The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non-BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.

SUMMARY Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis . Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

Madhu Pai and colleagues introduce the BCG World Atlas, an open access, user friendly Web site for TB clinicians to discern global BCG vaccination policies and practices and improve the care of their patients.

Healthcare workers (HCWs) are at increased risk of exposure to tuberculosis (TB). Traditionally, screening for latent TB infection (LTBI) is done using the tuberculin skin test (TST). Interferon-gamma release assays (IGRAs) are now increasingly being used for diagnosis of LTBI, but their role in HCW screening is unclear. A systematic review was conducted of all IGRA studies in HCWs to summarise their performance in cross-sectional and serial testing settings. By searching four electronic databases and other sources, all available studies using any one of the commercial IGRA assays in HCWs were retrieved and screened. 50 unique studies were identified which met the inclusion criteria including five from high TB incidence settings. Among 24 cross-sectional studies in low TB incidence settings, the pooled prevalence of positive IGRA using either test was significantly lower than for a positive TST. However, in high-incidence settings (n¼2) there were no consistent differences in the prevalence of positive tests. IGRAs showed good correlation with occupational risk factors for TB exposure in low-incidence settings. Only 10 studies assessed use of IGRA for serial testing and all showed large variation in the rates of conversions and reversions, with no data suggesting that IGRAs are better at identifying the incidence of new TB infection than the TST. The use of IGRAs instead of TST for one-time screening may result in a lower prevalence of positive tests and fewer HCWs who require LTBI treatment, particularly in low TB incidence settings. However, the use of IGRAs for serial testing is complicated by lack of data on optimum cut-offs for serial testing and unclear interpretation and prognosis of conversions and reversions. Further longitudinal research will be required to inform guidelines on serial testing using IGRAs.

The global extensively drug-resistant tuberculosis (TB) response plan calls for implementation of rapid tests to screen patients at risk of drug-resistant TB. Currently, two line probe assays exist, the INNO-LiPA1Rif.TB assay (Innogenetics, Ghent, Belgium) and the GenoType1 MTBDR assay (Hain LifeScience GmbH, Nehren, Germany). While LiPA studies have been reviewed, the accuracy of GenoType assays has not been systematically reviewed.The present authors carried out a systematic review and used meta-analysis methods appropriate for diagnostic accuracy. After the literature searches, 14 comparisons for rifampicin and 15 comparisons for isoniazid were identified in 10 articles that used GenoType MTBDR assays. Accuracy results were summarised in forest plots and pooled using bivariate randomeffects regression.The pooled sensitivity (98.1%, 95% confidence interval (CI) 95.9-99.1) and specificity (98.7%, 95% CI 97.3-99.4) estimates for rifampicin resistance were very high and consistent across all subgroups, assay versions and specimen types. The accuracy for isoniazid was variable, with lower sensitivity (84.3%, 95% CI 76.6-89.8) and more inconsistent than specificity (99.5%, .GenoType MDTBR assays demonstrate excellent accuracy for rifampicin resistance, even when used on clinical specimens. While specificity is excellent for isoniazid, sensitivity estimates were modest and variable. Together with data from demonstration projects, the meta-analysis provides evidence for policy making and clinical practice.

BackgroundVariability in interferon-gamma release assays (IGRAs) results for tuberculosis has implications for interpretation of results close to the cut-point, and for defining thresholds for test conversion and reversion. However, little is known about the within-subject variability (reproducibility) of IGRAs. Several national guidelines recommend a two-step testing procedure (tuberculin skin test [TST] followed by IGRA) for the diagnosis of LTBI. However, the effect of a preceding TST on subsequent IGRA results has been reported in studies with apparently conflicting results.Methodology/FindingsWe conducted a systematic review to synthesize evidence on within-subject variability of IGRA results and the potential boosting effect of TST. We searched several databases and reviewed citations of previous reviews on IGRAs. We included studies using commercial IGRAs, in addition to non-commercial versions of the ELISPOT assay. Four studies, fulfilling our predefined criteria, examined within-subject variability and 13 studies evaluated TST effects on subsequent IGRA responses. Meta-analysis was not considered appropriate because of heterogeneity in study methods, assays, and populations. Although based on limited data, within-subject variability was present in all studies but the magnitude varied (16-80%) across studies. A TST induced “boosting” of IGRA responses was demonstrated in several studies and although more pronounced in IGRA-positive (i.e. sensitized) individuals, also occurred in a smaller but not insignificant proportion of IGRA-negative subjects. The TST appeared to affect IGRA responses only after 3 days and may apparently persist for several months, but evidence for this is weak.Conclusions/SignificanceAlthough reproducibility data are scarce, significant within person IGRA variability has been reported. If confirmed in more studies, this has implications for the interpretation of results close to the cut-point and for definition of conversions and reversions. Although the effect of TST on IGRA results is likely to be inconsequential in IGRA-positive subjects, in IGRA-negative subjects, the interpretation of results may be confounded by a preceding TST if administered more than 3 days prior to an IGRA.

Over recent years, there has been an increasing acknowledgment of the diversity that exists among Mycobacterium tuberculosis clinical isolates. To facilitate comparative studies aimed at deciphering the relevance of this diversity to human disease, an unambiguous and easily interpretable method of strain classification is required. Presently, the most effective means of assigning isolates into a series of unambiguous lineages is the method of Gagneux et al. (S. Gagneux et al., Proc. Natl. Acad. Sci. USA 103:2869-2873, 2006) that involves the PCR-based detection of large sequence polymorphisms (LSPs). In this manner, isolates are classified into six major lineages, the majority of which display a high degree of geographic restriction. Here we describe an independent replicate of the Gagneux study carried out on 798 isolates collected over a 6-year period from mostly foreign-born patients resident on the island of Montreal, Canada. The original trends in terms of bacterial genotype and patient ethnicity are remarkably conserved within this Montreal cohort, even though the patient distributions between the two populations are quite distinct. In parallel with the LSP analysis, we also demonstrate that "clustered" tuberculosis (TB) cases defined through restriction fragment length polymorphism (RFLP) analysis (for isolates with >6 IS6110 copies) or RFLP in combination with spoligotyping (for isolates with <6 IS6110 copies) do not stray across the LSP-defined lineage boundaries. However, our data also demonstrate the poor discriminatory power of either RFLP or spoligotyping alone for these low-IS6110-copy-number isolates. We believe that this independent validation of the LSP method should encourage researchers to adopt this system in investigations aimed at elucidating the role of strain variation in TB.Infection with Mycobacterium tuberculosis, the bacillus responsible for tuberculosis (TB), still results in almost 2 million global deaths each year despite the availability of effective chemotherapy and a partially effective vaccine (bacillus Calmette-Guérin [Mycobacterium bovis BCG]) for well over half a century (43). Even though there have been real advances in our level of understanding of M. tuberculosis metabolic pathways and in the identification of potential virulenceassociated molecules since the advent of the "postgenomic era" (8), significant improvements with respect to treatment, diagnosis, and prevention of TB still remain elusive. Recent descriptions of variably expressed virulence factors and disease outcomes that are associated with particular lineages of M. tuberculosis further emphasize the layers of complexity that need to be overcome in our efforts to combat this devastating disease (6,25,31,32,38).While the fact that TB phenotypic diversity exists is no longer in dispute, there is heightened interest in epidemiological circles in establishing the relevance of this diversity to human disease. Of particular note are the recent publications suggesting that strains belonging to the M. tuberculosis W/...

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested.