Interferon-γ-Tests in der Tuberkulose-Diagnostik - Aktueller Stand

Zusammenfassung

Zur Diagnostik der latenten tuberkulösen Infektion (LTBI) stand bislang lediglich der Tuberkulinhauttest (THT) zur Verfügung. Dieses Verfahren weist jedoch weder eine 100 %ige Sensitivität, noch - und dies insbesondere aufgrund seiner Kreuzreaktogenität mit BCG und Umweltmykobakterien - eine 100 %ige Spezifität auf. Der Wunsch nach einem zuverlässigen in vitro-Test wird derzeit besonders in Deutschland noch dadurch verstärkt, dass aufgrund der vollständigen Umstellung von Stempeltest auf Tuberkulintestung nach Mendel-Mantoux und durch die Produktionseinstellung des bisher in Deutschland verwendeten Tuberkulins große Verunsicherung herrscht. Hersteller immunologischer Testverfahren, wie des QuantiFERON®-TB Gold In-Tube (ELISA-Verfahren) und des T SPOT-TB-Tests (ELISPOT-Verfahren), welche auf der Interferon-γ (IFN-γ)-Produktion sensibilisierter T-Lymphozyten basieren, bieten ihre Produkte als mögliche Alternative an. Dieser Beitrag vermittelt einen Überblick über die Funktionsweise der IFN-γ-Tests, die aktuelle Datenlage sowie die noch unbeantworteten wissenschaftlichen Fragestellungen, mögliche Anwendungsbereiche und Anforderungen an zukünftige klinische Studien. Obgleich die neuen Testverfahren das Potenzial haben, sich langfristig als hilfreiches zusätzliches diagnostisches Mittel anzubieten, ist ein kompletter Ersatz des Tuberkulinhauttests nach Einschätzung der Autoren verfrüht. Als ergänzende diagnostische Verfahren könnten sich die IFN-γ-Tests jedoch bereits jetzt durchaus als nützlich erweisen.

Abstract

Up to now the diagnosis of latent tuberculosis infection (LTBI) was based solely on the tuberculin skin test. However, this method offers neither 100 % sensitivity nor - and this is in particular due to its cross-reactivity with BCG and environmental mycobacteria - a 100 % specificity. The demand in Germany for a more reliable in vitro test is currently enhanced by the change from the multipuncture test to the intradermal (Mendel-Mantoux) test and by the uncertainty resulting from the ceased production of the tuberculin previously used in Germany. The manufacturers of immunologic test methods such as the QuantiFERON®-TB Gold In-Tube (ELISA assay) and the T SPOT-TB Test (ELISPOT assay), which are based on the Interferon-γ (IFN-γ) production of sensitized T lymphocytes, offer their products as possible alternatives. This article explains the function of the IFN-γ tests and gives an overview of the most recent data, possible indications and the open scientific questions to be investigated by future clinical studies. Although the new test methods have the potential to eventually prevail as an additional helpful diagnostic tool, the authors consider a complete replacement of the tuberculin skin test as premature. The IFN-γ tests may, however, prove already now to be a useful additional diagnostic method.

Literatur

• 1 Comstock G W, Livesay V T, Woolpert S F. The prognosis of a positive tuberculin reaction in childhood and adolescence.  Am J Epidemiol. 1974;  99 131-138
• 2 Vynnycky E, Fine P EM. Life time risks, incubation period, and serial interval of tuberculosis.  Am J Epidemiol. 2000;  152 247-263
• 3 American Thoracic Society, Prevention. CfDCa . Targeted tuberculin testing and treatment of latent tuberculosis infection.  Am J Respir Crit Care Med. 2000;  161 (Suppl) S221-S247
• 4 Schaberg T, Hauer B, Haas W. et al . Latente tuberkulöse Infektion: Empfehlungen zur präventiven Therapie bei Erwachsenen in Deutschland.  Pneumologie. 2004;  58 255-270
• 5 Loddenkemper R. Editorial zu „Theoretische und praktische Überlegungen bei Anwendung des Tuberkulintests”.  Pneumologie. 1997;  51 1023-1024
• 6 Rieder H L. Theoretische und praktische Überlegungen bei Anwendung des Tuberkulintests.  Pneumologie. 1997;  51 1025-1032
• 7 Sagebiel D, Hauer B, Haas W. et al . Zukünftige Tuberkulinversorgung in Deutschland.  Bundesgesundheitsbl-Gesundheitsforsch-Gesundheitsschutz. 2005;  48 477-482
• 8 Andersen P, Munk M E, Pollock J M. et al . Specific immune-based diagnosis of tuberculosis.  Lancet. 2000;  356 1099-1104
• 9 Huebner R E, Schein M F, Bass J B Jr. The tuberculin skin test.  Clin Infect Dis. 1993;  17 968-975
• 10 Hirtl T. Das Tuberkulin. Schriftenreihe Gesund in Wien. Wien: Literas Universitätsverlag 2000
• 11 NICE Guideline .Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. First draft for consultation. Juni 2005
• 12 Centers for Disease Control and Prevention .Draft guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. (http://www.cdc.gov/nchstp/tb/Federal_Register/default.htm) 2004/2005
• 13 Pai M, Riley L W, Colford J M Jr. Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review.  The Lancet Inf Dis. 2004;  4 761-776
• 14 US Food and Drug Administration .QuantiFERON®-TB-P010033 Summary of safety and effectiveness. Rockville, MD: Food and Drug Administration 2002 http//:www.fda.gov/cdrh/pdf/P010033b.pdf 2004
• 15 Mazurek G H, Villarino M E. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection.  MMWR. 2003;  52 15-18
• 16 Dheda K, Udwadia Z F, Huggett J F. et al . Utility of the antigen-specific interferon-γ assay for the management of tuberculosis.  Curr Opin Pulm Med. 2005;  11 195-202
• 17 Johnson P DR, Stuart R L, Grayson M L. et al . Tuberculin-purified protein derivative-, MPT-64-, and ESAT-6-stimulated gamma interferon responses in medical students before and after Mycobacterium bovis BCG vaccination and in patients with tuberculosis.  Clin Diagn Lab Immunol. 1999;  6 934-937
• 18 Cellestis .QuantiFERON®-TB Gold (In-Tube Method). Package Insert. www.cellestis.com
• 19 Katial R K. Immunodiagnostics for Latent Tuberculosis Infection. In: Madkour MM. (Hrsg): Tuberculosis. Springer Verlag 2003: S. 231-239
• 20 Cellestis .QuantiFERON®-TB Gold. Package Insert. www.cellestis.com
• 21 Lalvani A. Spotting latent infection: the path to better tuberculosis control.  Thorax. 2003;  58 916-918
• 22 Ferrara G, Losi M, Meacci M. et al . Routine hospital use of a new commercial whole blood interferon-γ assay for the diagnosis of tuberculosis infection.  Am J Crit Care Med. 2005;  172 631-635
• 23 Heaf F. The multiple puncture tuberculin test.  Lancet. 1951;  21 151-153
• 24 Brock I, Weldingh K, Lillebaek T. et al . Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts.  Am J Respir Care Med. 2004;  170 65-69
• 25 Mori T, Sakatani M, Yamagishi F. et al . Specific detection of tuberculosis infection. An interferon-γ-based assay using new antigens.  Am J Respir Crit Care Med. 2004;  170 59-64
• 26 Ravn P, Munk M E, Andersen A B. et al . Reactivation of tuberculosis during immunosuppressive treatment in a patient with positive QuantiFERON®-RD1 Test.  Scand Infect Dis. 2004;  3 36 499-501
• 27 Chapman A LN, Munkanta M, Wilkinson K A. et al . Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells.  AIDS. 2002;  16 2285-2293
• 28 Pathan A A, Wilkinson K A, Klenerman P. et al . Direct ex vivo analysis of antigen-specific IFN-γ-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment.  J Immunol. 2001;  167 5217-5225
• 29 Ravn P, Munk M E, Andersen Å B. et al . Prospective evaluation of a whole-blood test using mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10 for diagnosis of active tuberculosis.  Clin Diagn Lab Immunol. 2005;  12 491-496
• 30 Mazurek G H, LoBue P A, Daley C L. et al . Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection.  JAMA. 2001;  286 1740-1747
• 31 Fietta A, Meloni F, Cascina A. et al . Comparison of a whole-blood interferon-γ assay and tuberculin skin testing in patients with active tuberculosis and individuals at high or low risk of Mycobacterium tuberculosis infection.  Am J Infect Control. 2003;  31 347-353
• 32 Ewer K, Deeks J, Alvarez L. et al . Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak.  Lancet. 2003;  361 1168-1173
• 33 Kang Y A, Lee H W, Yoon H I. et al . Discrepancy between the tuberculin skin test and the whole-blood interferon γ assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country.  JAMA. 2005;  293 2756-2761
• 34 Pai M, Gokhale K, Joshi R. et al . Mycobacterium tuberculosis infection in health care workers in Rural India.  JAMA. 2005;  293 2746-2755
• 35 Lalvani A, Pathan A A, Durkan H. et al . Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells.  Lancet. 2001;  357 2017-2021
• 36 Hill P C, Brookes R H, Fox A. et al . Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against gradient of exposure in The Gambia.  CID. 2004;  38 66-973
• 37 Richeldi L, Ewer K, Losi M. et al . T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure.  Am J Respir Crit Care Med. 2004;  170 288-295
• 38 Brock I, Munk M E, Kok-Jensen A. et al . Performance of whole blood IFN-γ test for tuberculosis diagnosis based on PPD or the specific antigens ESAT-6 and CFP-10.  Int J Tuberc Lung Dis. 2001;  5 462-467
• 39 Lalvani A, Nagvenkar P, Udwadia Z. et al . Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians.  J Infect Dis. 2001;  183 469-477
• 40 Arend S M, Meijgaarden K E van, Boer K de. et al . Tuberkulin skin testing and in vitro T cell responses to ESAT-6 and culture filtrate protein 10 after infection with Mycobacterium marinum or M. kansasii.  J Infect Dis. 2002;  186 1797-1807
• 41 Geluk A, Meijgaareden K E van, Franken K L. et al . Identification and characterization of the ESAT-6 homologue of Mycobacterium leprae and T-cell cross reactivity with Mycobacterium tuberulosis.  Infect Immun. 2002;  70 2544-2548
• 42 Lein A D, Reyn C F von, Ravn P. et al . Cellular immune responses to ESAT-6 discriminate between patients with pulmonary disease due to Mycobacterium avium complex and those with pulmonary disease due to Mycobacterium tuberculosis.  Clin Diagn Lab Immunol. 1999;  6 606-609
• 43 Rolinck-Werninghaus C, Magdorf K, Stark K. et al . The potential of recombinant antigens ESAT-6, MPT63 and mig for specific discrimination of Mycobacterium tuberculosis and M. avium infection.  Eur J Pediatr. 2003;  162 534-536
• 44 Carrara S, Vincenti D, Petrosillo N. et al . Use of a T-cell based assay for monitoring efficacy of antituberculosis treatment.  Clin Inf Dis. 2004;  38 754-756
• 45 Al-Attiyah R, Mustafa A S, Abal A T. et al . Restoration of mycobacterial antigen-induced proliferation and interferon-gamma responses in peripheral blood mononuclear cells of tuberculosis patients upon effective chemotherapy.  FEMS Immunol Med Microbiol. 2003;  38 249-256
• 46 Ulrichs T, Anding P, Kaufmann S HE. et al . Numbers of IFN-γ-producing cells against ESAT-6 increase in tuberculosis patients during chemotherapy.  Int J Tuberc Lung Dis. 2000;  4 1181-1183
• 47 Vekemans J, Lienhardt C, Sillah J S. et al . Tuberculosis contacts but not patients have higher gamma interferon responses to ESAT-6 than do community controls in The Gambia.  Infect Immun. 2001;  69 6554-6557
• 48 Wu-Hsieh B A, Chen C K, Chang J H. et al . Long-lived immune response to early secretory antigenic target 6 in individuals who had recovered from tuberculosis.  Clin Infect Dis. 2001;  33 1336-1340
• 49 Stuart R L, Olden D, Johnson P DR. et al . Effect of anti-tuberculosis treatment on the tuberculin interferon-γ response in tuberculin skin test (TST) positive health care workers and patients with tuberculosis.  Int J Tuberc Lung Dis. 2000;  4 555-561
• 50 Nicol M P, Pienaar D, Wood K. et al . Enzyme-linked immunospot assay responses to early secretory antigenic Target 6, Culture Filtrate Protein 10, and Purified Protein Derivative among children with tuberculosis: implications for diagnosis and monitoring of therapy.  CID. 2005;  40 1301-1308
• 51 Dheda K, Chang J S, Kim L U. et al . Interferon gamma assays for tuberculosis.  Lancet Infect Dis. 2005;  5 324-325
• 52 Doherty T M, Demissie A, Menzies D. et al . Effect of sample handling on analysis of cytokine responses to Mycobacterium tuberculosis in clinical samples using ELISA, ELISPOT and quantitative PCR.  J Immunol Methods. 2005;  298 129-141
• 53 Arend S M, Engelhard A C, Groot G. et al . Tuberkulin skin testing compared with T-cell responses to Mycobacterium tuberculosis-specific and non-specific antigens for detection of latent infection in persons with recent tuberculosis contact.  Clin Diagn Lab Immunol. 2001;  8 1089-1096
• 54 Bellete B, Coberly J, Barnes G L. et al . Evaluation of a whole-blood interferon-gamma release assay for the detection of Mycobacterium tuberculosis infection in 2 study populations.  Clin Inf Dis. 2002;  34 1449-1456
• 55 Mazurek G H, LoBue P A, Daley C L. et al . Detection of Mycobacterium tuberculosis infection by whole-blood interferon-gamma assay.  Clin Infect Dis. 2003;  36 1207-1208
• 56 Rothel J S, Radford A J. Comparison of tuberculosis tests: finding truth or confirming the prejudice?.  Clin Inf Dis. 2003;  36 1206-1207
• 57 Schölvinck E, Wilkinson K A, Whelan A O. et al . Gamma interferon-based immunodiagnosis of tuberculosis: comparison between whole-blood and enzyme-linked immunospot methods.  J Clin Microbiol. 2004;  42 829-831
• 58 Doherty T M, Demissie A, Olobo J. et al . Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients.  J Clin Microbiol. 2002;  40 704-706
• 59 Barnes P F. Diagnosing latent tuberculosis infection. Turning glitter to gold.  Am J Respir Crit Care Med. 2004;  170 5-6
• 60 Pittius N CG Van, Gamieldien J, Hide W. et al . The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G + C Gram-positive bacteria.  Genome Biol. 2001;  2 research 004.1-0044.18
• 61 Harboe M, Oettinger T, Wiker H G. et al . Evidence for occurrence of the ESAT-6 protein in Mycobacterium tuberculosis and virulent Mycobacterium bovis and for its absence in Mycobacterium bovis BCG.  Infect Immun. 1996;  64 16-22
• 62 Martin-Casabona N, Bahrmand A R, Bennedsen J. et al . Non-tuberculous mycobacteria: patterns of isolation. A multi-country retrospective study.  Int J Tuberc Lund Dis. 2004;  8 1186-1193
• 63 Richeldi L, Ewer K, Losi M. et al . Early diagnosis of subclinical multidrug-resistant tuberculosis.  Ann Intern Med. 2004;  140 709-713
• 64 Elliott A M, Hurst T J, Balyeku M N. et al . The immune response to Mycobacterium tuberculosis in HIV-infected and uninfected adults in Uganda: application of a whole blood cytokine assay in an epidemiological study.  Int J Tuberc Lung Dis. 1999;  3 239-247
• 65 Liebeschuetz S, Bamber S, Ewer K. et al . Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study.  Lancet. 2004;  364 2196-2203

1 Beim Heaf-Test handelt es sich um eine überwiegend in Großbritannien verwendete Multipunkturmethode, mit der unter Verwendung eines speziellen Applikators Tuberkulin in die Haut eingebracht wird [23].