MycobacteriologyEvaluation of the diagnostic utility of a whole-blood interferon-γ assay for determining the risk of exposure to Mycobacterium tuberculosis in Bacille Calmette-Guerin (BCG)-vaccinated individuals
Introduction
Tuberculosis (TB) remains a global public health problem, with an estimated 3 million deaths and 8 million new cases yearly (Dye et al., 1999, Corbett et al., 2003). Most individuals infected with Mycobacterium tuberculosis control the bacilli and develop asymptomatic latent infection, a reservoir currently estimated to be one-third of the total human population. Latently infected individuals face a lifetime risk of reactivation with symptomatic TB disease depending upon their immune status (American Thoracic Society, 2000, World Health Organization, 2005). There is a dramatic increase in the risk of developing reactivation TB in HIV-coinfected individuals and in patients receiving anti-tumor necrosis factor (TNF) antibody-based therapies for, among other indications, rheumatoid arthritis (Odhiambo et al., 1999, Winthrop, 2006). Because HIV infection and the use of anti-TNF antibody therapeutics have become increasingly common, there is an urgent need for more efficient ways of diagnosing latent TB (Lawn et al., 2005, Aziz and Wright, 2005).
The tuberculin skin test (TST) has long been used as a gold standard for the diagnosis of latent TB (American Thoracic Society, 2000). The TST is a measure of a delayed-type hypersensitivity response to purified protein derivative (PPD). PPD is a mixture of mycobacterial antigens, some of which are shared between nontuberculous mycobacteria (NTM) and Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine strains (Anderson et al., 2000, Lee and Holzman, 2002). As a result, the TST is not adequate for the diagnosis of latent TB in populations with high BCG coverage and/or high levels of NTM exposure (Anderson et al., 2000, Mazurek et al., 2001, Ewer et al., 2003, Pai et al., 2004). The sensitivity also may be low in individuals with decreased immune function (i.e., AIDS and other immunosuppressive conditions, advanced TB, malnutrition) (Liebeschuetz et al., 2004). To increase the specificity of such tests, we used 2 M. tuberculosis-specific antigens, early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10). These proteins, encoded within the region of difference 1 (RD1) of the M. tuberculosis genome, are specific to M. tuberculosis and are not present in PPD, because they are obviously not encoded by BCG vaccine strains. In addition, immunoreactive orthologs are not expressed in most NTM species (Sorenson et al., 1995, Harboe et al., 1996, Anderson et al., 2000). Several studies have reported that RD1-based (ESAT-6 and/or CFP-10) interferon (IFN)-γ assays have higher specificity than TST and are less influenced by previous BCG vaccination (Ravn et al., 1999, Arend et al., 2000, Brock et al., 2001, Mori et al., 2004, Pai et al., 2004). Newer generation test kits using these 2 individual antigens have already been developed, and reports of their utility are now beginning to emerge (Pai et al., 2004, Kang et al., 2005). More recently, an enhanced and simplified QuantiFERON® assay has been developed using a mixture of overlapping peptides representing ESAT-6, CFP-10, and a portion of the TB antigen TB7.7 to enhance the sensitivity of the assay.
The aim of this study was to compare the usefulness of this enhanced IFN-γ based assay with PPD stimulation for the diagnosis of latent TB infection in Korea where BCG vaccination is mandatory.
Section snippets
Study subjects
There were 3 cohorts of study participants. Group A included 48 healthy students of a medical school in Busan and was considered to be a “low-risk group”. They consisted of 32 males and 16 females (mean age, 23.7 ± 0.2 years). All of them had a scar on the shoulder, indicating that they had been BCG vaccinated. Group B included 25 nurses who have been working for the past 1 to 27 years (mean, 12.6 ± 1.6 years) at the National Masan Tuberculosis Hospital (NMTH) in Masan, South Korea. All were
Whole-blood response to PPD in BCG-vaccinated healthy subjects and TB patients
Whole-blood IFN-γ production in response to PPD was measured in 3 cohorts of volunteers with very different risk of having latent or active TB. Group A was composed of healthy normal medical students. Both because of their age and their lack of clinical experience, we considered this group to be at relatively “low risk” for TB exposure. All of these volunteers had a BCG scar, and, as expected, stimulation of their whole blood with PPD identified 85.2% of group A as producing significant amounts
Discussion
In this study, we were successful in discriminating latent infection from BCG vaccination in 3 cohorts at varying risk for TB exposure using an IFN-γ assay kit based on the M. tuberculosis-specific antigens. TST is also likely to be a good indicator of latent infection in a population of BCG-unvaccinated subjects but is confounded by BCG vaccination (Brock et al., 2004). In the present study, we demonstrated that QuantiFERON® test kit clearly differentiated the BCG-vaccinated healthy
Acknowledgments
This work was partly funded by the International Research Division of NIAID, NIH.
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