LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Abstract

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-c release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection.In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Superior Sensitivity of Ex Vivo IFN-γ Release Assays as Compared to Skin Testing in Immunocompromised Patients

“…While these circadian dynamics of drug levels in transplant patients may directly contribute to impaired T cell function in the skin test in vivo, IGRAs have the advantage that blood samples can be drawn before the intake of immunosuppressive medication to ensure lowest possible drug levels. In addition, IGRAs may be superior, as IFN-g induction in vitro can be optimized with respect to antigen concentration, antigen composition or stimulation times (1,23). Moreover, the addition of costimulatory antibodies in the stimulatory reaction has been shown to increase T cell responses without compromising specificity (24,25).…”

“…The tuberculin skin test (TST) has been used for more than a century to diagnose a latent infection with Mycobacterium tuberculosis, which is defined indirectly by the presence of an immune response toward mycobacterial antigens (1). The skin test bears a number of drawbacks such as a need for a second visit to read the result or low specificity due to false-positive results after prior Bacille Calmette-Guerin (BCG) vaccination or infection with nontuberculous mycobacteria (NTM) (1,2).…”

“…The skin test bears a number of drawbacks such as a need for a second visit to read the result or low specificity due to false-positive results after prior Bacille Calmette-Guerin (BCG) vaccination or infection with nontuberculous mycobacteria (NTM) (1,2). Moreover, concerns exist on a low sensitivity among immunocompromised individuals such as patients with chronic renal failure or transplant recipients on immunosuppressive drug therapy (3)(4)(5).…”

“…In addition, unlike in skin testing where purified protein derivative (PPD) is used as a stimulus, the specificity for M. tuberculosis infection in IGRAs is higher due to the use of the M. tuberculosis-specific antigens early secreted antigenic target (ESAT)-6, and culture filtrate protein (CFP)-10 for the stimulatory reaction in vitro (1,6). The IGRA principle relies on the stimulation of blood cells, where the presence of a specific immunity is either quantified by the analysis of IFN-g in the supernatant using an enzyme-linked immunoassay (ELISA), or by direct quantitation of reactive T cells using the enzyme-linked immunospot (ELISPOT) assay or using intracellular cytokine-staining by flow cytometry (FACS analysis) (1,7). All three in vitro assays represent a promising alternative to skin testing, although this is difficult to address due to the lack of a gold standard for the detection of a latent infection with M. tuberculosis (1).…”

“…The IGRA principle relies on the stimulation of blood cells, where the presence of a specific immunity is either quantified by the analysis of IFN-g in the supernatant using an enzyme-linked immunoassay (ELISA), or by direct quantitation of reactive T cells using the enzyme-linked immunospot (ELISPOT) assay or using intracellular cytokine-staining by flow cytometry (FACS analysis) (1,7). All three in vitro assays represent a promising alternative to skin testing, although this is difficult to address due to the lack of a gold standard for the detection of a latent infection with M. tuberculosis (1). Moreover, knowledge on their sensitivity in immunocompromised individuals is limited until now.…”