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In a number of developing countries, particularly in Sub-Saharan Africa, infection with both M. tuberculosis and human immunodeficiency virus (HIV) is highly prevalent. HIV infection results in an impairment of the immune system and entails a substantial risk of TB in those individuals who are or become infected with the tubercle bacillus. Because persons with both infections have an increased risk of developing clinical TB and further transmitting M. tuberculosis infection, some of these countries are facing, or will have to face, a rapid upsurge of the TB problem. The interaction between HIV and M. tuberculosis infection poses a serious health problem which will result in a major increase in disease, death and health care service needs in many countries. Immediate action at the global, national and local levels is needed to address this problem. In their national plans of action, national AIDS and TB control programmes should include coordinated activities to reduce the impact of the problem and international organizations and donor countries should be encouraged to support them technically and financially. Control of this TB epidemic linked with HIV infection will depend largely on the availability of prompt diagnosis and adequate treatment for TB, and possibly of effective chemoprophylaxis, not just for HIV-infected persons but for other groups as well. To deal with this problem, a number of issues need to be studied urgently. In addition, a number of immediate steps can be taken by control programmes.
BACKGROUND: Mycobacterium vaccae has been advocated for immunotherapy in the treatment of tuberculosis and other infections caused by mycobacteria. OBJECTIVES: The objective of this review was to assess the effects of Mycobacterium vaccae for treating tuberculosis. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials register, Medline, Embase and reference lists of articles. We also contacted organisations and individuals working in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials of preparations of whole, killed Mycobacterium vaccae in patients with tuberculosis. DATA COLLECTION AND ANALYSIS: One reviewer assessed trial quality and extracted data. MAIN RESULTS: Four trials met the inclusion criteria. There was no effect on mortality (2 trials, RR 1.01, 95% CI 0.50 to 2.04); no consistent effect on sputum negativity or sputum culture; and a high level of adverse reactions. REVIEWER'S CONCLUSIONS: Immunotherapy with Mycobacterium vaccae does not appear to benefit patients with tuberculosis.
BACKGROUND: The number of people infected with tuberculosis continues to rise world-wide. Rifampicin-containing treatment regimens can achieve high cure rates. Intermittent drug treatment delivered in the community has the potential to improve adherence to treatment. OBJECTIVES: The objective of this review was to compare the effectiveness of rifampicin-containing short-course chemotherapy regimens, given two or three times a week, with similar regimens given daily in patients with pulmonary tuberculosis. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, and reference lists of articles. We contacted experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials of any multi-drug regimen containing rifampicin in patients with confirmed pulmonary tuberculosis. Treatment had to be given up to three times a week for up to nine months, with any initial daily dosing period not more than one month, and was compared to daily dosing throughout for the same period. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. MAIN RESULTS: One trial involving 399 patients was included. The trial compared treatment three times per week with daily treatment for six months. There was no difference in cure rate (198 out of 199 people in the intermittent group compared to all 200 in the daily group), but 5 patients relapsed in the group receiving intermittent therapy compared to one in the group receiving the daily regimen. REVIEWER'S CONCLUSIONS: There is not enough evidence to assess the equivalence of effect between fully intermittent, rifampicin-containing short-course chemotherapy and similar daily therapy in patients with pulmonary tuberculosis. Larger randomised studies are required to establish the effectiveness of fully intermittent, short-course chemotherapy.
Information on the risk of tuberculous infection in the Netherlands has been linked with information on the incidence of tuberculosis, in an attempt to estimate the risks of developing the disease following infection or reinfection. It was postulated that: (a) those with a recent primary infection had a characteristic risk of developing progressive primary tuberculosis; (b) those with a distant (i.e. not recent) primary infection and a recent reinfection had a characteristic risk of developing exogenous tuberculosis; and (c) those with a distant primary infection but no recent reinfection had a characteristic risk of developing endogenous tuberculosis. The information on the risk of tuberculous infection was used to estimate the size of the population in each of these infection classes for different age-groups and calendar years in the Netherlands. Using multiple regression to link these population figures with the information on tuberculosis incidence in the same age group and calendar year, it was possible to estimate the above risks of developing tuberculosis. For Netherlands males aged 15-69 years during the period 1951-70 the three risks of developing pulmonary tuberculosis were estimated to be: (a) 5.06 per cent annually (for 5 years) following primary infection; (b) 1.91 per cent annually (for 5 years) following reinfection; (c) 0.0253 per cent annually, after the first 5 years following primary infection, in the absence of reinfection. The corresponding (and significantly different) estimated annual risks of development of pulmonary tuberculosis for females were 5.85, 1.10 and 0.0020 per cent respectively. From these risks, it may be estimated that the degree of protection conferred by a distant primary infection, against pulmonary tuberculosis arising from a recent reinfection, was 63 per cent for males and 81 per cent for females. The estimated relative proportions of cases of progressive primary, exogenous and endogenous tuberculosis varied considerably with age and calendar year. Progressive primary tuberculosis was dominant at the younger ages, exogenous and endogenous tuberculosis at older ages. At these older ages, the great majority of cases in the Netherlands in the early 1950s appeared to be exogenous in origin, but by 1970, with the decrease in the risk of infection, the exogenous contribution had dwindled substantially, especially among males.
As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.
During the 1960s and 1970s tuberculosis was severely neglected in developing countries. Less than 50% of patients diagnosed were cured. However, an international breakthrough occurred in the 1980s with the excellent results from a short-course treatment: 80% cured. This was first achieved in Tanzania. Since 1993, this innovative approach has been known throughout the world as the 'directly observed treatment, short-course' (DOTS) strategy. Over the past 15 years the interest in international tuberculosis control has substantially improved. There has been a strong increase in the number of initiatives to rapidly extend the use of DOTS so that internationally set targets for tuberculosis control can be met (by 2005, 70% of infectious patients detected and 85% of these cured). The highest priority has been given to the 22 countries with the highest incidence of tuberculosis. There has been a significant increase in the number of countries implementing DOTS. The average rate of cure using DOTS is 80%. Since the 1970s the Royal Netherlands Tuberculosis Association (Koninklijke Nederlandse Centrale Vereniging tot Bestrijding der Tuberculose (KNCV)) has been involved in many international initiatives, such as the Stop TB Partnership, and it has participated in the development and implementation of policies for tuberculosis and tuberculosis-HIV control. However, there are still causes for concern: the number of tuberculosis patients is increasing in particular due to the tuberculosis-HIV co-epidemic and it is estimated that only 1 in 4 infectious tuberculosis patients were detected and treated in DOTS programmes during the year 2000.
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INTRODUCTION: The World Health Organization (WHO) has declared Tuberculosis (TB) a global emergency in 1993. Prevalence of TB and Human Immunodeficiency Virus (HIV) co-infection worldwide is 0.18% and about 8% TB cases have HIV infection. Effective chemotherapy has been available for treatment of TB for over 50 years now. In World Health Organization (WHO)-International Union Against Tuberculosis and Lung Disease (IUATLD) Working Group Global Anti-Tuberculosis Drug Resistance Surveillance (1994-1997), the incidence of MDR TB in Delhi was found to be 14%, of which primary multi-drug resistance was only 1.4%, indicating that most of MDR TB is acquired as a result of poor chemotherapy. DIAGNOSIS OF TB: Since TB is an infectious disease caused by Mycobacterium (M) tuberculosis the diagnosis of TB should (as far as possible) be by demonstration of M. tuberculosis on culture or acid-fast bacilli (AFB) on smear examination. The World Health Organization (WHO) has strongly recommended sputum smear examination as the preferred screening test and suggests examination of 3 deeply coughed out sputum samples - spot sample on day 1, overnight sample and a spot sample in the morning on day 2. Recently it has been shown that sputum smear positivity is greater than 90% where greater than 5 ml of sputum is used for smear diagnosis of pulmonary TB. Culture of M. tuberculosis is the gold standard for diagnosis of TB. Culture of mycobacteria is a much more sensitive test than smear examination and has been estimated to detect 10-100 viable mycobacteria per ml of sample and in case of active disease they are found to be 81% sensitive and 98.5% specific. Culture methods are also required for further drug sensitivity testing in cases of suspected drug resistant cases. Isoniazid and rifampicin resistance can be reliably measured; resistance to pyrazinamide, ethambutol, and streptomycin is more difficult due to limitations of technique. The therapeutic index for a given drug is low for certain second-line drugs such as ethionamide, cycloserine, viomycin and para amino salicylic acid (PAS) and it leads to misinterpretation of results due to failure to distinguish between sensitive and resistant strains. Misdiagnosis of MDR-TB due to laboratory related errors has been reported recently. MANAGEMENT OF TB: Chemotherapy of TB consists of prevention of infection, also called primary chemoprophylaxis, when isoniazid 5 mg/kg is given to prevent infection in newborn infants of infectious mothers till mother is sputum smear positive (2-3months). Treatment of latent tuberculosis, also called secondary chemoprophylaxis, when isoniazid 5 mg/kg is given for 6 months to prevent disease in infected persons (asymptomatic MT positive individuals) and treatment of disease with Short Course Chemotherapy (SCC), as per WHO categories. Essential anti-tuberculosis (ATT) drugs Isoniazid (H), Rifampicin (R), Ethambutol (E), Pyrazinamide (Z) and Streptomycin (S) are the essential first line anti-tuberculosis drugs. Anti TB regimen consists of two phases: an initial intensive phase (IIP) and a continuation phase (CP). Best effective SCC for treatment of TB, for adults and children, for pregnant and lactating females, for cases associated with diabetes mellitus and HIV infection, for cases with pre-existing liver diseases (but normal liver functions) and mild renal failure is 2EHRZ, 4HR given daily or thrice weekly. Higher dose SCC intermittent therapy given in thrice weekly (2E3H3R3Z3, 4H3R3) has now been advocated by WHO and implemented by the Revised National TB Control Programme. DOTS, directly observed therapy short course, where the patient takes the drugs under the direct observation (DO) of a health worker to ensure regularity of consumption of drugs. Fixed dose combinations (FDCs) drugs consisting of two or three antituberculosis medications, provide a realistic and welcome alternative to DO that minimizes the opportunity for a patient to selectively take only a single medication. MANAGEMENT OF TB IN SPECIAL SITUATIONS: Pregnancy: All drugs, that is, rifampicin, isoniazid, ethambutol, and pyrazinamide can be used during pregnancy. Streptomycin is not given due to ototoxicity to the fetus. Prophylactic pyridoxine in the dose of 10mg/day is recommended along with ATT. Diabetes mellitus: The drug regimen is same as in nondiabetic. Strict control of blood glucose is mandatory. Also, doses of oral hypoglycemic agents may have to be increased due to interaction with Rifampicin. Prophylactic pyridoxine is indicated. Renal failure: Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid. In acute renal failure, ethambutol should be given 8 hours before hemodialysis. In post renal transplant patients: Rifampicin-containing regimens are avoided as rifampicin causes increased clearance of cyclosporin. Pre-existing liver disease: In stable disease with normal liver enzymes, all anti-tuberculous drugs may be used but frequent monitoring of liver function tests is required. Treatment in unconscious patient (patients unable to swallow): If patients are fed by Ryle's tube or gastrostomy tube, usual doses and drugs may be powdered and administered avoiding feeds 2-3 hours before and after the dose. In cases where enterostomy has been performed or parenteral nutrition is being used, intramuscular streptomycin and isoniazid and intravenous quinolones may be used and switch to oral therapy once oral feed resume. Treatment of TB with HIV co-infection: In early stages the presentations of TB in TB-HIV co-infection is the same as HIV negative but in late stages extra-pulmonary and dissemination are common. The usual short course chemotherapy is indicated in HIV positive patients. The response is usually good but relapse is frequent. After initiating ATT or anti-retroviral therapy (ART) worsening of preexisting lesions or appearance of new lesions is seen, "paradoxical response" or "immune reconstitution phenomenon". Multidrug resistant TB can occur due to poor compliance to ATT due to behavioural pattern, increased incidence of side effects and malabsorption of drugs due to associated diarrhea. ART for HIV, containing protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) cannot be used along with R, as R induces metabolism of PI and reduces the efficacy. The various options are i) to postpone anti-retroviral therapy ii) to use no PI or NNRTI containing anti-retroviral combinations iii) to use certain PI/ and/or NNRTIs with modification in doses iv) Efavirenz (EFZ) or Saquinavir with Ritonavir, without the need to adjust the doses v) to use non R regimens e.g. 2SHEZ+10HE MANAGEMENT OF MDR TB: As far as possible treatment of MDR TB should be referred to specialized units with facilities for quality controlled DST and experienced in handling such cases. If such referrals are not possible, one must remember that while initiating or revising therapy for MDR-TB, drugs selection must rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence.
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OBJECTIVE: To determine the superoxide dismutase (SOD) activity from clinical isolates of Mycobacterium tuberculosis and to study the seroreactivity of SOD from M. tuberculosis H37Rv. DESIGN: Crude cell extracts of 16 strains of M. tuberculosis isolated from tuberculosis (TB) patients were assayed for SOD activity. SOD from H37Rv was partially purified and characterized, and the seroreactivity was studied by ELISA using sera from 36 active pulmonary TB and 31 leprosy patients. RESULTS: SOD activity was detected in all the 16 strains of M. tuberculosis and also in the medium of logarithmic and stationary cultures of H37Rv. SOD activity from H37Rv extract was not affected by 1 mM KCN or by 5 mM H2O2 and was only 20% inhibited by 10 mM NaN3, suggesting that it is a Mn-containing enzyme. SOD was partially purified from H37Rv extract by gel filtration chromatography as a tetramer of molecular weight (MW) of 80,000 and a subunit MW of approximately 23,000. A delayed type hypersensitivity was elicited by SOD in guinea pigs sensitized with H37Rv or M. leprae sonicate. ELISA using SOD as antigen indicated 100% positivity with TB sera, while 84% positivity was observed with leprosy sera. Western blotting with pooled TB and leprosy sera indicated the presence of antibodies to the 23 kD SOD protein. CONCLUSION: Our data indicate that M. tuberculosis strains are rich in SOD, and the secretion of SOD may play a valuable role in the pathogenesis of M. tuberculosis.
Tuberculosis in respiratory system is most common in mycobacterial infections. Eighty percent of the patients with pulmonary tuberculosis visit hospital because of the respiratory symptoms, and only 10% of them were discovered by chest X-ray mass screening. In order to confirm respiratory tuberculosis, various methods to obtain specimens for mycobacterial examination have been carried out; hypertonic saline nebulizing for sputum expectoration, trans-bronchoscopic biopsy, percutaneous needle aspiration, and so on. The recent development of imaging modalities including CT, MRI, and ultrasonogram have been much contributed to the improvement of diagnosis of pleural tuberculosis. Basically, the main treatment for respiratory tuberculosis is chemotherapy except chronic tuberculous thoracic empyema. The initial chemotherapy regimen should be chosen among the three arms; [INH + RFP + PZA + EB (or SM)] x 2-->[INH + RFP] x 6, [INH + RFP + EB (or SM)] x 6-->[INH + RFP] x 3-6, and [INH + RFP] x 6-9. The sputum positive patient is recommended to have the chemotherapy regimen including PZA. In the patients with tracheo-bronchial tuberculosis an attention should be paid for the airway narrowing or obstruction during and after the scheduled chemotherapy. For a part of patients with tuberculous pleurisy and thoracic empyema, a surgical treatment must be indicated.
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The host effector mechanisms against Mycobacterium tuberculosis infection are not well understood, and this remains a problem in the development of new vaccines and immunotherapies in tuberculosis (TB). Here, we studied the expression of genes for interferon gamma (IFN-gamma) and molecules involved in lymphocyte-mediated cytotoxicity [granzyme B (grzB), perforin, granulysin and Fas ligand (FasL)] against M. tuberculosis-infected macrophages. The kinetics of expression of these molecules were first established in peripheral blood mononuclear cells (PBMC) of healthy donors, and then investigated in TB patients with and without HIV-1 coinfection and appropriate control groups. We found that only IFN-gamma and grzB were induced by M. tuberculosis in PBMC from healthy purified protein derivative skin test reactive subjects. However, expression of neither gene nor IFN-gamma protein correlated with intracellular M. tuberculosis growth containment by macrophages. Mycobacterium tuberculosis induction of IFN-gamma, but not grzB, mRNA expression was significantly lower (P < 0.03) in TB patients as compared with healthy subjects.
Clinical strains of Mycobacterium tuberculosis can be divided into three principal genetic groups based on the single-nucleotide polymorphisms at the katG gene codon 463 and the gyrA gene codon 95. One subgroup of genetic group 1, the Beijing/W lineage, has been widely studied because of its worldwide distribution and association with outbreaks. In order to increase our understanding of the clinical and epidemiological relevance of the genetic grouping of M. tuberculosis clinical strains and the Beijing/W lineage, we investigated the genetic grouping of 679 clinical isolates of M. tuberculosis, representing 96.3% of culture-confirmed tuberculosis cases diagnosed in Arkansas between January 1996 and December 2000 using PCR and DNA sequencing. We assessed the associations of infections by different genetic groups of M. tuberculosis strains and infection by the Beijing/W lineage strains with the clinical and epidemiological characteristics of the patients using chi-square tests and multivariate logistic regression analysis. Of the 679 study isolates, 676 fell into one of the three principal genetic groups, with 63 (9.3%) in group 1, 438 (64.8%) in group 2, and 175 (25.9%) in group 3. After adjusting for potential confounding of age, gender, race/ethnicity, human immunodeficiency virus serostatus, and plcD genotype in a multivariate logistic regression model, patients infected by the Beijing/W lineage isolates were nearly three times as likely as patients infected with the non-Beijing/W lineage isolates to have an extrathoracic involvement (odds ratio [95% confidence interval], 2.85 [1.33, 6.12]). Thus, the Beijing/W lineage strains may have some special biological features that facilitate the development of extrathoracic tuberculosis.
Mycobacterium tuberculosis is an intracellular pathogen that readily survives and replicates in human macrophages. Host cells have developed various mycobactericidal and immunoregulatory mechanisms, such as the production of nitric oxide and inflammatory cytokines to control intracellular replication of M. tuberculosis. Inducible nitric oxide synthase (iNOS) is transcriptionally under the control of IFN-gamma and TNF-alpha. IL-12 provides a crucial link between activated mononuclear phagocytes and T cells by regulating the production of IFN-gamma. In this study, we investigated the production of nitric oxide (NO), TNF-alpha and IL-12 by the peripheral blood monocytes (PB Mn) of patients suffering from multidrug-resistant tuberculosis (MDR-TB). The cells were infected with M. tuberculosis and stimulated with IFN-gamma or activated with mycobacterial subcellular components. The results were compared with those from cases of newly diagnosed TB and healthy controls. Nitric oxide production was significantly depressed in PB Mn from MDR-TB patients. Infected monocytes from newly diagnosed TB patients produced significantly higher levels of NO as compared to those from MDR-TB patients or normal controls. The subcellular fraction of M. tuberculosis-like whole cell lysate (WCL), culture filtrate protein (CFP) and lipoarabinomannan (LAM) induced higher concentrations of NO release in PB Mn from newly diagnosed TB patients as compared to those from MDR-TB patients. Cell culture supernatant from PB Mn assayed at 48 h after infection or stimulation demonstrated significantly depressed release of TNF-alpha and IL-12 from MDR-TB cases as compared to the fresh cases. We observed a definite correlation between nitric oxide release and TNF-alpha production, irrespective of low or high production in MDR-TB or fresh cases, respectively. The present data suggest that peripheral blood monocytes of MDR-TB patients typically show signs of immunosuppression. Whether such immunodepression is the cause or the effect of MDR-TB merits further investigation.
A simple and sensitive passive haemagglutination (PHA) test has been evaluated in the serology of human tuberculosis. Double aldehyde stabilized red cells were sensitized with cell extracts and PPD antigens from M. tuberculosis (H37Rv) and used as reagents in the test. The study was conducted on sera from 71 bacteriologically confirmed cases of tuberculosis and their controls, inclusive of 59 healthy blood donors and 28 non-tuberculous chest disease patients. In addition, 318 random samples of sera and 107 finger prick blood samples collected on filter papers from apparently healthy people were examined. For comparative evaluation, tuberculous patients' sera were examined by enzyme linked immunosorbent assay (ELISA) and crossed immunoelectrophoresis (CIE). The distribution of IgG and IgM type antimycobacterial antibodies (AMA) in tuberculous patients' sera was evaluated by a modified PHA test. The results of the study indicated that the PHA test was a sensitive method for the quantitation of antibodies, which could be demonstrated in all groups of sera studied. The PHA test and ELISA with the antigens used were not found to be specific enough for the serodiagnosis of tuberculosis; the results indicated the need to investigate several immunological approaches for this purpose. Both tests did differentiate between the mean AMA levels of tuberculous patients and their controls and both showed treated and relapsed cases of tuberculosis to contain higher serum levels of antibodies than did new cases. Both tests were found to be more sensitive than CIE with the intermediate gel technique. The PHA test was found to be sensitive enough for the measurement of antibodies in finger-prick blood samples, indicating its potential for field studies.