Cenário atual da tuberculose / Current scenario of tuberculosis

Mesmo após 133 anos desde a descoberta do Mycobacterium tuberculosis, a tuberculose continua ser uma das principais causas de morte por doenças infecciosas no mundo, principalmente em países em desenvolvimento.O objetivo deste estudo foi mostrar aspectos relevantes da doença visando uma atualização literária e a busca de um olhar mais atento à problemática da tuberculose no contexto atual. Foram utilizados 130 artigos advindos das bases LILACS, MEDLINE/PUBMED, SCielo, Paho, Biblioteca Cochrane, WHOLIS, IBECS e Scopus, com as principais palavras-chaves selecionadas em terminologia em saúde encontradas no DECS. As espécies pertencentes ao Complexo M. tuberculosis compartilham cerca de 99% de identidade do DNA,com sequências altamente conservadas, mas diferem na distribuição geográfica, patogenicidade e hospedeiros. O mecanismo de resistência clinicamente significativo para rifampicina é uma mutação do gene rpoB, que codifica o alvo desse antibiótico. Há grandes avanços no diagnóstico da TB, com novos instrumentos de biologia molecular e testes rápidos, mas ainda não substituem os métodos clássicos bacteriológicos, apesar de suas conhecidas limitações. Atualmente, a associação de métodos moleculares, principalmente aqueles baseados em reações da PCR tem proporcionado grande impulso nos estudos da epidemiologia molecular do MT. Embora haja uma diminuição do número de casos no mundo, dentre os desafios da doença estão a necessidade de pesquisas na área, envolvimento político para solucionar as questões sociais atribuídas à TB, treinamento permanente dos profissionais e monitoramento de vigilância dos casos para eliminar a doença no cenário mundial.

Even 133 years after the discovery of Mycobacterium tuberculosis, tuberculosis continues to be one of the main causes of death due to infectious diseases worldwide, especially in developing countries. The objective of this study was, after a survey of recent publications, to show issues relevant to the disease and to takea closer look at the tuberculosis problem in the current context. A total of 130 articles were found in the LILACS, MEDLINE/PubMed, SciELO, Paho, Cochrane Library, WHOLIS, IBECS and Scopus databases using the main keywords selected from health terminology of MeSH. Species belonging to the M. tuberculosis complex have highly conserved sequences and share about 99% DNA identity, but differ in their geographic distribution, pathogenicityand host. The clinically significant mechanismof rifampicin resistance is due to a mutation of the rpoB gene which encodes the target of the antibiotic. Great advances in the diagnosis of tuberculosis have occurred, with new molecular biology tools and rapid tests, but without replacing classical bacteriological methods, despite their known limitations. Recently, the association of molecular methods, especially based on PCR, has provided great impetus in molecular epidemiology studies of M. tuberculosis. Although the number of cases in the world has decreased, among the challenges are the need for further research, political involvement to solve social issues linked to tuberculosis, permanent training and the surveillance of cases in order to eliminate the disease on the world stage.

Tuberculosis pulmonar en un paciente con lepra lepromatosa: presentación de un caso / Pulmonary tuberculosis in a patient with lepromatous leprosy: presentation of a case

La tuberculosis y la lepra fueron enfermedades prevalentes durante el primer milenio en Europa, pero ya después, la lepra disminuyó en frecuencia. Por su parte, la tuberculosis se señala en un tercio de la población mundial, reportándose cada año diez millones de casos nuevos, a la vez que mueren tres millones de los existentes. La lepra, aunque se plantea, que está en vías de extinción, aún afecta a un millón de personas de países, para un 1 por ciento de prevalencia. En la actualidad, en muy raras ocasiones coinciden estas patologías. El objetivo de este trabajo fue mostrar el caso de un paciente con una lepra lepromatosa, que poco tiempo después de tratado por esta enfermedad, desarrolló una tuberculosis pulmonar. Para lograr lo propuesto se relacionó el estudio clínico y de laboratorio practicado al enfermo y se mostraron fotografías ilustrativas de ambos procesos. Luego de la revisión de la literatura, se llegó a la conclusión que estas entidades cuando coinciden en un solo sujeto son inusuales, y no han sido reportadas en Cuba(AU)

Tuberculosis and leprosy were prevalent diseases during the first millennium in Europe, but then leprosy decreased in frequency. On the other hand, tuberculosis affects a third of the world population, reporting ten millions of new cases every year, and dying three millions of them. Leprosy, which is considered in extinction, still affects a million of persons, for 1 per cent of prevalence. Nowadays, these diseases rarely coincide. The objective of this work was showing the case of a patient with lepromatous leprosy who, shortly after being treated for this disease, developed pulmonary tuberculosis. To achieve our proposal we made a relation of the clinical and laboratory study of the patient and showed illustrative pictures of both processes. After reviewing the literature, we arrived to the conclusion that these entities are unusual when coinciding in one person, and they have not being reported in Cuba(AU)

BCG vaccine: efficacy and indications for vaccination and revaccination.

OBJECTIVES: To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications. SOURCES OF DATA: A systematic review of the literature was made by searching PubMed and selecting studies carried out in the last 50 years. The studies were grouped according to their design (clinical trials, case-control studies, and meta-analyses) and the results were presented separately for each type of study. Other relevant topics such as BCG and HIV/AIDS, use of tuberculin skin test, issues related to vaccine scars and to the development of new vaccines were also reviewed. SUMMARY OF THE FINDINGS: BCG vaccine has been used since 1921. However, the data concerning its use are variable and inconsistent. The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important. Nevertheless, results regarding pulmonary tuberculosis have been inconsistent, either showing no efficacy or a protective efficacy rate around 80%. There is some evidence that a second dose of BCG vaccine does not increase its protective efficacy. Studies have shown that BCG vaccine protects against leprosy. The development of new vaccines to replace BCG in the future has been investigated. CONCLUSIONS: Despite the hope that a new vaccine against tuberculosis will be available in the future, BCG vaccine, in spite of its deficiencies, is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis, especially in countries where this disease has moderate to high levels of incidence.

Vacina BCG: eficácia e indicações da vacinação e da revacinação / BCG vaccine: efficacy and indications for vaccination and revaccination

OBJETIVOS: Revisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e discutir as suas principais indicações e contra-indicações. FONTES DOS DADOS: Utilizando o PubMed, foi realizada uma revisão sistemática da literatura abrangendo um período de, aproximadamente, 50 anos. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clínicos, estudos de caso-controle e meta-análises. Outros tópicos relevantes, como a BCG e HIV/AIDS, o uso do teste tuberculínico, aspectos relacionados à cicatriz vacinal e ao desenvolvimento de novas vacinas, dentre outros, foram também revistos. SíNTESE DOS DADOS: A vacina BCG é utilizada desde 1921. Apesar disso, ainda apresenta controvérsias e aspectos não esclarecidos. O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é bastante significativa. No entanto, em relação à forma pulmonar, os resultados são discordantes, variando de ausência de efeito a níveis próximos a 80 por cento. Há evidências de que uma segunda dose da BCG não aumenta o seu efeito protetor. Estudos demonstram proteção da vacina contra a hanseníase. Pesquisas sobre novas vacinas que, no futuro, poderão vir a substituir a BCG estão sendo realizadas. CONCLUSÕES:Apesar da expectativa de que, no futuro, venhamos a ter uma nova vacina para a tuberculose, no presente e ainda por muitos anos, a vacina BCG, apesar de suas deficiências, mantém-se como um importante instrumento nos esforços para controle dos efeitos danosos da tuberculose, sobretudo em países em que essa doença ocorre em médias e elevadas taxas de incidência.

Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8+ cells, interferon-gamma recovery and reduction of lung injury.

A DNA vaccine based on the heat-shock protein 65 Mycobacterium leprae gene (pHSP65) presented a prophylactic and therapeutic effect in an experimental model of tuberculosis. In this paper, we addressed the question of which protective mechanisms are activated in Mycobacterium tuberculosis-infected mice after immune therapy with pHSP65. We evaluated activation of the cellular immune response in the lungs of infected mice 30 days after infection (initiation of immune therapy) and in those of uninfected mice. After 70 days (end of immune therapy), the immune responses of infected untreated mice, infected pHSP65-treated mice and infected pCDNA3-treated mice were also evaluated. Our results show that the most significant effect of pHSP65 was the stimulation of CD8+ lung cell activation, interferon-gamma recovery and reduction of lung injury. There was also partial restoration of the production of tumour necrosis factor-alpha. Treatment with pcDNA3 vector also induced an immune stimulatory effect. However, only infected pHSP65-treated mice were able to produce significant levels of interferon-gamma and to restrict the growth of bacilli.

Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis.

All the trials of immunotherapy of tuberculosis with killed Mycobacterium vaccae, published or not, that are known to the authors are reviewed here. Following an introduction giving a brief account of some earlier immunotherapies for tuberculosis, the origins of the concept of immunotherapy with M.vaccae are considered. Progress is traced from the early work with irradiation-killed organisms in leprosy to the study in London of modulation of tuberculin skin-test responses, and the first comparative trials in The Gambia and Kuwait. In the last of these studies, dosages and different preparations were compared. As a result of this subsequent studies have used 109 heat-killed organisms, equivalent to 1mg wet-weight of bacilli, as a standard dose. A series of small trials in Argentina, India, Nigeria, Romania, South Africa and Vietnam have pioneered the way forward, disclosing geographic variability, with South Africa as the only country where almost no effects were recorded. Together the studies have shown that a single dose may not be sufficient. These studies have confirmed the mode of action of M.vaccae to be regulation of cell-mediated immunity with enhancement of Th1 and down-regulation of Th2, and they have shown benefits in faster bacteriological conversion, reduction in ESR, recovery of body weight and resolution of radiological opacities, leading to better recovery from the disease even when given to patients receiving directly observed therapy, short-course (DOTS). Three major randomised, placebo-controlled and partly blinded trials have been carried out in Africa. The first, in South Africa showed no M.vaccae-related effects. The second trial, in Uganda, confirmed the observations made in the earlier studies of faster sputum conversion and better radiological clearance. The third trial, in Zambia and Malawi, showed a trend towards benefits in the treatment of HIV seronegative patients but failed to show beneficial effects in HIV seropositive patients. Studies in patients with multi-drug-resistant tuberculosis have shown that multiple doses of immunotherapy are required in most cases, and that these markedly improve cure-rates for these patients. This is especially so when they are also treated with chemotherapy tailored to the resistance pattern of their infecting organisms. A small study has just commenced in which repeated doses of M.vaccae are being administered to a group of patients who have failed treatment with DOTS-Plus (directly observed therapy with drugs selected on the basis of drug susceptibility profiles). Late in the investigation came publications from China supporting and confirming the data in both drug-sensitive and drug-resistant disease, by the use of multiple injections of their own different preparation of M.vaccae. The trial that is now beginning in Vietnam of 3 doses of M.vaccae in the treatment of newly diagnosed pulmonary tuberculosis, is accompanied by a chemotherapeutic regimen with a shortened continuation phase. If this important study is successful, immunotherapy with killed M.vaccae should be introduced into the treatment regimens for tuberculosis worldwide.

Pulmonary necrosis resulting from DNA vaccination against tuberculosis.

The use of DNA constructs encoding mycobacterial proteins is a promising new approach to vaccination against tuberculosis. A DNA vaccine encoding the hsp60 molecule of Mycobacterium leprae has previously been shown to protect against intravenous infection of mice with Mycobacterium tuberculosis in both the prophylactic and immunotherapeutic modes. It is shown here, however, that this vaccine was not effective in a more realistic aerosol infection model or in a model of latent tuberculosis in the lungs. Moreover, when given in an immunotherapeutic model the immunized mice developed classical Koch reactions characterized by multifocal discrete regions of cellular necrosis throughout the lung granulomas. Similar and equally severe reactions were seen in mice given a vaccine with DNA coding for the Ag85 antigen of M. tuberculosis. This previously unanticipated safety problem indicates that DNA vaccines should be used with caution in individuals who may have already been exposed to tuberculosis.

Public and private providers' quality of care for tuberculosis patients in Kampala, Uganda.

SETTING: The role of the private sector in tuberculosis treatment in developing countries in sub-Saharan Africa is largely unknown. In recent years, many fee-for-service clinics have opened up in Kampala, Uganda. Little is known about the tuberculosis caseload seen in private clinics or the standard of care provided to the patients. OBJECTIVE: To compare the appropriateness of tuberculosis care in private and public clinics, and the extent of the tuberculosis burden handled in the private sector. DESIGN: Cross-sectional survey in private and public clinics treating tuberculosis patients in Kampala, Uganda, during June to August 1999. MEASUREMENTS: Clinics were evaluated for appropriateness of care. This was defined as provision of proper diagnosis (sputum smear microscopy as the primary means of diagnosis), treatment (short-course chemotherapy, with or without directly observed therapy), outcome evaluation (smear microscopy at 6 or 7 months) and case notification in accordance with the Uganda National Tuberculosis and Leprosy Programme. RESULTS: A total of 114 clinics (104 private, 10 public) were surveyed. Forty-one per cent of the private clinics saw three or more new tuberculosis patients each month. None of the public or private clinics met all standards for appropriate tuberculosis care. Only 24% of all clinics adhered to WHO-recommended treatment guidelines. Public clinics, younger practitioners and practitioners with advanced degrees were most likely to provide appropriate care for tuberculosis. CONCLUSION: The private sector cares for many tuberculosis cases in Kampala; however, a new programme that offers continuing medical education is needed to improve tuberculosis care and to increase awareness of national guidelines for tuberculosis care.

Mycobacterial infections: are the observed enigmas and paradoxes explained by immunosuppression and immunodeficiency?

The enigmas and paradoxes observed in tuberculous patients, in Bacille Calmette-Guérin-vaccinated people and in Bacille Calmette-Guérin-treated cancer patients have been examined, in an attempt to explain them through the mechanisms of immunodeficiency and immunosuppression. A dual effect is postulated: an immunosuppression induced by the infecting mycobacteria that adds to a pre-existing or emerging state of immunodeficiency of the infected individual. The immunological cellular and humoral anergies observed at the beginning of a tuberculous therapy are usually lifted after the first two weeks of treatment. This restoration of immune responsiveness may be attributed to the destruction or to the growth inhibition of immunosuppressive mycobacteria. The observation that drugs cytocidal in vitro do not always sterilize the patients under treatment whereas bacteriostatic drugs do, may find an explanation in the dual immunosuppression induced by cytocidal drugs and mycobacteria. The fact that Bacille Calmette-Guérin applied as an immunotherapy to residual cancer has either a favorable or an unfavorable action may be due to the immunosuppressive activity attached to some Bacille Calmette-Guérin strains and to some cancers. The variable protective activity of Bacille Calmette-Guérin vaccines may be due to the immunological status of the vaccinated people and the compositional differences between strains. The protective activity of subunit vaccines in experimental models can be attributed to the elimination of immunosuppressive factors present in whole killed mycobacteria.

Immunotherapy with Mycobacterium vaccae as an adjunct to chemotherapy in the treatment of pulmonary tuberculosis.

47 patients with adult-type pulmonary tuberculosis attending the Chest Diseases Hospital in Kuwait were given a single injection of 10(9) irradiation-killed M. vaccae after 1 month of a 9-month course of chemotherapy. The patients were followed-up for 3 more months in double blind comparison with 65 patients given an injection of saline (placebo). The immunotherapeutic injection produced a small local lesion in 44/47 patients, 18 of which ulcerated and produced small scars. Immunotherapy made no measurable difference to the bacteriological, biochemical, haematological, or radiological parameters measured. However it was associated with significantly improved weight gain, reduced size of skin test response to Tuberculin, increased lymphocyte proliferation to common mycobacterial antigens, and increased antibody levels to mycobacterial antigens. The changes in skin test and LTT responses were related and occurred in 29% of patients whose recognition of common mycobacterial antigens returned to normal. The remaining patients did not differ in these respects from those receiving placebo. The proportion of patients whose responses were improved was very similar to that achieved using the same immunotherapeutic agent in a group of treated multibacillary leprosy patients.

[Tuberculosis control in Malawi. Time distribution of cessation of treatment and proposals for reorientation of the program]. / Contrôle antituberculeux au Malawi. Répartition dans le temps des abandons de traitement et propositions pour une réorientation du programme.

In Kasungu district (Malawi), the patients with pulmonary tuberculosis are admitted in the district hospital for two months and then referred to the private organization LEPRA for further ambulatory treatment. Out of 73 patients found with positive expectoration for AAFB during 8 months, 54 were actually referred to LEPRA, 4 were sent to another hospital on died, and 15 defaulted. Later on 15% of the patients referred to LEPRA were lost to follow up during one year. 2/3 of defaulting happened during the 2 first months of the treatment. Furthermore the infectious patients case finding rate is likely to be very low. Those observations lead to propose three prioritary actions to improve tuberculosis control: case finding amelioration, relinquishment of compulsory long duration admissions, and integration of the tuberculosis care network into the general health system.

Immune responses and immunostimulation in tuberculosis therapy.

Despite a reasonably extensive literature on cellular and humoral immune responses in tuberculous disease, abnormalities tend to be secondary rather than predisposing to disease. No discrete immune deficiency or failure, which would explain the progression from non-infection to infection with Mycobacterium tuberculosis to tuberculous disease, has been identified. There is evidence that tuberculous disease occurs in a spectrum, analogous to leprosy, and it would seem that if immunostimulants, as adjuncts to standard therapy, are to be of any value in the treatment of tuberculosis, they should be used for non-reactive tuberculosis patients. The range of immunostimulants currently available tends to be indiscriminate in action and their targets in tuberculous disease largely uncertain; their role in therapy in discussed.