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.

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

We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB1 Gold In-Tube (QFT-G-IT) and the T-SPOT1.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI).The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-c release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated.Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT1.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases.IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis.12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Metaanalysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure).Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage f600 mg versus .600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg.The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Decreasing exposure to airborne particulates appears to attenuate the decline in lung function related to exposure to PM10. The effects are greater in tests reflecting small-airway function.

Background Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.Methods In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) followup for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims:(1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixedeffects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).Findings In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19•0% [95% CI 8•4-37•4]). The effectiveness of preventive therapy was 63% (adjusted HR 0•37 [95% CI 0•30-0•47]) among all exposed children, and 91% (adjusted HR 0•09 [0•05-0•15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 9...

OBJECTIVES: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. METHODS: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50 years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11 year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. RESULTS: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6 528 individuals (70%) agreed to the health examination and 5 973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5 kg in 11 years and 28% of smokers in 1991 had quit by the time of the reassessment. The most powerful approach for studying long-term effects from ambient air pollution on health is the long-term prospective follow-up of well-defined population-based cohorts with well-characterized air pollution exposure information (European Science Foundation 1998). There are currently only five cohort studies in adults, with published results, that address the long-term impact of air pollution (Abbey et al. 1999;Dockery et al. 1993;Finkelstein et al. 2004;Hoek et al. 2002; Pope et al. 2002;. All studies but one are based in the US and three of them (Dockery et al. 1993;Hoek et al. 2002; Pope et al. 2002), have only published findings related to mortality. The relation of longterm exposure to air pollution with respiratory and cardiovascular health and morbidity has yet to be measured in a large prospective cohort study in Europe. The large European Community Respiratory Health Survey (ECRHS) de- Probst-Hensch NM, et al. Follow-up of SAPALDIA 2, 1991-2003 signed to measure natural history and risk factors for respiratory diseases (particularly asthma and allergy) across Europe has recently included air pollution exposure assessment in its protocol (Burney et al. 1994;Hazenkamp-von Arx et al. 2004). However, the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) is the only prospective cohort study of respiratory and cardiovascular health in adults in Europe with detailed individual residential exposure hi...

The effect of long-term exposure to air pollutants was studied in a cross-sectional population-based sample of adults (aged 18 to 60 yr; n = 9,651) residing in eight different areas in Switzerland. Standardized medical examination included questionnaire data, lung function tests, skin-prick testing, and end-expiratory CO concentration. The impact of annual means of air pollutants on FVC and FEV1 was tested (controlling for age and age squared, sex, height, weight, educational level, nationality, and workplace exposure). Analyses were done separately for healthy never-smokers, ex-smokers (controlling for pack-yr), for current smokers (controlling for cigarettes per day and pack-yr smoked), and for the whole population. Significant and consistent effects on FVC and FEV1 were found for NO2, SO2, and particulate matter < 10 microm (PM10) in all subgroups and in the total population, with PM10 showing the most consistent effect of a 3.4% change in FVC per 10 microg/m3. Results for ozone were less consistent. Atopy did not influence this relationship. The limited number of study areas and high intercorrelation between the pollutants make it difficult to assess the effect of one single pollutant. Our conclusion is that air pollution from fossil fuel combustion, which is the main source of air pollution with SO2, NO2, and PM10 in Switzerland, is associated with decrements in lung function parameters in this study.