Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected withMycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected withM. tuberculosis, thein vivotuberculin skin test and theex vivointerferon-γ 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 withM. tuberculosisafter 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 onM. tuberculosislatency 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.

Interferon-γ release assays (IGRAs) are now established for the immunodiagnosis of latent infection withMycobacterium tuberculosisin many countries. However, the role of IGRAs for the diagnosis of active tuberculosis (TB) remains unclear.Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001–November 2009 that evaluated the evidence of using QuantiFERON-TB® Gold in-tube (QFT-G-IT) and T-SPOT.TB®directly on blood or extrasanguinous specimens for the diagnosis of active TB.The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75–84%) and 48% (95% CI 39–58%) for QFT-G-IT, and 81% (95% CI 78–84%) and 88% (confirmed and unconfirmed cases) (95% CI 82–92%) for T-SPOT.TB®, respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75–82%) and 82% (95% CI 70–91%) for QFT-G-IT, and 59% (95% CI 56–62%) and 82% (95% CI 78–86%) for T-SPOT.TB®, respectively.Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB).Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette–Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection withMycobacterium tuberculosis.Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistentM. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB.This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles.

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection withMycobacterium tuberculosisfrom progressing to active disease. The best available proxy for diagnosing latent infection withM. tuberculosisis the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ basedex vivoassay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection withM. tuberculosisin the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positiveM. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.