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Ana Rodríguez-Regal,1 Laura Ramos-Rúa,2 Luis Anibarro-García,3 Ana María Lopez Real,4 María del Campo Amigo-Jorrín1 1Department of Neurology, Complejo Hospitalario Universitario de Pontevedra (CHUP), Pontevedra, Spain; 2Department of Neurology, Hospital Público de Monforte, Lugo, Spain; 3Department of Internal Medicine, Complejo Hospitalario Universitario de Pontevedra (CHUP), Pontevedra, Spain; 4Department OfNeurology, Complejo Hospitalario Universitario de Coruña (CHUAC), La Coruña, SpainCorrespondence: María del Campo Amigo-JorrínComplejo Hospitalario Universitario de Pontevedra (CHUP), Avda. Eduardo Pondal 4-6G, Pontevedra 36003, Spain, Tel +34 619583752Email mcampoamigo@gmail.comBackground: Dimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) such as gastrointestinal (GI) AE, flushing and lymphopenia are the main cause of treatment discontinuation. The aim of this study was to evaluate the effectiveness of DMF, and to assess strategies to reduce treatment discontinuation rates in routine clinical practice.Patients and Methods: Ninety patients started DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information regarding treatment and the management of AE, along with medical prescriptions. Clinical and analytical data were collected at clinical visits performed at least 6-monthly, and disease progression was evaluated by brain magnetic resonance imaging (MRI).Results: Prior to DMF, 78.7% of patients had an annualized relapse rate (ARR) of 1.07 (range: 1– 3) and median Expanded Disability Status Scale (EDSS) score of 1.0 (range: 0– 2). At final follow-up, ARR and median EDSS scores were significantly reduced to 0.09 (range: 0– 2; p

Resumen Objetivo El objetivo del estudio fue conocer la tendencia de las variables relacionadas con la tuberculosis (TB) en Espana a partir del registro del Programa Integrado de Investigacion en Tuberculosis (PII-TB) de la Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) y evaluar el PII-TB mediante indicadores relacionados con sus objetivos cientificos. Metodo Estudio transversal multicentrico de base poblacional de casos nuevos de TB registrados prospectivamente por el PII-TB entre 2006 y 2016. La tendencia temporal de variables cuantitativas se realizo mediante un modelo de regresion lineal y las cualitativas mediante la prueba de χ2 de tendencia lineal. Resultados Se analizaron 6.892 casos de TB con una mediana anual de 531. La tendencia general fue significativamente decreciente en mujeres, inmigrantes, privados de libertad y en tratados inicialmente con 3 farmacos. Se incrementaron significativamente la tendencia de grupos de 40 -50 anos y > 50 anos, primera atencion por especialista de zona, hospitalizacion, retraso diagnostico, localizacion diseminada y extrapulmonar unica, cultivo (+), realizacion de antibiogramas, resistencia a farmacos, tratamiento directamente observado, prolongacion del tratamiento y muerte por otra causa. Los objetivos cientificos del PII-TB que incrementaron significativamente fueron las publicaciones alcanzando un maximo de 8 en 2016 y con un factor de impacto total de 49,664, y tambien mejoraron los proyectos iniciados anualmente, presentaciones en congresos y las tesis o tesinas. Conclusiones El PII-TB proporciona informacion relevante sobre la TB y sus factores asociados en Espana. Se ha formado un amplio equipo de investigadores y se han detectado aspectos cientificos positivos y otros mejorables.

Objective The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives. Method Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend. Results A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant down-ward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40−50 and >50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture(+), drug susceptibility testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49.664, numbers of projects initiated annually, presentations at conferences, and theses. Conclusions PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved.

12 pages, 7 figures, 2 tables.-- This article is licensed under a Creative Commons Attribution 4.0 International License, Tuberculosis (TB) is the most lethal infection among infectious diseases. The specific aim of this study was to establish panels of serum protein biomarkers representative of active TB patients and their household contacts who were either infected (LTBI) or uninfected (EMI-TB Discovery Cohort, Pontevedra Region, Spain). A TMT (Tamdem mass tags) 10plex-based quantitative proteomics study was performed in quintuplicate containing a total of 15 individual serum samples per group. Peptides were analyzed in an LC-Orbitrap Elite platform, and raw data were processed using Proteome Discoverer 2.1. A total of 418 proteins were quantified. The specific protein signature of active TB patients was characterized by an accumulation of proteins related to complement activation, inflammation and modulation of immune response and also by a decrease of a small subset of proteins, including apolipoprotein A and serotransferrin, indicating the importance of lipid transport and iron assimilation in the progression of the disease. This signature was verified by the targeted measurement of selected candidates in a second cohort (EMI-TB Verification Cohort, Maputo Region, Mozambique) by ELISA and nephelometry techniques. These findings will aid our understanding of the complex metabolic processes associated with TB progression from LTBI to active disease, EMI-TB is a European Union Horizon2020-funded action (Grant No. 643558) focused on selecting and developing a novel vaccine candidate for TB

Globally, it is estimated that one-quarter of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb), also known as latent tuberculosis infection (LTBI). Recently, this condition has been referred to as tuberculosis infection (TBI), considering the dynamic spectrum of the infection, as 5–10% of the latently infected population will develop active TB (ATB). The chances of TBI development increase due to close contact with index TB patients. The emergence of multidrug-resistant TB (MDR-TB) and the risk of development of latent MDR-TB has further complicated the situation. Detection of TBI is challenging as the infected individual does not present symptoms. Currently, there is no gold standard for TBI diagnosis, and the only screening tests are tuberculin skin test (TST) and interferon gamma release assays (IGRAs). However, these tests have several limitations, including the inability to differentiate between ATB and TBI, false-positive results in BCG-vaccinated individuals (only for TST), false-negative results in children, elderly, and immunocompromised patients, and the inability to predict the progression to ATB, among others. Thus, new host markers and Mtb-specific antigens are being tested to develop new diagnostic methods. Besides screening, TBI therapy is a key intervention for TB control. However, the long-course treatment and associated side effects result in non-adherence to the treatment. Additionally, the latent MDR strains are not susceptible to the current TBI treatments, which add an additional challenge. This review discusses the current situation of TBI, as well as the challenges and efforts involved in its control.

We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB22TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD81 T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-g) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB2-TB1 value.0.6 IU.ml(-1) was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2>TB1 result in the contact, IMID, and ASPFA groups, respectively (P = 0.591). The adjusted odds ratios (aORs) for an association between a TB2-TB1 result of >0.6 IU.ml(-1) and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 15.4%, and 17.7% with close, frequent, and sporadic contact had a TB2>TB1 result (P = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB2-TB1 difference of.0.6 IU.ml(-1) was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection. IMPORTANCE Contact tuberculosis tracing is essential to identify recently infected people, who therefore merit preventive treatment. However, there are no diagnostic tests that can determine whether the infection is a result of a recent exposure or not. It has been suggested that by using the QuantiFERON-TB gold plus, an interferon gamma (IFN-gamma) release assay, a difference in IFN-gamma production between the two antigen tubes (TB2 minus TB1) of.0.6 IU.ml(-1) could serve as a proxy marker for recent infection. In this large multinational study, infected individuals could not be classified according to the risk of recent exposure based on differences in IFN- g in TB1 and TB2 tubes that were higher than 0.6 IU.ml(-1). QuantiFERON-TB gold plus is not able to distinguish between recent and remotely acquired tuberculosis infection, and it should not be used for that purpose in contact tuberculosis tracing. Funding Agencies|Department of Clinical Sciences of the University of Barcelona

Purpose Hypothyroidism has traditionally been associated with obesity, whereas hyperthyroidism has been linked to being underweight. However, very few studies have assessed these associations. The aim of this work is to evaluate the association between thyroid dysfunction and body mass index (BMI) at baseline and after normalization of the hormone levels. Patients and methods A retrospective, observational study of a cohort of otherwise healthy patients that were referred for evaluation of thyroid dysfunction to the Endocrine Department of Pontevedra University Complex Hospital, Spain was conducted. We collected data of BMI and thyroid hormone levels before treatment and after normalization of thyroid function within a follow-up period of 12 months. Results A total of 330 patients were initially selected for the study. In order to exclude variables that for any reason could influence on BMI, 235 were excluded for further studies. Another 61 patients were also excluded because incomplete data on their medical records, failure to achieve euthyroidism, or lost to follow-up. Therefore, the eligible final study group consisted of 34 patients (17 with hypothyroidism and 17 with hyperthyroidism). No differences were observed in mean baseline BMI between hypo and hyperthyroid patients (27.07±3.22 vs 26.39±4.44, p=0.609). Overweight or obesity was observed in 76.5% and 58.8% of hypothyroid and hyperthyroid patients, respectively (p=0.23). After normalization of thyroid function, the weight of hypothyroid patients decreased from 70.93±10.06 kg to 68.68±10.14 (p=0.000), while the weight of hyperthyroid patients increased from 65.45±11.64 kg to 68.37±12.80 (p=0.000). Their mean BMI was 26.22±3.36 and 27.57±4.98 (p=0.361) for hypo- and hyperthyroid patients, respectively. 58.8% and 64.7% patients remained in the overweight/obesity range in each group (p=0.72). Conclusion Untreated thyroid dysfunction is not associated with BMI. Normalization of thyroid levels significantly changed the weight of patients, but remaining most patients within overweight ranges.

Diagnosis of tuberculous uveitis (TBU) is often challenging and is usually made after excluding other causes of uveitis. We analysed the characteristics of TBU and variables associated with visual outcome. A retrospective, observational analysis was performed in patients with presumptive TBU who were started on specific TB treatment between January 2006 and June 2016. Demographic, clinical, radiological, analytical and ophthalmic examination variables were studied. After completing TB treatment, a follow-up of at least 9 months was performed. A univariate and logistic regression analysis was applied to identify the variables associated with visual acuity and recurrences of uveitis. Forty affected eyes of 24 individuals were identified; 79% of patients were diagnosed during the last 3 years of the study period. Median delay from onset of symptoms to diagnosis was 12 weeks. Loss of visual acuity was the most frequent symptom (87.5%). Posterior uveitis was the most frequent localization (72.9%); 19 patients (79.2%) presented at least one of the Gupta signs predictive of TBU, but there were no confirmed diagnoses. There was improvement in visual acuity in 74.4% of the eyes, but a complete response was achieved only in 56.4%. There was recurrence in two patients. The initiation of treatment ≥ 24 weeks after onset of symptoms was significantly associated with no improvement (p = 0.026). TBU can cause permanent damage to visual acuity, particularly in patients with delayed diagnosis. A prompt initiation of systemic TB treatment is essential to improve visual prognosis.

Summary Objectives To identify new potential host biomarkers in blood to discriminate between active TB patients, uninfected (NoTBI) and latently infected contacts (LTBI). Methods A blood cell count was performed to study parent leukocyte populations. Peripheral blood mononuclear cells (PBMCs) were isolated and a multi-parameter flow cytometry assay was conducted to study the distribution of basal and Mycobacterium tuberculosis (Mtb)-stimulated lymphocytes. Differences between groups and the area under the ROC curve (AUC) were investigated to assess the diagnostic accuracy. Results Active TB patients presented higher Monocyte-to-lymphocyte and Neutrophil-to-lymphocyte ratios than LTBI and NoTBI contacts (p 0.8). Lymphocyte subsets with differences (p >0.05; AUC >0.7) between active TB and both contact groups include the basal distribution of Th1/Th2 ratio, Th1-Th17, CD4+ Central Memory (TCM) or MAIT cells. Expression of CD154 is increased in Mtb-activated CD4+ TCM and Effector Memory T cells in active TB and LTBI compared to NoTBI. In CD4+ T cells, expression of CD154 showed a higher accuracy than IFNγ to discriminate Mtb-specific activation. Conclusions We identified different cell subsets with potential use in tuberculosis diagnosis. Among them, distribution of CD4 TCM cells and their expression of CD154 after Mtb-activation are the most promising candidates.

The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives.Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend.A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant downward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40-50 and50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture(+), sensitivity testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49,664, numbers of projects initiated annually, presentations at conferences, and theses.PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved.

Resumen Objetivo Analizar los costes directos e indirectos derivados del diagnostico y tratamiento de la tuberculosis (TB) y sus factores asociados. Pacientes y metodos Estudio prospectivo de pacientes diagnosticados de TB entre septiembre de 2014 y septiembre de 2015. Se calcularon los costes directos (estancias hospitalarias, consultas, estudios diagnosticos y tratamiento), e indirectos (absentismo laboral y perdida de productividad, estudio de contactos y medidas rehabilitadoras). Los costes se compararon atendiendo a las variables: edad, sexo, pais de origen, ingreso hospitalario, pruebas diagnosticas, tratamiento, resistencia farmacologica, tratamiento directamente observado (TDO) y dias de baja laboral. Se compararon proporciones mediante Chi cuadrado y las variables significativas se incluyeron en un modelo de regresion logistica calculandose las odds ratio (OR) y sus correspondientes intervalos de confianza del 95% (IC). Resultados Fueron incluidos 319 pacientes con una edad media de 56,72 ± 20,79 anos. El coste medio fue de 10.262,62 ± 14.961,66 €, y aumentaba significativamente en relacion con el ingreso hospitalario, el uso de la PCR, la realizacion de baciloscopia y cultivo, antibiograma, tomografia axial computarizada de torax, biopsia pleural, tratamiento de mas de 9 meses, TDO y baja laboral. En el analisis multivariante mantenian asociacion independiente: ingreso hospitalario (OR = 96,8; IC: 29-472,3), antibiograma (OR = 4,34; IC: 1,71-12,1), tomografia axial computarizada de torax (OR = 2,25; IC: 1,08-4,77), TDO (OR = 20,76; IC: 4,11-148) y baja laboral (OR = 26,9; IC: 8,51-122). Conclusion La Tuberculosis acarrea un gasto sanitario significativo. Medidas dirigidas a mejorar el control de la enfermedad y disminuir los ingresos hospitalarios serian importantes para reducirlo.

Interferon-gamma release assays are widely used for the diagnosis of tuberculosis infection in Spain. However, there is no consensus on their application in specific clinical scenarios. To develop a guide-line for their use, a panel of experts comprising specialists in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine, together with a methodologist, conducted a systematic literature search, summarized the findings, rated the quality of the evidence, and formulated recommendations following the Grading of Recommendations of Assessment Development and Evaluations methodology. This document provides evidence-based guidance on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in patients at risk of tuberculosis or suspected of having active disease. The guidelines will be applicable to specialist and primary care, and public health.

Interferon-gamma release assays are widely used for the diagnosis of tuberculosis infection in Spain. However, there is no consensus on their application in specific clinical scenarios. To develop a guideline for their use, a panel of experts comprising specialists in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine, together with a methodologist, conducted a systematic literature search, summarized the findings, rated the quality of the evidence, and formulated recommendations following the GRADE (Grading of Recommendations of Assessment Development and Evaluations) methodology. This document provides evidence-based guidance on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in patients at the risk of tuberculosis or suspected of having active disease. The guidelines will be applicable to specialist and primary care, and public health.

Resumen Introduccion Las normativas internacionales y espanolas recomiendan el tratamiento intensivo de la tuberculosis (TB) con cuatro farmacos. El objetivo es determinar si en Espana se sigue esta recomendacion y los factores asociados a utilizar tres farmacos (pauta estandar sin etambutol). Metodologia Estudio multicentrico descriptivo, retrospectivo, en el que se analizaron los datos de los pacientes diagnosticados de TB en practicamente todas las Comunidades Autonomas espanolas entre 2007 y 2012. El estudio de factores asociados a prescribir tres farmacos se baso en regresion logistica, calculandose las odds ratio (OR) y sus correspondientes intervalos de confianza del 95% (IC). Resultados Se incluyeron 3.189 pacientes, de los que 1.413 (44,3%) fueron tratados con tres farmacos. Este porcentaje fue del 41,2% en los pacientes con baciloscopia positiva, del 36,1% en los que tenian al menos resistencia a un farmaco, del 31,4% en los que tenian infeccion por VIH y del 24,8% en los inmigrantes. Los factores asociados al uso de tres farmacos fueron: ser mujer (OR = 1,18; IC: 1,00-1,39); ser autoctono (OR = 3,09; IC: 2,58-3,70); estar jubilado (OR = 1,42; IC: 1,14-1,77); vivir sin techo (OR = 3,10; IC: 1,52-6,43), vivir solo (OR = 1,62; IC: 1,11-2,36) o en familia (OR = 1,97; IC: 1,48-2,65); ser atendido por especialistas de zona (OR = 1,37; IC: 1,10;1,70); no estar infectado por el VIH (OR = 1,63; IC: 1,09-2,48) y tener baciloscopia negativa con cultivo positivo (OR = 1,59; IC: 1,25-2,02). Conclusiones Existe una proporcion importante de tratamiento intensivo con tres farmacos. Se deben seguir las recomendaciones del tratamiento de la TB, tanto en la practica clinica habitual como por parte del Plan para la Prevencion y Control de la TB en Espana.

In our work, we aim to identify new candidate host biomarkers to discriminate between active TB patients (n = 28), latent infection (LTBI; n = 27) and uninfected (NoTBI; n = 42) individuals. For that, active TB patients and their contacts were recruited that donated serum and saliva samples. A multiplex assay was performed to study the concentration of different cytokines, chemokines and growth factors. Proteins with significant differences between groups were selected and logistic regression and the area under the ROC curve (AUC) was used to assess the diagnostic accuracy. The best marker combinations that discriminate active TB from NoTBI contacts were [IP-10 + IL-7] in serum and [Fractalkine + IP-10 + IL-1α + VEGF] in saliva. Best discrimination between active TB and LTBI was achieved using [IP-10 + BCA-1] in serum (AUC = 0.83) and IP-10 in saliva (p = 0.0007; AUC = 0.78). The levels of TNFα (p = 0.003; AUC = 0.73) in serum and the combination of [Fractalkine+IL-12p40] (AUC = 0.83) in saliva, were able to differentiate between NoTBI and LTBI contacts. In conclusion, different individual and combined protein markers could help to discriminate between active TB and both uninfected and latently-infected contacts. The most promising ones include [IP-10 + IL-7], [IP-10 + BCA-1] and TNFα in serum and [Fractalkine + IP-10 + IL-1α + VEGF], IP-10 and [Fractalkine+IL-12p40] in saliva. Xunta de Galicia | Ref. ED431C 2016/041 Ministerio de Ecucación, Cultura y Deporte | Ref. FPU 13/03026

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (MTB). Roughly one third of the world's population carries MTB in a dormant form. TB is responsible for the death of more than 1.8 million people each year. EMI-TB (Eliciting mucosal immunity in TB) is an EU Horizon2020 funded action focused on selecting and developing a novel vaccine candidate for TB. Our specific aim (CSIC, Vigo, Spain) is to establish a panel of protein biomarkers representative of those individuals that had been in contact with a patient with microbiological confirmed pulmonary TB but did not get infected. Samples (serum, saliva and sputum) were collected from volunteer patients (TB: pulmonary TB; LTBI: contacts with latent TB infection; non-LTBI: contacts without evidence of latent TB infection). Quantitative proteomics were done using TMT10plex (Thermo) and a LC-Orbitrap Elite platform. Modulated proteins were selected after exhaustive manual review of the processed data and non-parametric statistical analysis with R software. We have found a unique proteomic signature in the sputum of non-LTBI contacts, consisting in a set of 32 proteins mainly involved in regulation of endopeptidase activity, defense against pathogens and perception of bitter taste. This suggests that nasal and oral mucosa play a critical role in the initial entry of the pathogen in the host, opening a new window for eliciting the mucosal immunity to enhance the innate immune response as the first barrier to fight infection. We are starting a validation in a functional model of MTB infection in order to test the biological and clinical significance of our findings.

BACKGROUND: Screening strategies based on interferon-? release assays in tuberculosis contact tracing may reduce the need for preventive therapy without increasing subsequent active disease. METHODS: We conducted an open-label, randomized trial to test the noninferiority of a 2-step strategy with the tuberculin skin test (TST) followed by QuantiFERON-TB Gold In-Tube (QFT-GIT) as a confirmatory test (the TST/QFT arm) to the standard TST-alone strategy (TST arm) for targeting preventive therapy in household contacts of patients with tuberculosis. Participants were followed for 24 months after randomization. The primary endpoint was the development of tuberculosis, with a noninferiority margin of 1.5 percentage points. RESULTS: A total of 871 contacts were randomized. Four contacts in the TST arm and 2 in the TST/QFT arm developed tuberculosis. In the modified intention-to-treat analysis, this accounted for 0.99% in the TST arm and 0.51% in the TST/QFT arm (-0.48% difference; 97.5% confidence interval [CI], -1.86% to 0.90%); in the per-protocol analysis, the corresponding rates were 1.67% and 0.82% in the TST and TST/QFT arms, respectively (-0.85% difference; 97.5% CI, -3.14% to 1.43%). Of the 792 contacts analyzed, 65.3% in the TST arm and 42.2% in the TST/QFT arm were diagnosed with tuberculosis infection (23.1% difference; 95% CI, 16.4% to 30.0%). CONCLUSIONS: In low-incidence settings, screening household contacts with the TST and using QFT-GIT as a confirmatory test is not inferior to TST-alone for preventing active tuberculosis, allowing a safe reduction of preventive treatments. CLINICAL TRIALS REGISTRATION: NCT01223534.

Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and low-income countries. Conclusions: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users.

18 p.-4 fig.-6 tab. López, María et al., Acinetobacter baumannii is an important pathogen that causes nosocomial infections generally associated with high mortality and morbidity in Intensive Care Units (ICUs). Currently, little is known about the Quorum Sensing (QS)/Quorum Quenching (QQ) systems of this pathogen. We analyzed these mechanisms in seven clinical isolates of A. baumannii. Microarray analysis of one of these clinical isolates, Ab1 (A. baumannii ST-2_clon_2010), previously cultured in the presence of 3-oxo-C12-HSL (a QS signalling molecule) revealed a putative QQ enzyme (α/ß hydrolase gene, AidA). This QQ enzyme was present in all non-motile clinical isolates (67% of which were isolated from the respiratory tract) cultured in nutrient depleted LB medium. Interestingly, this gene was not located in the genome of the only motile clinical strain growing in this medium (A. baumannii strain Ab421_GEIH-2010 [Ab7], isolated from a blood sample). The AidA protein expressed in E. coli showed QQ activity. Finally, we observed downregulation of the AidA protein (QQ system attenuation) in the presence of H2O2 (ROS stress). In conclusion, most of the A. baumannii clinical strains were not surface motile (84%) and were of respiratory origin (67%). Only the pilT gene was involved in surface motility and related to the QS system. Finally, a new QQ enzyme (α/ß hydrolase gene, AidA protein) was detected in these strains., This study was funded by grant PI13/02390 awarded to MT within the State Plan for R+D+I 2013-2016 (National Plan for Scientific Research, Technological Development and Innovation 2008-2011) and co-financed by the ISCIII-Deputy General Directorate of evaluation and Promotion of Research - European Regional Development Fund "A way of Making Europe" and Instituto de Salud Carlos III FEDER, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

SETTING Galicia, Spain. OBJECTIVE To describe changes in tuberculosis (TB) epidemiology and characteristics in Galicia, Spain, during the period 1996-2011. DESIGN Retrospective observational descriptive study of data obtained from the Tuberculosis Information System. The Galician Tuberculosis Prevention and Control Programme, created in 1994, is based in seven tuberculosis units that actively collect data on case finding and follow-up of all cases of TB in the region. RESULTS TB incidence fell from 72.9 cases per 100,000 population in 1996 to 24.6 in 2011 (respectively 40.5 and 14.2 in patients aged

Oncohematological patients undergoing chemotherapy who have latent tuberculosis infection (LTBI) are at a high risk of developing active tuberculosis (TB). The identification and treatment of these patients can prevent LTBI progressing to active TB. This study analyzed the degree of adherence with and safety of the treatment of latent tuberculosis infection (TLTBI) in oncohematological patients undergoing antineoplastic chemotherapy.This is a retrospective study of a cohort of oncohematological patients receiving TLTBI and antineoplastic chemotherapy simultaneously, between January 2007 and June 2010. The proportions of toxicity and adherence to TLTBI in these patients were compared with a non-oncohematological control group, matched for age, sex, and year in which the TLTBI was started. In addition, a minimum 2-year follow-up was carried out for all patients.A total of 105 patients who received TLTBI were included, 21 of whom had received antineoplastic chemotherapy simultaneously. The mean age of the patients was 63 years. There were no significant baseline differences in transaminase values. The percentages of patients completing treatment were 76.2% in the control group and 71.4% in the oncohematological group [risk ratio (RR): 1.07, 95% confidence interval (CI): 0.79-1.43]. The voluntary dropout proportion was similar in both groups (12.3 vs. 11.8%, RR: 1.05, 95% CI: 0.25-4.42). Treatment was discontinued because of toxicity in three oncohematological patients and in 11 patients from the control group (RR: 1.14; 95% CI: 035-3.66). No patient developed TB during the follow-up period.The safety of TLTBI is not influenced by simultaneous antineoplastic chemotherapy in oncohematological patients.

Objective To analyze the direct and indirect costs of diagnosis and management of tuberculosis (TB) and associated factors. Patients and methods Prospective study of patients diagnosed with TB between September 2014 and September 2015. We calculated direct (hospital stays, visits, diagnostic tests, and treatment) and indirect (sick leave and loss of productivity, contact tracing, and rehabilitation) costs. The following cost-related variables were compared: age, gender, country of origin, hospital stays, diagnostic testing, sensitivity testing, treatment, resistance, directed observed therapy (DOT), and days of sick leave. Proportions were compared using the chi-squared test and significant variables were included in a logistic regression analysis to calculate odds ratio (OR) and corresponding 95% confidence intervals. Results 319 patients were included with a mean age of 56.72±20.79 years. The average cost was €10,262.62±14,961.66, which increased significantly when associated with hospital admission, polymerase chain reaction, sputum smears and cultures, sensitivity testing, chest computed tomography, pleural biopsy, drug treatment longer than nine months, DOT and sick leave. In the multivariate analysis, hospitalization (OR=96.8; CI 29–472), sensitivity testing (OR=4.34; CI 1.71–12.1), chest CT (OR=2.25; CI 1.08–4.77), DOT (OR=20.76; CI 4.11–148) and sick leave (OR=26.9; CI 8.51–122) showed an independent association with cost. Conclusion Tuberculosis gives rise to significant health spending. In order to reduce these costs, more control of transmission, and fewer hospital admissions would be required.

Interferon-gamma release assays are widely used for the diagnosis of tuberculosis infection in Spain. However, there is no consensus on their application in specific clinical scenarios. To develop a guide-line for their use, a panel of experts comprising specialists in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine, together with a methodologist, conducted a systematic literature search, summarized the findings, rated the quality of the evidence, and formulated recommendations following the Grading of Recommendations of Assessment Development and Evaluations methodology. This document provides evidence-based guidance on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in patients at risk of tuberculosis or suspected of having active disease. The guidelines will be applicable to specialist and primary care, and public health.

Resumen La integridad del eje interleucina 12/interferon gamma (IL-12/INF-γ) es esencial para un correcto control de la infeccion por Mycobacterium tuberculosis. El objetivo del presente estudio fue evaluar si la alta incidencia de tuberculosis (TB) en Galicia (Espana) podria estar relacionada con una respuesta alterada en el eje IL-12/INF-γ en los pacientes con TB. Se estudio a 20 enfermos con TB y 21 controles sanos: 7 con prueba de la tuberculina positiva (PT+) y 14 con prueba de la tuberculina negativa (PT–). El estudio del eje IL-12/INF-γ se realizo mediante la determinacion de los niveles de INF-γ y la expresion celular de los receptores IL-12Rβ1 e INF-γR1 en linfocitos y monocitos, respectivamente. Los ensayos se realizaron tanto a nivel basal, como tras estimulacion mediante incubacion in vitro de celulas mononucleares de sangre periferica con fitohemaglutinina (PHA) y derivado proteico purificado (PPD). Se analizaron y compararon las respuestas de los enfermos y de los controles sanos. La estimulacion in vitro con PHA y PPD incremento de forma significativa los niveles de INF-γ, y la expresion celular de los marcadores IL-12Rβ1 y INF-γR1 respecto a los niveles basales, tanto en el grupo de enfermos con TB, como en el de controles sanos (con PT+ y PT–). Todo ello es indicativo de una respuesta inmunitaria adecuada en todos los grupos, en los que la funcionalidad del eje IL-12/INF-γ esta conservada en los pacientes analizados con TB en Galicia. Aunque nuestro estudio no ha analizado todas las vias de alteracion posibles del eje IL-12/INF-γ, las altas tasas de enfermedad que historicamente se observan en esta comunidad no parecen estar causadas por una disfuncion de la respuesta inmunitaria a este nivel.

Resumen Debe sospecharse tuberculosis pulmonar en pacientes con sintomas respiratorios durante mas de 2–3 semanas. La inmunodepresion puede modificar la presentacion clinica y radiologica. La radiografia de torax presenta manifestaciones muy sugerentes de tuberculosis, aunque en ocasiones atipicas. Las pruebas radiologicas complejas (tomografia computarizada, resonancia magnetica) son mas utiles en la tuberculosis extrapulmonar. En el diagnostico, siempre que sea posible, se utilizaran al menos 3 muestras seriadas representativas de la localizacion clinica. La baciloscopia y el cultivo con medios liquidos deben realizarse en todos los casos. Las tecnicas de amplificacion genetica son coadyuvantes en la sospecha moderada o alta de tuberculosis. En los casos nuevos de tuberculosis, se recomienda administrar isoniacida, rifampicina, etambutol y piracinamida (HREZ) durante 2 meses e isoniacida mas rifampicina durante 4 meses mas, con las excepciones de los casos de meningitis, en que se alargara hasta 12 meses, y de la tuberculosis espinal con afeccion neurologica y la silicosis, hasta 9 meses. Se recomiendan las formulaciones combinadas. En pacientes con infeccion por el VIH deben realizarse los ajustes necesarios con el tratamiento antirretroviral. Debe realizarse antibiograma para farmacos de primera linea a todos los aislamientos iniciales de pacientes nuevos. El control del tratamiento es una de las actividades mas importantes en el abordaje de la tuberculosis. En la infeccion tuberculosa la prueba de tuberculina (PT) es positiva cuando es ≥5 mm y los metodos de deteccion de produccion de interferon gamma (IGRA) se recomiendan en combinacion con la prueba de la tuberculina. La pauta estandar de tratamiento de la infeccion es de 6 meses con isoniacida. En la tuberculosis pulmonar se aplicara aislamiento respiratorio durante 3 semanas o hasta obtener 3 muestras con baciloscopia negativa.

Pulmonary TB should be suspected in patients with respiratory symptoms longer than 2-3 weeks. Immunosuppression may modify clinical and radiological presentation. Chest X-ray shows very suggestive, albeit sometimes atypical, signs of TB. Complex radiological tests (CT scan, MR) are more useful in extrapulmonary TB. At least 3 serial representative samples of the clinical location are used for diagnosis whenever possible. Bacilloscopy and liquid medium cultures are indicated in all cases. Genetic amplification techniques are coadjuvant in moderate or high TB suspicion. Administration of isoniazid, rifampicin, ethambutol and pyrazinamide (HREZ) for 2 months and HR for 4 additional months is recommended in new cases of TB, except in cases of meningitis in which treatment should continue for up to 12 months and up to 9 months in spinal TB with neurological involvement, and in silicosis. Appropriate adjustments with antiretroviral treatment should be made in HIV patients. Combined therapy is recommended to avoid development of resistance. An antibiogram to first line drugs should be performed in all the initial isolations of new patients. Treatment control is one of the most important activities in TB management. The Tuberculin Skin Test (TST) is positive in TB infection when >or=5mm, and Interferon-Gamma Release Assays (IGRA) are recommended in combination with TT. The standard treatment schedule for infection is 6 months with isoniazid. In pulmonary TB, respiratory isolation is applied for 3 weeks or until 3 negative bacilloscopy samples are obtained.

Carbapenem-resistant Acinetobacter baumannii (CRAb) is a major source of nosocomial infections in Spain associated with the production of OXA-58-like or OXA-24/40-like β-lactamase enzymes. We analysed the plasmids carrying the bla(OXA-24/40)-like gene in CRAb isolates obtained a decade apart.The presence of β-lactamases was screened for by PCR (metallo-β-lactamases, carbapenem-hydrolysing class D β-lactamases, GES and KPC) in 101 CRAb isolates obtained in two multicentre studies (GEIH/REIPI-Ab-2000 and GEIH/REIPI-Ab-2010; n = 493 Acinetobacter spp). We analysed the distribution and characterization of the plasmids carrying the bla(OXA-24/40)-like gene and sequenced two plasmids, AbATCC223p (2000) and AbATCC329p (2010) from A. baumannii ATCC 17978 transformants.Acquisition of the bla(OXA-24/40)-like gene was the main mechanism underlying resistance to carbapenems (48.7% in 2000 compared with 51.6% in 2010). This gene was mainly isolated in ST2 A. baumannii strains in both studies, although some novel STs (ST79 and ST80) appeared in 2010. The gene was located in plasmids (8-12 kbp) associated with the repAci2 or repAci2/repGR12 types. The sequences of AbATCC223p (8840 bp) and AbATCC329p (8842 bp) plasmids were similar, particularly regarding the presence of the genes encoding the AbkA/AbkB proteins associated with the toxin/antitoxin system. Moreover, the abkA/abkB gene sequences (96% identity) were also located in plasmids harbouring the bla(OXA-58)-like gene.The action of OXA-24/40 and OXA-58 β-lactamase-like enzymes represents the main mechanism underlying resistance to carbapenems in Spain in the last decade. AbkA/AbkB proteins in the toxin/antitoxin system may be involved in the successful dissemination of plasmids carrying the bla(OXA-24/40)-like gene, and probably also the bla(OXA-58)-like gene, thus contributing to the plasmid stability.

The tuberculin skin test (TST) is the established procedure for diagnosis of latent tuberculosis infection (LTBI) among the contacts of an infectious tuberculosis (TB) case. TST may convert to positive ≤8 weeks after Mycobacterium tuberculosis infection, an interval that is usually referred to as the “window period”. A negative TST obtained

Previous reports have identified interleukin-2 (IL-2), quantified in the supernatants of QuantiFERONA multicentre study of 161 consecutive adult patients undergoing evaluation for active TB at eight TB Units in Spain. Interferon-γ (IFN-γ) and IL-2 were assessed in the supernatant of QFT after 16-24 h and 72 h of incubation. The accuracy of IL-2 for indicating latent TB infection (LTBI) was assessed by receiving operating characteristic curves. .Twenty-eight participants were not infected, 43 had LTBI, 69 had TB, and 21 were not classifiable. Median (interquartile range) IL-2 concentrations after 72 h of incubation were 0.0 pg/mL (0.0-0.0) in uninfected individuals, 261.0 pg/mL (81.0-853.0) in LTBI individuals, 166.5 pg/mL (33.5-551.5) in patients with extrapulmonary TB, 95.0 pg/mL (26.0-283.0) in patients with smear-negative pulmonary TB, and 38.5 pg/mL (7.5-178.0) in patients with smear-positive pulmonary TB (p0.0001). The area under the curve of the receiving operating characteristic curve (95% CI) of IL-2 after 72 h of incubation for the diagnosis of LTBI was 0.63 (0.53-0.74) when all TB cases were considered as a single group, ranging from 0.59 (0.47-0.71) to 0.72 (0.58-0.85) when only extrapulmonary and smear-positive pulmonary TB cases respectively were considered.Quantification of IL-2 in the supernatant of QFT after a prolonged incubation is not useful to distinguish between LTBI and active disease in clinical practice.