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1.
Nat Commun ; 11(1): 2917, 2020 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-32518235

RESUMEN

The human- and animal-adapted lineages of the Mycobacterium tuberculosis complex (MTBC) are thought to have expanded from a common progenitor in Africa. However, the molecular events that accompanied this emergence remain largely unknown. Here, we describe two MTBC strains isolated from patients with multidrug resistant tuberculosis, representing an as-yet-unknown lineage, named Lineage 8 (L8), seemingly restricted to the African Great Lakes region. Using genome-based phylogenetic reconstruction, we show that L8 is a sister clade to the known MTBC lineages. Comparison with other complete mycobacterial genomes indicate that the divergence of L8 preceded the loss of the cobF genome region - involved in the cobalamin/vitamin B12 synthesis - and gene interruptions in a subsequent common ancestor shared by all other known MTBC lineages. This discovery further supports an East African origin for the MTBC and provides additional molecular clues on the ancestral genome reduction associated with adaptation to a pathogenic lifestyle.


Asunto(s)
Genoma Bacteriano , Mycobacterium tuberculosis/clasificación , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Anciano , ADN Bacteriano/genética , Evolución Molecular , Variación Genética , Genómica , Genotipo , Humanos , Funciones de Verosimilitud , Límite de Detección , Masculino , Mutación , Mycobacterium tuberculosis/aislamiento & purificación , Fenotipo , Filogenia , Rifampin/farmacología , Rwanda , Uganda
2.
Nat Commun ; 11(1): 1949, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32327653

RESUMEN

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.


Asunto(s)
Citosol/inmunología , Interleucina-1beta/metabolismo , Mycobacterium tuberculosis/patogenicidad , Transducción de Señal/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Proteínas Bacterianas/genética , Células Cultivadas , Citocinas/metabolismo , Femenino , Genoma Bacteriano/genética , Humanos , Evasión Inmune , Inmunomodulación , Inflamasomas/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Masculino , Ratones , Mutación , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Filogenia , Polimorfismo de Nucleótido Simple , Tuberculosis Pulmonar/microbiología , Virulencia/genética
3.
Proc Natl Acad Sci U S A ; 117(15): 8494-8502, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32229570

RESUMEN

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex (MTBC) that vary in virulence and transmissibility. While genome-wide association studies have uncovered several mutations conferring drug resistance, much less is known about the factors underlying other bacterial phenotypes. Variation in the outcome of tuberculosis infection and diseases has been attributed primarily to patient and environmental factors, but recent evidence indicates an additional role for the genetic diversity among MTBC clinical strains. Here, we used metabolomics to unravel the effect of genetic variation on the strain-specific metabolic adaptive capacity and vulnerability. To define the functionality of single-nucleotide polymorphisms (SNPs) systematically, we developed a constraint-based approach that integrates metabolomic and genomic data. Our model-based predictions correctly classify SNP effects in pyruvate kinase and suggest a genetic basis for strain-specific inherent baseline susceptibility to the antibiotic para-aminosalicylic acid. Our method is broadly applicable across microbial life, opening possibilities for the development of more selective treatment strategies.


Asunto(s)
Antituberculosos/farmacología , Genómica/métodos , Interacciones Huésped-Patógeno , Metaboloma , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleótido Simple , Tuberculosis/genética , Ácido Aminosalicílico/farmacología , Genoma Bacteriano , Estudio de Asociación del Genoma Completo , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Fenotipo , Filogenia , Piruvato Quinasa/metabolismo , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Virulencia
4.
Am J Trop Med Hyg ; 102(4): 728-730, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32100700

RESUMEN

In this study, we report an investigation of a tuberculosis (TB) outbreak in a high school in China. Eleven students with active TB were identified. A culture-negative 17-year-old girl was considered as index case affected by pulmonary and meningeal TB. Screening results indicated latent TB in 32.8% of the students in the classroom of index case, whereas a significantly decreased prevalence of TB infection was found among students on the same floor, ranging from 1.3 to 8.2%. Genotyping revealed that all the Mycobacterium tuberculosis (MTB) isolates belonged to Beijing spoligotype international types 1 (SIT1). In conclusion, a diagnostic delay for the culture-negative index case played an important role in the transmission of Beijing genotype MTB strain in the boarding school in Yunnan. The separate locations of classrooms and sufficient air ventilation contributed to the significant difference in proportions of TB infection between classmates and other students in this outbreak.


Asunto(s)
Brotes de Enfermedades , Mycobacterium tuberculosis/clasificación , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/microbiología , Adolescente , China/epidemiología , Femenino , Humanos , Masculino , Instituciones Académicas
5.
Lancet Respir Med ; 8(4): 368-382, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32066534

RESUMEN

BACKGROUND: Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal. METHODS: In this two-cohort diagnostic accuracy study, we used sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results. FINDINGS: Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21). INTERPRETATION: In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings. FUNDING: South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.


Asunto(s)
Técnicas Bacteriológicas/métodos , Mycobacterium tuberculosis/clasificación , Esputo/microbiología , Tuberculosis Pulmonar/diagnóstico , Adulto , Estudios de Cohortes , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/microbiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Distribución Aleatoria , Recurrencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sudáfrica/epidemiología , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/microbiología
6.
BMC Infect Dis ; 20(1): 120, 2020 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32041530

RESUMEN

BACKGROUND: While several studies have assessed the associations between biological factors and tuberculosis (TB) transmission, our understanding of the associations between TB transmission and social and economic factors remains incomplete. We aimed to explore associations between community TB transmission and socio-economic factors within a high TB-HIV burdened setting. METHODS: We conducted a cross-sectional molecular epidemiology study among adult patients attending a routine TB clinic. Demographic and clinical data were extracted from TB registers and clinical folders; social and economic data were collected using interviewer-administered questionnaires; Mycobacterium tuberculosis isolates were genotyped and classified as clustered/non-clustered using IS6110-based Restriction Fragment Length Polymorphism. Composite "social" and "economic" scores were generated from social and economic data. Data were analyzed using StataCorp version 15.0 software. Stratified, bivariable analyses were performed using chi-squared. Wilcoxon signed rank tests; univariable and multivariable logistic regression models were developed to explore associations in the social, economic, traditional and composite TB risk factors with TB transmission. RESULTS: Of the 505 patient Mtb  strains, 348(69%) cases were classified as clustered and 157(31%) were non-clustered. Clustered cases were more likely to have lived longer in the study community, (odds ratio [OR] = 1.05, 95% Confidence interval [C.I]:1.02-1.09, p = 0.006); in the same house (OR = 1.04, C.I: 0.99-1.08, p = 0.06); and had increased household crowding conditions (i.e fewer rooms used for sleeping, OR = 0.45, C.I:0.21-0.95, p = 0.04). Although a higher proportion of clustered cases had a low economic score, no statistically significant association was found between clustering and either the economic score (p = 0.13) or social score (p = 0.26). CONCLUSIONS: We report a novel association between Mtb transmission and prolonged stay within a high burdened community. Transmission was also associated with fewer rooms for sleeping in a household. Increased social interaction and prolonged residence in a high burdened community are important factors linked to Mtb transmission, possibly due to increased probability of higher effective contact rates. The possible importance of degrees of poverty within low socio-economic setting warrants further study.


Asunto(s)
Mycobacterium tuberculosis/genética , Tuberculosis/epidemiología , Tuberculosis/transmisión , Adolescente , Adulto , Anciano , Ciudades , Análisis por Conglomerados , Estudios Transversales , ADN Bacteriano/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/aislamiento & purificación , Factores de Riesgo , Factores Socioeconómicos , Sudáfrica/epidemiología , Adulto Joven
7.
Nat Commun ; 11(1): 684, 2020 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-32019932

RESUMEN

Mycobacterium tuberculosis (Mtb) strains are classified into different phylogenetic lineages (L), three of which (L2/L3/L4) emerged from a common progenitor after the loss of the MmpS6/MmpL6-encoding Mtb-specific deletion 1 region (TbD1). These TbD1-deleted "modern" lineages are responsible for globally-spread tuberculosis epidemics, whereas TbD1-intact "ancestral" lineages tend to be restricted to specific geographical areas, such as South India and South East Asia (L1) or East Africa (L7). By constructing and characterizing a panel of recombinant TbD1-knock-in and knock-out strains and comparison with clinical isolates, here we show that deletion of TbD1 confers to Mtb a significant increase in resistance to oxidative stress and hypoxia, which correlates with enhanced virulence in selected cellular, guinea pig and C3HeB/FeJ mouse infection models, the latter two mirroring in part the development of hypoxic granulomas in human disease progression. Our results suggest that loss of TbD1 at the origin of the L2/L3/L4 Mtb lineages was a key driver for their global epidemic spread and outstanding evolutionary success.


Asunto(s)
Evolución Molecular , Mycobacterium tuberculosis/genética , Tuberculosis/microbiología , Animales , Cobayas , Humanos , Ratones , Ratones Endogámicos C3H , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/patogenicidad , Filogenia , Eliminación de Secuencia , Virulencia
8.
Eur J Med Res ; 24(1): 38, 2019 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-31806020

RESUMEN

BACKGROUND: Increasing incidence of multidrug-resistant Mycobacterium tuberculosis infections is hampering global tuberculosis control efforts. Kuwait is a low-tuberculosis-incidence country, and ~ 1% of M. tuberculosis strains are resistant to rifampicin and isoniazid (MDR-TB). This study detected mutations in seven genes predicting resistance to rifampicin, isoniazid, pyrazinamide, ethambutol and streptomycin in MDR-TB strains. Sequence data were combined with spoligotypes for detecting local transmission of MDR-TB in Kuwait. METHODS: Ninety-three MDR-TB strains isolated from 12 Kuwaiti and 81 expatriate patients and 50 pansusceptible strains were used. Phenotypic drug susceptibility was determined by MGIT 460 TB/960 system. Mutations conferring resistance to rifampicin, isoniazid, pyrazinamide, ethambutol and streptomycin were detected by genotype MTBDRplus assay and/or PCR sequencing of three rpoB regions, katG codon 315 (katG315) + inhA regulatory region, pncA, three embB regions and rpsL + rrs-500-900 regions. Spoligotyping kit was used, spoligotypes were identified by SITVIT2, and phylogenetic tree was constructed by using MIRU-VNTRplus software. Phylogenetic tree was also constructed from concatenated sequences by MEGA7 software. Additional PCR sequencing of gidB and rpsA was performed for cluster isolates. RESULTS: Pansusceptible isolates contained wild-type sequences. Mutations in rpoB and katG and/or inhA were detected in 93/93 and 92/93 MDR-TB strains, respectively. Mutations were also detected for pyrazinamide resistance, ethambutol resistance and streptomycin resistance in MDR-TB isolates in pncA, embB and rpsL + rrs, respectively. Spoligotyping identified 35 patterns with 18 isolates exhibiting unique patterns while 75 isolates grouped in 17 patterns. Beijing genotype was most common (32/93), and 11 isolates showed nine orphan patterns. Phylogenetic analysis of concatenated sequences showed unique patterns for 51 isolates while 42 isolates grouped in 16 clusters. Interestingly, 22 isolates in eight clusters by both methods were isolated from TB patients typically within a span of 2 years. Five of eight clusters were confirmed by additional gidB and rpsA sequence data. CONCLUSIONS: Our study provides the first insight into molecular epidemiology of MDR-TB in Kuwait and identified several potential clusters of local transmission of MDR-TB involving 2-6 subjects which had escaped detection by routine surveillance studies. Prospective detection of resistance-conferring mutations can identify possible cases of local transmission of MDR-TB in low MDR-TB settings.


Asunto(s)
Antituberculosos/uso terapéutico , Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana Múltiple/genética , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Incidencia , Kuwait/epidemiología , Masculino , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/aislamiento & purificación , Filogenia , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/transmisión
9.
Int J Mycobacteriol ; 8(4): 366-370, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31793507

RESUMEN

Background: Strains of the Beijing sublineage of Mycobacterium tuberculosis have caused large outbreaks of tuberculosis, often involving multidrug resistance strains and this genetically highly conserved family of strains predominates in some geographic areas. For most of the countries of Latin America, no country-wide studies about the prevalence of the Beijing lineage are available. Methods: In this study, we determine the prevalence of the Beijing sublineage in Ecuador, using a large nation-wide sample of 991 isolates from the years 2014-2016 and with the strains, in case-related-proportional representation, emerging from most of the provinces of the country. The isolates were genotyped with asinglenucleotidespecific polymorphism (SNP) polymerase chain reaction for the Beijing sublineage. SNPpositive strains were confirmed as belonging to this lineage with 24 mycobacterial interspersed repetitive unitvariable number of tandem repeat and DNA sequencing. Results: We identified only four Beijing isolates in this collection of 991 strains and calculated a prevalence rate of 0.43%. Conclusions: Our study shows a limited dissemination of the Beijing strains in the Ecuadorian population. This in contrast with the neighbor countries of Peru and Colombia were locally a prevalence of up to 16% has been reported.


Asunto(s)
Tamizaje Masivo/estadística & datos numéricos , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleótido Simple , Tuberculosis/epidemiología , Tuberculosis/microbiología , ADN Bacteriano/aislamiento & purificación , Farmacorresistencia Bacteriana , Ecuador/epidemiología , Genotipo , Humanos , Repeticiones de Minisatélite , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Prevalencia , Análisis de Secuencia de ADN
10.
PLoS Comput Biol ; 15(12): e1007527, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31815935

RESUMEN

Next-generation sequencing based base-by-base distance measures have become an integral complement to epidemiological investigation of infectious disease outbreaks. This study introduces PANPASCO, a computational pan-genome mapping based, pairwise distance method that is highly sensitive to differences between cases, even when located in regions of lineage specific reference genomes. We show that our approach is superior to previously published methods in several datasets and across different Mycobacterium tuberculosis lineages, as its characteristics allow the comparison of a high number of diverse samples in one analysis-a scenario that becomes more and more likely with the increased usage of whole-genome sequencing in transmission surveillance.


Asunto(s)
Mycobacterium tuberculosis/genética , Tuberculosis/transmisión , Mapeo Cromosómico , Biología Computacional , Simulación por Computador , ADN Bacteriano/genética , Bases de Datos Genéticas/estadística & datos numéricos , Brotes de Enfermedades/estadística & datos numéricos , Genoma Bacteriano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Epidemiología Molecular/estadística & datos numéricos , Mycobacterium tuberculosis/clasificación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Tuberculosis/epidemiología , Tuberculosis/microbiología , Secuenciación Completa del Genoma
11.
Euro Surveill ; 24(50)2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31847944

RESUMEN

BackgroundWhole genome sequencing (WGS) is a reliable tool for studying tuberculosis (TB) transmission. WGS data are usually processed by custom-built analysis pipelines with little standardisation between them.AimTo compare the impact of variability of several WGS analysis pipelines used internationally to detect epidemiologically linked TB cases.MethodsFrom the Netherlands, 535 Mycobacterium tuberculosis complex (MTBC) strains from 2016 were included. Epidemiological information obtained from municipal health services was available for all mycobacterial interspersed repeat unit-variable number of tandem repeat (MIRU-VNTR) clustered cases. WGS data was analysed using five different pipelines: one core genome multilocus sequence typing (cgMLST) approach and four single nucleotide polymorphism (SNP)-based pipelines developed in Oxford, United Kingdom; Borstel, Germany; Bilthoven, the Netherlands and Copenhagen, Denmark. WGS clusters were defined using a maximum pairwise distance of 12 SNPs/alleles.ResultsThe cgMLST approach and Oxford pipeline clustered all epidemiologically linked cases, however, in the other three SNP-based pipelines one epidemiological link was missed due to insufficient coverage. In general, the genetic distances varied between pipelines, reflecting different clustering rates: the cgMLST approach clustered 92 cases, followed by 84, 83, 83 and 82 cases in the SNP-based pipelines from Copenhagen, Oxford, Borstel and Bilthoven respectively.ConclusionConcordance in ruling out epidemiological links was high between pipelines, which is an important step in the international validation of WGS data analysis. To increase accuracy in identifying TB transmission clusters, standardisation of crucial WGS criteria and creation of a reference database of representative MTBC sequences would be advisable.


Asunto(s)
Epidemiología Molecular/métodos , Tipificación de Secuencias Multilocus/métodos , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleótido Simple , Tuberculosis/epidemiología , Secuenciación Completa del Genoma/métodos , Transmisión de Enfermedad Infecciosa , Monitoreo Epidemiológico , Humanos , Repeticiones de Minisatélite , Mycobacterium tuberculosis/aislamiento & purificación , Países Bajos , Secuencias Repetidas en Tándem , Tuberculosis/diagnóstico , Tuberculosis/transmisión
12.
Emerg Infect Dis ; 25(11): 2152-2154, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31625855

RESUMEN

Mycobacterium microti is a member of the Mycobacterium tuberculosis complex that causes pathology in many mammals. M. microti infections have been found in some countries in Europe. We report an outbreak of tuberculosis caused by M. microti in wild boars in Spain.


Asunto(s)
Mycobacterium tuberculosis , Sus scrofa/microbiología , Enfermedades de los Porcinos/epidemiología , Enfermedades de los Porcinos/microbiología , Tuberculosis/veterinaria , Animales , Brotes de Enfermedades , Geografía Médica , Historia del Siglo XXI , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/genética , Vigilancia en Salud Pública , España/epidemiología , Porcinos , Enfermedades de los Porcinos/historia
13.
PLoS One ; 14(10): e0223610, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31626647

RESUMEN

INTRODUCTION: Recurrent tuberculosis (TB) is one of the main challenges in TB control. Genotyping based on Mycobacterial Interspersed Repetitive Units-Variable Tandem Repeats (MIRU-VNTR) has been widely used to differentiate between relapse and reinfection, which are the two main causes of recurrent TB. There is a lack of data regarding the causes of TB recurrence in Georgia, and while differentiating between relapse and reinfection plays a key role in defining appropriate interventions, the required genotyping methodologies have not been implemented. The objective of this study was to implement MIRU-VNTR genotyping at the National Center for Tuberculosis and Lung Diseases (NCTBLD) and differentiate between relapse and reinfection in multidrug resistant (MDR-) TB patients from Tbilisi, Georgia. METHODS: Recurrent MDR tuberculosis cases from 2014-2016 diagnosed at NCTLD were included in the study when bacterial samples from both episodes were available. Genotyping based on the MIRU-VNTR 24 loci was implemented and used for differentiating between relapse and reinfection. Paired samples showing the same MIRU-VNTR pattern or one locus difference were classified as relapse, while two and more loci differences were treated as reinfection. Exact logistic regression was used to identify predictors of recurrence. RESULTS: Thirty two MDR-TB patients (64 samples) were included and MIRU-VNTR 24 typing was performed on the corresponding paired samples. Of the 32 patients, 25 (83.3%) were identified as relapse while 5 (16.7%) were due to re-infection. Patients with a history of incarceration were significantly associated with TB reinfection (p< 0.05). CONCLUSION: Recurrent TB in MDR patients in Georgia are mainly caused by relapse, raising concerns on the efficacy of the TB control program. An association between incarceration and reinfection likely reflects high levels of ongoing TB transmission in prisons, indicating the need for better TB infection control measures in these settings. Our results add to the rationale for implementing genotypic surveillance of TB more broadly to support TB control in Georgia.


Asunto(s)
ADN Bacteriano , Repeticiones de Minisatélite , Tipificación Molecular , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/genética , Tuberculosis/epidemiología , Tuberculosis/microbiología , Adulto , Femenino , Georgia (República)/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Vigilancia en Salud Pública , Recurrencia
14.
Am J Trop Med Hyg ; 101(6): 1308-1311, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31628738

RESUMEN

Two Mycobacterium tuberculosis strains-M (sublineage 4.1) and Ra (sublineage 4.3)-have long prevailed in Argentina among patients with multidrug-resistant tuberculosis (MDR-TB). Recently, budget constraints have hampered the surveillance of MDR-TB transmission. Based on whole-genome sequence analysis, we used M- and Ra-specific single nucleotide polymorphisms to tailor two multiplex allele-specific polymerase chain reactions (PCRs), which we applied to 252 stored isolates (95% of all newly diagnosed MDR-TB cases countrywide, 2015-2017). Compared with the latest data available (2007-2009), the M strain has receded (80/324 to 20/252, P < 0.0001), particularly among cross-border migrants (12/58 to 0/53, P = 0.0003) and HIV-infected people (30/97 to 7/74, P = 0.0007), but it still accounts for 4/12 new cases of extensively drug-resistant TB. Differently, the Ra strain remained stable in frequency (39/324 to 33/252) and contributed marginally to the extensive drug-resistance load (1/12). Our novel strategy disclosed recent trends of the two major MDR-TB strains, providing meaningful data to allocate control interventions more efficiently.


Asunto(s)
ADN Bacteriano/genética , Farmacorresistencia Bacteriana Múltiple , Epidemias/estadística & datos numéricos , Tuberculosis Extensivamente Resistente a Drogas/microbiología , Mycobacterium tuberculosis/genética , Alelos , Antituberculosos/farmacología , Argentina/epidemiología , Tuberculosis Extensivamente Resistente a Drogas/epidemiología , Genotipo , Humanos , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma
15.
PLoS One ; 14(10): e0222925, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31613905

RESUMEN

BACKGROUND: High quality diagnostic services are crucial for tuberculosis (TB) diagnosis, treatment and control. A strong laboratory quality management system (QMS) is critical to ensuring the quality of testing and results. Recent initiatives to improve TB laboratory quality have focused on low and middle-income countries, but similar issues also apply to high-income countries. METHODS AND FINDINGS: Using a multipronged approach reviews of facilities, equipment, processes (purchasing, pre-analytic, analytic and post-analytic), staff, health and safety, documentation, information management and organization based on the ISO 15189 and the twelve quality system essentials were conducted between October 2015 and January 2016 at the National TB Reference Laboratory in Germany. Outcome assessment included proportion of smear positive slides, proportion of contaminated liquid cultures and DNA contamination rates before and after implementation of QMS. The odds ratio for these outcomes was calculated using a before/after comparison. Reviews highlighted deficiencies across all twelve quality system essentials and were addressed in order of priority and urgency. Actions aimed at improving analytical quality, health and safety and information management were prioritised for initial implementation in parallel with each other. The odds ratio for a sample to be tested as microscopically positive increased by 2.08 (95%CI 1.41-3.06) comparing the time before with the time after implementation of quality managed fluorescence microscopy. Liquid culture contamination rates decreased from 23.6- 7.6% in April-July 2016 to <10% in November 2017-March 2018. The proportion of negative controls showing evidence of DNA contamination decreased from 38.2% in 2013 to 8.1% in 2017, the corresponding odds ratio was 0.14 (95%CI 0.07-0.29). CONCLUSION: This study showed marked improvement on quality indicators after implementation of a QMS in a National TB Reference Laboratory. The challenges and lessons learned in this study are valuable not just for high-income settings, but are equally generalizable to other laboratories.


Asunto(s)
Laboratorios/normas , Microscopía/normas , Mycobacterium tuberculosis/clasificación , Control de Calidad , Tuberculosis Pulmonar/diagnóstico , ADN Bacteriano/genética , Alemania , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Salud Laboral/normas , Oportunidad Relativa , Estándares de Referencia , Reproducibilidad de los Resultados , Tuberculosis Pulmonar/microbiología
16.
BMC Infect Dis ; 19(1): 851, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31615439

RESUMEN

BACKGROUND: In Lao People's Democratic Republic (PDR), tuberculosis (TB) prevalence was estimated at 540/100,000 in 2011. Nevertheless, little is known about the genetic characteristics and anti-TB drug resistance of the Mycobacterium tuberculosis population. The main objective of this work was to study the genetic characteristics and drug resistance of M. tuberculosis population collected during the first National TB Prevalence Survey (TBPS) of Lao PDR (2010-2011). METHODS: Two hundred and twenty two isolates collected during TBPS (2010-2011) were analyzed with the GenoType MTBDRplus test for M. tuberculosis identification and drug resistance detection. Then, 206 of the 222 isolates were characterized by spoligotyping and MIRU-VNTR typing. RESULTS: Among the 222 M. tuberculosis isolates, 11 were mono-resistant to isoniazid and 2 were resistant to isoniazid and rifampicin (MDR-TB), using the GenoType MTBDRplus test. Among the 202 genetically characterized isolates, the East African-Indian (EAI) family was predominant (76.7%) followed by the Beijing (14.4%) and T (5.5%) families. EAI isolates came from all the country provinces, whereas Beijing isolates were found mainly in the northern and central provinces. A higher proportion of Beijing isolates was observed in people younger than 35 years compared to EAI. Moreover, the percentage of drug resistance was higher among Beijing (17.2%) than EAI (5.2%) isolates, and the two MDR-TB isolates belonged to the Beijing family. Combined analysis of the MIRU-VNTR and spoligotyping results (n = 202 isolates) revealed an estimated clustering rate of 11% and the occurrence of mini-outbreaks of drug-resistant TB caused by Beijing genotypes. CONCLUSIONS: The EAI family, the ancient and endemic family in Asia, is predominant in Lao PDR whereas the prevalence of Beijing, the most harmful M. tuberculosis family for humans, is still low, differently from neighboring countries. However, its association with drug resistance, its presence in young patients and its potential association with recent transmission suggest that the Beijing family could change TB epidemiological pattern in Lao PDR. Therefore, efficient TB control and surveillance systems must be maintained and reinforced to prevent the emergence of highly transmissible and drug-resistant strains in Lao PDR, as observed in neighboring countries.


Asunto(s)
Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Adolescente , Adulto , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Análisis por Conglomerados , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Femenino , Genotipo , Humanos , Isoniazida/farmacología , Isoniazida/uso terapéutico , Laos/epidemiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/aislamiento & purificación , Filogenia , Prevalencia , Rifampin/farmacología , Rifampin/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Adulto Joven
17.
Int J Infect Dis ; 89: 122-127, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31639521

RESUMEN

OBJECTIVE: To evaluate the utility of a volunteer health development army in conducting population screening for active tuberculosis (TB) in a rural community in southern Ethiopia. METHODS: A population-based cross-sectional survey was conducted in six kebeles (the lowest administrative units). Volunteer women community workers led a symptom screening programme to identify adults ≥15 years of age with TB in the community. Individuals with a cough for ≥2 weeks had spot and morning sputum samples taken, which were examined using acid-fast bacillus (AFB) smear microscopy, culture, and Xpert MTB/RIF. RESULTS: All 24517 adults in the study area had a symptom screen performed; 544 (2.2%) had had a cough for ≥2 weeks. Among those with a positive symptom screen, 13 (2.4%) were positive on sputum AFB smear microscopy, 13 (2.4%) had a positive culture, and 32 (5.8%) had a positive Xpert MTB/RIF test. Overall, 34 TB cases (6%) were identified by culture and/or Xpert, corresponding to a prevalence of 139 per 100000 persons. CONCLUSIONS: This study demonstrated the capability of community health workers (volunteer and paid) to rapidly conduct a large-scale population TB screening evaluation and highlight the high yield of such a programme in detecting previously undiagnosed cases when combined with Xpert MTB/RIF testing. This could be a model to implement in other similar settings.


Asunto(s)
Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Agentes Comunitarios de Salud/estadística & datos numéricos , Estudios Transversales , Etiopía/epidemiología , Femenino , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Prevalencia , Sensibilidad y Especificidad , Esputo/microbiología , Tuberculosis Pulmonar/microbiología , Adulto Joven
18.
J Med Microbiol ; 68(11): 1622-1628, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31596198

RESUMEN

Introduction. Nosocomial transmission of Mycobacterium tuberculosis is an important health issue and the detection of tuberculosis (TB) cases is the main tool for controlling this disease.Aim. We aimed to assess the possible occurrence of nosocomial transmission of M. tuberculosis in a reference hospital for HIV/AIDS patients and evaluate both the performance of the Xpert MTB/RIF (Xpert) platform and drug resistance profiles.Methodology. We evaluated the performance of the Xpert platform. Samples that tested positive on the BACTEC MGIT 320 (MGIT320) platform were submitted for genotyping and drug susceptibility testing.Results. In this study, pulmonary and extrapulmonary samples from 407 patients were evaluated, and among these, 15.5 % were diagnosed with TB by the MGIT320 platform, with a TB/HIV coinfection rate of 52.4 %. The Xpert platform gave positive results for TB for 11 samples with negative results on the MGIT320 platform. In the genotyping results, 53.3 % of the strains clustered; of these strains, half were in two of the four clusters formed, and the patients had visited the hospital on the same day. Drug resistance was observed in 11.7 % of the strains.Conclusion. Putative nosocomial transmission of M. tuberculosis was detected, showing that genotyping is a powerful approach for understanding the dynamics of M. tuberculosis transmission, especially in a high-burden TB and HIV landscape.


Asunto(s)
Infecciones por VIH/complicaciones , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Pulmonar/microbiología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Antibióticos Antituberculosos/farmacología , Técnicas de Laboratorio Clínico , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/microbiología , Estudios Transversales , Farmacorresistencia Bacteriana , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Filogenia , Tuberculosis , Tuberculosis Pulmonar/diagnóstico
19.
PLoS One ; 14(9): e0222078, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31479485

RESUMEN

Mycobacterium canettii is a smooth bacillus related to the Mycobacterium tuberculosis complex. It causes lymph nodes and pulmonary tuberculosis in patients living in countries of the Horn of Africa, including Djibouti. The environmental reservoirs of M. canettii are still unknown. We aimed to further decrypt these potential reservoirs by using an original approach of High-Throughput Carbon and Azote Substrate Profiling. The Biolog Phenotype profiling was performed on six clinical strains of M. canettii and one M. tuberculosis strain was used as a positive control. The experiments were duplicated and authenticated by negative controls. While M. tuberculosis metabolized 22/190 (11%) carbon substrates and 3/95 (3%) nitrogen substrates, 17/190 (8.9%) carbon substrates and three nitrogen substrates were metabolized by the six M. canettii strains forming the so-called corebiologome. A total at 16 carbon substrates and three nitrogen substrates were metabolized in common by M. tuberculosis and the six M. canettii strains. Moreover, at least one M. canettii strain metabolized 36/190 (19%) carbon substrates and 3/95 (3%) nitrogen substrates for a total of 39/285 (13%) substrates. Classifying these carbon and nitrogen substrates into ten potential environmental sources (plants, fruits and vegetables, bacteria, algae, fungi, nematodes, mollusks, mammals, insects and inanimate environment) significantly associated carbon and nitrogen substrates metabolized by at least one M. canettii strain with plants (p = 0.006). These results suggest that some plants endemic in the Horn of Africa may serve as ecological niches for M. canettii. Further ethnobotanical studies will indicate plant usages by local populations, then guiding field microbiological investigations in order to prove the definite environmental reservoirs of this opportunistic tuberculous pathogen.


Asunto(s)
Microbiología Ambiental , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium tuberculosis/aislamiento & purificación , Mycobacterium tuberculosis/metabolismo , Micobacterias no Tuberculosas/aislamiento & purificación , Micobacterias no Tuberculosas/metabolismo , Tuberculosis/microbiología , África Oriental , Animales , Técnicas de Tipificación Bacteriana , Reservorios de Enfermedades/microbiología , Djibouti , Ensayos Analíticos de Alto Rendimiento , Humanos , Mycobacterium tuberculosis/clasificación , Micobacterias no Tuberculosas/clasificación , Fenotipo , Plantas/microbiología , Tuberculosis Ganglionar/microbiología , Tuberculosis Pulmonar/microbiología
20.
Biomedica ; 39(Supl. 2): 78-92, 2019 08 01.
Artículo en Inglés, Español | MEDLINE | ID: mdl-31529836

RESUMEN

INTRODUCTION: Tuberculosis continues to be a public health priority. Indigenous peoples are vulnerable groups with cultural determinants that increase the risk of the disease. OBJECTIVE: To determine molecular epidemiology and phenotypical features and of Mycobacterium tuberculosis isolates from indigenous people in Colombia during the period from 2009 to 2014. MATERIALS AND METHODS: We conducted an analytical observational study; we analyzed 234 isolates to determine their patterns of sensitivity to antituberculosis drugs and their molecular structures by spoligotyping. RESULTS: The isolates came from 41 indigenous groups, predominantly the Wayúu (13.10%) and Emberá Chamí (11.35%). We found 102 spoligotypes distributed among seven genetic families (37.2% LAM, 15.8% Haarlem, 8.1% T, 3.4% U, 2.6% S, 2.1% X, and 0.9%, Beijing). The association analysis showed that the non-clustered isolates were related to prior treatment, relapse, orphan spoligotypes, and the Beijing family. The H family presented an association with the Arhuaco and Camëntsá indigenous groups, the U family was associated with the Wounaan group, and the T family was associated with the Motilón Barí group. CONCLUSIONS: This is the first national study on M. tuberculosis characterization in indigenous groups. The study evidenced that diagnosis in indigenous people is late. We described 53% of orphan patterns that could be typical of the Colombian indigenous population. The high percentage of grouping by spoligotyping (62%) could indicate cases of active transmission, a situation that should be corroborated using a second genotyping marker. A new Beijing spoligotype (Beijing-like SIT 406) was identified in Colombia.


Asunto(s)
Indios Sudamericanos , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antituberculosos/farmacología , Niño , Preescolar , Colombia/epidemiología , Cultura , Diagnóstico Tardío , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Fenotipo , Reacción en Cadena de la Polimerasa , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Secuencias Repetitivas de Ácidos Nucleicos , Tuberculosis/epidemiología , Tuberculosis/etnología , Adulto Joven
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