When to start treatment? Dilemma illustrated by a paediatric case of extensively drug-resistant tuberculosis of the central nervous system.

An HIV-positive mother infected her daughter with extensively drug-resistant Mycobacterium tuberculosis. Despite adhering to the then current guidelines for prevention, the infant was diagnosed with extensively drug-resistant pulmonary tuberculosis at the age of 4 months and developed tuberculous meningitis. After a short delay, appropriate treatment was initiated, followed by an inhospital stay at a specialised hospital. The infant became generally well, but had delayed neurological development. Secondary hydrocephalus due to tuberculous meningitis required a ventriculoperitoneal shunt. After 2 years of microbiologically and clinically effective tuberculosis treatment and several shunt complications, the HIV-negative child died at the age of 28 months ‒ with radiological signs of a shunt infection. The reason for the fatal outcome was probably related to inadequate risk reduction of airborne mother-to-child transmission, inappropriate chemoprophylaxis and delayed initiation of adequate treatment.

Extensively Drug-Resistant Tuberculosis in the Time of COVID-19-How has the Landscape Changed for Pakistan?

The incidence of extensively drug-resistant tuberculosis (XDR-TB) has been rising consistently in Pakistan, and the country is likely to experience another surge of cases in the midst of the COVID-19 crisis. It is imperative to consider how the rising proportion of XDR-TB is best tackled during the pandemic; this includes finding a solution to the problem of non-adherence at the level of community-based healthcare, the utility and practicality of simultaneous testing for COVID-19 and TB, and reconciliation of the World Health Organization's recommendation of home-based treatment with the need for frequent monitoring of anti-tubercular therapy in XDR-TB. Operational research is needed expeditiously to bypass these limitations.

Molecular epidemiology of drug resistant Mycobacterium tuberculosis in Africa: a systematic review.

BACKGROUND: The burden of drug resistant tuberculosis in Africa is largely driven by the emergence and spread of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains. MDR-TB is defined as resistance to isoniazid and rifampicin, while XDR-TB is defined as MDR-TB with added resistance to any of the second line injectable drugs and any fluoroquinolone. The highest burden of drug resistant TB is seen in countries further experiencing an HIV epidemic. The molecular mechanisms of drug resistance as well as the evolution of drug resistant TB strains have been widely studied using various genotyping tools. The study aimed to analyse the drug resistant lineages in circulation and transmission dynamics of these lineages in Africa by describing outbreaks, nosocomial transmission and migration. Viewed as a whole, this can give a better insight into the transmission dynamics of drug resistant TB in Africa. METHODS: A systematic review was performed on peer reviewed original research extracted from PubMed reporting on the lineages associated with drug resistant TB from African countries, and their association with outbreaks, nosocomial transmission and migration. The search terms "Tuberculosis AND drug resistance AND Africa AND (spoligotyping OR molecular epidemiology OR IS6110 OR MIRU OR DNA fingerprinting OR RFLP OR VNTR OR WGS)" were used to identify relevant articles reporting the molecular epidemiology of drug resistant TB in Africa. RESULTS: Diverse genotypes are associated with drug resistant TB in Africa, with variations in strain predominance within the continent. Lineage 4 predominates across Africa demonstrating the ability of "modern strains" to adapt and spread easily. Most studies under review reported primary drug resistance as the predominant type of transmission. Drug resistant TB strains are associated with community and nosocomial outbreaks involving MDR- and XDR-TB strains. The under-use of molecular epidemiological tools is of concern, resulting in gaps in knowledge of the transmission dynamics of drug resistant TB on the continent. CONCLUSIONS: Genetic diversity of M. tuberculosis strains has been demonstrated across Africa implying that diverse genotypes are driving the epidemiology of drug resistant TB across the continent.

Modeling Missing Cases and Transmission Links in Networks of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Patterns of transmission of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases worldwide in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa, diagnosed in 2011-2014. We tested scenarios in which cases were missing at random, missing differentially by clinical characteristics, or missing differentially by transmission (i.e., cases with many links were under- or oversampled). Under the assumption that cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases, and models provided evidence for super-spreading. To our knowledge, this is the first analysis to have assessed support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving super-spreading.

Tuberculosis congénita pre-extensivamente resistente a drogas: reporte de caso / Pre-extensively drug-resistant congenital tuberculosis: case report

RESUMEN La tuberculosis en el lactante es un cuadro de difícil diagnóstico por las pruebas diagnósticas que muchas veces resultan negativas y por la dificultad de identificar la fuente de transmisión. Se presenta el caso de un lactante varón de un mes de vida que presenta irritabilidad, taquipnea, fiebre, pobre ganancia de peso desde el nacimiento y hepatomegalia, además, tiene el antecedente materno de tuberculosis pre-extensivamente resistente a drogas y reacción granulomatosa tuberculoide con tinción auramina positiva para bacilos ácido-alcohol resistentes en la histopatología de placenta. Ante la sospecha de tuberculosis congénita, es referido al Instituto Nacional de Salud del Niño para estudio diagnóstico y tratamiento; el paciente presenta una evolución clínica favorable y sin reacciones adversas al tratamiento. El diagnóstico de tuberculosis congénita debe considerarse en lactantes con signos clínicos sugestivos de la enfermedad y mantener la sospecha ante la presencia del antecedente materno de infección por Mycobacterium tuberculosis.

ABSTRACT Tuberculosis in infants is a clinical case difficult to diagnose by regular testing which often yield negative results; additionally, the source of transmission is difficult to identify. This work presents the case of a one-month old nursing boy presenting irritability, tachypnea, fever, poor gain weight from birth, and hepatomegaly. Additionally, he had the maternal history of pre-extensively drug- resistant tuberculosis and tuberculoid granulomatosis reaction with positive auramine tincture for acid-alcohol resistant bacilli at histopathology of the placenta. With a suspected congenital tuberculosis, he was referred to the National Children's Health Institute for diagnosis and treatment. The patient showed a favorable clinical evolution and no adverse reactions to treatment. The diagnosis of congenital tuberculosis must be considered in infants with suggestive clinical signs of the disease and such suspicion must be maintained with the presence of a maternal history of Mycobacterium tuberculosis infection.

Extensively drug-resistant tuberculosis in South Africa: genomic evidence supporting transmission in communities.

Despite evidence that transmission is driving an extensively drug-resistant TB (XDR-TB) epidemic, our understanding of where and between whom transmission occurs is limited. We sought to determine whether there was genomic evidence of transmission between individuals without an epidemiologic connection.We conducted a prospective study of XDR-TB patients in KwaZulu-Natal, South Africa, during the 2011-2014 period. We collected sociodemographic and clinical data, and identified epidemiologic links based on person-to-person or hospital-based connections. We performed whole-genome sequencing (WGS) on the Mycobacterium tuberculosis isolates and determined pairwise single nucleotide polymorphism (SNP) differences.Among 404 participants, 123 (30%) had person-to-person or hospital-based links, leaving 281 (70%) epidemiologically unlinked. The median SNP difference between participants with person-to-person and hospital-based links was 10 (interquartile range (IQR) 8-24) and 16 (IQR 10-23), respectively. The median SNP difference between unlinked participants and their closest genomic link was 5 (IQR 3-9) and half of unlinked participants were within 7 SNPs of at least five participants.The majority of epidemiologically-unlinked XDR-TB patients had low pairwise SNP differences with at least one other participant, consistent with transmission. These data suggest that much of transmission may result from casual contact in community settings between individuals not known to one another.

Spatial Patterns of Extensively Drug-Resistant Tuberculosis Transmission in KwaZulu-Natal, South Africa.

Background: Transmission is driving the global drug-resistant tuberculosis (TB) epidemic; nearly three-quarters of drug-resistant TB cases are attributable to transmission. Geographic patterns of disease incidence, combined with information on probable transmission links, can define the spatial scale of transmission and generate hypotheses about factors driving transmission patterns. Methods: We combined whole-genome sequencing data with home Global Positioning System coordinates from 344 participants with extensively drug-resistant (XDR) TB in KwaZulu-Natal, South Africa, diagnosed from 2011 to 2014. We aimed to determine if genomically linked (difference of ≤5 single-nucleotide polymorphisms) cases lived close to one another, which would suggest a role for local community settings in transmission. Results: One hundred eighty-two study participants were genomically linked, comprising 1084 case-pairs. The median distance between case-pairs' homes was 108 km (interquartile range, 64-162 km). Between-district, as compared to within-district, links accounted for the majority (912/1084 [84%]) of genomic links. Half (526 [49%]) of genomic links involved a case from Durban, the urban center of KwaZulu-Natal. Conclusions: The high proportions of between-district links with Durban provide insight into possible drivers of province-wide XDR-TB transmission, including urban-rural migration. Further research should focus on characterizing the contribution of these drivers to overall XDR-TB transmission in KwaZulu-Natal to inform design of targeted strategies to curb the drug-resistant TB epidemic.

The use of whole-genome sequencing in cluster investigation of a multidrug-resistant tuberculosis outbreak.

We used whole-genome sequencing (WGS) to delineate transmission networks and investigate the benefits of WGS during cluster investigation.We included clustered cases of multidrug-resistant (MDR) tuberculosis (TB)/extensively drug-resistant (XDR) TB linked by mycobacterial interspersed repetitive unit variable tandem repeat (MIRU-VNTR) strain typing or epidemiological information in the national cluster B1006, notified between 2007 and 2013 in the UK. We excluded from further investigation cases whose isolates differed by greater than 12 single nucleotide polymorphisms (SNPs). Data relating to patients' social networks were collected.27 cases were investigated and 22 had WGS, eight of which (36%) were excluded as their isolates differed by more than 12 SNPs to other cases. 18 cases were ruled into the transmission network based on genomic and epidemiological information. Evidence of transmission was inconclusive in seven out of 18 cases (39%) in the transmission network following WGS and epidemiological investigation.This investigation of a drug-resistant TB cluster illustrates the opportunities and limitations of WGS in understanding transmission in a setting with a high proportion of migrant cases. The use of WGS should be combined with classical epidemiological methods. However, not every cluster will be solvable, regardless of the quality of genomic data.

Prevalence, associated factors, outcomes and transmission of extensively drug-resistant tuberculosis among multidrug-resistant tuberculosis patients in São Paulo, Brazil: a cross-sectional study.

OBJECTIVES: To describe the prevalence, associated factors, treatment outcomes and transmission of extensively drug-resistant (XDR) tuberculosis (TB) in the state of São Paulo, Brazil, for 2011 to 2013. METHODS: Drug susceptibility testing to first- and second-line drugs was performed by BACTEC MGIT 960 and molecular typing, by IS6110 restriction fragment length polymorphism. Clinical, epidemiologic and demographic data were obtained from surveillance information systems for TB. Patients were divided into three groups: multidrug resistant (MDR) TB (resistance to at least isoniazid and rifampicin), pre-XDR-TB (MDR-TB resistant to a fluoroquinolone or to at least one of the second-line injectable drugs) and XDR-TB (MDR-TB resistant to a fluoroquinolone and to at least one of the second-line injectables). RESULTS: Among the 313 MDR-TB patients identified, the prevalence of XDR-TB and pre-XDR-TB was 10.2% (n = 32) and 19.2% (n = 60), respectively. Compared to MDR-TB patients, XDR-TB patients were more likely to be female (odds ratio (OR) = 2.74, 95% confidence interval (CI), 1.29-5.83), have a history of TB (OR = 5.16; 95% CI, 1.52-17.51) and present higher death rates (OR= 3.74; 95% CI 1.70-8.25). XDR-TB transmission was observed in households, between neighbours and between a patient and a healthcare worker in a hospital. CONCLUSIONS: The prevalence of XDR-TB in the state of São Paulo is close to that estimated globally. Most of the XDR-TB patients were treated previously for TB and presented the lowest successful outcome rates. Because transmission of XDR-TB occurred, it is important that timely diagnosis of drug resistance is performed.

Molecular epidemiology of multi- and extensively-drug-resistant Mycobacterium tuberculosis in Ireland, 2001-2014.

OBJECTIVES: The primary objective of this work was to examine the acquisition and spread of multi-drug resistant (MDR) tuberculosis (TB) in Ireland. METHODS: All available Mycobacterium tuberculosis complex (MTBC) isolates (n = 42), from MDR-TB cases diagnosed in Ireland between 2001 and 2014, were analysed using phenotypic drug-susceptibility testing, Mycobacterial-Interspersed-Repetitive-Units Variable-Number Tandem-Repeat (MIRU-VNTR) genotyping, and whole-genome sequencing (WGS). RESULTS: The lineage distribution of the MDR-TB isolates comprised 54.7% Euro-American, 33.3% East Asian, 7.2% East African Indian, and 4.8% Indo-Oceanic. A significant association was identified between the East Asian Beijing sub-lineage and the relative risk of an isolate being MDR. Over 75% of MDR-TB cases were confirmed in non-Irish born individuals and 7 MIRU-VNTR genotypes were identical to clusters in other European countries indicating cross-border spread of MDR-TB to Ireland. WGS data provided the first evidence in Ireland of in vivo microevolution of MTBC isolates from drug-susceptible to MDR, and from MDR to extensively-drug resistant (XDR). In addition, they found that the katG S315T isoniazid and rpoB S450L rifampicin resistance mutations were dominant across the different MTBC lineages. CONCLUSIONS: Our molecular epidemiological analyses identified the spread of MDR-TB to Ireland from other jurisdictions and its potential to evolve to XDR-TB.

[Pre-extensively drug-resistant congenital tuberculosis: case report]. / Tuberculosis congénita pre-extensivamente resistente a drogas: reporte de caso.

Tuberculosis in infants is a clinical case difficult to diagnose by regular testing which often yield negative results; additionally, the source of transmission is difficult to identify. This work presents the case of a one-month old nursing boy presenting irritability, tachypnea, fever, poor gain weight from birth, and hepatomegaly. Additionally, he had the maternal history of pre-extensively drug- resistant tuberculosis and tuberculoid granulomatosis reaction with positive auramine tincture for acid-alcohol resistant bacilli at histopathology of the placenta. With a suspected congenital tuberculosis, he was referred to the National Children's Health Institute for diagnosis and treatment. The patient showed a favorable clinical evolution and no adverse reactions to treatment. The diagnosis of congenital tuberculosis must be considered in infants with suggestive clinical signs of the disease and such suspicion must be maintained with the presence of a maternal history of Mycobacterium tuberculosis infection.

La tuberculosis en el lactante es un cuadro de difícil diagnóstico por las pruebas diagnósticas que muchas veces resultan negativas y por la dificultad de identificar la fuente de transmisión. Se presenta el caso de un lactante varón de un mes de vida que presenta irritabilidad, taquipnea, fiebre, pobre ganancia de peso desde el nacimiento y hepatomegalia, además, tiene el antecedente materno de tuberculosis pre-extensivamente resistente a drogas y reacción granulomatosa tuberculoide con tinción auramina positiva para bacilos ácido-alcohol resistentes en la histopatología de placenta. Ante la sospecha de tuberculosis congénita, es referido al Instituto Nacional de Salud del Niño para estudio diagnóstico y tratamiento; el paciente presenta una evolución clínica favorable y sin reacciones adversas al tratamiento. El diagnóstico de tuberculosis congénita debe considerarse en lactantes con signos clínicos sugestivos de la enfermedad y mantener la sospecha ante la presencia del antecedente materno de infección por Mycobacterium tuberculosis.

Frequência e perfil epidemiológico de pacientes com tuberculose multirresistente e extensivamente resistente em um hospital de referência na cidade do Rio de Janeiro / Frequency and epidemiological profile of patients with multidrug-resistant and extensively drug-resistant tuberculosis in a reference hospital in the city of Rio de Janeiro

A Tuberculose Multirresistente (TBMR) é um dos grandes problemas de saúde enfrentados em países em desenvolvimento, apresentando-se como um grande desafio global para o controle da Tuberculose (TB). Destacamos ainda o surgimento de formas mais graves de resistência, como a Tuberculose Extensivamente Resistente (TB-XDR). No Brasil foram implantadas diversas estratégias e ações com o objetivo de garantir o controle da doença, sua erradicação e redução nos indices de abandono terapêutico. Porém, na cidade do Rio de Janeiro, o índice de incidência da doença permanece elevado e se destaca como um dos mais altos do Brasil. O presente estudo tem por objetivos, avaliar a frequência e o perfil epidemiológico de pacientes com TBMR e TB-XDR diagnosticados em um Hospital de referência no município do Rio de Janeiro, no período de 2016 a 2018, com a determinação de contribuir para a geração de dados epidemiológicos sobre a situação da doença na cidade do Rio de Janeiro, identificar o grupo de pessoas mais vulneráveis, ajudar a completar o quadro clínico da doença além de estimular outros estudos, sobre o conhecimento da TBMR e TB-XDR. Estudo foi descritivo transversal. Os dados foram secundários coletados através de informações disponíveis em prontuários de pacientes diagnosticados com TB que tiveram como desfecho de interesse a resistência às medicações. Para a obtenção dos dados foi utilizado um instrumento estruturado, que possibilitou a captura de informações referentes à frequencia, o perfil sociodemográfico, características clínico-epidemiológicas, dentre outros. Foi realizada análise das variáveis sociodemógraficas, epidemiológicas e história de tratamento anterior com os resultados coletados armazenados em um banco de dados específico, sendo as análises de frequências e de associações realizadas por meio do software estatístico SPSS. Foram coletados dados de 100 pacientes com TBMR, 44% deles abandonaram o tratamento anteriormente. Dos pacientes investigados 61.6% eram do sexo masculino e 38.4% do sexo feminino. A média de idade encontrada neste estudo foi de 37.9 anos, com a variação entre 18 e 77 anos, 45.3% se declararam pardos e 39.3% possuíam de 4-7 anos de estudo, 19% dos pacientes apresentaram coinfecção HIV/TBMR, foi verificada associação entre abandono de tratamento anterior e caso de TBMR. Podemos concluir que os pacientes que foram encaminhados para tratamento no hospital de estudo apresentaram uma taxa elevada de casos de abandono de tratamento de tuberculose, o que se faz necessário o incremento de ações de planejamento para a adesão ao tratamento da tuberculose.

Multidrug-resistant tuberculosis (MDR-TB) is one of the major health problems faced in developed and developing countries, presenting itself as a major global challenge for Tuberculosis (TB) control. We also highlight the emergence of more severe forms of resistance, such as Extensively Resistant Tuberculosis (TB-XDR). In Brazil several strategies and actions were implemented with the objective of guaranteeing the control of the disease, its eradication and reduction in the rates of therapeutic abandonment. However, in the city of Rio de Janeiro, the incidence rate of the disease remains high and stands out as the highest in Brazil. The present study aims to evaluate the prevalence and epidemiological profile of patients with MDR-TB and MDR-TB diagnosed in a reference hospital in the city of Rio de Janeiro, from 2016 to 2018, with the determination to contribute to the generation epidemiological data on the disease situation in the city of Rio de Janeiro, identifying the group of most vulnerable individuals, helping to complete the clinical picture of the disease, and stimulating other studies on the knowledge of MDR-TB and XDR-TB. The thesis is that patients with MDR-TB and XDR-TB reported in a referral hospital in the city of Rio de Janeiro had abandoned previous treatment. Descriptive cross-sectional study. The data were collected through information available in medical records of patients diagnosed with TB who had as an outcome of interest the resistance to medications. To obtain the data, a structured instrument was used, which enabled the capture of information regarding prevalence, sociodemographic profile, clinical and epidemiological characteristics, among others. An analysis of sociodemographic, epidemiological and previous treatment history was performed with the collected data stored in a specific database, and the frequency and association analyzes were performed using the SPSS statistical software. Data were collected from 100 patients with MDR-TB, 44% of whom had previously discontinued treatment. Of the patients investigated, 61.6% were male and 38.4% female. The mean age found in this study was 37.9 years, ranging from 18 to 77 years, 45.3% were declared pardos and 39.3% had 4-7 years of schooling, 19% of the patients had HIV / MDR coinfection, was verified association between early cessation of treatment and case of MDR-TB. We can conclude that the study hospital had a high rate of cases of abandonment of tuberculosis treatment, which necessitates an increase in planning actions for adherence to tuberculosis treatment.

La Tuberculosis Multirresistente (TBMR) es uno de los grandes problemas de salud enfrentados en los países desarrollados y en desarrollo, presentándose como un gran desafío global para el control de la Tuberculosis (TB). Estamos de acuerdo con el surgimiento de formas más graves de resistencia, la Tuberculosis Extensivamente Resistente (TB-XDR). En Brasil se implantaron diversas estrategias y acciones con el objetivo de garantizar el control de la enfermedad, su erradicación y reducción en las tasas de abandono terapéutico. Sin embargo, en la ciudad de Río de Janeiro, el índice de incidencia de la enfermedad permanece elevado y se destaca como el más alto de Brasil. El presente estudio tiene por objetivos, evaluar la prevalencia y el perfil epidemiológico de pacientes con TBMR y TB-XDR diagnosticados en un Hospital de referencia en el municipio de Río de Janeiro, en el período de 2016 a 2018, con la determinación de contribuir a la generación de datos epidemiológicos sobre la situación de la enfermedad en la ciudad de Río de Janeiro, identificar el grupo de personas más vulnerables, ayudar a completar el cuadro clínico de la enfermedad además de estimular otros estudios, sobre el conocimiento de la TBMR y TB-XDR. la tesis es que los pacientes de TBMR y TB-XDR notificados en un hospital de referencia en la ciudad de Río de Janeiro tuvieron abandono de tratamiento anterior. Estudio descriptivo transversal. Los datos fueron recolectados a través de informaciones disponibles en prontuarios de pacientes diagnosticados con TB que tuvieron como resultado de interés la resistencia a las medicaciones. Para la obtención de los datos se utilizó un instrumento estructurado, que posibilitó la captura de informaciones referentes a la prevalencia, el perfil sociodemográfico, características clínico-epidemiológicas, entre otros. Se realizaron análisis de las variables sociodemóficas, epidemiológicas e historia de tratamiento anterior con los resultados recogidos almacenados en un banco de datos específico, siendo los análisis de frecuencias y de asociaciones realizadas por medio del software estadístico SPSS. Se recogieron datos de 100 pacientes con TBMR, el 44% de ellos abandonaron el tratamiento anteriormente. De los pacientes investigados 61.6% eran del sexo masculino y 38.4% del sexo femenino. La media de edad encontrada en este estudio fue de 37.9 años, con la variación entre 18 y 77 años, el 45.3% se declaró pardos y el 39.3% poseía de 4-7 años de estudio, el 19% de los pacientes presentaron coinfección VIH / TBMR, fue verificada asociación entre el abandono del tratamiento anterior y el caso de TBMR. Podemos concluir que el hospital de estudio presentó una tasa elevada de casos de abandono de tratamiento de tuberculosis, lo que se hace necesario el incremento de acciones de planificación para la adhesión al tratamiento de la tuberculosis.

Epidemiology of Drug-Resistant Tuberculosis.

As we move into the era of the Sustainable Development Goals (SDGs), the World Health Organization (WHO) has developed the End TB strategy 2016-2035 with a goal to end the global epidemic of tuberculosis (TB) by 2035. Achieving the targets laid out in the Strategy will require strengthening of the whole TB diagnosis and treatment cascade, including improved case detection, the establishment of universal drug susceptibility testing and rapid treatment initiation. An estimated 3.9% of new TB cases and 21% of previously treated cases had rifampicin-resistant (RR) or multidrug-resistant (MDR) TB in 2015. These levels have remained stable over time, although limited data are available from major high burden settings. In addition to the emergence of drug resistance due to inadequate treatment, there is growing evidence that direct transmission is a large contributor to the RR/MDR-TB epidemic. Only 340,000 of the estimated 580,000 incident cases of RR/MDR-TB were notified to WHO in 2015. Among these, only 125,000 were initiated on second-line treatment. RR/MDR-TB epidemics are likely to be driven by direct transmission. The most important risk factor for MDR-TB is a history of previous treatment. Other risk factors vary according to setting but can include hospitalisation, incarceration and HIV infection. Children have the same risk of MDR-TB as adults and represent a diagnostic and treatment challenge. Rapid molecular technologies have revolutionized the diagnosis of drug-resistant TB. Until capacity can be established to test every TB patient for rifampicin resistance, countries should focus on gradually expanding their coverage of testing. DNA sequencing technologies are being increasingly incorporated into patient management and drug resistance surveillance. They offer additional benefits over conventional culture-based phenotypic testing, including a faster turn-around time for results, assessment of resistance patterns to a range of drugs, and investigation of strain clustering and transmission.

Contact investigation after a fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an aircraft, Germany, July 2013.

In July 2013, a passenger died of infectious extensively drug-resistant tuberculosis (XDR-TB) on board of an aircraft after a 3-hour flight from Turkey to Germany. Initial information indicated the patient had moved about the aircraft coughing blood. We thus aimed to contact and inform all persons exposed within the aircraft and to test them for newly acquired TB infection. Two-stage testing within 8 weeks from exposure and at least 8 weeks after exposure was suggested, using either interferon gamma release assays (IGRAs) or tuberculin skin test (TST). The TST cut-off was defined at a diameter > 10 mm; for differentiation between conversion and boosting, conversion was defined as increase of skin induration > 5 mm. Overall, 155 passengers and seven crew members were included in the investigation: the questionnaire response rate was 83%; 112 (69%) persons were tested at least once for TB infection. In one passenger, who sat next to the area where the patient died, a test conversion was registered. As of March 2017, no secondary active TB cases have been reported. We describe an unusual situation in which we applied contact tracing beyond existing European guidelines; we found one latent tuberculosis infection in a passenger, which we consider probably newly acquired.

Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study.

BACKGROUND: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. METHODS: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). FINDINGS: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 µm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. INTERPRETATION: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. FUNDING: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa.

BACKGROUND: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Urgent Implementation in a Hospital Setting of a Strategy To Rule Out Secondary Cases Caused by Imported Extensively Drug-Resistant Mycobacterium tuberculosis Strains at Diagnosis.

Current migratory movements require new strategies for rapidly tracking the transmission of high-risk imported Mycobacterium tuberculosis strains. Whole-genome sequencing (WGS) enables us to identify single-nucleotide polymorphisms (SNPs) and therefore design PCRs to track specific relevant strains. However, fast implementation of these strategies in the hospital setting is difficult because professionals working in diagnostics, molecular epidemiology, and genomics are generally at separate institutions. In this study, we describe the urgent implementation of a system that integrates genomics and molecular tools in a genuine high-risk epidemiological alert involving 2 independent importations of extensively drug resistant (XDR) and pre-XDR Beijing M. tuberculosis strains from Russia into Spain. Both cases involved commercial sex workers with long-standing tuberculosis (TB). The system was based on strain-specific PCRs tailored from WGS data that were transferred to the local node that was managing the epidemiological alert. The optimized tests were available for prospective implementation in the local node 33 working days after receiving the primary cultures of the XDR strains and were applied to all 42 new incident cases. An interpretable result was obtained in each case (directly from sputum for 27 stain-positive cases) and corresponded to the amplification profiles for strains other than the targeted pre-XDR and XDR strains, which made it possible to prospectively rule out transmission of these high-risk strains at diagnosis.

XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing.

OBJECTIVES: We describe the first published cluster of extensively drug resistant Tuberculosis (XDR-TB) in the UK and show how early whole genome sequencing (WGS) of Mtb can assist in case management and contact investigations. METHODS: We describe the contact tracing investigation undertaken after the presentation of an adult with XDR-TB. Active cases were treated with an XDR-TB drug regimen and contacts underwent a programme of follow-up for 2 years. All isolates of Mycobacterium tuberculosis (Mtb) were assessed early using whole genome sequencing (WGS) as well as routine drug susceptibility testing (DST). RESULTS: Thirty-three contacts were screened. In the first year one confirmed and one probable case were identified through contact tracing. A further possible case was identified through epidemiological links. Two confirmed cases were identified through WGS 2 years later. Twenty-five (80%) contacts without evidence of tuberculosis were adherent to 1 year of follow-up and 14 (45%) were adherent to 2 years of follow-up. WGS of Mtb was used to guide drug choices, rapidly identify transmission events, and alter public health management. CONCLUSION: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.

Drug resistance characteristics and cluster analysis of M. tuberculosis in Chinese patients with multiple episodes of anti-tuberculosis treatment.

BACKGROUND: Tuberculosis (TB) patients with multiple episodes of anti-TB treatment represent an important source of TB transmission, as well as a serious threat to the control of drug resistant TB, due to the high risk of multidrug and extensively drug resistance (MDR/XDR) and elongating infectiousness of this patient group. In this study we analyzed the possible risk of development and transmission of MDR and XDR in TB patients with multiple episodes of previous treatment history. METHODS: The study subjects were pulmonary TB patients who had at least two episodes of previous anti-TB treatment. A total of 166 eligible patients were identified from 10 counties/districts distributed in east, west, north, south and central China. Drug susceptibility test (DST) was performed by proportion method on LJ-media for the 1st line anti-TB drugs and a line probe assay was used to detect mutations related to resistance of the key 2nd-line drugs. Genotyping of M. tuberculosis (Mtb) was performed with MIRU-VNTR and Spoligotyping. RESULTS: Resistances to 1st-line drugs was observed in 122 (73.5%) of the 166 Mtb isolates with 97 (58.4%) being MDR-TB. Mutations relevant to 2nd-line drug resistance was seen in 63 isolates, including 35 MDR-TB isolates (30 pre-XDR, 5 XDR-TB). The Spoligotyping revealed 83.1% Mtb isolates belonged to the Beijing family. The MIRU-VNTR based genotyping revealed 32 (19.3%) of patients were infected with more than one strain. The number of previous TB treatment episode was found being significantly associated with the risk of MDR-TB and XDR-TB. Among the remaining 134 patients infected with a single Mtb strain, MIRU-VNTR revealed a high homogeneity of strain especially within Beijing family despite the polymorphic variations along with geographic locations. CONCLUSIONS: The high genetic relatedness and risk of MDR-TB and subsequent pre-XDR and XDR-TB among repeatedly treated patients suggest the establishment of M/XDR Mtb in this specific patient population. It highlights the urgent needs of providing DST of both 1st- and 2nd-line drugs before and during the medication in China's MDR-TB control program. Furthermore, the possibility of infection with multiple strains should also be considered to be associated with the drug resistance, which calls for the modification of treatment regimen.