Efficacy of the 6-month thrice-weekly regimen in the treatment of new sputum smear-positive pulmonary tuberculosis under clinical trial conditions.

Background. Under the Revised National Tuberculosis Control Programme of India, patients with new smear-positive pulmonary tuberculosis are treated with a thrice-weekly regimen of antitubercular drugs (2H3R3Z3E3/4H3R3 [H isoniazid, R rifampicin, Z pyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacy and tolerability of this regimen under clinical trial conditions in HIV-negative patients with newly diagnosed smear-positive pulmonary tuberculosis. Methods. We retrospectively analysed the data on patients assigned to the control regimen (2H3R3Z3E3/4H3R3) in two clinical trials during 2001–06 at the National Institute for Research in Tuberculosis, Chennai, India. Results. Of the 268 patients treated with this regimen, data for efficacy analysis were available for 249. At the end of treatment, of 249 patients, 238 (96%) had a favourable status. Treatment failure occurred in the remaining 11: 7 in whom the organisms were initially drug-susceptible and 4 with initial drug resistance. Of the 238 patients who had a favourable status at the end of treatment, 14 (6%) had recurrence of tuberculosis during the following 24 months. In the intention-to-treat analysis, 245 (94%) of 262 patients had a favourable status at the end of treatment. Of the 28 patients with initial drug resistance, 24 (86%) had a favourable outcome. Only 4 of these 24 patients were found to have recurrence of tuberculosis in 2 years of follow-up. Among the 221 patients initially infected with drug-susceptible organisms, drug resistance did not develop in any of the 7 patients in whom the treatment failed or the 10 who had recurrence of tuberculosis. Further, 5 of the 7 patients in whom the treatment failed continued to excrete drug-susceptible bacilli at 6 months. Adverse drug reactions were observed in 38 (14%) of the 262 patients. Only 3 (1.1%) needed a modification in the treatment. Conclusion. This thrice-weekly 6-month regimen of antitubercular drugs, when administered under full supervision, is associated with a high rate of favourable treatment outcomes in HIV-negative patients with newly diagnosed sputum smearpositive pulmonary tuberculosis. There are few adverse drug reactions in these patients.

Perceptions of gender and tuberculosis in a south Indian urban community.

BACKGROUND: The Revised National Tuberculosis Control Programme (RNTCP) in India advocating Directly Observed Treatment-Short course (DOTS) detects nearly three times more male than female TB patients. The reasons for this difference are unclear. An understanding of the community's health beliefs, perceptions on the disease and behaviour towards TB patients may throw some light on this issue. MATERIAL AND METHODS: A qualitative study using focus group discussions was conducted among men and women of younger and older age groups from lower income neighbourhoods. The information obtained was grouped into themes which included, understanding of TB, vulnerability, access to health care and social responses. Gender differences in community perceptions on TB seem to be critical in issues related to marriage. RESULTS: The stigma of TB is more visible in women than men when it comes to marriage. Men and children were perceived to get preferential attention by their families during illness. While the younger age group, irrespective of gender, accessed care from private providers, the older group preferred a government facility. Awareness of TB was acceptable but it seemed more associated as a respiratory disease and the common symptom associated with TB was cough. CONCLUSION: This study highlights the need for gender specific intervention strategies to enhance better access of TB services.

Interleukin-12B & interleukin-10 gene polymorphisms in pulmonary tuberculosis.

BACKGROUND & OBJECTIVE: Cytokines play an important role in anti-tuberculosis immune response. Skewing of immunity from protective to pathogenic may involve a shift in Th1-Th2 paradigm. Cytokine gene polymorphism is known to be associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. The aim of this study was to know whether Interleukin-12B 3' UTR (Taq1) (A/C) and Interleukin-10 (-1082 G/A) gene polymorphisms were associated with susceptibility to pulmonary tuberculosis. METHODS: IL -10 (-1,082 G/A) and IL-12B gene polymorphisms were studied in 132 pulmonary TB (PTB) patients and 143 normal healthy subjects (NHS), using DNA based polymerase chain reaction (PCR) with sequence specific primers and restriction digestion. RESULTS: The allelic as well as genotypic frequencies of Interleukin -10 (-1082) and Interleukin -12B (3'UTR Taq 1) did not differ significantly between the patients and controls. INTERPRETATION & CONCLUSION: Our findings suggested that IL -10 (-1082 G/A) and IL -12B 3'UTR (Taq I) (A/C) gene polymorphisms were not associated either with susceptibility or resistance to pulmonary tuberculosis in the south Indian population.

Interferon gamma (IFNgamma) & interleukin-4 (IL-4) gene variants & cytokine levels in pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Cytokine gene polymorphisms may alter Th1/Th2 balance with major implications in tuberculosis. The aim of our study was to find out whether Interferon gamma +874A and IL-4 -590T polymorphisms were associated with susceptibility to pulmonary tuberculosis as well as the level of IFNgamma and IL-4 in south Indian population. METHODS: Interferon gamma +874A and IL-4 -590T promoter polymorphisms were studied in 129 pulmonary tuberculosis (PTB) patients and 127 normal healthy subjects (NHS) and were associated with culture filtrate and live Mycobacterium tuberculosis induced IFNgamma and IL-4 production in peripheral blood mononuclear cells (PBMCs). IL-4 gene variants were also associated with IgG antibody levels against M. tuberculosis culture filtrate antigen. RESULTS: The variant IFNgamma genotypes and IFNgamma levels between genotypes did not differ significantly in patients and controls. Significantly increased frequency of variant IL-4 'CT' genotype in PTB patients (P<0.05) and 'CC' genotype in control group (P<0.01) was observed. IL-4 levels were detectable in very few subjects and the IgG levels did not differ between the three IL-4 genotypes. INTERPRETATION & CONCLUSION: The study suggests a lack of functional association of Interferon gamma +874A polymorphism in tuberculosis in south Indian population. The higher frequency of IL-4 'CT' genotype in PTB suggests a possible association of IL-4 -590T promoter polymorphism with susceptibility to tuberculosis, and the 'CC' genotype may be associated with protection.

Elevated percentage of perforin positive cells in active pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Perforin is one of the major effector molecules of cytotoxic cells associated with killing of cells harbouring intracellular bacterial infection. The precise role of perforin positive cells in tuberculosis still remains controversial. The present study was done to determine the number of circulating CD4(+) and CD8(+) perforin positive cells to assess the level of cytotoxic response against Mycobacterium tuberculosis in patients with pulmonary tuberculosis. METHODS: Intracellular perforin and surface CD4 and CD8 staining of peripheral blood lymphocytes was done using specific monoclonal antibodies and enumerated using flowcytometry. RESULTS: A significantly decreased total lymphocytes (P<0.01), CD4 (P<0.001) and CD8 (P<0.01) lymphocyte counts in PTB patients was observed compared to normal healthy individuals (NHS). Intracellular perforin staining showed significantly elevated percentages of total (P<0.05) and CD8 (P<0.01) perforin positive cells in PTB patients compared to NHS. However, the absolute counts of total, CD4 and CD8 cells positive for perforin were similar in patients and NHS. INTERPRETATION & CONCLUSION: Our results suggest that during active stage of pulmonary tuberculosis there was an increased percentage of CD8 cells positive for perforin, irrespective of their absolute counts. Further, CD8(+) perforin positive cells may have increased cytolytic activity against M. tuberculosis in active pulmonary tuberculosis.

Rifampicin-induced renal toxicity during retreatment of patients with pulmonary tuberculosis.

Rifampicin is a crucial component of treatment regimens for tuberculosis and has been in use since the early 1970's. It is usually considered safe. Rarely life-threatening complications like acute renal failure or acute thrombocytopaenia may manifest during treatment with rifampicin. In our experience at the Tuberculosis Research Centre of treating more than 8000 pulmonary and extrapulmonary tuberculosis patients with rifampicin-containing regimens over the last 30 years, we are reporting 3 cases of probably rifampicin-induced acute renal failure. Despite extreme therapeutic safety of this drug the clinician must be aware of this rare complication, which if detected early is completely reversible.

Current trends in chemotherapy of tuberculosis.

After treptomycin, which heralded the era of antibacterial chemotherapy for tuberculosis (TB), many important advances have made available treatment regimens that are almost 100 per cent curative. Randomised clinical trials by the Tuberculosis Research Centre, in Chennai and British Medical Research Council in East Africa and in the Far East have helped to establish many of the principles of antituberculosis chemotherapy. With successes have also come fresh challenges. Mycobacterium tuberculosis becomes rapidly resistant to the drugs used against it and in the last decade, the HIV epidemic has had an adverse impact on the global epidemiology of tuberculosis, with many countries in Sub-Saharan Africa experiencing a 2-3 fold increase in their TB burden. While the currently recommended treatment regimens are very effective, they have failed to control the burden of TB in the developing countries due to less than satisfactory implementation of the control programmes. Faced with the dual threat of multidrug resistant TB and the HIV/facilitated increase in TB, the WHO has instituted a Global TB Control Programme based on the directly observed treatment shortcourse (DOTS) strategy. Much of the principles of this strategy have come out of research in India. As part of this strategy, the Government of India is implementing a Revised National Tuberculosis Control Programme (RNTCP). Under the RNTCP standardized treatment regimens are prescribed for different treatment categories. Already more than 80 per cent of the population is covered by this Programme and full coverage is slated for 2005. Meanwhile, fresh research is ongoing to shorten treatment duration, a measure that should greatly aid TB control.

Scrofula revisited: an update on the diagnosis and management of tuberculosis of superficial lymph nodes.

Lymph node tuberculosis is a disease of great antiquity. It is the commonest form of extra-pulmonary tuberculosis, and is probably the commonest cause of chronic lymphadenitis in children. Even after the advent of effective chemotherapy for tuberculosis, it still poses considerable problems in diagnosis and management. The disease usually presents as a painless lymphadenopathy of the superficial lymph nodes of insidious onset, which may proceed to abscess and sinus formation if neglected. Cervical nodes are most commonly affected, but multiple node involvement is common. Differential diagnosis include other infections, neoplasia, congenital conditions in the head and neck and rarely, drug reactions. Diagnosis, whenever feasible, should be made on the basis of histological evidence after lymph node biopsy. Diagnosis made on clinical grounds has poor specificity and will result in a great degree of over diagnosis. Recently, the role of fine needle aspiration cytology as an initial screening procedure has been recognized. The Tuberculosis Research Centre carried out the first clinical trial which established the efficacy of short course chemotherapy in the treatment of childhood lymph node tuberculosis. In 168 children with biopsy confirmed lymph node tuberculosis treated with an intermittent six month regimen, the cure rate after five years was 95%. The Revised National Tuberculosis Control Programme recommends that patients with lymph node tuberculosis (Category 3) should be treated with rifampicin and isoniazid three times a week for six months, with pyrazinamide for the first two months.

A histological spectrum of host responses in tuberculous lymphadenitis.

A total of 446 lymph node biopsy specimens showing histological evidence of tuberculosis were classified into four groups based on the organization of the granuloma, the type and numbers of participating cells and the nature of necrosis. These were, hyperplastic (22.4%)--a well-formed epithelioid cell granuloma with very little necrosis, reactive (54.3%)--a well-formed granuloma consisting of epithelioid cells, macrophages, lymphocytes and plasma cells with fine, eosinophilic caseation necrosis, hyporeactive (17.7%)--a poorly organized granuloma with macrophages, immature epithelioid cells, lymphocytes and plasma cells and coarse, predominantly basophilic caseation necrosis and nonreactive (3.6%)--unorganized granuloma with macrophages, lymphocytes, plasma cells and polymorphs with non caseating necrosis. Though the number of bacilli in the sections differed in each group, there were no differences in culture positivity, Mantoux reaction or the clinical features. It is likely that the spectrum of histological responses seen in tuberculous lymphadenitis is the end result of different pathogenic mechanisms underlying the disease.

Persisting alveolitis in miliary tuberculosis despite treatment with short-course chemotherapy.

Bronchoalveolar lavages in two patients with miliary tuberculosis have shown lymphocytic alveolitis. A 6-month regimen with an initial intensive 2-month phase resulted in remarkable clinical and radiographic improvement in both. However, bronchoalveolar lavage following treatment has shown that there was a persistence of lymphocytic alveolitis, though with reduced intensity. The significance of the persisting alveolitis, despite treatment, is not known at present. There is also a suggestion that compartment-alisation of lymphocytes may occur in miliary tuberculosis of the lung.