Participation of researchers from the Brazilian Network
of Tuberculosis Research in the activities of the Brazilian
Journal of Pulmonolog y, official publication of the
Brazilian Society of Pulmonology and Phthisiology
AFRÂNIO LINEU KRITSKI (TE SBPT)
Th is is s u e o f t h e J o r n a l Br a s ile ir o d e P n e u m o n o lo g ia (J BP, Bra z ilia n J o u rn a l o f Pu lmon ary Medicin e) is a collect ion of art icles regarding tuberculosis (TB). It was conceived as a companion to the publication of the proceedings and conclusions of the I Encontro Nacional de Tuberculose (1st National 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 Brazil and is the culmination of efforts by the think tank known as the Inteligência Nacional em TB (National TB Knowledge Base), which is composed of representatives of various entities. The Secretaria de Vigilãncia em Saúde do Ministério da Saúde (Ministry of Health, Department of Healt h Oversight ), t he Sociedade Brasileira de Pulmonologia e Tisiologia (SBPT, Brazilian Society of Pulmonology and Phthisiology) and the Rede Brasileira de Pesquisa em Tuberculose (Rede- TB, Brazilian Tuberculosis Research Network) are all represented. The impact of their actions, agreed upon in a transparent and cordial way, can be seen as much in the content of the event as in the nature of the articles published in this issue of the journal. These articles provide unequivocal evidence of the interdisciplinary and horizontal quality of Rede- TB act ivit ies. When t he posit ion of J PB associate editor for TB was created, there were only two TB- related articles under review. On May 14, 2004, Rede- TB researchers were invited, and readily agreed, to work in collaboration with the JBP. Since then, 20 original articles, 3 review articles and 2 case reports have been submitted for publication. Th ese 2 5 a rt icles a d d ress va rio u s sp h eres o f knowledge: epidemiology (4), diagnosis (6), clinical medicine and treatment (7), operational research (4 ), m o lecu lar ep id em io lo g y (1 ), g en et ics (1 ),
im m u n o lo g y(1 ) an d ch em o p ro p h ylaxis(1 ). Th e reviewers should be complimented on their agility, which made it possible to have a sufficient number of TB- relat ed art icles approved for pu blicat ion before the deadline for this issue. Although it was not possible, in the current issue, to publish all of the TB- related manuscripts submitted, many of these extremely relevant and high- quality articles will appear in subsequent issues of the JBP.
In response to a joint proposal put forth by t he govern men t al project s Pólos de Edu cação Permanente (Poles of Continuing Education) and
expansion of scientific knowledge in the area, orient t e c h n o lo g ic a l d e ve lo p m e n t a n d p r o m o t e innovation in the manufacture of drugs, vaccines and other basic health- care materials. In addition, the project intends to bring the guidelines of the
Plano Nacional de Ciência Tecnologia e Inovação Te c n o ló g ic a (Na t io n a l P la n f o r Sc ie n t if ic Technology and Technological Innovation) in line wit h t h e h ea lt h - ca re n eed s o f t h e Bra zilia n p o p u la t io n . It is g en era lly a ccep t ed t h a t t h e t radit ion al con cept s regardin g healt h research should be revised. In addition to studies conducted in the clinical, biomedical and public health fields, there is a need for additional research in the areas o f h u m a n scie n ce s, a p p lie d so cia l scie n ce s, mat hemat ical scien ces, eart h scien ces, agrarian sciences and engineering. This goal will only be achieved when represen t at ives of t hese variou s fields work in collaboration in a transparent and inclusive way in order to identify and prioritize the gaps in treatment, teaching and dissemination of technological scientific knowledge, as well as in the incorporation of new technologies.
In analyzing the articles in this issue of the JBP, it is important to remember that, in many c a s e s , m u n ic ip a l a d m in is t r a t o r s , s t a t e administrators, universities, university hospitals and the Central Public Health Laboratories, as well as industry officials, all contributed to the quality of the data presented. Many studies were conducted in health centers presenting minimal organizational co n d it io n s (i.e. t h e exist en ce o f p a t ien t - ca re protocols). However, in consonance with the tools of scientific methodology provided by the parent organization, the staff members of these clinics were u su ally able t o respon d t o qu est ion s of practical relevance at various levels of clinical care. What follows is a summary of the articles.
RUFFINO- NETTO A. proposes a new “formula” to highlight the fact that, despite advances in the understanding of the technical, biological, clinical and epidemiological aspects, the social dimension of TB must be considered, valued and used as a quality- of- life indicator.
BARROSO EC et al. submitted a masters thesis based on a study conducted in Ceará. This is a case- control study, in which 1309 individuals in contact with 302 multi resistant TB and drug-sen sit ive TB pat ien t s were an alyzed. The dat a collect ed su ggest t hat t here is lit t le differen ce
between the incidence of active TB cases resulting from contact with drug- sensitive TB patients and the incidence of those resulting from contact with m u lt id ru g - resist an t TB p at ien t s. Th eir resu lt s demon st rat e t he u rgen t n eed for st rat egies t o retard the emergence of multidrug- resistant TB. Such strategies might include implementation of the “directly observed treatment strategy” (devised by the World Health Organization and currently on the Brazilian Ministry of Health list of priorities), as well as appropriate monitoring, in reference cen t ers, of all in dividu als havin g con t act wit h patients suspected of having multidrug- resistant pulmonary TB.
NEVES DD et al. present a doctoral thesis based on a study carried out in the city of Rio de Janeiro. In a cross- sectional study regarding diagnosis of pleural TB in patients treated at a university hospital in Rio de Janeiro, the authors analyzed clinical, radiological and laboratory- testing variables. In those patients whose adenosine deaminase (ADA) was higher than 39 U/ L, sensitivity was 95% and, e ve n w h e n in c lu d in g t h e p r e va le n c e o f lymphocytes (> 50%) in the TB diagnosis criteria, specificity was also 95%. Since diagnostic tests may be the best source of financial savings for public health services, the authors suggest that ADA t est in g , u sin g t h e Giu st i t ech n iq u e, b e implemented in reference health centers for pleural TB treatment.
re-treatment rate of 51.2% and a post- abandonment rate of 79%. Sputum smear microscopy was carried out in 67.3% of the cases and was positive in 84%. Culture for Mycobacterium tuberculosis (Mtb) was performed in only 8.3% of cases. The rifampin-isoniazid- pyrazinamide- ethambutol combination, which is recommended for re- treatment, was used in o n ly 3 4 . 4 % o f t h e c a s e s . Th e s t u d y d em o n st ra t es t h a t TB is u n d errep o rt ed , la t e diagn osis is common , recommen ded laborat ory exams are underused and the guidelines of the Ministry of Health are not followed. Therefore, since t h ese d a t a resu lt fro m a la ck o f TB- co n t ro l strategies in practice in hospitals, there is an urgent n eed for chan ge in t he cu rren t pu blic healt h policies, which only prioritize the treatment of primary TB. In addition, the participation of medical students made it possible to create the League of Students, which, in cooperation with the SES and with the medical schools, has been active in TB-related academic activities in the state of Rio de Janeiro.
BRITO RC et al. submitted a masters thesis based on a joint effort by the SES of Rio de Janeiro, the UFRJ and the Universidade Estadual do Rio de Jan eiro (Rio de Jan eiro St at e Un iversit y). In a retrospective study conducted from 1996 to 1998 at a university reference hospital for the treatment of TB and AIDS, the authors observed a high (3.6%) ra t e o f p rim a ry resist a n ce t o t h e rifa m p icin -isoniazid combination. This rate was higher than that reported in health clinics. In the multivariate analysis, primary resistance was correlated with b ein g a h ea lt h p ro fessio n a l. Th ese fin d in g s u n d ersco re t h e n eed t o im p lem en t effect ive biosafety measures in hospital environments, as well as the need for the bacteriology laboratories of such reference hospitals to routinely perform culture exams and anti- TB drug sensitivity tests.
OGUSKU MM and SALEM JI present a doctoral thesis based on research conducted at the Instituto Nacion al de Pesqu isas Aeroespaciais (Nat ion al Institute of Aerospace Research) in the state of Amazonas. Strains of Mtb isolated from patients were analyzed. The objective was to determine the relevan ce of variou s polymerase chain react ion (PCR) tests to diagnose TB through identification of the target DNA sequences most often reported in medical literature (IS6110, 38 kDa, MPB64 and 65 kDa). The prot ocol u sed in processin g t he
clinical samples, together with the specific primers used to amplify the 123- bp fragment of the IS6110
sequ en ce, demon st rat ed great er efficacy in t he diagnosis of pulmonary (paucibacillary) TB than that reported in the literature. The authors found a positivity of 92.1%, diagnostic concordance of 0.9143, co- posit ivit y of 94.7% and co- negat ivit y of 100%. These results demonstrate the need to con sider an alyzin g t he gen et ic profiles of Mt b strains from various regions of the country prior t o co m m e rcia liz in g n e w m o le cu la r b io lo g y techniques.
SOARES LCP et al. present a study resulting from a Mast ers t hesis combin ed wit h fin din gs obtained from research conducted at the UFRJ and at the Faculdade de Medicina de Campos (FMC, Campos School of Medicine). In 2002, a two- phase cross- sectional study using a tuberculin test (TT) was carried out involving 316 students from the FMC, which is located in a rural area of the state of Rio de Janeiro. The authors observed a higher rate of positive TTs paralleling the period of contact wit h act ive- TB pat ient s being t reat ed at a st at e hospital that is a reference center for the emergency treatment of infectious and contagious diseases (including TB). Internships at the hospital help these students meet their graduation requirements. The incidence of positive PT in the first test was 1.4%, compared with 7.9% in the second test. These results draw attention to the need for a higher level of engagement of medical schools and the affiliated university hospitals. The authors suggest that, upon entry into university, health professionals (doctors, nurses) who will come into contact with act ive TB in hospit als be su bmit t ed t o rou t in e investigation using the two- TT process. In addition, t hey recommen d t hat , in order t o iden t ify TT conversion, these professionals be continually re-evaluated over the course of medical school, and t hat t he chemoprophylaxis recommended in t he guidelines established by the Ministry of Health be made available.
isolated from patients treated at a health clinic in Port o Alegre. The proport ion of clu st er st rain s (g en o t yp ic g ro u p in g s), wh ich su g g est recen t infection, was 29.1%, and the epidemiological link among them was 37.5%. Molecular biology studies, co m b in e d wit h clin ica l a n d e p id e m io lo g ica l analyses such as the present study, are of great r e le va n c e s in c e t h e y m a y p r o m o t e b e t t e r understanding of the dynamics of TB transmission and assist local administrators in revising TB control priorities.
RIBEIRO MO et al. submitted a Masters thesis developed in cooperation with the UFRJ and Lacen SES- RS. Since it takes several weeks to receive the results of sensitivity tests, the authors carried out a s t u d y a s s e s s in g t h e a c c u r a c y o f r a p id phenotyping techniques for determining resistance to rifampicin and isoniazid in Mtb strains, using redox indicators (MTT, Alamar blue) in a liquid m ed iu m . Co m p a rin g t h e resu lt s t o t h e g o ld standard, the concordance rate was 95% and the results were obtained in 7 days, compared to 28 days using the traditional method. In light of these results, it is necessary to validate these new tests in o t h er referen ce lab o rat o ries an d carry o u t subsequent cost- effectiveness studies in order to an alyze t he relat ion ship bet ween t he clin ical/ epidemiological data and the laboratory data. For these new tests to be utilized and commercialized in the future, it is necessary that such studies be carried out in centers accredited by the Agência Nacional de Vigilância Sanitária (National Agency of Sanitary Monitoring) and in compliance with the recognized standards of Good Clinical Practice and Good Laboratory Practice.
OLIVEIRA MM et al. This article is the product of a doctoral thesis, expanded upon through a joint effort by the UFRJ, the Fundação Oswaldo Cruz
(FIOCRUZ, Oswaldo Cru z Fou n dat ion ) an d t he health departments of the states of Rio de Janeiro and Goiás. In this original study, in our milieu, the au t h o rs an alyzed t h e p o t en t ial ro le o f sin g le nucleotide polymorphisms in the promoter region of the gene codifying TNF- ± at the - 238 and - 308 posit ions in TB suscept ibilit y. The - 238A allele correlated significantly with TB susceptibility and severity of clinical forms (p = 0.00002). On the other hand, the - 308A allele correlated significantly with protection against other pulmonary forms of t he disease (p = 0.02). Further research into such
correlations and Mtb virulence might confirm their value as indicators of clinical severity, especially in groups of individuals who have been recently infected and are at risk for developing the forms of TB that present high rates of morbidity and mortality.
RODRIGUES JUNIOR JM et al. The aut hors of this study state that DNA vaccines may become an important tool for TB control worldwide. The two antigens studied by Brazilian researchers – antigen 85 and 65- kDa mycobact erial heat shock prot ein (hsp65) – and analyzed in pre- clinical trials, protect against experimental infection with virulent Mtb. Immunization with hsp65 DNA not only presents t herapeu t ic act ivit y (capable of cu rin g an imals infected with sensitive and resistant TB) but also induces secretion of Th1- type cytokines, thereby creating a favorable environment for the long-awaited eradication of the bacillus. In addition, the innovative approach adopted by the group of researchers is worthy of note. In cooperation with the Rede- TB, this strategy has made it possible to fu lfill an ot her dream: t he implemen t at ion of a system known as the Sistema Virtuoso de Inovação Tecnológica (Trustworthy System of Technological Innovation) in Brazil. This system creates effective and transparent interaction between the university (fo r in ven t io n an d n ew id eas) an d lead ers in Brazilian industry (for technological innovation), such as Nanocore Biotechnology, with the support of governmental institutions. Through this joint effort it was also possible to advance studies that demonstrate the efficacy of other formulations and means of administering the vaccine.
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.
REFERENCES
1 . Ru ffin o Net t o A. A carga da t u bercu lose: reflexões sobre o t ema. J Bras Pn eu mol 2004; 30:398- 400
2 . Barro so EC, Mo t a RMS, Pin h eiro VGVF, Cam p elo CL, Rodrigu es JL. Ocorrên cia de t u bercu lose doen ça en t re c o n t a t o s d e t u b e r c u lo s e s e n s í ve l e t u b e r c u lo s e mu lt irresist en t e. J Bras Pn eu mol 2004; 30:401- 8 3 . Neves DD, Dia s RM, Alves d a Cu n h a AJ L, d a Silva
Ch ib a n t e AM Re n d im e n t o d e va r iá ve is c lí n ic a s , ra d io ló g ica s e la b o ra t o ria is p a ra o d ia g n ó st ico d a t u bercu lose pleu ral. J Bras Pn eu mol 2004; 30:409- 16 4 . Selig L, Belo M, Alves da Cunha AJL, Teixeira Eg, Brito, R; Luna Al, Trajman A. Óbitos atribuídos à tuberculose no estado do Rio de Janeiro. J Bras Pneumol 2004; 30: 417-24 5 . Brit o RC, Gou n der D, Bon fim de Lima D, Siqu eira H,
Cavalcan t i Hr, Pereira Mm , Krit ski AL Resist ên cia aos m e d ic a m e n t o s a n t it u b e r c u lo s e d e c e p a s d e Myco b a ct e riu m t u b e rcu lo sis iso la d a s d e p a cie n t e s a t e n d id o s e m h o s p it a l g e r a l d e r e f e r ê n c ia p a r a t rat amen t o de aids n o Rio de Jan eiro. J bras Pn eu mol 2 0 0 4 ; 3 0 :4 2 5 - 3 2
6 . Ogusku MM e SALEM JI. Análise de diferentes primers utilizados na PCR visando o diagnóstico da tuberculose no estado do Amazonas. J Bras Pneumol 2004; 30:433-9 7 . Soares LCP, Qu eiroz Mello FC, Krit ski AL Prevalên cia da prova t u bercu lín ica posit iva en t re alu n os da gradu ação da Facu ldade de Medicin a de Campos, Rio de Jan eiro. J Bras Pn eu mol 2004; 30:440- 7
8 . Borges M, Cafru n e PI, Possu elo LG, Valim ARM, Ribeiro MO, Ro sse t t i MLR. An á lise m o le cu la r d e ce p a s d e Mycobact eriu m t u bercu losis proven ien t es de u m cen t ro d e sa ú d e a m b u la t o ria l em Po rt o Aleg re, RS. J Bra s Pn eu m o l 2 0 0 4 ; 3 0 :4 4 8 - 5 4
9 . Ribeiro MO, Gomes MS, Sen n a SG, Rosset t i NLR, Fon seca LS . Avaliação de t est es rápidos em microplacas u san do in d icad o res d e viab ilid ad e celu lar p ara d et erm in ação d a s u s c e p t ib ilid a d e d e c e p a s d e Myc o b a c t e r iu m t u bercu losis a ison iazida e rifampicin a. J bras Pn eu mol 2 0 0 4 ; 3 0 :4 5 5 - 6 0
1 0 . Oliveira MM, Sim ião d a Silva J CS, Fon seca- Co st a J F, Am im LH, Lo red o CCS, Mello H, Qu eiro z, LF, Mello FCQ, Lapa e Silva JR, Krit ski AL e San t os AR. Dist ribu ição d e p o lim o rfism o s d e b a se ú n ica (SNPs) n o g en e d e TNF-α (- 238/ - 308) en t re pacien t es com TB e ou t ras
p n e u m o p a t ia s : m a r c a d o r e s g e n é t ic o s d e su scept ibilidade a ocorrên cia de TB? J Bras Pn eu mol 2004; 30:461- 7
11 . Ro d rig u es J ú n io r J N, d e Melo Lim a K, Ca st elo AANC, Ma rt in s VLCB, Ap a recid a d o s Sa n t o s S, Fa ccio li LH, Silva CL. É p o ssível u m a va cin a g ên ica a u xilia r n o c o n t r o le d a t u b e r c u lo s e ? J Br a s P n e u m o l 2 0 0 4 ; 3 0 : 4 6 8 - 7 7
1 2 . La p a e Silva J R, Bo é c h a t N. O re ssu rg im e n t o d a t u b ercu lo se: im p a ct o d o est u d o d a im u n o p a t o g en ia pu lmon ar. J Bras Pn eu mol 2004; 30:478- 84
