuberculosis patients with different degrees of pulmonary involvement. FEMS Immunol Med Microbiol 1997;18:203–207.
10.
Conover WJ (ed): Practical Nonparametric Statistics, ed 2. New York, Wiley, 1980, chap 5, pp 229–239.
11.
Karnak D, Beder S, Kayacan O, Ibis E, Oflaz G: Neuron-specific enolase and lung cancer. Am J Clin Oncol 2005;28:586–590.
12.
Deveci F, Akbulut HH, Turgut T, Muz MH: Changes in serum cytokine levels in active tuberculosis with treatment. Mediators Inflamm 2005;5:256–262.
13.
Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A, Trinchieri G: CD4+ T cell clones producing both interferon-γ and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 1999;92:224–234.
14.
Tsao TC, Hong J, Huang C, Yang P, Liao SK, Chang KS: Increased TNF-α, IL-1β and IL-6 levels in the bronchoalveolar lavage fluid with the upregulation of their mRNA in macrophages lavaged from patients with active pulmonary tuberculosis. Tuber Lung Dis 1999;79:279–285.
15.
Tsao TC, Hong J, Li LF, Hsieh MJ, Liao SK, Chang KS: Imbalances between tumor necrosis factor-α and its soluble receptor antagonist in BAL fluid of cavitary pulmonary tuberculosis. Chest 2000;117:103–109.
16.
Tsao TCY, Li LF, Hsieh M, Liao S, Chang KS: Soluble TNF-α receptor and IL-1 receptor antagonist elevation in BAL in active pulmonary tuberculosis. Eur Respir J 1999;14:490–495.
17.
Tahhan M, Ugurman F, Gozu A, Akkalyoncu B, Samurkasoglu B: Tumour necrosis factor-alpha in comparison to adenosine deaminase in tuberculous pleuritis. Respiration 2003;70:270–274.
18.
Condos R, Rom WN, Liu YM, Schulger NW: Local immune responses correlate with presentation and outcome in tuberculosis. Am J Respir Crit Care Med 1998;157:729–735.
19.
Law K, Weiden M, Harkin T, Tchou-Wong K, Chi C, Rom WN: Increased release of interleukin-1β, interleukin-6 and tumor necrosis factor-α by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis. Am J Respir Crit Care Med 1996;153:799–804.
20.
Theilmann L, Meyer U, Kommerell B, Dierkesmann R, Moller A: Alpha tumor necrosis factor in the serum of patients with sarcoidosis, tuberculosis or bronchial cancer (in German). Pneumologie 1990;44:735–738.
21.
Chyczewska E, Mroz RM, Kowal E: TNF-alpha, IL-1 and IL-6 concentration in bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC). Rocz Akad Med Bialymst 1997;42(suppl 1):123–135.
22.
Georgiades G, Myrianthefs P, Venetsanou K, Kyroudi A, Kittas C, Baltopoulos G: Temperature and serum proinflammatory cytokine changes in patients with NSCLC after BAL. Lung 2003;181:35–47.
23.
Global Initiative for Chronic Obstructive Lung Disease (GOLD): Pathogenesis, Pathology and Pathophysiology. Bethesda, National Institutes of Health, 2001, chap 4, pp 28–43.
24.
Matanic D, Beg-Zec Z, Stojanovic D, Matakoric N, Flego V, Milevoj-Ribic F: Cytokines in patients with lung cancer. Scand J Immunol 2003;57:173–178.
25.
Mo XY, Sarawar SR, Doherty PC: Induction of cytokines in mice with parainfluenza pneumonia. J Virol 1995;69:1288–1291.
26.
Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM: Disseminated tuberculosis in interferon γ gene-disrupted mice. J Exp Med 1993;178:2243–2247.
27.
Pearl JE, Saunders B, Ehlers S, Orme IM, Cooper AM: Inflammation and lymphocyte activation during mycobacterial infection in the interferon-γ deficient mouse. Cell Immunol 2001;211:43–50.
28.
Hirsch CS, Toossi Z, Othieno C, Johnson JL, Schwander SK, Robertson S, Wallis RS, Edmonds K, Okwera A, Mugerwa R, Peters P, Ellner JJ: Depressed T-cell interferon γ responses in pulmonary tuberculosis: analyses of underlying mechanisms and modulation with therapy. J Infect Dis 1999;180:2069–2073.
29.
Seah GT, Scott GM, Rook GAW: Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis. J Infect Dis 2000;181:385–389.
30.
Smith SM, Klein MR, Sillah J, McAdam KP, Dockrell HM: Decreased IFN-γ and increased IL-4 production by human CD8+ T cells in response to Mycobacterium tuberculosis in tuberculosis patients. Tuberculosis 2002;82:7–13.
31.
Turner J, Corrah T, Sabbally S, Whittle H, Dockrell HM: A longitudinal study of in vitro IFNγ production and cytotoxic T cell responses of tuberculosis patients in The Gambia. Tuber Lung Dis 2000;80:161–169.
32.
Verbon A, Juffermans N, Van Deventer SJH, Speelman P, Van Deutekom H, Van Der Poll T: Serum concentrations of cytokines in patients with active tuberculosis and after treatment. Clin Exp Immunol 1999;115:110–113.
33.
Toossi Z, Kleinhenz ME, Ellner JJ: Defective IL-2 production and responsiveness in human pulmonary tuberculosis. J Exp Med 1986;163:1162–1172.
34.
Torres M, Herrera T, Villareal H, Rich EA, Sada E: Cytokine profiles for peripheral blood lymphocytes from patients with active pulmonary tuberculosis and healthy household contacts in response to the 30-kilodalton antigen of Mycobacterium tuberculosis. Infect Immun 1998;66:176–180.
35.
Haslam PL, Baughmann RP: Guidelines for measurement of acellular components and recommendations for standardization of bronchoalveolar lavage (BAL). Eur Respir Rev 1999;9:106–112.
36.
Reynolds PR, Cosio MG, Hoidal JR: Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells. Am J Respir Cell Mol 2006;35:314–319.
37.
Kim Y, Kim K, Joe J, Park H, Lee M, Kim Y, Choi Y, Park S: Changes in the levels of interferon-gamma and transforming growth factor-beta influence bronchial stenosis during the treatment of endobronchial tuberculosis. Respiration 2007;74:202–207.
38.
Jafari C, Ernst M, Kalsdorf B, Greinert U, Diel R, Kirsten D, Marienferd K, Lalvani A, Lange C: Rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage enzyme-linked immonuspot. Am J Respir Crit Care Med 2006;174:963–964.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.