A presente publicação que reúne manuscritos sobre tuberculose (TB) foi delineada para ser divulgada no mesmo momento da realização do I Encontro Nacional de Tuberculose, que ocorrerá em Brasília, 30 de junho a 3 de julho de 2004.

Os organismos patogênicos, como parte de um processo natural, interagem com o ambiente, buscando estabilidade dinâmica e seus nichos ecológicos, sejam estes internos ou externos a outros organismos.

Recentemente of Jornal Brasileiro de Pneumologia (JBP) mudou de nome e formato. Na ocasião destaquei que a maior mudança não estava na sua aparência mas sim na sua estrutura (1 REF 1 EDITORIAL JBP, JAN -FEV2004).

Background: Since the first years of antituberculosis chemotherapy, there has been controversy regarding the transmissibility, infectiousness, virulence and pathogenicity of susceptible and drug-resistant strains of Mycobacterium tuberculosis. Objective: To determine the incidence of active tuberculosis (TB) among individuals cohabiting with patients infected with susceptible and multidrug-resistant tuberculosis (MDR-TB). Methods: A case-control study was conducted. Cases of MDR-TB were defined as those infected with M. tuberculosis strains resistant to at least rifampin and isoniazid. Susceptible TB cases (controls) were defined as those first treated at approximately the same time as the first treatment of the MDR-TB cases - and cured by the time of the interview. Study cases were selected on the basis of the results of susceptibility tests, using the proportion method, carried out at the Central Laboratory of Public Health of the State of Ceará. The control group consisted of patients enrolled in the Tuberculosis Control Program between 1990 and 1999. Results: We evaluated 126 patients and 176 controls. The number of individuals sharing the household with patients was 557 in the MDR-TB group and 752 in the controls. The average number of exposed individuals per index case was 4.42 and 4.27 among patients and controls, respectively. Of the 557 MDR-TB-exposed individuals, 4.49% (25)received antituberculosis treatment after the respective index case had begun treatment, compared to 5.45% (41/752) among the controls ( p = 0.4468). Microepidemics of MDRTB were confirmed in eight families. Conclusion: Our results suggest that the incidence of active TB is comparable between households inhabited by MDRTB patients and those inhabited by susceptible-TB patients.

Keywords: Tuberculosis, multidrug-resistant/epidemiology. Tuberculosis/trasmission.

Background: In Brazil, tuberculosis is the major cause of pleural effusion. In more than 50% of cases, treatment has been initiated prior to confirmation of the diagnosis. Our objective was to identify factors that can contribute to the diagnosis. Method: We studied 215 consecutive patients with pleural effusion: 104 from tuberculosis (TB) and 111 from other causes (41 were from malignancies, 29 involved transudation, 28 were parapneumonic and 13 were from other etiologies). Clinical, radiological and laboratorial variables were evaluated for differences between the two groups, individually or in combination. Results: Male gender and PPD > 10 mm were significantly more frequent in the tuberculosis group. Radiological features were similar in both groups. Among the continuous variables, adenosine deaminase (ADA), percentile of cells, protein and age performed better as isolated diagnostic criteria. Between the group with tuberculosis and that with pleural effusion from other causes, no significant differences were found in Lactate dehydrogenase, total leukocytes or duration of disease. The correlation of ADA with any other welldeveloped continuous variable showed an LR+ > 10 and an LR- < 0.1, which effectively confirmed or ruled out a diagnosis of tuberculous pleural effusion. Conclusions: In patients with ADA levels > 39 at 95% sensitivity, the specificity can be improved to more than 90% if we consider non purulent effusion or effusion with a predominance of lymphocytes (> 50%).

Keywords: Tuberculosis, pleural/diagnosis. Adenosine deaminase/diagnosis use. Sensitivity and specificity.

Background: In 1998, tuberculosis incidence and mortality rates in the state of Rio de Janeiro (RJ) were the highest in Brazil. However, the RJ tuberculosis database (SINAN-TBRJ) has proven unreliable. Objective: To evaluate the current tuberculosis control program by analyzing tuberculosis-attributed deaths. Methods: Descriptive studies of the SINAN-TB-RJ and tuberculosis mortality (SIM-TB-RJ) databases were carried out. Both databases were linked using the Reclink program. A study based on medical records was performed in the five hospitals where the greatest numbers of tuberculosis deaths occurred. Results: In the SINAN-TB-RJ database, 16,567 cases were registered in adults (> 14 years of age). Pulmonary disease was present in 13,989 (84.5%), of whom 8223 (56.8%) presented sputum smears that were positive for acid fast bacilli. Anti-HIV testing, recommended for all patients with tuberculosis, was performed in only 4141 (25%) of tuberculosis cases. The SIM-TB-RJ database showed 1146 deaths that were attributed to tuberculosis. Only 478 (41.7%) of those had been reported to the health care system (SINAN-TB-RJ). Among the 302 medical records analyzed, 154 (50.9%)recorded hospitalizations of up to 10 days and 143 (47.3%) had respiratory symptoms for more than 60 days before diagnosis. Among 125 cases of retreatment, the RHZE regimen recommended by the Brazilian Ministry of Health was prescribed for only 43 (34.4%). Conclusion: This study demonstrates weakness in the RJ tuberculosis control program, characterized by delayed diagnosis, limited use of the recommended tests, poor reporting, and non-compliance with the Ministry of Health guidelines.

Keywords: Tuberculosis. Epidemiology. Program Evaluation

Background: Tuberculosis become important challenge to health care settings. Brazil has high prevalence of the disease and Rio de Janeiro has high incidence rates with 30% of cases notified at hospitals. Objective: To evaluate prevalence of initial and acquired drug resistance at a general hospital, reference for aids treatment in Rio de Janeiro and to identify associated factors. Methods: Mycobacterium tuberculosis strains from 165 patients were analyzed, between August 1996 and February 1998. Results: Twenty per cent (33/165) were resistant to at least one drug; 13% (12/165) to isoniazid; 3.64% (6/ 165) to rifampin and 3.64% (6/165) to both. Among HIV seropositive subjects (52/165); 28.85% (15/52) were resistant to at least one drug. Acquired resistance occurred in 15.79% of 19 patients that mentioned previous antiTB treatment. Association statistically significant was found with non cavitation on X-ray in bivariate analyses ( P=0.05). Eighty four patients refereed no previous treatment (NPT). Resistance to 1 or more drugs was found in 28.57% (24/84) of NPT patients. Association statistically significant with initial resistance was found with health care workers (P=0.004), unemployment (P=0.03), and diarrhea (P=0.01) in bivariate analyses. On multivariate analyses, health care workers ( P=0.002) remained significantly associated with initial resistance. Conclusions: High resistance rates was found. It corroborates that hospitals needs attention for TB control especially which concerns to health care works infection.

Keywords: Mycobacterium tuberculosis. Drug resistance. Disease transmission, patient to professional. Hospitals.

Background: Various primers are being tested for the detection of Mycobacterium tuberculosis DNA. The accuracy of the polymerase chain reaction (PCR) depends on the target sequence used and whether the test will be performed in culture or in clinical specimens. Objectives: To identify DNA sequences, specifically those commonly reported as targets for diagnosis of tuberculosis (TB), in clinical samples of M. tuberculosis strains. Method: Eighty-one clinical samples from suspected TB patients were initially processed and submitted to bacilloscopy (smear) and culture, and PCR was performed with specific primers for the following targets: IS 6110, 65 kDa, 38 kDa and MPB64. Results: Smear and culture results were negative in 24 samples, as was the PCR. The 19 samples testing smear positive, as well as the isolated strains, were 100% positive on PCR, with the exception of the 89.4% result from PCR with MPB64 primers. In the 38 smear negative and culture positive samples, PCR results were inconsistent. The primers specific for amplifying the 123 bp IS 6110 fragment gave the highest positivity (92.1%), diagnostic agreement (0.9143), co-positivity (94.7%) and co-negativity (100%). Conclusion: The IS 6110, 38 kDa, MPB64 and 65 kDa sequences were found in the genome of all M. tuberculosis strains isolated in patients from the state of Amazonas. The protocol for processing the clinical samples prior to PCR analysis and the specific primers used to amplify the 123bp IS 6110 fragment showed a greater efficiency in diagnosing pulmonary (paucibacillary) tuberculosis in comparison to published data.

Keywords: Primers/PCR. Diagnosis/Tuberculosis. Mycobacterium tuberculosis.

Background: The Hospital Ferreira Machado, utilized, in part, as a clinical training center for graduate students from the Faculdade de Medicina de Campos, admitted 65 tuberculosis (TB) patients in 2001. Objective: To estimate the prevalence of positive tuberculin skin tests (TST) among medical students during distinct periods of their training and to identify and analyze correlated factors. To compare positivity rates, taking into account the booster effect, and estimate incidence of positive TST by class year. Methods: A cross-sectional study was conducted among 500 students registered in the first semester of 2002. Using a structured and validated questionnaire, data regarding demographics, BCG vaccination and potential exposure to TB patients were obtained. A professional licensed by the Health Department administered the TSTs, and the twostep Mantoux method (PPD Rt23) was used. Results: Of the 500 eligible subjects, 316 (63.2%) were excluded. Analysis showed increasing two-step TST positivity rates corresponding to extent of clinical experience (4%, 6.4% and 13.1%) and a tendency toward correlation with professional level. The highest percentage of positive TSTs was found during the period of clinical training, which corresponded to the time of greatest exposure to patients (1000 hours). Conclusions: a) the TST positivity rate was high (7.9%) among students; b) TST was correlated with in-hospital training stage; c) evaluation of the booster effect lead us to highly recommended boosters in order to reduce the number of false-negative TST results.

Keywords: Tuberculin. Tuberculin test. Tuberculosis. Students/Medical. Cross-sectional studies.

Background: Tuberculosis is an ancient disease, which still remains one of the major ills faced by mankind in the 21st century. In recent decades, new technologies employing the knowledge gained from molecular biology studies have allowed for more accurate detection of tuberculosis and increased investigation of the etiology and epidemiology of the disease. Aim: Evaluating the degree of similarity among strains of Mycobacterium tuberculosis provided by the Phthisiology Sector of Centro de Saúde Navegantes (Navegantes Health Clinic) in Porto Alegre, RS, Brazil. Method: A retrospective study was performed involving RFLP typing of 55 sputum samples from outpatients examined at the Centro de Saúde Navegantes. The results of the genotyping were correlated to the conventional epidemiology data. Results: A single pattern was seen in 39 (70.9%) of the isolates, whereas 16 isolates (29.1%) showed clustering patterns and were grouped into 8 clusters of 2 patients each. An epidemiological link was found for 6 (37.5%) of the 16 patients in the clusters. Conclusion: The appropriate combination of conventional epidemiology and genotyping of M. tuberculosis contributes to a better understanding of the dynamics of tuberculosis transmission even when such a study is performed in a single, isolated health clinic.

Keywords: Mycobacterium tuberculosis. Transmission. Polymorphism, Restriction Fragment Length. Epidemiology.

Background: Knowledge of the rates of drug resistance is one of the pillars of tuberculosis control program evaluation. Data from low-resource countries are scarce and results are delayed due to the techniques employed. There is therefore an urgent need for evaluation of faster and less onerous testing methods. Objective: To compare the performance of rapid colorimetric assays for phenotyping that employ oxidationreduction indicators to determine the susceptibility profile of Mycobacterium tuberculosis with the gold-standard proportion method on Lowenstein-Jensen Medium. Method: We analyzed 166 M. tuberculosis strains of known susceptibility. Minimal inhibition concentrations for isoniazid and rifampicin were determined in microplates, using a liquid medium and Alamar Blue and tetrazolium bromide indicators. To measure agreement the Kappa value was used. Cutoff values between sensitive and resistant strains were defined as 0.2µg/mL and 1.0µg/mL for isoniazid and rifampicin, respectively. Results: There was 100% concordance between Alamar Blue and tetrazolium bromide methods in the determination of minimal inhibition concentrations. Agreement between the colorimetric method and the Lowenstein-Jensen was 95% for isoniazid and rifampicin. Using the colorimetric method, results were obtained within 7 days, in contrast to the 28 days required for the conventional method. Conclusions: Assays to determine minimal inhibition concentrations in liquid medium and employing oxidationreduction indicators proved to be rapid and inexpensive. This method has the potential to become a faster, alternative method for determining susceptibility of M. tuberculosis strains in developing countries.

Keywords: Mycobacterium tubercolis. Disease susceptibility. Isoniazid/therapeutic use. Rifampin/therapeutic use.

Background: Host genetic factors may play a role in the susceptibility to active tuberculosis (TB), and several polymorphisms in different cytokine coding genes have been described and associated with diseases to date. Objectives: To investigate whether polymorphisms within the promoter region of the TNF-á (-238/-308) coding genes are associated to the occurrence of active TB. Methods: SNPs within the TNF-á gene were analyzed by PCR-RFLP among two groups of individuals: patients with TB (n = 234, and patients non TB (n = 113). Results: In this study, the presence of the -238A allele was associated with susceptibility to TB disease occurrence and severity (p = 0,00002; OR = 0,15; IC = 0,06-0,36. On the contrary, the -308A allele was associated with protection to the occurrence of another pulmonary diseases. Conclusions: These results suggest the importance of genetics studies on TB occurrence. Further studies are needed pursuing a better understanding of the human pathogenesis of M. tb.

Keywords: Tuberculosis/genetics. Polymorphism, single nucleotide/genetics. Tumor necrosis factor/genetics. Alleles. Genotype. Lung diseases.

The DNA vaccines currently under pre-clinical and clinical development may prove to be important tools in combating infectious diseases, such as tuberculosis, for which no safe and effective form of prevention has yet been developed. In recent years, several studies have aimed to develop a DNA vaccine encoding mycobacterial proteins such as antigen 85 (Ag85) and the 65-kDa mycobacterial heat shock protein (hsp65). The latter is protective against virulent infection with Mycobacterium tuberculosis (including multidrugresistant strains). The hsp65 DNA vaccine, currently under clinical evaluation in Brazil for cancer therapy, is able to induce the secretion of Th1 cytokines, such as gamma-interferon, associated with disease control. Furthermore, this vaccine stimulates cytotoxic CD8 and CD4 T-cell clones that can be characterized as memory cells, which are responsible for effective and longlasting immunity against tuberculosis. When used as a therapeutic agent in inoculated mice, the hsp65 DNA vaccine promotes changes in the immunity profile, triggering the secretion of Th1 cytokines and establishing a favorable environment for the elimination of bacilli. The results also demonstrate that the route of administration, as well as the formulation in which the vaccine is administered, fundamentally influence the pattern and duration of the immune response induced. Taking all currently available data into account, we can conclude that a DNA vaccine against tuberculosis could contribute significantly to the control of the disease.

Keywords: Tuberculosis/epidemiology. Vaccines, DNA/therapeutic use. Heat shock proteins. Auto-immunity.

The resurgence of tuberculosis as one of the most important infectious diseases to affect mankind came after the illusion that the disease was under control and would be eradicated before the end of the 20th Century. Over the last 10 years, in association with American and European research centers, our group at the Universidade Federal do Rio de Janeiro has been dedicated to investigating the pathogenic mechanisms involved in pulmonary tuberculosis. Due to its frequency and role in transmission, pulmonary tuberculosis is the most serious form of the disease. Our hypothesis is that the establishment of latent infection and its progression to active disease depend on an imbalance between activating and deactivating cytokines at the disease site. Despite the presence of protective mechanisms such as the macrophage expression of phenotypes (denoting cellular and molecular activation of agents involved in protection, such as nitric oxide and interferon-ã), tuberculosis progresses. A possible explanation for this is the concomitant presence at the site of infection of molecules such as interleukin-10 and TGF-â, which are able to deactivate previously activated macrophages. Recent data suggest that mycobacteria secrete proteins capable of inducing interleukin-10, thus contributing to overcoming host protective mechanisms. Susceptible individuals would be more able to produce larger amounts of these molecules due to genetic polymorphisms that facilitate interleukin-10 production at infection onset. The understanding of these mechanisms could advance the prevention and discovery of new therapeutic targets for the control of tuberculosis.

Keywords: Tuberculosis/ethiology. Tuberculosis pulmonary/pathology.

Tuberculosis chemoprophylaxis is a therapeutic measure for the prevention of infection by Mycobacterium tuberculosis or to avoid development of the disease in individuals already infected with it. Isoniazid is the most commonly used therapy; however, the use of rifampicin and pyrazinamide has recently been introduced. The objectives of this study were to review the results of the principal studies evaluating the indications for chemoprophylaxis with isoniazid alone and in association with other drugs, its efficacy in the prevention of tuberculosis with respect to the different risk groups and the alternative regimens available. A systematic revision of the medical literature was carried out with particular emphasis on clinical trials and meta-analyses. Official records were also consulted. Those studies involving randomized clinical trials on the use of isoniazid, rifampicin or pyrazinamide in HIV-positive or negative patients were selected. Isoniazid continues to be effective for the prevention of tuberculosis in populations of both HIV-negative and HIV-positive individuals. The standard dose of 5-15 mg/kg/day has shown similar protection over treatment periods ranging from six to twelve months. The risk of developing hepatitis was less than 1%; however monitoring during treatment is recommended in patients over 35 years of age and in users of alcohol. Studies involving treatment regimens with other forms of medication were inconclusive and new studies would have to be performed to evaluate the efficacy of these regimens in populations at high risk of developing tuberculosis.

Keywords: Tuberculosis. Chemoprophylaxis. Isoniazid.

Os bacilos que causam a tuberculose estão agrupados no complexo Mycobacterium tuberculosis, composto por: M. tuberculosis, M. bovis subsp. bovis, M. africanum e M. microti, além da cepa vacinal M. bovis BCG. Tem sido proposta a inclusão de novas espécies neste complexo, como M. canettii, uma variante de M. tuberculosis encontrada na região da Somália(1), M. caprae, agente etiológico de tuberculose em caprinos(2), e M. pinnipedii, que causa tuberculose em leões marinhos, mas que também pode infectar o homem(3).