RESUMO

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.

Thisissue of the Jornal Brasileiro dePneumonologia (JBP, Brazilian Journal of Pulmonary Medicine) is acollection of articles regarding tuberculosis (TB). It was conceived as acompanion to the publication of the proceedings and conclusions of the I Encontro Nacional de Tuberculose (1stNational Tuberculosis Forum), to be held in Brasilia from June 30 to July 3,2004. The forum represents a milestone in the history of Phthisiology in Braziland is the culmination of efforts by the think tank known as the Inteligência Nacional em TB (National TBKnowledge Base), which is composed of representatives of various entities. The Secretaria de Vigilãncia em Saúde doMinistério da Saúde (Ministry of Health, Department of Health Oversight),the Sociedade Brasileira de Pulmonologiae Tisiologia (SBPT, Brazilian Society of Pulmonology and Phthisiology) andthe Rede Brasileira de Pesquisa emTuberculose (Rede-TB, Brazilian Tuberculosis Research Network) are allrepresented. The impact of their actions, agreed upon in a transparent andcordial way, can be seen as much in the content of the event as in the natureof the articles published in this issue of the journal. These articles provideunequivocal evidence of the interdisciplinary and horizontal quality of Rede-TBactivities. When the position of JPB associate editor for TB was created, therewere only two TB-related articles under review. On May 14, 2004, Rede-TBresearchers were invited, and readily agreed, to work in collaboration with theJBP. Since then, 20 original articles, 3 review articles and 2 case reportshave been submitted for publication. These 25 articles address various spheresof knowledge: epidemiology (4), diagnosis (6), clinical medicine and treatment(7), operational research (4), molecular epidemiology (1), genetics (1),immunology (1) and chemoprophylaxis (1). The reviewers should be complimentedon their agility, which made it possible to have a sufficient number ofTB-related articles approved for publication before the deadline for thisissue. Although it was not possible, in the current issue, to publish all ofthe TB-related manuscripts submitted, many of these extremely relevant andhigh-quality articles will appear in subsequent issues of the JBP.

Inresponse to a joint proposal put forth by the governmental projects Pólos de Educação Permanente (Poles ofContinuing Education) and Parque Produtivo(Productivity Estate), a re-evaluation of the functions and interrelationshipsamong the various entities affecting TB control is currently underway. Thisre-assessment involves the federal Ministries of Health, Science andTechnology, and Education, as well as public and private medical schools. Inaddition, state and municipal administrations, health councils, medicalsocieties such as the SBPT, professional organizations such as the Conselho Regional de Medicina do Rio deJaneiro (CREMERJ) and nongovernmental organizations dealing with TB or HIV,as well as research networks such as the Rede-TB, were included in thisproject. Conferences have been held on the subjects of scientific technologyand technological innovation, the accreditation status of university hospitalshas been scrutinized, and the subject of university reform has been discussedin depth. The Rede-TB researchers have been working in cooperation with theSBPT, using the JBP as a communication vehicle. Their objectives are to identifyshortcomings and challenges yet to be met in the fields of science, technologyand technological innovation, propose directives that encourage the expansionof scientific knowledge in the area, orient technological development andpromote innovation in the manufacture of drugs, vaccines and other basichealth-care materials. In addition, the project intends to bring the guidelinesof the Plano Nacional de CiênciaTecnologia e Inovação Tecnológica (National Plan for Scientific Technologyand Technological Innovation) in line with the health-care needs of theBrazilian population. It is generally accepted that the traditional conceptsregarding health research should be revised. In addition to studies conductedin the clinical, biomedical and public health fields, there is a need foradditional research in the areas of human sciences, applied social sciences,mathematical sciences, earth sciences, agrarian sciences and engineering. Thisgoal will only be achieved when representatives of these various fields work incollaboration in a transparent and inclusive way in order to identify andprioritize the gaps in treatment, teaching and dissemination of technologicalscientific knowledge, as well as in the incorporation of new technologies.

Inanalyzing the articles in this issue of the JBP, it is important to rememberthat, in many cases, municipal administrators, state administrators,universities, university hospitals and the Central Public Health Laboratories,as well as industry officials, all contributed to the quality of the datapresented. Many studies were conducted in health centers presenting minimalorganizational conditions (i.e. the existence of patient-care protocols). However,in consonance with the tools of scientific methodology provided by the parentorganization, the staff members of these clinics were usually able to respondto questions of practical relevance at various levels of clinical care. Whatfollows is a summary of the articles.

RUFFINO-NETTO A. proposes a new"formula" to highlight the fact that, despite advances in the understanding ofthe technical, biological, clinical and epidemiological aspects, the socialdimension of TB must be considered, valued and used as a quality-of-lifeindicator.

BARROSO EC et al. submitted a mastersthesis based on a study conducted in Ceará. This is a case-control study, inwhich 1309 individuals in contact with 302 multidrug-resistant TB anddrug-sensitive TB patients were analyzed. The data collected suggest that thereis little difference between the incidence of active TB cases resulting fromcontact with drug-sensitive TB patients and the incidence of those resultingfrom contact with multidrug-resistant TB patients. Their results demonstratethe urgent need for strategies to retard the emergence of multidrug-resistantTB. Such strategies might include implementation of the "directly observedtreatment strategy" (devised by the World Health Organization and currently onthe Brazilian Ministry of Health list of priorities), as well as appropriatemonitoring, in reference centers, of all individuals having contact withpatients suspected of having multidrug-resistant pulmonary TB.

NEVES DD et al. present a doctoralthesis based on a study carried out in the city of Rio de Janeiro. In across-sectional study regarding diagnosis of pleural TB in patients treated ata university hospital in Rio de Janeiro, the authors analyzed clinical,radiological and laboratory-testing variables. In those patients whoseadenosine deaminase (ADA) was higher than 39 U/L, sensitivity was 95% and, evenwhen including the prevalence of lymphocytes (> 50%) in the TB diagnosiscriteria, specificity was also 95%. Since diagnostic tests may be the bestsource of financial savings for public health services, the authors suggestthat ADA testing, using the Giusti technique, be implemented in referencehealth centers for pleural TB treatment.

SELIGL et al. This paper was firstpresented as a doctoral thesis and is the result of a collaboration of the Secretaria Estadual de Saúde (SES, StateDepartment of Health), UniversidadeFederal do Rio de Janeiro (UFRJ, Rio de Janeiro Federal University), Universidade Gama Filho and the Liga de Estudantes (League of Students).Inthis study, data from the Rio de Janeiro TB Sistemade Informação de Agravos de Notificação (SINAN-TB-RJ, TB Case RegistryDatabase) and Sistema de Informação deMortalidade (SIM-TB-RJ, TB Mortality Database) were cross-referenced andthe medical records from five hospitals were carefully analyzed with the aid ofmedical students. Only 41.7% of the deaths reported in the SIM-TB-RJ between1995 and 1998 appeared in the SINAN-TB-RJ. Approximately 26.6% of the cases ofTB reported in the state of Rio de Janeiro were nosocomial (acquired in ahospital). Analysis of the medical records of in-patients showed a re-treatmentrate of 51.2% and a post-abandonment rate of 79%. Sputum smear microscopy wascarried out in 67.3% of the cases and was positive in 84%. Culture for Mycobacterium tuberculosis (Mtb) wasperformed in only 8.3% of cases. The rifampin-isoniazid-pyrazinamide-ethambutolcombination, which is recommended for re-treatment, was used in only 34.4% ofthe cases. The study demonstrates that TB is underreported, late diagnosis iscommon, recommended laboratory exams are underused and the guidelines of theMinistry of Health are not followed. Therefore, since these data result from alack of TB-control strategies in practice in hospitals, there is an urgent needfor change in the current public health policies, which only prioritize thetreatment of primary TB. In addition, the participation of medical studentsmade it possible to create the League of Students, which, in cooperation withthe SES and with the medical schools, has been active in TB-related academicactivities in the state of Rio de Janeiro.

BRITO RC et al. submitted a mastersthesis based on a joint effort by the SES of Rio de Janeiro, the UFRJ and the Universidade Estadual do Rio de Janeiro(Rio de Janeiro State University). In a retrospective study conducted from 1996to 1998 at a university reference hospital for the treatment of TB and AIDS,the authors observed a high (3.6%) rate of primary resistance to therifampicin-isoniazid combination. This rate was higher than that reported inhealth clinics. In the multivariate analysis, primary resistance was correlatedwith being a health professional. These findings underscore the need toimplement effective biosafety measures in hospital environments, as well as the need for thebacteriology laboratories of such reference hospitals to routinely performculture exams and anti-TB drug sensitivity tests.

OGUSKU MM and SALEM JI present a doctoralthesis based on research conducted at the InstitutoNacional de Pesquisas Aeroespaciais (National Institute of AerospaceResearch) in the state of Amazonas. Strains of Mtb isolated from patients were analyzed. The objective was to determine therelevance of various polymerase chain reaction (PCR) tests to diagnose TBthrough identification of the target DNA sequences most often reported inmedical literature (IS6110, 38 kDa,MPB64 and 65 kDa). The protocol used in processing the clinical samples,together with the specific primers used to amplify the 123-bp fragment of theIS6110 sequence, demonstrated greaterefficacy in the diagnosis of pulmonary (paucibacillary) TB than that reportedin the literature. The authors found a positivity of 92.1%, diagnosticconcordance of 0.9143, co-positivity of 94.7% and co-negativity of 100%. Theseresults demonstrate the need to consider analyzing the genetic profiles of Mtb strains from various regions of thecountry prior to commercializing new molecular biology techniques.

SOARES LCP et al. present a studyresulting from a Masters thesis combined with findings obtained from researchconducted at the UFRJ and at the Faculdadede Medicina de Campos (FMC, Campos School of Medicine). In 2002, atwo-phase cross-sectional study using a tuberculin test (TT) was carried out involving316 students from the FMC, which is located in a rural area of the state of Riode Janeiro. The authors observed a higher rate of positive TTs paralleling theperiod of contact with active-TB patients being treated at a state hospitalthat is a reference center for the emergency treatment of infectious andcontagious diseases (including TB). Internships at the hospital help thesestudents meet their graduation requirements. The incidence of positive PT inthe first test was 1.4%, compared with 7.9% in the second test. These resultsdraw attention to the need for a higher level of engagement of medical schoolsand the affiliated university hospitals. The authors suggest that, upon entryinto university, health professionals (doctors, nurses) who will come intocontact with active TB in hospitals be submitted to routine investigation usingthe two-TT process. In addition, they recommend that, in order to identify TTconversion, these professionals be continually re-evaluated over the course ofmedical school, and that the chemoprophylaxis recommended in the guidelinesestablished by the Ministry of Health be made available.

BORGES N et al. analyze data from aMasters thesis with the help of the SES of Rio Grande do Sul, the Secretaria Municipal de Saúde de PortoAlegre (Porto Alegre Municipal Department of Health) and the Universidade Luterana (LutheranUniversity). The authors conducted a retrospective study, compiling clinicaland epidemiological data and performing molecular typing of Mtb strainsisolated from patients treated at a health clinic in Porto Alegre. Theproportion of cluster strains (genotypic groupings), which suggest recentinfection, was 29.1%, and the epidemiological link among them was 37.5%. Molecularbiology studies, combined with clinical and epidemiological analyses such asthe present study, are of great relevance since they may promote betterunderstanding of the dynamics of TB transmission and assist localadministrators in revising TB control priorities.

RIBEIRO MO et al. submitted a Mastersthesis developed in cooperation with the UFRJ and Lacen SES-RS. Since it takesseveral weeks to receive the results of sensitivity tests, the authors carriedout a study assessing the accuracy of rapid phenotyping techniques fordetermining resistance to rifampicin and isoniazid in Mtb strains, using redoxindicators (MTT, Alamar blue) in a liquid medium. Comparing the results to thegold standard, the concordance rate was 95% and the results were obtained in 7days, compared to 28 days using the traditional method. In light of theseresults, it is necessary to validate these new tests in other referencelaboratories and carry out subsequent cost-effectiveness studies in order toanalyze the relationship between the clinical/epidemiological data and thelaboratory data. For these new tests to be utilized and commercialized in thefuture, it is necessary that such studies be carried out in centers accreditedby the Agência Nacional de VigilânciaSanitária (National Agency of Sanitary Monitoring) and in compliance withthe recognized standards of Good Clinical Practice and Good LaboratoryPractice.

OLIVEIRAMM et al. This article is the productof a doctoral thesis, expanded upon through a joint effort by the UFRJ, the Fundação Oswaldo Cruz (FIOCRUZ, OswaldoCruz Foundation) and the health departments of the states of Rio de Janeiro andGoiás. Inthis original study, in our milieu, the authors analyzed the potential role ofsingle nucleotide polymorphisms in the promoter region of the gene codifyingTNF-+ at the -238 and -308positions in TB susceptibility. The -238A allele correlated significantly withTB susceptibility and severity of clinical forms (p = 0.00002). On the other hand, the -308A allele correlatedsignificantly with protection against other pulmonary forms of the disease (p = 0.02). Further research into suchcorrelations and Mtb virulence might confirm their value as indicators ofclinical severity, especially in groups of individuals who have been recentlyinfected and are at risk for developing the forms of TB that present high ratesof morbidity and mortality.

RODRIGUES JUNIOR JM et al. The authors of thisstudy state that DNA vaccines may become an important tool for TB controlworldwide. The two antigens studied by Brazilian researchers - antigen 85 and65-kDa mycobacterial heat shock protein (hsp65) - and analyzed in pre-clinicaltrials, protect against experimental infection with virulent Mtb. Immunization with hsp65 DNA not onlypresents therapeutic activity (capable of curing animals infected with sensitiveand resistant TB) but also induces secretion of Th1-type cytokines, therebycreating a favorable environment for the long-awaited eradication of thebacillus. In addition, the innovative approach adopted by the group ofresearchers is worthy of note. In cooperation with the Rede-TB, this strategyhas made it possible to fulfill another dream: the implementation of a systemknown as the Sistema Virtuoso de InovaçãoTecnológica (Trustworthy System of Technological Innovation) in Brazil. Thissystem creates effective and transparent interaction between the university(for invention and new ideas) and leaders in Brazilian industry (fortechnological innovation), such as Nanocore Biotechnology, with the support ofgovernmental institutions. Through this joint effort it was also possible toadvance studies that demonstrate the efficacy of other formulations and meansof administering the vaccine.

LAPAE SILVA and NEIO BOECHAT. In this article, the authors emphasize the need tocombine clinical, immunological and genetic approaches in studying theestablishment of latent TB and the development of active TB, with the aim ofidentifying an imbalance between activating and deactivating cytokines thatcould affect the microbicidal function of macrophages. In addition, the authorsrecommend that the role of the bacilli in this context be studied since thereis evidence that mycobacteria secrete proteins capable of inducing theexpression of key cytokines, such as IL-10, thereby deceiving the defensemechanisms. Understanding these mechanisms may further advances in preventionas well as in the discovery of new therapeutic targets for TB control.

CRISTINA VIANA-NIERO C and LEÃO SC. These authors comment on the utility of using molecular biology techniques to differentiate between Mtb and Mycobacterium bovis, which is also of interest to those working in the field of veterinary medicine. In European strains, the authors show the results from their analysis of a new marker, the mtp40 genomic fragment, that is exclusive to Mtb and absent from the M. bovis genome. The authors suggest that this marker be analyzed in combination with other markers in mycobacterium strains isolated in various regions of the country for the differential diagnosis between Mtb and M. bovis.

Afrânio Lineu Kritski (TE-SBPT)

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