A nationwide study of multidrug-resistant tuberculosis in Portugal 2014-2017 using epidemiological and molecular clustering analyses.

BACKGROUND: Increasing multidrug-resistant tuberculosis (MDR-TB) incidence is a major threat against TB eradication worldwide. We aim to conduct a detailed MDR-TB study in Portugal, an European country with endemic TB, combining genetic analysis and epidemiological data, in order to assess the efficiency of public health containment of MRD-TB in the country. METHODS: We used published MIRU-VNTR data, that we reanalysed using a phylogenetic analysis to better describe MDR-TB cases transmission occurring in Portugal from 2014 to 2017, further enriched with epidemiological data of these cases. RESULTS: We show an MDR-TB transmission scenario, where MDR strains likely arose and are transmitted within local chains. 63% of strains were clustered, suggesting high primary transmission (estimated as 50% using MIRU-VNTR data and 15% considering epidemiological links). These values are higher than those observed across Europe and even for sensitive strains in Portugal using similar methodologies. MDR-TB cases are associated with individuals born in Portugal and evolutionary analysis suggests a local evolution of strains. Consistently the sublineage LAM, the most common in sensitive strains in Europe, is the more frequent in Portugal in contrast with the remaining European MDR-TB picture where immigrant-associated Beijing strains are more common. CONCLUSIONS: Despite efforts to track and contain MDR-TB strains in Portugal, their transmission patterns are still as uncontrolled as that of sensitive strains, stressing the need to reinforce surveillance and containment strategies.

A complex scenario of tuberculosis transmission is revealed through genetic and epidemiological surveys in Porto.

BACKGROUND: Tuberculosis (TB) incidence is decreasing worldwide and eradication is becoming plausible. In low-incidence countries, intervention on migrant populations is considered one of the most important strategies for elimination. However, such measures are inappropriate in European areas where TB is largely endemic, such as Porto in Portugal. We aim to understand transmission chains in Porto through a genetic characterization of Mycobacterium tuberculosis strains and through a detailed epidemiological evaluation of cases. METHODS: We genotyped the M. tuberculosis strains using the MIRU-VNTR system. We performed an evolutionary reconstruction of the genotypes with median networks, used in this context for the first time. TB cases from a period of two years were evaluated combining genetic, epidemiological and georeferencing information. RESULTS: The data reveal a unique complex scenario in Porto where the autochthonous population acts as a genetic reservoir of M. tuberculosis diversity with discreet episodes of transmission, mostly undetected using classical epidemiology alone. CONCLUSIONS: Although control policies have been successful in decreasing incidence in Porto, the discerned complexity suggests that, for elimination to be a realistic goal, strategies need to be adjusted and coupled with a continuous genetic characterization of strains and detailed epidemiological evaluation, in order to successfully identify and interrupt transmission chains.

Intra-urban variation in tuberculosis and community socioeconomic deprivation in Lisbon metropolitan area: a Bayesian approach.

BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) is a recognized threat to global efforts to TB control and remains a priority of the National Tuberculosis Programs. Additionally, social determinants and socioeconomic deprivation have since long been associated with worse health and perceived as important risk factors for TB. This study aimed to analyze the spatial distribution of non-MDR-TB and MDR-TB across parishes of the Lisbon metropolitan area of Portugal and to estimate the association between non-MDR-TB and MDR-TB and socioeconomic deprivation. METHODS: In this study, we used hierarchical Bayesian spatial models to analyze the spatial distribution of notification of non-MDR-TB and MDR-TB cases for the period from 2000 to 2016 across 127 parishes of the seven municipalities of the Lisbon metropolitan area (Almada, Amadora, Lisboa, Loures, Odivelas, Oeiras, Sintra), using the Portuguese TB Surveillance System (SVIG-TB). In order to characterise the populations, we used the European Deprivation Index for Portugal (EDI-PT) as an indicator of poverty and estimated the association between non-MDR-TB and MDR-TB and socioeconomic deprivation. RESULTS: The notification rates per 10,000 population of non-MDR TB ranged from 18.95 to 217.49 notifications and that of MDR TB ranged from 0.83 to 3.70. We identified 54 high-risk areas for non-MDR-TB and 13 high-risk areas for MDR-TB. Parishes in the third [relative risk (RR) = 1.281, 95% credible interval (CrI): 1.021-1.606], fourth (RR = 1.786, 95% CrI: 1.420-2.241) and fifth (RR = 1.935, 95% CrI: 1.536-2.438) quintile of socioeconomic deprivation presented higher non-MDR-TB notifications rates. Parishes in the fourth (RR = 2.246, 95% CrI: 1.374-3.684) and fifth (RR = 1.828, 95% CrI: 1.049-3.155) quintile of socioeconomic deprivation also presented higher MDR-TB notifications rates. CONCLUSIONS: We demonstrated significant heterogeneity in the spatial distribution of both non-MDR-TB and MDR-TB at the parish level and we found that socioeconomically disadvantaged parishes are disproportionally affected by both non-MDR-TB and MDR-TB. Our findings suggest that the emergence of MDR-TB and transmission are specific from each location and often different from the non-MDR-TB settings. We identified priority areas for intervention for a more efficient plan of control and prevention of non-MDR-TB and MDR-TB.

Evaluation of drug-resistant tuberculosis treatment outcome in Portugal, 2000-2016.

Treatment of drug-resistant tuberculosis (TB), which is usually less successful than that of drug-susceptible TB, represents a challenge for TB control and elimination. We aimed to evaluate treatment outcomes and to identify the factors associated with death among patients with MDR and XDR-TB in Portugal. We assessed MDR-TB cases reported for the period 2000-2016, using the national TB Surveillance System. Treatment outcomes were defined according to WHO recommendations. We identified the factors associated with death using logistic regression. We evaluated treatment outcomes of 294 MDR- and 142 XDR-TB patients. The treatment success rate was 73.8% among MDR- and 62.7% among XDR-TB patients (p = 0.023). The case-fatality rate was 18.4% among MDR- and 23.9% among XDR-TB patients. HIV infection (OR 4.55; 95% CI 2.31-8.99; p < 0.001) and resistance to one or more second-line injectable drugs (OR 2.73; 95% CI 1.26-5.92; p = 0.011) were independently associated with death among MDR-TB patients. HIV infection, injectable drug use, past imprisonment, comorbidities, and alcohol abuse are conditions that were associated with death early on and during treatment. Early diagnosis of MDR-TB and further monitoring of these patients are necessary to improve treatment outcome.

Using Bayesian spatial models to map and to identify geographical hotspots of multidrug-resistant tuberculosis in Portugal between 2000 and 2016.

Multidrug-resistant tuberculosis (MDR-TB) is a major threat to the eradication of tuberculosis. TB control strategies need to be adapted to the necessities of different countries and adjusted in high-risk areas. In this study, we analysed the spatial distribution of the MDR- and non-MDR-TB cases across municipalities in Continental Portugal between 2000 and 2016. We used Bayesian spatial models to estimate age-standardized notification rates and standardized notification ratios in each area, and to delimitate high- and low-risk areas, those whose standardized notification ratio is significantly above or below the country's average, respectively. The spatial distribution of MDR- and non-MDR-TB was not homogeneous across the country. Age-standardized notification rates of MDR-TB ranged from 0.08 to 1.20 and of non-MDR-TB ranged from 7.73 to 83.03 notifications per 100,000 population across the municipalities. We identified 36 high-risk areas for non-MDR-TB and 8 high-risk areas for MDR-TB, which were simultaneously high-risk areas for non-MDR-TB. We found a moderate correlation (ρ = 0.653; 95% CI 0.457-0.728) between MDR- and non-MDR-TB standardized notification ratios. We found heterogeneity in the spatial distribution of MDR-TB across municipalities and we identified priority areas for intervention against TB. We recommend including geographical criteria in the application of molecular drug resistance to provide early MDR-TB diagnosis, in high-risk areas.

Evaluation of a gene-by-gene approach for prospective whole-genome sequencing-based surveillance of multidrug resistant Mycobacterium tuberculosis.

Whole-genome sequencing (WGS) offers unprecedented resolution for tracking Mycobacterium tuberculosis transmission and antibiotic-resistance spread. Still, the establishment of standardized WGS-based pipelines and the definition of epidemiological clusters based on genetic relatedness are under discussion. We aimed to implement a dynamic gene-by-gene approach, fully relying on freely available software, for prospective WGS-based tuberculosis surveillance, demonstrating its application for detecting transmission chains by retrospectively analysing all M/XDR strains isolated in 2013-2017 in Portugal. We observed a good correlation between genetic relatedness and epidemiological links, with strongly epilinked clusters displaying mean pairwise allele differences (AD) always below 0.3% (ratio of mean AD over the total number of shared loci between same-cluster strains). This data parallels the genetic distances acquired by the core-SNV analysis, while providing higher resolution and epidemiological concordance than MIRU-VNTR genotyping. The dynamic analysis of strain sub-sets (i.e., increasing the number of shared loci within each sub-set) also strengthens the confidence in detecting epilinked clusters. This gene-by-gene strategy also offers several practical benefits (e.g., reliance on freely-available software, scalability and low computational requirements) that further consolidated its suitability for a timely and robust prospective WGS-based laboratory surveillance of M/XDR-TB cases.

Association of Leukotriene A4 Hydrolase with Tuberculosis Susceptibility Using Genomic Data in Portugal.

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the eicosanoid pathway. lta4h locus polymorphisms have previously been linked to tuberculosis (TB) susceptibility and disease outcome in a Vietnamese dataset, but further studies suggested that those results were poorly reproducible. We, therefore, compared the full set of variants (113 SNPs) within the gene in a Portuguese dataset of 112 TB patients and 120 controls, using both the frequency of SNPs and haplotypes, in order to assess their association with TB susceptibility. Although we obtained no significant differences between the TB patients and the control group, linkage analysis showed that an extensively typed polymorphism, rs17525495, was associated with 21 other SNPs, all displaying evidence of association to lower LTA4H expression. While the derived alleles of these SNPs showed a moderately higher frequency in the TB group, differences were not significant. In contrast to Asian populations, where these SNPs are much more frequent, the low frequencies of candidate SNPs in Europeans render them less pertinent in a public health context. Consequently, the typing of specific polymorphisms as a strategy to establish preventive measures and differential TB drug treatments is important but needs to take into consideration that haplotypic background and structure can be substantially different in distinct geographic regions.

Migration Flow and Its Impact on Tuberculosis Notification in Portugal.

INTRODUCTION: Tuberculosis notification in Portugal has decreased in the last few years. As a consequence of the economic crisis, emigration has increased and immigration has decreased. Immigrants are a risk group for tuberculosis. Most emigrants are 20-44 years old and belong to the age group most affected by tuberculosis. OBJECTIVE: To describe the decrease in tuberculosis notification in Portugal over the last years from a demographical point of view. METHODS: Mathematical analysis was performed to quantify the effect of the migration movements (separately and simultaneously) on tuberculosis notification in Portugal from 2008 to 2014. We calculated the estimated tuberculosis notification for each year during the period of study: 1) fixing immigration rate and tuberculosis rate in immigrants at 2008 values; 2) fixing emigration rate and tuberculosis rate in emigrants at 2008 values; 3) fixing both phenomenons at 2008 values. RESULTS: The differences between the observed and the estimated numbers were small (≤0.5 cases/100000 inhabitants). DISCUSSION: Impact of the migration movements on tuberculosis notification rate does not seem to be significant when analyzed for each phenomenon individually and simultaneously, by our model. This might mean that we have to concentrate our efforts in other risk factors for tuberculosis.

Gaps and barriers to tuberculosis screening among anti-tumor necrosis factor prescribers.

Delegates from the Tuberculosis Committee of the Portuguese Pulmonology Society, the Portuguese Rheumatology Society, the Portuguese Dermatology and Venereology Society and the Portuguese Gastroenterology Society, have revised and updated, in 2012, their guidelines for the diagnosis and treatment of latent tuberculosis infection and active tuberculosis in patients that are candidates for therapy with biologic drugs. In order to identify perceived barriers to tuberculosis screening among patients candidate to anti-TNF treatment, we performed a cross-sectional survey including rheumatologists, gastroenterologists and dermatologists who prescribed anti-TNF agents, identified by the respective Scientific Societies, throughout Portugal. Ninety-five physicians (85 specialist and 10 trainees with more than 3 years of practice) participated in the survey, including 42 rheumatologists (response rate 28%), 32 dermatologists (12% response) and 21 gastroenterologists (4% response). No information was collected on non-respondents. This study showed that most of the participants were aware of tuberculosis risk and that they screened patients for tuberculosis following guidelines.

The Effect of a Basic Basket on Tuberculosis Treatment Outcome in the Huambo Province, Angola / Efecto de una cesta básica alimentaria en el resultado del tratamiento de la tuberculosis en la provincia de Huambo, Angola

No disponible

Effect of Isoniazid Resistance on the Tuberculosis Treatment Outcome / Efecto de la resistencia a la isoniazida en el resultado del tratamiento de la tuberculosis

No disponible

Migration Flow and Its Impact on Tuberculosis Notification in Portugal / El flujo de migratorio y su impacto en la notificación de tuberculosis en Portugal

Introduction: Tuberculosis notification in Portugal has decreased in the last few years. As a consequence of the economic crisis, emigration has increased and immigration has decreased. Immigrants are a risk group for tuberculosis. Most emigrants are 20-44 years old and belong to the age group most affected by tuberculosis. Objective: To describe the decrease in tuberculosis notification in Portugal over the last years from a demographical point of view. Methods: Mathematical analysis was performed to quantify the effect of the migration movements (separately and simultaneously) on tuberculosis notification in Portugal from 2008 to 2014. We calculated the estimated tuberculosis notification for each year during the period of study: 1) fixing immigration rate and tuberculosis rate in immigrants at 2008 values; 2) fixing emigration rate and tuberculosis rate in emigrants at 2008 values; 3) fixing both phenomenons at 2008 values. Results: The differences between the observed and the estimated numbers were small (≤0.5 cases/100. 000 inhabitants). Discussion: Impact of the migration movements on tuberculosis notification rate does not seem to be significant when analyzed for each phenomenon individually and simultaneously, by our model. This might mean that we have to concentrate our efforts in other risk factors for tuberculosis (AU)

Introducción: La notificación de casos de tuberculosis en Portugal ha disminuido en los últimos años. Como consecuencia de la crisis económica, la emigración ha aumentado y la inmigración ha disminuido. Los inmigrantes son un grupo de riesgo para la tuberculosis. La mayoría de los emigrantes tienen entre 20 y 44 años y pertenecen al grupo de edad más afectado por la tuberculosis. Objetivo: Describir la disminución de la notificación de casos tuberculosis en Portugal en los últimos años, desde un punto de vista demográfico. Métodos: Se realizó un análisis matemático para cuantificar el efecto de los movimientos migratorios (por separado y simultáneamente) en la notificación de casos de tuberculosis en Portugal de 2008 a 2014. Se calculó la notificación de casos de tuberculosis estimada para cada año durante el período de estudio. La notificación estimada de tuberculosis para cada año del periodo de estudio se calculó: 1) fijando las tasas de inmigración y de tuberculosis en inmigrantes con datos del año 2008; 2) fijando las tasas de emigración y de tuberculosis en emigrantes con datos del año 2008, y 3) fijando ambos fenómenos con datos del año 2008. Resultados: Las diferencias entre los valores observados y los valores estimados fueron pequeñas (≤ 0,5 casos/100.000 habitantes). Discusión: Según el modelo matemático propuesto en este trabajo, el impacto de los movimientos migratorios en la tasa de notificación de casos de tuberculosis en Portugal no parece ser significativo cuando se analiza cada fenómeno tanto individual como simultáneamente. Estos datos indicarían que deberíamos concentrar los esfuerzos en identificar otros factores de riesgo para la tuberculosis (AU)