Angela Maria Werneck Barreto

Tuberculosis in Rio de Janeiro prisons, Brazil: an urgent public health problem

The tuberculosis incidence rate in prisons in Rio de Janeiro State, Brazil, was 30 times higher in 2004 than in the general population and is probably underestimated, particularly given the difficult access to care in the prison setting. To obtain a better estimate, a survey used systematic X-ray screening and showed a prevalence rate of 4.6% in one such detention facility, A (n = 1,052). Two additional surveys, in facilities B (n = 590) and C (n = 1,372), showed even higher prevalence rates (6.3% and 8.6% respectively). A comparison of socio-demographic characteristics between A, B, and C showed a heterogeneous prison population. As compared to facility A, inmates in B and C come from poorer urban communities and have more frequent histories of incarceration and tuberculosis. These differences, consistent with the prevalence data, imply the necessary adaptation of tuberculosis control programs to each detention facilitys epidemiological and socio-demographic profile.Em 2004, a taxa de incidencia da tuberculose nas prisoes do Estado do Rio de Janeiro, Brasil, foi trinta vezes superior a da populacao geral do Estado. Essa taxa provavelmente e subestimada, especialmente pela dificuldade de acesso ao servico de saude nesse ambiente. Com o objetivo de melhor avaliar a situacao, um primeiro inquerito radiologico sistematico foi realizado e mostrou taxa de prevalencia de 4,6% (prisao A, n = 1.052). Dois inqueritos adicionais revelaram, nas unidades B (n = 590) e C (n = 1.372), taxas maiores (6,3% e 8,6%, respectivamente). A comparacao das caracteristicas socio-demograficas das prisoes A, B e C mostrou que a populacao encarcerada nao e homogenea. Em comparacao com prisao A, os individuos encarcerados nas prisoes B e C sao oriundos de comunidades mais desfavorecidas e tem mais frequentemente historia de encarceramento anterior e de tuberculose. Essas diferencas, coerentes com os dados de prevalencia, implicam a adaptacao das medidas de controle da tuberculose ao perfil epidemiologico e socio-demografico de cada unidade prisional.

Usefulness of IS6110-restriction fragment length polymorphism typing of Brazilian strains of Mycobacterium tuberculosis and comparison with an international fingerprint database

Strains of Mycobacterium tuberculosis isolated from 219 different tuberculosis patients, 115 from patients residing in Rio de Janeiro, 79 from Rio Grande do Sul and the remaining from other regions of the country, were analyzed by IS6110-restriction fragment length polymorphism fingerprinting. The IS6110-DNA patterns from these strains were highly polymorphic: 174 different patterns were observed and 25 patterns were shared by 70 isolates (32%). Most strains (93.4%) had multicopy patterns and only 17% of clustered strains had less than six IS6110 copies. Strain clustering was significantly higher for isolates from Rio Grande do Sul (36.7%) in comparison with strains from Rio de Janeiro (22.6%), but only when using high stringency during cluster analysis. Upon screening of an international database containing 3,970 fingerprints of M. tuberculosis strains, 15% of the patterns of Brazilian strains (21% of the strains) were identical to a fingerprint of an isolate from another country and one particular eight-band pattern forming the largest Brazilian cluster was detected in seven additional countries, suggesting that international transmission of tuberculosis from and to Brazil could be occurring frequently. Alternatively,preferential use of certain IS6110 integration sites could also be important in high-copy number strains, having important consequences for the use of databases for epidemiological studies on a large scale.

Estudo de efetividade de esquemas alternativos para o tratamento da tuberculose multirresistente no Brasil

Purpose: To determine the effectiveness of alternative regimens for treating confirmed MDR TB cases in outpatient units: Methods: MDR TB cases were defined as culture isolation of M. tuberculosis resistant in vitro to at least rifampin/isoniazide and a third drug of standard regimens in Brazil, according to both the conventional method and the BACTEC system. Design: Multicentric non-randomized controlled clinical trial. From April 95 to December 97 187 patients were enrolled. As of April 98, there were 36 patients under treatment. The authors analyzed 149 patients that had an average 14 months of treatment duration. The regimens used were chosen according to sensitivity tests: 1) streptomycin (S)/ofloxacin (OFX)/terizidon (TZ)/ethambutol (E)/clofazimine (CZ) or capreomycin (CM)/OFX/TZ/CZ/E or amicacyn/OFX/TZ/E/CZ. Demography: Male, 68.4%; female, 31.5%; mean age-36.9 years; HIV prevalence 1.9%; primary resistance rate - 8%. Outcomes: cured-treated for 12 months with six months after two consecutive negative culture; abandoned-discontinued treatment and consultations; died _ deaths due to TB after two months of treatment; failed - remained positive in culture throughout the 12 months. Results: 120 (79.5%) patients converted to negative culture within 3 months. Cured: 53%, failed 31%, died 6%, abandoned 10%. Conclusions: The major predictor to MDR TB in Brazil is previous irregular and/or incomplete treatment. Sputum conversion rate was high and favorable overall response was 53%. Clinical implications: Because TB is endemic in Brazil and the number of MDR cases due to acquired resistance is increasing, greater efforts are needed to implement supervised treatment in tuberculosis particularly for non compliant patients.

Evaluation of indirect susceptibility testing of Mycobacterium tuberculosis to the first- and second-line, and alternative drugs by the newer MB/BacT system

In order to evaluate the Organon Teknika MB/BacT system used for testing indirect susceptibility to the alternative drugs ofloxacin (OFLO), amikacin (AMI), and rifabutin (RIF), and to the usual drugs of standard treatment regimes such as rifampin (RMP), isoniazid (INH), pyrazinamide (PZA), streptomycin (SM), ethambutol (EMB), and ethionamide (ETH), cultures of clinical specimens from 117 patients with pulmonary tuberculosis under multidrug-resistant investigation, admitted sequentially for examination from 2001 to 2002, were studied. Fifty of the Mycobacterium tuberculosis cultures were inoculated into the gold-standard BACTEC 460 TB (Becton Dickinson) for studying resistance to AMI, RIF, and OFLO, and the remaining 67 were inoculated into Lowenstein Jensen (LJ) medium (the gold standard currently used in Brazil) for studying resistance to RMP, INH, PZA, SM, EMB, and ETH. We observed 100% sensitivity for AMI (80.8-100), RIF (80.8-100), and OFLO (78.1-100); and 100% specificity for AMI (85.4-100), RIF (85.4-100), and OFLO (86.7-100) compared to the BACTEC system. Comparing the results obtained in LJ we observed 100% sensitivity for RMP (80-100), followed by INH-95% (81.8-99.1), EMB-94.7% (71.9-99.7), and 100% specificity for all drugs tested except for PZA-98.3 (89.5-99.9) at 95% confidence interval. The results showed a high level of accuracy and demonstrated that the fully automated, non-radiometric MB/BacT system is indicated for routine use in susceptibility testing in public health laboratories.

Isoniazid-resistant Mycobacterium tuberculosis strains arising from mutations in two different regions of the katG gene

OBJECTIVE To analyze and compare the mutations in two different regions of the katG gene, which is responsible for isoniazid (INH) resistance. METHODS We analyzed 97 multidrug-resistant Mycobacterium tuberculosis strains isolated in cultures of sputum samples obtained from the Professor Hélio Fraga Referral Center, in Brasília, Brazil. Another 6 INH-sensitive strains did not present mutations and were included as controls. We used PCR to amplify two regions of the katG gene (GenBank accession no. U06258)-region 1, (from codon 1 to codon 119) and region 2 (from codon 267 to codon 504)-which were then sequenced in order to identify mutations. RESULTS Seven strains were resistant to INH and did not contain mutations in either region. Thirty strains carried mutations in region 1, which was characterized by a high number of deletions, especially at codon 4 (24 strains). Region 2 carried 83 point mutations, especially at codon 315, and there was a serine-to-threonine (AGC-to-ACC) substitution in 73 of those cases. The analysis of region 2 allowed INH resistance to be diagnosed in 81.4% of the strains. Nine strains had mutations exclusively in region 1, which allowed the proportion of INH-resistant strains identified to be increased to 90.6%. CONCLUSIONS The number of mutations at codon 315 was high, which is consistent with cases described in Brazil and in other countries, and the analysis of region 1 resulted in a 9.2% increase in the rate at which mutations were identified.

Extensive Mycobacterium tuberculosis circulation in a highly endemic prison and the need for urgent environmental interventions

Aimed at assessing the circulation of Mycobacterium tuberculosis in a highly endemic prison, this 13-month prospective study was performed on strains isolated from tuberculosis (TB) cases detected passively and actively. We used X-ray screening of newly admitted inmates and mass screening at the beginning of the study and again 1 year later. Of the 94 strains genotyped by restriction fragment-length polymorphism, 79 (84·0%) belonged to one of the 12 identified clusters (2-21 strains each), including two main clusters (18 and 21 cases, respectively). A history of TB treatment was reported in 22/79 (27·8%) clustered cases. Time-space distribution of clustered cases was predominantly consistent with transmission, in micro-epidemics. Given the dominant pattern of exogenous infection and the extensive strain circulation, effective TB control should emphasize reduction of overcrowding and improvement of environmental measures as a complement to detection and treatment of cases.

Clinical evolution of a group of patients with multidrug-resistant TB treated at a referral center in the city of Rio de Janeiro, Brazil.

OBJECTIVE To analyze the clinical characteristics and evolution of a group of patients with positive sputum cultures for multidrug-resistant (MDR) Mycobacterium tuberculosis and treated at a referral center in the city of Rio de Janeiro, Brazil. METHODS Based on the positive results in sputum cultures for MDR M. tuberculosis, 50 patients were selected, and their clinical data were obtained from the Brazilian Ministry of Health MDR-TB Database. The frequencies of noncompliance, relapses, failures and previous treatments for TB up to diagnosis of MDR-TB were compiled. The radiological patterns were classified as unilateral or bilateral, and with or without cavitation. Two years after the end of the standard treatment for MDR-TB, the outcome (cure, failure, noncompliance or death) for each patient was evaluated and reassessed every two years. The post-treatment follow-up period was eight years. RESULTS The mean number of previous treatments was 2.3 +/- 0.9. The mean interval between the initial diagnosis and the development of MDR-TB was 2.0 +/- 1.7 years. Two years after the initial treatment for MDR-TB, 2 patients had abandoned treatment, 8 had died, 18 had been cured, and 22 had presented treatment failure. The bivariate analysis showed that bilateral pulmonary involvement and cavitary pattern markedly reduced the chances for cure, with a relative risk of 1-0.6 (40%) and 1-0.7 (30%), respectively. At the end of the follow-up period, 2 patients had abandoned treatment, 9 had presented treatment failure, 17 had been cured, and 22 had died. CONCLUSIONS Bilateral pulmonary involvement and cavity pattern greatly reduced the chances for cure of the patients with MDR-TB. Most patients who presented treatment failure died within the 8-year follow-up period.

Insights into the population structure of Mycobacterium tuberculosis using spoligotyping and RDRio in a southeastern Brazilian prison unit

Tuberculosis (TB) is still a serious public health problem, continuing to be an important threat for confined populations. We used spoligotyping to estimate the genotypic clades of Mycobacterium tuberculosis isolates from inmates in two blocks in a southeastern Brazilian prison unit, with TB incidence rate of 8185/100.000. The Latin American Mediterranean (LAM) clade is well represented in the country, and the LAM specific molecular markers, RD(Rio) large sequence polymorphism and the SNP on the Rv3062 [ligB(1212)], were used to characterize spoligotype signatures from prison isolates. Typing of RD(Rio) and ligB increase LAM clade from 66.7% (n=72/108) to 69.4% (n=75). The LAM2 SIT17 (n=23) and SIT179 (n=12) signatures comprised one third of all isolates, followed by Haarlem (11.5%, n=12), T (8.7%, n=9) and X (5.7%, n=6) clades. Strains with unknown signatures represented 5.5% (n=6), and four (3.7%) did not match any lineage. We observed RD(Rio) among 64 (59.2%) isolates, and 54 (50%) were of the LAM clade. In particular, the LAM2/RD(Rio) sub-lineage was significantly associated with clustering (p=0.02) and its frequency was higher (32%) when compared to that of the previous general TB cases in RJ (4.29%). Overall cluster frequency defined by spoligotyping/IS6110-RFLP was 62%. The two evolutionary markers helped to evaluate some LAM signature misconceptions and demonstrate that LAM2/RD(Rio) was found with high frequency, hitherto being unnoticed. All these data, allied to high clustering, imply that public health measures to minimize the escalation of TB in prison is essential, and both spoligotyping as well as RD(Rio) would be useful tools to monitor the effects of the measures with respect to M. tuberculosis lineage variation.

Inquérito epidemiológico da resistência às drogas usadas no tratamento da tuberculose no Brasil 1995-97 - IERDTB. Parte I: aspectos metodológicos

Este é o primeiro de três artigos sobre o Inquérito epidemiológico da resistência às drogas usadas no tratamento da tuberculose no Brasil – IERDTB que foi conduzido entre 1995 e 1997. Nessa primeira publicação da série, estão apresentados os aspectos metodológicos mais importantes desta pesquisa que é reconhecida por sua importância no programa de investigação da tuberculose no nosso país. Esta pesquisa, depois de divulgada por diversos meios e para diferentes platéias seu planejamento, sua metodologia, seu desenvolvimento seus resultados são agora apresentados de modo sistemático, para que uma clientela que, até agora, a ela não teve acesso, passe a conhecê-la. Os detalhes do planejamento desta pesquisa, incluindo a apresentação das opções metodológicas, são apresentados pela publicação na íntegra do protocolo de pesquisa, para que, em seguida, outros dois artigos sejam publicados. O primeiro, sobre a validação e confiabilidade das medidas realizadas neste estudo, e o segundo, com a descrição dos resultados, sua discussão e as principais conclusões desta investigação. Espera-se com esta trilogia completar o ciclo de divulgação desta investigação que teve início nas discussões com técnicos da Organização Mundial de Saúde, das Secretarias Estaduais de Saúde e dos Laboratório de Saúde Pública do Brasil.