Rational use of immunodiagnostic tools for tuberculosis infection23.10.2009
Prof. Massimo Amicosante, from the University of Rome “Tor Vergata”, and Prof. Roumiana Markova from the NCIPD are developing joint projects in the field of the immunodiagnosis of tuberculosis infection to improve the current diagnostic systems. They summarised the present state of art in the field in the overview article "Rational use of immunodiagnostic tools for tuberculosis infection”.
At the beginning of the twenty-first century, tuberculosis (TB) still remains a major challenge for humanity, with enormous health and socio-economic impacts. WHO data report that approximately two billion people are infected with Mycobacterium tuberculosis (MTB), and each year about 9 million develop active TB and two million die from TB. The number of diseased in Eastern Europe over the past 10 years has increased by more than 25%.
This "renaissance" of TB has received a boost by the lethal combination of TB and AIDS, as co-infected people with HIV and MTB, due to the strong immune deficiency, more often develop active TB. Serious problems are also represented by the MDR and XDR forms of MTB, indicated now by the WHO as "threat to the entire world community".
As active tuberculosis leads to the rapid spread of MTB throughout the body, the expressed diagnosis and effective therapy of TB patients as well as the preventive therapy of the exposed/infected people are the most important components of programs for the control of TB.
Until recently, the tuberculin skin test (TST), made by the Mantuox method, appeared to be the only means for assessing the immune response to MTB in both latent and active TB infection. TST for more than 100 years had been considered the gold standard in immunodiagnosis of TB infection. However, the long experience in using this test showed that it is affected by many problems in its implementation like possible errors and limitations both in measurement of skin reaction, subjective interpretation, influence by previous BCG vaccination or re-immunization, and boost effects due to a previous test. Consequently, its specificity is very low in certain clinical settings, especially in BCG-vaccinated individuals.
In recent years, there has been the need to create new, more reliable immunodiagnostic tests to prove both the latent and active TB infection. With the help of intensive comparative DNA analysis several areas of the MTB genome have been detected which are not present in all BCG vaccine strains and most non-tuberculosis mycobacteria, such as the RD1 region (Region of Differences-1). This region has been the object of extensive studies to identify antigens suitable for immunodiagnosis and to develop new vaccines. The most relevant antigens identified in this region were the ESAT-6 (Early Secreted Antigen Target-6) and the CFP-10 (Culture Filtrate Protein-10), which were found to be highly immunogenic. These two proteins are the basis for new tests, based on IFN-gamma release (IGRAs), which are among the greatest achievements in the last hundred years in the diagnosis of MTB infection. The biggest advantage of the new IGRA tests is their high specificity. Their testing in different clinical conditions has shown that they possess several advantages over the TST.
At present two commercial versions of IGRA tests for tuberculosis infection are available: the QuantiFERON-TB Gold developped by Cellestis (Australia) and the T-SPOT.TB develped by Oxford Immunotec (UK).
Bulgaria was the first country in Europe to introduce the QuantiFERON-TB test in the routine practice for immunodiagnosis of TB infection. Further, both new IFN-gamma-based assays QuantiFERON-TB and T-SPOT.TB were introduced for the first time in Bulgaria at the NCIPD.
In the past years, it has been accumulated a large amount of data on the use of IGRA tests in different clinical settings. In many countries different schemes and algorithms for the use of IGRAs, alone or in combination with the TST, have been recommended for the most appropriate use of these tests in clinical practice. Based on all recommendations till now, the following conclusions could be drawn:
The most preferred use of IGRAs is the “two-step model” in which the first test performed is the TST, then to confirm the positive IGRA test is applied;
This approach approach is particularly preferred in countries with mandatory BCG immunization;
The direct use of IGRA tests is prefered in some specific patient groups such as:
o Patients receiving anti-TNF-alpha therapy
o Immunosuppressed patients (HIV/AIDS, post-transplant patients receiving immunosuppressive therapy, patients on haemodialisis, cancer patients)
o Children from different age groups
Although ther IGRAs are still expensive, and for economic reasons are not yet included in national programs to control TB, there are strong evidences of the benefits, both technical and economical of IGRA tests compared to the TST, namely: (1) high specificity (> 99%) and sensitivity (93%) (2) IGRAs avoid false positive results in TST due to prior BCG immunization and cross-reactivity with environmental mycobacteria (3) IGRAs avoid the subjectivity in the interpretation and reporting the TST (4) reduce the need of additional medical testing (radiology, etc) in the case of a false positive result of the TST (5) IGRAs allow to adequately treat only subjects truely infected with MTB (6) IGRAs avoid unnecessary anti-TB treatment and its toxicity (7) IGRAs avoid the boost effect due to repeated application of TST (8) IGRAs need only one visit to the person examined (9) IGRAS in its overall reduce the price of control of TB infection.
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