Chest
Volume 131, Issue 6, June 2007, Pages 1898-1906
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Translating Basic Research Into Clinical Practice
Diagnosing Tuberculosis Infection in the 21st Century: New Tools To Tackle an Old Enemy

https://doi.org/10.1378/chest.06-2471Get rights and content

The century-old tuberculin skin test (TST) was until recently the only means of diagnosing latent tuberculosis infection (LTBI). Recent advances in mycobacterial genomics and human cellular immunology have resulted in two new blood tests that detect tuberculosis infection by measuring in vitro T-cell interferon (IFN)-γ release in response to two unique antigens that are highly specific for Mycobacterium tuberculosis but absent from bacille Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria. One assay, the enzyme-linked immunospot (ELISpot) [T-SPOT.TB; Oxford Immunotec; Oxford, UK] enumerates IFN-γ–secreting T cells, while the other assay measures IFN-γ concentration in supernatant by enzyme-linked immunosorbent assay (ELISA) [QuantiFERON-TB Gold; Cellestis; Carnegie, Australia]. A large and growing clinical evidence base indicates that both tests are more specific than the skin test because they are not confounded by prior BCG vaccination. In active tuberculosis, ELISA has similar sensitivity to the skin test, while ELISpot is significantly more sensitive. Current cross-sectional evidence suggests that for diagnosis of LTBI, sensitivity of ELISA is similar to TST, while ELISpot appears more sensitive. High specificity will enable clinicians to avoid unnecessary preventive treatment in BCG-vaccinated persons without infection who commonly have false-positive TST results. High sensitivity could enable accurate targeting of preventive treatment to patients with infection at the highest risk of progression to active tuberculosis who frequently have false-negative TST results due to impaired cellular immunity. However, longitudinal studies are needed to define the predictive value of positive blood test results for progression to tuberculosis.

Section snippets

Diagnosing Latent Tuberculosis Infection in the 20th Century

The biology of latent tuberculosis infection (LTBI) is poorly understood, and the condition has hitherto been defined by a positive tuberculin skin test (TST) result in an asymptomatic person exposed to tuberculosis with no clinical or radiographic signs of active tuberculosis. The clinical relevance of this definition is that it carries a small but significant forward risk of progression to active tuberculosis, which is significantly increased in persons with suppressed or immature (ie, young

Translation From Bench to Bedside

Advances in mycobacterial genomics in the late 1990s identified an M tuberculosis genomic segment that is deleted from all strains of BCG vaccine and most environmental mycobacteria, denoted region of difference-1.3 Two proteins encoded by this stretch of DNA, early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), are strong targets of T-helper type 1 T cells in patients with M tuberculosis infection.45 Therefore, a T-cell response to these antigens could, in

Rapidly Expanding Clinical Evidence Base in the Last 5 Years

A large and rapidly growing number of clinical studies with these assays have been published since 2001. The ELISpot evidence base is comprised predominantly of studies using the Lalvani ELISpot test, which has recently been developed into the T-SPOT.TB test (Oxford Immunotec; Oxford, UK) [Table 1]. Therefore, all published studies using either of these assay formats are reviewed here, and the assays are denoted as ELISpot. For QuantiFERON-TB Gold (Cellestis; Carnegie, Australia), studies using

Clinical Performance in People at High Risk of Progression to Tuberculosis

The strategy for diagnosis and treatment of LTBI is based on targeted tuberculin testing, which targets persons at highest risk of progression from LTBI to active tuberculosis.28 This includes all recently infected people (ie, tuberculosis contacts) and people with suppressed or immature (ie, young children) cellular immune systems. Table 2, Table 3, Table 4, Table 5 summarize the performance of the tests in immunocompetent contacts, but what of the high-risk groups in whom the TST has poor

Reliability of the Blood Tests in Routine Use

Indeterminate results can arise for a variety of reasons, but the most significant cause is a failed positive control, which usually reflects underlying cellular immune suppression. Indeterminate results are quite common with ELISA in routine practice, ranging from 12 to 21%,12152529 and are associated with young age (< 5 years), old age (> 80 years),25 and immunosuppression due to a variety of causes, including HIV infection, in which indeterminate results become more common with lower CD4

Direct Comparison of the Blood Tests

Studies directly comparing the two blood tests in the same study populations have recently been published. In patients with active tuberculosis, three reports121331 compared blood tests in a total of 134 patients; the sensitivity of ELISpot was 83 to 95% compared to 74 to 83% for ELISA, and this difference was statistically significant in the largest study.13 Two studies compared the tests head-to-head in persons at risk of LTBI; in a low-prevalence country, close contacts of pulmonary

Summary of Clinical Data

The conclusions from the published studies to date are that neither blood test is confounded by BCG vaccination and both are therefore more specific than the TST. Both tests are more sensitive than the TST in active tuberculosis, with ELISpot having higher sensitivity than ELISA. ELISpot also performs well in HIV-coinfected tuberculosis patients and young children with tuberculosis, but published data with ELISA in these patient populations are lacking. In LTBI, ELISpot probably has higher

From Clinical Trials to Clinical Practice

What should clinicians do with blood test results in practice? Current national guidelines3233 recommend the use of blood tests for diagnosis of LTBI and as an adjunct for the evaluation of patients with suspected tuberculosis. But national guidelines vary, reflecting residual uncertainty about the clinical status of persons with discordant TST and blood test results. Current European guidelines, of which those published by the UK National Institute of Health and Clinical Excellence32 (NICE)

Effect of Treatment on Blood Test Results

The impact of treatment on blood test results has been studied for ELISpot in tuberculosis patients and, more recently, in persons with LTBI. In general, the magnitude of ELISpot responses declines significantly with treatment in both active tuberculosis1023 and LTBI,4041 raising the interesting possibility that the quantitative, dynamic readout of ELISpot might be used to monitor treatment response. This would be particularly useful in LTBI, for which there are no clinical or laboratory

Impact on Clinical Practice Today

The high specificity of both blood tests will lessen the number of persons inappropriately treated on the basis of false-positive TST results caused by prior BCG vaccination. This represents an enabling step for tuberculosis elimination programs in low prevalence countries where, as the prevalence of LTBI declines, an increasing proportion of positive TST results are falsely positive. High diagnostic sensitivity in young children (as evidenced for ELISpot) and immunosuppressed populations (as

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      Immune diagnostic tests based on sensitized T-cells contribute largely to detection of M. tuberculosis infection. Originally – and for almost a century – the tuberculin skin test (TST) was the only available test for diagnosis of M. tuberculosis infection but limited TST specificity led to the invention of alternative methods, the so called IFNγ-release assays (IGRA; e.g. QuantiFERON, T-SPOT.TB))1. IGRA tests are based on short-term in vitro stimulation of peripheral blood immune cells and detect M. tuberculosis infection with higher specificity as compared to the TST2,3.

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    Professor Lalvani is a named inventor for several patents underpinning T-cell–based diagnosis filed by the University of Oxford since 1996. Regulatory approval and commercialization of the Lalvani ELISpot (T-SPOT.TB) has been undertaken by a spin-out company of the University of Oxford (Oxford Immunotec Ltd.; Oxford, UK), in which Professor Lalvani has a share of equity and to which he acts as scientific advisor in a nonexecutive capacity. The University of Oxford has a share of equity in Oxford Immunotec Ltd.

    Professor Lalvani is supported by a Wellcome Senior Research Fellowship in Clinical Science.

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