Genetic Epidemiology of Tuberculosis Susceptibility: Impact of Study Design

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB

Interferon-γ Release Assays for Diagnosing Mycobacterium tuberculosis Infection in Renal Dialysis Patients

Background and objectives: End-stage renal disease (ESRD) patients are at high risk for tuberculosis (TB). IFN-γ release assays that assess immune responses to specific TB antigens offer potential advantages over tuberculin skin testing (TST) in screening such patients for Mycobacterium tuberculosis infection. This study sought to determine whether IFN-γ release assay results are more closely associated with recent TB exposure than TST results

Rapid Identification of the Mycobacterium tuberculosis Complex by Combining the ESAT-6/CFP-10 Immunochromatographic Assay and Smear Morphology▿

Early secretory antigen 6 (ESAT-6) and cell filtrate protein 10 (CFP-10) are two antigens secreted as a complex by the replicating Mycobacterium tuberculosis complex (MTC). Recently, an immunochromatographic assay (ICA) using a monoclonal antibody against the ESAT-6/CFP-10 complex was developed for the purpose of MTC detection. In this study, the efficacy of the assay was tested with 603 BACTEC cultures that were incubated for 3 additional days after positive signals appeared in the BACTEC MGIT 960 system. Bacterial isolates were recovered from these 603 BACTEC cultures, and 332 MTC isolates, 270 nontuberculosis mycobacterial isolates, and 1 Nocardia isolate were identified by using standard biochemical assays. The ESAT-6/CFP-10 assay detected 322 MTC cultures, resulting in a sensitivity of 97% and a specificity of 97.4%. To reduce the false-negative rate and improve the sensitivity, either serpentine cording in an acid-fast bacillus stain of the cultural smear, the ESAT-6/CFP-10 assay, or a combination of both was used for MTC detection. The sensitivity was then increased to 99.1%, and the negative predictive value increased to 98.9%, but the specificity decreased to 94.8% and the positive predictive value decreased to 95.9%. However, a combination of serpentine cording in cultural smears and the positivity of the ICA resulted in the specificity and positive predictive values of 100%. Therefore, BACTEC cultures with both serpentine cording and positivity of the ESAT-6/CFP-10 assay could be reported to contain MTC directly. The ESAT-6/CFP-10 assay may be an alternative of the Capilia assay (MPB64-ICA) as a convenient and cost-effective method for identification of MTC in culture

Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

RATIONALE:Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. OBJECTIVES:We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment. MATERIALS AND METHODS:We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24. RESULTS:There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index. CONCLUSIONS:Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression

Role of the Clinical Mycobacteriology Laboratory in Diagnosis and Management of Tuberculosis in Low-Prevalence Settings▿

Tuberculosis (TB) remains a global epidemic, despite a significant decline in reported cases in the United States between 2008 and 2009. While the exact nature of this decline is unclear, one thing remains certain: TB, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, is no longer restricted to developing regions of the globe. It is of vital importance that both public and private mycobacteriology laboratories maintain the ability to detect and identify Mycobacterium tuberculosis from patient specimens, as well as correctly determine the presence of antibiotic resistance. To do this effectively requires careful attention to preanalytical, analytical, and postanalytical aspects of testing. Respiratory specimens require digestion and concentration followed by fluorescence microscopy. The Centers for Disease Control and Prevention (CDC) recommends the performance of a direct nucleic acid amplification method, regardless of smear results, on specimens from patients in whom the suspicion of tuberculosis is high. Liquid-based technologies are more rapid and sensitive for the detection of M. tuberculosis in culture and nucleic acid probes, but biochemicals are preferred for identification once growth is detected. Susceptibility testing is most often done using either the agar proportion method or a commercial broth system. New genotypic and phenotypic methods of susceptibility testing include first- and second-line agents and are promising, though not yet widely available. Finally, gamma interferon release assays are preferred to the tuberculin skin test for screening certain at-risk populations, and new CDC guidelines are available that assist clinicians in their use

<i>Mycobacterium tuberculosis</i> (Mtb) specific T cell responses during antituberculosis treatment in subjects with baseline malnutrition (BMI≤17).

<p>The subgroup of subjects, who started therapy with a BMI≤17 with baseline and week 24 analyzable ELISPOT data (n = 11) are shown. The magnitude of the Mtb specific T cell response is shown by IFN-γ ELISPOT to ESAT-6 and CFP-10 and reported in spot forming units per 250,000 T cells. Connected lines at baseline and week 24 reflect a individual subject's profile for the Mtb specific CD4⁺ T cell response (A) and the Mtb specific CD8⁺ T cell response (B).</p

Microbiologic burden of <i>mycobacterium tuberculosis</i> in relation to duration of treatment.

<p>Definition of abbreviations: col.  =  colonies</p>*<p>Total n (%) calculated less missing data and contamination</p