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-c 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 with Mycobacterium tuberculosis.Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-c 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 persistent M. 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.KEYWORDS: Interferon-c release assay, tuberculin skin test, tuberculosis, tumour necrosis factor T umour necrosis factor (TNF) and TNF receptors play a key role in mediating immune responses in acute and chronic inflammation [1][2][3]. Over the past decade, TNF antagonists in the form of anti-TNF monoclonal antibodies or TNF fusion protein have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and inflammatory bowel disease [4][5][6][7]. Tuberculosis (TB) is a granulomatous disease caused by infection with Mycobacterium tuberculosis.Most of the individuals who are thought to have become infected with M. tuberculosis will never develop TB due to the control exercised by the host immune system [8,9]. One of the key cytokines in the immune response against infection with M. tuberculosis is TNF, which is also critical for the integrity of the granuloma [10]. Individuals who are being treated with anti-TNF therapies are at increased risk of developing TB. Following TNF antagonist therapy, the relative risk for TB is increased 1.6-25.1 times, depending on the clinical setting and the TNF antagonist used [4,7,11,12]. The majority of cases of TB related to TNF antagonist therapies occur in close temporal proximity to

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence.This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

Contact investigation to identify individuals with tuberculosis and latent infection with Mycobacterium tuberculosis is an important component of tuberculosis control in low tuberculosis incidence countries. This document provides evidence-based and best-practice policy recommendations for contact tracing among high-and medium-priority contacts in a variety of settings. It provides a basis for national guidelines on contact investigation and tuberculosis outbreak management, and should support countries and tuberculosis control managers in evaluating and revising national policies. A review of existing guidelines, a literature search, several meetings and consultation with experts were used to formulate and grade recommendations for action during contact investigation.Available tests to identify individuals with latent infection with M. tuberculosis are designed to identify immune response against mycobacterial antigens and have variable predictive value for the likelihood to develop active tuberculosis in different populations. Contact investigation should therefore be limited to situations with a clear likelihood of transmission or to those with a higher probability of developing active tuberculosis, for instance, young children and immunocompromised persons. A risk assessment-based approach is recommended, where the need to screen contacts is prioritised on the basis of the infectiousness of the index case, intensity of exposure and susceptibility of contacts.

As tuberculosis (TB) rates continue to decline in native populations in most low TB incidence countries, the proportion of TB patients born outside their country of residence ('foreign-born') increases. Some low-incidence countries have experienced a substantial increase in TB rates related to recent increases in the number of asylum seekers and other migrants from TB-endemic countries. However, average TB rates among the foreign-born in low-incidence countries declined moderately in 2009-2015. TB in foreign-born individuals is commonly the result of reactivation of latent infection with Mycobacterium tuberculosis acquired outside the host country. Transmission is generally low in low-incidence countries, and transmission from migrants to the native population is often modest. Variations in levels and trends in TB notifications among the foreign-born are likely explained by differences and fluctuations in the number and profile of migrants, as well as by variations in TB control, health and social policies in the host countries. To optimise TB care and prevention in migrants from endemic to low-incidence countries, we propose a framework for identifying possible TB care and prevention interventions before, during and after migration. Universal access to high-quality care along the entire migration pathway is critical. Screening for active TB and latent tuberculous infection should be tailored to the TB epidemiology, adapted to the needs of specific migrant groups and linked to treatment. Ultimately, the long-term TB elimination goal can be reached only if global health and socio-economic inequalities are dramatically reduced. Low-incidence countries, most of which are among the wealthiest nations, need to contribute through international assistance.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-c release assays (IGRAs), QuantiFERON-TB1 Gold In-tube (QFT-GIT) and T-SPOT.TB1, and the tuberculin skin test (TST) in immigrants contacts.Immigrant close contacts of sputum smear-positive TB patients were included when aged o16 yrs and their TST result was o5 mm 0 or 3 months after diagnosis of the index patient.Contacts were followed for the next 2 yrs for development of TB disease.Of 339 immigrant contacts with TST o5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB1, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB1. The PPV for progression to TB during this period was 9/28853.1% (95% CI 1.3-5.0%) for TST o10 mm, 7/ 18453.8% (95% CI 1.7-5.9%) for TST o15 mm, 5/17852.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/ 18153.3% (95% CI 1.3-5.3%) for T-SPOT.TB1. Sensitivity was 100%, 88%, 63% and 75%, respectively.The predictive values of QFT-GIT, T-SPOT.TB1 and TST for progression to TB disease among immigrant close contacts were comparable.