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© Borgis - Postępy Nauk Medycznych 4/2015, s. 289-293
*Dagmara Borkowska, Ewa Augustynowicz-Kopeć
Czy testy IGRA mogą okazać się pomocne w diagnostyce gruźlicy płuc i postaci pozapłucnych?
Can Interferon-Gamma Release Assays be helpful for the diagnosis of pulmonary and extrapulmonary tuberculosis?
Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Warsaw
Head of Department: prof. Ewa Augustynowicz-Kopeć, MD, PhD
Streszczenie
Rozpoznanie gruźlicy płuc i gruźliczego zapalenia opłucnej standardowymi metodami diagnostyki mikrobiologicznej jest trudne i długotrwałe. Obecnie, duże nadzieje wiąże się z komórkami limfocytów T wydzielającymi interferon-gamma w odpowiedzi na antygeny Mycobacterium tuberculosis i wykorzystanie tej reakcji immunologicznej do diagnostyki gruźlicy. W pracy przedstawiono przegląd najnowszych publikacji dotyczących tego tematu. Testy IGRA wykonane z krwi obwodowej nie rozróżniają aktywnej postaci choroby od latentnego zakażenia prątkami gruźlicy. Wykrywanie limfocytów T w BALf i płynie z opłucnej przy użyciu testu T-SPOT.TB (technika ELISPOT) jest obiecującym narzędziem do diagnostyki zarówno gruźlicy płuc, jak i postaci pozapłucnych. Takie wykorzystanie testu może okazać się istotne dla chorych z negatywnym wynikiem bakterioskopii plwociny lub chorych podejrzanych o gruźlicę niepotwierdzoną bakteriologicznie. W aktywnej gruźlicy limfocyty T wydzielają interferon-gamma i wędrują do miejsca zmienionego chorobowo. Dodatni wynik T-SPOT.TB z BALf i innych płynów może być pomocny w szybkiej diagnostyce gruźlicy. W chwili obecnej ilość opublikowanych wyników badań uniemożliwia jednoznaczną ocenę przydatność IGRA do wykrywania aktywnej gruźlicy z materiałów diagnostycznych takich jak BALf i płyn z opłucnej.
Summary
The diagnosis of pulmonary tuberculosis and tuberculous pleurisy standard methods is difficult and slow. Now, high hopes to cells of T cells secreting interferon-gamma in response to antigens of Mycobacterium tuberculosis. Use of the immune response to TB diagnosis. A systematic review was performed of latest publications. Interferon-γ release assays (IGRA) on peripheral blood mononuclear cells cannot distinguish active from latent tuberculosis infection. But detection of Mycobacterium tuberculosis-specific T-cells in the bronchoalveolar lavage or pleural effusion using IGRA (ELISPOT assay) is a promising tool for the diagnosis of active pulmonary or extrapulmonary tuberculosis in patients with negative acid-fast bacilli smears and suspected tuberculosis patients. In TB, antigen-specific T-cells expand and are recruited to the site of infection. Positive T-SPOT.TB performed in BALf and another fluid could be helpful in rapid TB diagnosis. At present, there is little research. Further studies are needed to confirm the usefulness of IGRA to detect active TB.
Introduction
Tuberculosis remains a major health problem, approximately 8 million of newly detected patients are recorded each year in the world and approximately 1.5 million deaths (1, 2). In Poland, 7250 cases of tuberculosis were recorded in 2013 and the incidence of all forms of tuberculosis was 18.8 and it is still higher than the average incidence rate in the European Union. Pulmonary tuberculosis was the dominant form of tuberculosis in Poland, 94.3%, and extrapulmonary tuberculosis accounted for approximately 5.7% of the registered cases. The most common form of extrapulmonary location was tuberculous pleurisy – 34.2% of all cases. In accordance with the recommendations of the WHO obtaining cultures of M. tuberculosis complex from diagnostic material of patients still remains the gold standard for the diagnosis of tuberculosis. In Poland, bacteriological confirmation of TB was obtained for 4825 patients in 2013 which accounted for 66.6% of all patients (3).
Due to the sparsely mycobacterial nature of diagnostic materials obtained from patients with suspected tuberculosis, achieving a positive microbiological test result is, in many cases, not possible. Despite the application of modern diagnostic methods, obtaining a microbiological result confirming a TB case sometimes lasts for several weeks (4, 5). Therefore, the whole time we are searching for methods of approximating diagnosis and putting them into routine diagnostics. Serological diagnostics, that is, detection of antibodies against a pathogen, plays a supporting role in many infectious diseases. In the case of tuberculosis, due to a marginal part of the humoral response as a response to infection by a mycobacterium, these methods have not been applied in the diagnostic panel.
The cutaneous tuberculin test still plays an auxiliary role in the diagnosis. Tuberculin RT 23 is a mixture of 200 non-specific antigens that can be administered intradermally in the volar surface of the forearm. The skin reaction result is read after 48-72 hours, measuring the diameter of infiltration. Positive TST result does not decide whether an infection is caused by a tuberculosis mycobacterium, Bacille Calmette-Guerin vaccination (BCG), non-tuberculosis mycobacteria (4, 6). Results of numerous studies have shown limited specificity of the tuberculin test, particularly in populations vaccinated with BCG.
At present, high hopes are associated with the release of innovative interferon-γ release assays (IGRA).WHO and ECDC recommend performing IGRAs of peripheral blood for the diagnosis of latent tuberculosis infection, even before clinical symptoms (1, 7). As a re sult of infection with Mycobacterium tuberculosis, T cells producing interferon-gamma appear in blood. During IGRAs, another T-cell stimulation happens with antigens encoded in the RD1 region of the genome of Mycobacterium tuberculosis: ESAT-6, CFP10. Measuring the amount of interferon-gamma release is an indicator of infection. IGRA tests from peripheral blood cannot distinguish between the active form of tuberculosis and latent infection with Mycobacterium tuberculosis. Results of the IGRD T-SPOT.TB test used in the case of other diagnostic materials than blood, such as cerebrospinal fluid, bronchoalveolar lavage fluid and pleural fluid, point to new diagnostic possibilities of tuberculosis and its extrapulmonary form (8).
IGRA tests
Interferon-Gamma Release Assays (IGRA) from peripheral blood for the diagnosis of latent tuberculosis infection have were approved for clinical use in 2001 (5). The advantage of IGRA tests over the tuberculin test is a lack of cross-reactivity with BCG vaccine and most environmental mycobacteria (6, 7, 9-12). The assays used antigens specific for Mycobacterium tuberculosis: ESAT-6, CFP 10, TB7.7, RD1 encoded in the region of the genome of Mycobacterium tuberculosis. The region does not exist in the strains belonging to the BCG vaccine strain species Mycobacterium bovis and environmental mycobacteria, excluding M. marinum, M. kansasii and M. szulgai (6, 7, 9-12). In Poland, there are two IGRAs available: QuantiFERON and T-SPOT TB. The principle of operation is based on the measurement of interferon-gamma (IFN-γ), as produced by T lymphocytes in response to antigens of Mycobacterium tuberculosis or identification of T cells secreting IFN-γ (7, 9-12). The advantage of IGRA is to get a result in less than 2 days, simple interpretation is based on standardized methods and there is no need to re-visit a patient in a healthcare facility, as is the case of TST (tab. 1) (4, 6, 12).
Table 1. Brief characteristics of IGRAs of peripheral blood.
IGRA blood testsT-SPOT.TBQuantiFERON (TB GOLD or TB GOLD IN-TUBE)
Measurement techniqueELISpotELISA
RD1 region antigensESAT-6, CFP10ESAT-6, CFP10 (TB7.7, IN-TUBE version)
Material and amountPeripheral blood, the amount depends on the age of the subject: 2 ml children under 2 years of age, children 2-4 years 4 ml, 6 ml older children and adults. One tube of lithium heparin1 ml of peripheral blood in each of 3 special test tubes from the manufacturer
Visit to the facility11
Time to get a resultTwo daysTwo days or longer
Sensitivity78-95%46-78%
Specificity87-100%98-100%
BCG and environmental mycobacteriaNo cross-reactionNo cross-reaction
Principle of readingNumber of single cells secreting IFN-γ, or dark blue spots – spots on the well membraneConcentration of IFN-γ in the tube
Interpretation – positive resultNumber of spots ≥ 6 at least in one of two wells with antigens, negative control ≤ 10 spots, positive control ≥ 20 spotsConc. of IFN-γ ≥ 0.35 IU/ml and ≥ 25% of the negative control, negative control ≤ 8.0 IU/ml, positive control of each range
Recently, in the world literature, there have been reports on the use of IGRAs for the diagnosis of active lung tuberculosis with BALf and the extrapulmonary form with pleural fluid. The phenomenon of cellular compartmentalization of immune response occurs during the active tuberculosis (4). In the peripheral blood, immune cells, particularly T-lymphocytes, after antigen recognition, proliferate and are transformed into memory cells, migrating to the lesion site. On the surface of the memory cells, there are homing receptors that enable targeted cell transfer. As a result of the selective recruitment of leukocytes, the cells necessary for effective defense reaction are attracted to inflammatory sites (13). In connection with that, the number of T cells is significantly higher in the lesion site, e.g. in the lungs, pleura, than in the peripheral blood. This may be one reason why IGRA has negative results in patients with severe forms of tuberculosis (4, 14, 15). Jafari et al. showed in their study that the active form of tuberculosis from bronchoalveolar lavage fluid with negative smear result can be quickly confirmed using the T-SPOT.TB test (16-19). Results of other studies have shown the ability to confirm the tuberculous pleurisy using the T-SPOT.TB test of pleural fluid (2, 20-23).
The use of the T-SPOT.TB in the diagnosis of pulmonary tuberculosis and the extrapulmonary form – review of the literature

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Piśmiennictwo
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otrzymano: 2015-01-30
zaakceptowano do druku: 2015-03-05

Adres do korespondencji:
*Dagmara Borkowska
Department of Microbiology
National Tuberculosis and Lung Diseases Research Institute
ul. Płocka 26, 01-138 Warszawa
tel. +48 (22) 431-21-79
fax +48 (22) 431-21-82
d.borkowska@igichp.edu.pl

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