Screening for latent tuberculosis infection (LTBI) is indicated before immunosuppressive therapies but is complicated by lack of a gold standard and limited by, e.g., immunosuppression. This study... Show moreScreening for latent tuberculosis infection (LTBI) is indicated before immunosuppressive therapies but is complicated by lack of a gold standard and limited by, e.g., immunosuppression. This study aimed to investigate a series of patients diagnosed with LTBI during screening before immunosuppressive therapy, describing how the use of diagnostic tests and treatment evolved over time. This retrospective cohort study included all individuals diagnosed with LTBI during screening before intended immunosuppressive therapy in a tertiary care hospital between January 2000 and December 2017. Evidence for LTBI, including history, tuberculin skin test (TST), QuantiFERON (QFT) result and suggestive lesions on chest radiography (CXR), and CT scan if available, was analyzed. The study included 295 individuals with LTBI, with median follow-up of 3.8 years (IQR 1.7-7.4 years). During screening, TST, QFT, and CXR were positive in 80.8%, 53.4%, and 22.7%, respectively. Chest CT revealed lesions associated with past tuberculosis infection in around 70%, significantly more frequent than CXR. In patients diagnosed with LTBI, we observed that the use of TST declined over time whereas the use of QFT increased, and that isoniazid was replaced with rifampicin as preferential treatment. Preventive treatment was started in 82.3%, of whom 88.6% completed treatment. During follow-up, no individuals developed active tuberculosis. The diagnosis of LTBI was based on history, TST, QFT, and/or CXR in nearly every possible combination, but mostly on TST and QFT. The most striking trends were the decreased use of TST, increased use of QFT, and the replacement of isoniazid with rifampicin for treatment. Show less
Tuberculosis (TB) remains one of the most serious public health problems with one third of the world population latently infected with Mycobacterium tuberculosis. The diagnosis of LTBI relied until... Show moreTuberculosis (TB) remains one of the most serious public health problems with one third of the world population latently infected with Mycobacterium tuberculosis. The diagnosis of LTBI relied until recently on the tuberculin skin test (TST) where a crude mixture of antigens is injected intradermally and induration is measured after 74 hours. False-positive test results occur frequently and are due to cross-reactivity with prior BCG-vaccination or infection with other Mycobacteria. A few years ago new in-vitro assays have been developed who use the TB-specific antigens ESAT-6 and CFP-10. They are commonly referred to as interferon-g release assays (IGRA) and have been evaluated in the studies described in this thesis. These studies have shown that IGRA have added value for the specific diagnosis of LTBI, but as is the case for any other assay, they have limitations as well. The results of IGRA should therefore be interpreted carefully in the light of the setting and the complete clinical data. Future research should not be limited to enhance the performance of IGRA but also include new opportunities, like an improved skin test of the detection of bacterial products in clinical specimens. Show less
This thesis focuses on cellular immunity against mycobacteria during latency with the aim to contribute to improved immunodiagnosis of latent TB and to gain insight into immune responses which play... Show moreThis thesis focuses on cellular immunity against mycobacteria during latency with the aim to contribute to improved immunodiagnosis of latent TB and to gain insight into immune responses which play a role in controlling latent infection. Several new highly M. tuberculosis-specific peptides mixtures were identified to optimize the sensitivity of immunodiagnostic assays. The performance of interferon-gamma-release-assays (IGRA) for detection of latent TB were evaluated. Two short-incubation IGRA, QuantiFERON-TB Gold and T-SPOTTM.TB, were found to correlate better to the level of exposure to M. tuberculosis than the tuberculin skin test (TST), indicating that these assays are very sensitive for detection of recent infections. However, short-incubation IGRA are less sensitive than prolonged-incubation IGRA and TST for detection of latent TB acquired in the past. The search for proteins that are specifically targeted by the immune system during latency led to the identification of several antigens encoded within the DosR-regulon. This set of genes of M. tuberculosis is strongly upregulated by during in vitro models of latency. These antigens, including 16kDa _-crystallin, were preferentially recognized by latently infected individuals, which suggest that T-cell responses to latency antigens are associated with natural protection against reactivation of TB, warranting their further study as vaccine candidates. Show less
