Clinical Aspects of Immune Responses in Tuberculosis

Abstract

INTRODUCTION Tuberculosis (TB) is a challenging disease for several reasons. These challenges include the global heterogeneous context, with large differences in incidence and diagnostic facilities. The lack of a gold standard for latent TB infection (LTBI) is another challenge, both for clinical practice and for research. Despite many years of research, the complex host-microbe interaction is still incompletely understood, and difficulties persist in the establishment of a quick and definite diagnosis, especially in extrapulmonary TB. Furthermore, it remains difficult to distinguish the different stages of the disease. In this thesis, we focus on several clinical and immunological aspects of TB and how the immune response against M. tuberculosis could facilitate diagnosis of the different disease manifestations. OBJECTIVES AND METHODS 1. LTBI screening and the development of TB is evaluated in patients treated with TNF-α inhibitor therapy in daily clinical practice. 2. Several applications for Interferon Gamma Release Assays (IGRA) in extra-sanguineous body-fluids are evaluated. a. The positive predictive value (PPV) of TB specific ELISpot in bronchoalveolar lavage (BAL) and pleural fluid in real-life clinical practice is evaluated for the diagnosis of TB, together with an attempt to increase the PPV. b. The two commercial IGRA (ELISpot and Quantiferon) are discussed for application in extra-sanguineous body fluids. c. T-lymphocyte responsiveness to the PPD antigen (ELISpot) is measured in patients with sarcoidosis compared to patients with other causes of interstitial lung disease. d. The feasibility of a PPD-based ELISpot in the urine and bladder fluids of patients with bladder malignancies after treatment with intravesical BCG-instillations is explored. 3. QuantiFERON-TB Gold PLUS together with several potential markers are evaluated for the ability to discriminate between active and latent TB. RESULTS AND CONCLUSIONS 1. None of the patients diagnosed with and treated for LTBI developed TB during TNF-α inhibitor therapy. Two patients with negative LTBI screening developed TB, probably due to travelling to TB-endemic countries during TNF-α inhibitor therapy, which should be mentioned as a risk. 2. IGRA in extra-sanguineous body-fluids is possible with different antigens. a. The PPV of TB-specific ELISpot in BAL and pleural fluid could be increased using a cut-off for the ratio between the extra-sanguineous and systemic interferon-gamma responses. b. TB-specific ELISpot in extra-sanguineous body fluids is preferred above Quantiferon for the diagnosis of TB. c. There is no difference between PPD reactivity in blood and BAL fluid in patients with sarcoidosis compared to patients with other interstitial lung disease. d. IGRA with PPD antigen in urine and bladder fluid is possible, but the clinical value remains uncertain. 3. QuantiFERON-plus does not discriminate between active and latent TB, but adenosine deaminase and I-309 are promising markers for this purpose.