Clinical and epidemiological features of tuberculosis isolated from critically ill patients / Tuberculosis en la unidad de cuidados intensivos: características clínicas y epidemiológicas

Human tuberculosis is still a major world health concern. In Uruguay, contrary to the world trend, an increase in cases has been observed since 2006. Although the incidence of MDR-resistant strains is low and no cases of XDR-TB were registered, an increase in the number of patients with severe tuberculosis requiring critical care admission was observed. As a first aim, we performed the analysis of the genetic structure of strains isolated from patients with severe tuberculosis admitted to an intensive care unit. We compared these results with those corresponding to the general population observing a statistically significant increase in the Haarlem genotypes among ICU patients (53.3% vs 34.7%; p;<;0.05). In addition, we investigated the association of clinical outcomes with the genotype observing a major incidence of hepatic dysfunctions among patients infected with the Haarlem strain (p;<;0.05). The cohort presented is one of the largest studied series of critically ill patients with tuberculosis.

La tuberculosis (TB) aún representa un problema mayor de salud pública. En Uruguay, contrariamente a la tendencia mundial, se ha observado un incremento en el número de casos desde 2006. Aunque la incidencia de casos de multidrogorresistencia (MDR) es baja y no se han reportados casos de resistencia a fármacos de primera y segunda línea de tratamiento (XDR), se ha observado un incremento en el número de casos con TB grave, que requieren internación en unidad de terapia intensiva (CTI). Como primer objetivo del presente trabajo, se analizó la estructura genética de cepas de Mycobacterium tuberculosis aisladas de pacientes internados en CTI. Comparamos estos resultados con los obtenidos con cepas circulantes en la comunidad. Observamos un incremento estadísticamente significativo del genotipo Haarlem en los pacientes internados en CTI (53,3 vs. 34,7%; p;<;0,05). Además, investigamos la asociación del desenlace clínico con el genotipo, y encontramos una mayor incidencia de disfunción hepática en los pacientes infectados con la cepa Haarlem (p;<;0,05). La cohorte presentada en este trabajo corresponde a una de las series con mayor número de pacientes con tuberculosis que requirieron internación en CTI.

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.

Extensively drug-resistant tuberculosis in India: A review.

Background & objectives: Extensively drug resistant tuberculosis (XDR-TB) has become a new threat for the control of TB in many countries including India. Its prevalence is not known in India as there is no nation-wide surveillance. However, there have been some reports from various hospitals in the country. Methods: We have reviewed the studies/information available in the public domain and found data from 10 tertiary care centres in 9 cities in India. Results: A total of 598 isolates of XDR Mycobacterium tuberculosis have been reported in the studies included. However, the reliability of microbiological methods used in these studies was not checked and thus the XDR-TB data remained invalidated in reference laboratories. Interpretation & conclusions: Systematic surveillance and containment interventions are urgently needed.

New approaches in the diagnosis and treatment of susceptible, multidrug-resistant and extensively drug resistant tuberculosis

Tuberculosis [TB] is killing nearly two million people worldwide every year. The current global burden of TB is mainly due to the expanding human immunodeficiency virus infection and its association with active TB disease and increasing resistance of Mycobacterium tuberculosis strains to most-effective [first-line] anti-TB drugs. Incomplete/ improper treatment of TB patients leads to evolution of drug-resistant M. tuberculosis strains as a result of chromosomal mutations in genes encoding drug targets. Sequential accumulation of mutations in target genes generate multidrug-resistant [resistant atleast to rifampin and isoniazid] M. tuberculosis [MDR-TB] and extensively drug-resistant [additionally resistant to fluoroquinolones and an injectable anti-TB agent] M. tuberculosis [XDR-TB] strains. While proper treatment of susceptible TB has > 95% cure rate, effective treatment of MDR-TB is difficult in developing countries as it is heavily dependent on rapid diagnosis, supervised aggressive therapy with several [5 - 6] expensive, toxic and less efficacious drugs for 18 - 24 months and regular monitoring for bacteriological and clinical improvement. Treatment of XDR-TB is far more difficult even in developed countries. Several anti-TB drugs with novel mechanism of action are under clinical development, which may shorten treatment duration of susceptible TB to around three months and also help in effective treatment of MDR-TB / XDR-TB

Prevalence of extensively drug-resistant tuberculosis among patients with multidrug-resistant tuberculosis: a retrospective hospital-based study.

Background & objective: Extensively drug-resistant tuberculosis (XDR-TB) is a difficult-to-treat form of multidrug-resistant tuberculosis (MDR-TB). High rates of XDR-TB have been reported from India. We sought to ascertain the prevalence of XDR-TB among patients with MDR-TB treated at a tertiary care centre in New Delhi, India. Methods: Case records of patients treated for MDR-TB at the All India Institute of Medical Sciences hospital, New Delhi, between 1997 and 2003 were retrospectively reviewed. All patients underwent a pretreatment drug-susceptibility testing (DST) to first- as well as second-line drugs. XDR-TB was defined as TB caused by bacilli showing resistance to rifampicin and isoniazid in addition to any fluoroquinolone and to at least one of the three following injectable drugs: capreomycin, kanamycin, and amikacin. Results: A total of 211 laboratory-confirmed cases of MDR-TB were reviewed. The mean age of the patients was 33 ± 12 yr. Fifty one (24%) patients were females. All patients were sero-negative for human immunodeficiency virus infection. Five of the 211 MDR-TB patients had XDR-TB. The prevalence of XDR-TB was 2.4 per cent among MDR-TB patients. Interpretation & conclusion: Our results showed that XDR-TB was rare among patients with MDR-TB treated between 1997 and 2003 at our centre. Unreported selection bias might have been responsible for the high prevalence of XDR-TB reported in previous hospital-based studies from India.

Comparative growth pattern of multi drug resistance versus susceptible isolates of Mycobacterium tuberculosis in mice lungs.

Background & objectives: Rise in prevalence of multi-drug resistance (MDR) in tubercle bacilli is a serious cause of concern. As mutations with two house keeping genes rpoB and katG are associated with resistance to two important anti-tubercular drugs rifampicin and isoniazid respectively, there is a need to understand the growth kinetics of organisms with such mutated genes in experimental animals. This study was undertaken to study the growth kinetics of susceptible as well multi-drug resistance Mycobacterium tuberculosis isolates in mice. Methods: Two MDR (having mutations in rpoB and catG) and two drug susceptible isolates of M. tuberculosis along with H37Rv were grown in mice after aerogenic infection. Results: The MDR isolates grew slowly up to 3 wk though the growth was significantly different from sensitive strains. However, after 3 wk, the growth in sensitive as well MDR strains was similar, suggesting that even the mutations in the MDR strains did not have any impact on the growth kinetics. Interpretation & conclusions: The effect of mutations in other parts of these genes need to be studied. Retention of property of MDR strains to establish infection after aerogenic infection has epidemiological significance in terms of the transmission of MDR tuberculosis.

Mutações no gene nat de isolados de Mycobacterium tuberculosis: efeito na atividade enzimática e no perfil de resistência à isoniazida / Mutation in the nat gene of Mycobacterium tuberculosis strains: effect on the enzymatic activity and on the isoniazid-resistance profile

Como entre 25%-50% dos isolados de Mycobacterium tuberculosis resistentes à INH não apresentam mutações nos genes katG, inhA, ahpC e kasA que possam justificar sua resistência, foi proposta a influência de mutações específicas no gene nat nos mecanismos de resistência e atividade da NAT. Todos os isolados obtidos (n=125) foram identificados e caracterizados através da amplificação pela PCR da IS6110 e por MIRU-VNTR, respectivamente. A determinação da concentração inibitória mínima (CIM) foi realizada pelo método REMA. Após triagem de mutações nos genes caracteristicamente envolvidos com resistência pela PCR-SSCP, seguida de seqüenciamento de DNA, foram selecionados 45 isolados para o estudo de mutações específicas (pela PCR e sequenciamento) e expressão gênica do mRNA do gene nat através da RT-PCR em tempo real. Confirmou-se que mutação no gene katG é a mais correlacionada com a resistência à INH, pois 68,4% das cepas resistentes apresentaram mutação neste gene. Mutações na região promotora do gene inhA, na região intergênica oxyR-ahpC e no gene kasA foram encontradas em 8,8%, 5,6% e 21,6% dos isolados, respectivamente...

High frequency of resistance to the drugs isoniazid and rifampicin among tuberculosis cases in the city of Cabo de Santo Agostinho, an urban area in Northeastern Brazil

The objective of the present study was to investigate the frequency and risk factors for developing multidrug-resistant tuberculosis in Cabo de Santo Agostinho, PE. This was a prospective study conducted from 2000 to 2003, in which suspected cases were investigated using bacilloscopy and culturing. Out of 232 confirmed cases of tuberculosis, culturing and antibiotic susceptibility tests were performed on 174. Thirty-five of the 174 cultures showed resistance to all drugs. The frequencies of primary and acquired resistance to any drug were 14 percent and 50 percent respectively, while the frequencies of primary and acquired multidrug resistance were 8.3 percent and 40 percent. Previous tuberculosis treatment and abandonment of treatment were risk factors for drug resistance. The high levels of primary and acquired resistance to the combination of isoniazid and rifampicin contributed towards the difficulties in controlling tuberculosis transmission in the city.

O objetivo do presente estudo foi investigar a freqüência e fatores de risco para o desenvolvimento de tuberculose multidroga resistente, na Cidade do Cabo de Santo Agostinho, PE. Este é um estudo prospectivo realizado entre 2000-2003 onde casos suspeitos foram investigados por baciloscopia e cultura. De 232 casos de tuberculose confirmados, 174 tiveram cultura e antibiograma realizados. Trinta e cinco das 174 culturas mostraram resistência a qualquer uma das drogas. A freqüência de resistência primária e adquirida a qualquer droga foi 14 por cento e 50 por cento respectivamente enquanto a freqüência primária e adquirida para multidroga resistência foi 8,3 por cento e 40 por cento. Tratamento prévio para tuberculose ou abandono de tratamento consistiu em fatores de risco para resistência a drogas. Os altos níveis de resistência primária e adquirida a combinação isoniazida e rifampicina contribuem para as dificuldades no controle da transmissão da tuberculose no Cabo.