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Peripheral T Cell Interferon- Responses and Latent Tuberculosis

Although Dr. Mori and colleagues (1) have pointed out the cross-reactivity of Mycobacterium tuberculosis antigens (early secreted antigenic target 6-kD protein [ESAT-6] and culture filtrate protein 10 [CFP-10]) with environmental mycobacteria (M. marinum, M. szulgai and M. kansasii), they failed to mention the significant cross-reactivity with other mycobacteria, such as M. leprae. The latter organism shares a significant amino acid sequence homology with M. tuberculosis ESAT-6 (2, 3). Moreover, such cross-reactivity has been shown to affect the specificity of M. tuberculosis IFN- responses to ESAT-6 and CFP-10 antigens in countries where both diseases are endemic (4). In developed countries like the UK and the United States, a large burden of tuberculosis (TB) disease and, hence, latent TB infection in close contacts occurs in the recent immigrant population (5). These individuals often come from areas where both tuberculosis and leprosy are endemic (Indian Sub-continent, Africa, and South America). It would therefore be expected that, unlike the Japanese population in whom the study was performed, such exposure would be a confounding factor when diagnosing latent TB infection using an ESAT-6–based IFN- assay. Furthermore, the exposure and load of environmental mycobacteria in developing countries also is much greater; such mycobacterial antigens have been shown to induce IFN- responses (6). Therefore, studies are required to validate these findings in populations that are representative of individuals who have emigrated from developing countries and have settled in Europe and the United States. These individuals will comprise a significant majority of those being assessed for latent TB infection.

For the purposes of sensitivity assessment in latent TB infection, Mori and colleagues (1) extrapolate from the sensitivity results of active tuberculosis cases. This is a reasonable approach as there is no gold standard for the diagnosis of latent TB infection. However, such an approach is dependent on the sensitivity of the assay in the particular population being studied. Indeed, in various populations, the sensitivity of an ESAT-6 IFN-–based assay for active tuberculosis was found to vary between 35 and 92% (reviewed in Reference 4). This standardized assay (1) therefore requires validation in different populations of patients with clinical tuberculosis before a more accurate assessment of sensitivity can be made.

As there is no gold standard for diagnosing latent TB infection and there is cross-reactivity with other mycobacteria, the crucial question that requires further study is whether treatment of those identified by the assay as having latent TB infection will actually reduce the incidence of subsequent clinical tuberculosis.

Keertan Dheda, Graham Rook and Alimuddin Zumla

University College London and Royal Free Medical School London, United Kingdom

FOOTNOTES

Conflict of Interest Statement: K.D., G.R., and A.Z. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

REFERENCES

1. Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, Shigeto E, Harada N, Mitarai S, Okada M, et al. Specific detection of tuberculosis infection: an interferon-–based assay using new antigens. Am J Respir Crit Care Med 2004;170:59–64.[Abstract/Free Full Text]
2. Geluk A, Van Meijgaarden KE, Franken KL, Subronto YW, Wieles B, Arend SM, Sampaio EP, de Boer T, Faber WR, Naafs B, et al. Identification and characterization of the ESAT-6 homologue of Mycobacterium leprae and T-cell cross-reactivity with Mycobacterium tuberculosis. Infect Immun 2002;70:2544–2548.[Abstract/Free Full Text]
3. Geluk A, Van Meijgaarden KE, Franken KL, Wieles B, Arend SM, Faber WR, Naafs B, Ottenhoff TH. Immunological crossreactivity of the Mycobacterium leprae CFP-10 with its homologue in Mycobacterium tuberculosis. Scand J Immunol 2004;59:66–70.[CrossRef][Medline]
4. Cardoso FL, Antas PR, Milagres AS, Geluk A, Franken KL, Oliveira EB, Teixeira HC, Nogueira SA, Sarno EN, Klatser P, et al. T-cell responses to the Mycobacterium tuberculosis–specific antigen ESAT-6 in Brazilian tuberculosis patients. Infect Immun 2002;70:6707–6714.[Abstract/Free Full Text]
5. Maguire H, Dale JW, McHugh TD, Butcher PD, Gillespie SH, Costetsos A, Al-Ghusein H, Holland R, Dickens A, Marston L, et al. Molecular epidemiology of tuberculosis in London 1995–7 showing low rate of active transmission. Thorax 2002;57:617–622.[Abstract/Free Full Text]
6. Arend SM, Van Meijgaarden KE, de Boer K, de Palou EC, Van Soolingen D, Ottenhoff TH, van Dissel JT. Tuberculin 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.[CrossRef][Medline]

From the Authors:

The specificity concerns of Dheda and colleagues were raised previously by van Pittius and colleagues (1) and discussed by Geluk and colleagues (1), who suggested that, although early secreted antigenic target 6-kD protein (ESAT-6) and culture filtrate protein 10 (CFP-10) are shared by Mycobacterium leprae and M. kansasii and some rare or nonpathogenic mycobacteria, or both, this is likely to be of little diagnostic consequence. That nontuberculous infections can cross-react in this test was demonstrated by our observation that all three M. kansasii cases showed positive reactions. However, cross-reactivity of exposure to nonpathogenic mycobacteria has not been clearly demonstrated, and this should be further studied both experimentally and epidemiologically. Because the regional prevalence of nontuberculous mycobacteria encoding ESAT-6, CFP-10 (or homologs), or both is not always quantifiable, particularly in tropical areas, regional studies may be warranted. However, our study was conducted in Japan where the influence of such infections is considered negligible, as suggested by the high specificity observed, and we implicitly assumed the same state predominates for most situations in the developed world, with some reservations for the cases of testing immigrants.

Dr. Dheda and colleagues cite the range of sensitivity of the test with ESAT-6 by Cardoso and colleagues (2). This is inappropriate, because this review is based on the comparison of studies using quite different testing methods and antigen preparations. Many of the previous studies referred to by Dheda and colleagues used only ESAT-6, in contrast to the use of both CFP-10 and ESAT-6 peptides in the standardized method that we report. It is clear from both our study and previous reports reviewed (3) that the use of both antigens increases sensitivity. Based on the above arguments and on a report that the ethnicity has no effect in IFN- release testing (4), I think the regional studies on determining the test's sensitivity in tuberculosis cases as suggested by Dr. Dheda and colleagues is of lower priority.

Despite a small possibility of lower specificity in some situations, the use of whole-blood IFN- responses to ESAT-6 and CFP-10 as an immunodiagnostic characteristic for both active and latent tuberculosis clearly has specificity and sensitivity that are superior to alternative screening methods.

Toru Mori

Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association Tokyo, Japan

FOOTNOTES

Conflict of Interest Statement: T.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

REFERENCES

1. Gey van Pittius NC, Warren RM, van Helden PD. ESAT-6 and CFP-10: what is the diagnosis? Infect Immun 2002;70:6509–6510; author reply, p. 6511.
2. Cardoso FLL, Antas PRZ, Milagres AS, Geluk A, Franken KLMC, Oliveira EB, Teixeira HC, Nogueira SA, Sarno EN, Klatser P, et al. T-cell responses to the Mycobacterium tuberculosis–specific antigen ESAT-6 in Brazilian tuberculosis patients. Infect Immun 2002;70:6707–6714.
3. Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, Shigeto E, Harada N, Mitarai S, Okada M, et al. Specific detection of tuberculosis infection: an interferon-–based assay using new antigens. Am J Respir Crit Care Med 2004;170:59–64.
4. Mazurek GH, LoBue PA, Daley CL, Bernardo J, Lardizabal AA, Bishai WR, Iademarco MF, Rother JS. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001;286:1740–1747.[Abstract/Free Full Text]

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