Advances in TB diagnostics
In view of these limitations, there is a need for less complicated and more accurate diagnostic tests. Beyond the current efforts to prevent, detect and cure TB, new tools are needed to radically transform the fight against TB, to contain the threat of drug-resistant strains such as MDR-
TB and XDR-
TB and to seriously target elimination of tuberculosis.
Tuberculin Skin Test (TST)
The Mantoux TST, which uses five tuberculin units of purified protein derivative, is the standard method for detecting infection by M. tuberculosis.
The reaction is measured as millimeters of induration after 48 to 72 hours.
Since TST is the only way to determine asymptomatic infection by M.
tuberculosis, the false-negative rate cannot be calculated. The relatively low
sensitivity and specificity of TST make the test very useful for persons at high
risk for TB infection or disease but undesirable for use in persons at low risk.
Moreover, TST cannot easily distinguish between latent infection and active
disease. Also, TST is less sensitive in immuno-compromised persons.
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Diagnostic Challenges In TB
Despite the enormous global burden of TB and the overall low rates of case
detection, conventional approaches to diagnosis continue to rely on tests that
have major drawbacks.
- Today's most commonly used diagnostic tool, the light microscope, is more than 100 years old and is relatively insensitive (particularly in the presence of HIV co-infection), giving no indication of drug susceptibility
- Culture is technically complex and slow
- Determination of drug susceptibility is even more technically complex and slower yet
- Chest radiography is nonspecific
- Tuberculin skin testing is imprecise, and the results are often nonspecific
New Approaches To Diagnosis
Significant improvement in the understanding of molecular biology of M. tuberculosis has led to the development of newer diagnostic techniques of tuberculosis.Advances in the diagnostics for latent TB infection, active TB infection and for rapid detection of drug resistance have been briefly described in the sections below.
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Diagnostics For Latent TB Infection4
The tuberculin skin test was, until recently, the only tool available for detecting Latent TB Infection. Although the TST is useful in clinical practice, it has several known limitations. Because of advances in immunology and genomics, for the first time, an alternative has emerged in the form of a family of T-cell-based in vitro assays that detect IFN-y. These assays detect cellular immune response by measuring IFN-y released by T cells after stimulation by M. tuberculosis antigens.
Early versions of IFN-y Assays (IGRAs) used Purified Protein Derivative (PPD) as the stimulating antigen, but these tests have been replaced by newer versions that use antigens (Early Secreted Antigen Target-6 [ESAT-6] and Culture Filtrate Protein-10 [CFP-10]) that are substantially more specific for M. tuberculosis than PPD. These proteins, encoded by genes located within the Region of Difference 1 (RD1) segment of the M. tuberculosis genome, are more specific for M. tuberculosis than PPD because they are not shared with the Bacillus Calmette-Guerin (BCG) vaccine strains or certain non-tuberculous mycobacterial species of clinical relevance.
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Two IFN-y assays, based on RD1 antigens, are available as commercial kits: the QuantiFERON-TB Gold assay (Cellestis Ltd., Carnegie, Australia) and the T SPOT-TB (Oxford Immunotec, Oxford, UK). The QuantiFERON-TB Gold assay is a whole blood, ELISA-based test, whereas the T SPOT-TB test uses peripheral blood mononuclear cells and enzyme linked immunospot (ELISPOT) technology. The QuantiFERON-TB Gold assay comes in two formats: a 24-well culture plate format and a newer, simplified, in-tube format. The QuantiFERON-TB Gold assay has FDA-approval.
Novel T-cell based assays (T SPOT-TB and QuantiFERON-TB Gold assay) may improve the ability to diagnose M. tuberculosis infection, which has particular relevance in HIV-infected or severely malnourished children in whom the traditional TST pe
rforms poorly. However, just like TST, IFN-y assay cannot easily distinguish between latent infection and active disease.