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Background: Tuberculosis (TB) management continues to be a challenge globally; weakened immunity plays a significant role in the reactivation of TB. There is limited information on hematological parameters in patients with pulmonary TB and its association with outcome., Objectives: We present hematological parameters of newly diagnosed sputum-positive pulmonary TB patients enrolled in a randomized, clinical trial that assessed the efficacy and safety of 3 and 4 regimens using moxifloxacin., Materials and Methods: Blood hematological parameters at baseline, comparison of the baseline and end of treatment values, including the monocytes by lymphocytes ratio (M/L), neutrophil lymphocyte ratio (N/L), and platelet lymphocyte ratio (P/L) between the patients with favorable and unfavorable TB treatment outcome, and among different age group and sex presented in this paper., Results: Among the total 1059 patients, 782 were males, the mean hemoglobin (HB) ± standard deviation (SD) was 11.5 g/dL ± 2.0, the mean white blood cell (WBC) count ± SD was 9800 ± 3009 and the mean platelet count (in lakhs) ± SD was 4.24 ± 1.42 cells/uL. There was an increase from baseline in the mean hemoglobin, eosinophil, and lymphocyte count and a decrease in mean neutrophil, monocyte counts to the end of treatment. There was a decrease in baseline mean total WBC count posttreatment, both in favorable (10,271 cells/uL ± 3007 SD to 6689 cells/uL ± 1837 SD, [P ≤ 0.001]), and unfavorable TB outcome patients., Conclusion: An increase in HB, and a decrease in WBC count, M/L, N/L, and P/L ratio is possible at the end of TB treatment and future studies to correlate blood hematology parameters with TB treatment outcome., (Copyright © 2024 Copyright: © 2024 Indian Journal of Public Health.)

Background: Shortening tuberculosis (TB) treatment duration is a research priority. We tested the efficacy and safety of 3- and 4-month regimens containing moxifloxacin in a randomised clinical trial in pulmonary TB (PTB) patients in South India., Methods: New, sputum-positive, adult, HIV-negative, non-diabetic PTB patients were randomised to 3- or 4-month moxifloxacin regimens [moxifloxacin (M), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] or to a control regimen (2H 3 R 3 Z 3 E 3 /4R 3 H 3 ) [C]. The 4 test regimens were 3R 7 H 7 Z 7 E 7 M 7 [M3], 2R 7 H 7 Z 7 E 7 M 7 /2R 7 H 7 M 7 [M4], 2R 7 H 7 Z 7 E 7 M 7 /2R 3 H 3 M 3 [M4-I] or 2R 7 H 7 Z 7 E 7 M 7 /2R 3 H 3 E 3 M 3 [M4-IE]. Treatment was directly observed. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The primary end point was TB recurrence post-treatment., Results: Of 1371 patients, randomised, modified intention-to-treat (ITT) analysis was done in 1329 and per-protocol (PP) analysis in 1223 patients. Regimen M3 was terminated due to high TB recurrence rates. 'Favourable' response at end of treatment was 96-100% in the moxifloxacin regimens and 93% in the control  regimen. Among these, the TB recurrence occurred in 4.1% in the M4 regimen and in 4.5% in the control regimen and demonstrated equivalence within a 5% margin (95% CI -3.68, 4.55). Similar findings were observed in modified ITT analysis. The TB recurrence rates in the M4-I and M4-IE regimens did not show equivalence with the control regimen. Sixteen (1.4%) of 1087 patients in the moxifloxacin regimens required treatment modification., Conclusion: The 4-month daily moxifloxacin regimen [M4] was found to be equivalent and as safe as the 6-month thrice-weekly control regimen., (© 2020 John Wiley & Sons Ltd.)

Objectives: To explore whether non-tuberculous mycobacteria (NTM) are associated with tubal disease leading to infertility., Design: Prospective observational study., Setting: Teaching hospital., Population: Women with tubal factor infertility., Methods: In all, 173 infertile women with tubal disease were investigated for genital tuberculosis, Chlamydia trachomatis and Neisseria gonorrhoeae using polymerase chain reaction, culture and histopathological examination. On culture, NTM were grown in 23.7% of endometrial samples. The mycolic characteristics of these organisms were analysed., Main Outcome Measure: Whether NTM are associated with tubal disease leading to infertility., Results: The organisms identified in association with tubal disease were Mycobacterium tuberculosis in 30%, gonococci in 1.7%, Chlamydia in 7.5% and NTM in 23.7% of cases. Mycobacterium chelonae was the predominant organism identified by high-performance liquid chromatography. In ten women, for whom there was laparoscopic evidence of tubal disease, the only organism that was grown was NTM, and the tests for other organisms were negative. Tests for possible environment (theatre, instruments) contamination was reported negative., Conclusion: While evaluating infertile women for tubal disease, culture studies revealed a high prevalence of NTM in the endometrium. In the absence of M. tuberculosis, gonococci and Chlamydia infection, the presence of NTM suggests the possibility that these organisms may be responsible for tubal damage leading to infertility., Tweetable Abstract: On evaluating the causes of tubal disease, NTM were associated with tubal disease., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Introduction: There is lack of information on the proportion of new smear-positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice-weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome., Objective: To estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined., Methodology: Adult (aged ≥ 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared "treatment success" at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years (with 95% confidence interval [95%CI]). Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence., Results: Of the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2-21.6] and TB recurrence rate per 100 person-years was 12.7 [95% CI: 0.4-25]. TB recurrence per 100 person-years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence., Conclusion: A substantial proportion of new smear positive PTB patients successfully treated with 6 -month thrice-weekly regimen have TB recurrence under program settings., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: None

Background: Contact investigation is an active case finding strategy to increase detection of Tuberculosis (TB) and a key component of TB control programs. The household contacts are at a higher risk of exposure than members of the general population. The information on the value and yield of household contact screening and the approaches used in high incidence settings like India is limited., Objective: To evaluate the yield of active case finding in household contacts of newly diagnosed smear positive TB patients and the factors associated with increased yield., Method: Retrospective record review of the household contacts of newly diagnosed sputum smear positive patients (index case) enrolled in a clinical trial at National Institute of Research in Tuberculosis, Chennai during the period 2007-2014. A sequential screening algorithm with chest x-ray followed by symptom screen was employed to identify presumptive TB patients., Results: 643 household contacts of 280 index TB patients were identified out of which 544 (85%) consented for screening. 71/544 (13%) patients had an abnormal chest radiograph and out of them 70% were symptomatic. A total of 29/544 (5.3%) contacts were found to have TB among whom 23/29 (79%) were sputum smear positive. The number needed to screen (NNS) to identify a new TB case among all household contacts was 19 and among those with an abnormal CXR was 02. Age group > 44 years, male gender and siblings of the index case was associated with abnormal chest radiograph whereas age group between 15-44 was significantly associated with developing TB disease among household contacts., Conclusion: Active screening among household contacts is an effective way to improve TB case detection. The yield for new TB cases among contacts with abnormal x-ray was high in this study and the use of Chest X-rays in combination with symptom screen is recommended., Competing Interests: The authors have declared that no competing interests exist.

Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMPs). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels were previously shown to distinguish active from latent TB, as well as successfully treated Mycobacterium tuberculosis infection. MMP-1 expression is also associated with active TB. In this study, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations, as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other nontuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied the expression of HO-1 and MMP-1 in M. tuberculosis-infected human and murine macrophages. We found that infection of macrophages with live virulent M. tuberculosis is required for robust induction of high levels of HO-1 but not MMP-1. In addition, we observed that CO, a product of M. tuberculosis-induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients., (Copyright © 2015 by The American Association of Immunologists, Inc.)

CD8(+) T cells secreting Type1 and Type 17 cytokines and cytotoxic molecules play a major role in immunity and protection against pulmonary tuberculosis (PTB), although their role in tuberculous lymphadenitis (TBL) is not well known. To identify the distribution and function of CD8(+) T cells expressing Type1, Type 2 and Type 17 cytokines and cytotoxic molecules in TBL, we examined baseline and mycobacterial-antigen specific immune responses in the whole blood of individuals with PTB and compared them with TBL. TBL is characterized by elevated frequencies of baseline and mycobacterial-antigen stimulated CD8(+) T cells expressing Type 1 (IL-2 and TNFα) and Type 17 (IL-17A and IL-17F) cytokines in comparison to PTB individuals. In contrast, TBL individuals exhibited diminished frequency of CD8(+) T cells expressing perforin, granzyme B and CD107a. The blockade of IL-1R and IL-6R during antigenic stimulation resulted in significantly diminished frequencies of CD8(+) T cells expressing Type 1 and Type 17 cytokines in TBL. Therefore, our data suggest that TBL is characterized by an IL-1 and IL-6 dependent expansion of CD8(+) T cells expressing Type 1 and Type 17 cytokines as well as altered frequencies of cytotoxic molecules, reflecting an important association of these cells with the pathogenesis of TBL., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The increased prevalence of type 2 diabetes mellitus (T2DM) in countries endemic for TB poses a serious complication in the clinical management of this major infectious disease. Understanding the impact of T2DM on TB and the determinants of comorbidity is critical in responding to this growing public health problem with better therapeutic approaches. Here, we performed an exploratory study assessing a series of biologic parameters that could serve as markers of pathogenesis in TB with T2DM., Methods: Cross-sectional analyses of levels of heme oxygenase-1 (HO-1), acute phase proteins, tissue metalloproteinases, and tissue inhibitors of metalloproteinase (TIMPs) as well as cytokines and chemokines were performed in plasma samples from individuals with active pulmonary TB or with coincident TB and T2DM from South India., Results: Compared with patients with TB without diabetes, those with coincident T2DM exhibited increased Mycobacterium tuberculosis bacillary loads in sputum. Plasma levels of HO-1 but not of other acute phase proteins were higher in patients with TB and T2DM than in patients without diabetes, independent of bacillary sputum loads. HO-1 concentrations also positively correlated with random plasma glucose, circulating glycosylated hemoglobin, and low-density lipoprotein levels. Moreover, patients with coincident TB and T2DM exhibited increased plasma levels of TIMP-4 and elevated peripheral blood neutrophil counts, which, when considered together with HO-1, resulted in increased power to discriminate individuals with active TB with and without T2DM., Conclusions: Elevated plasma levels of HO-1 and TIMP-4 and peripheral blood neutrophil counts are potential single and combined markers of pathogenesis in TB and T2DM.

Rationale: Type 2 diabetes mellitus is a major risk factor for the development of active tuberculosis, although the biological basis underlying this susceptibility remains poorly characterized., Objectives and Methods: To identify the influence of coincident diabetes mellitus on cytokine levels in pulmonary tuberculosis, we examined circulating levels of a panel of cytokines and chemokines in the plasma of individuals with tuberculosis with diabetes and compared them with those of individuals without diabetes., Measurements and Main Results: Tuberculosis with diabetes is characterized by elevated circulating levels of type 1 (IFN-γ, tumor necrosis factor-α, and IL-2), type 2 (IL-5), and type 17 (IL-17A) cytokines but decreased circulating levels of IL-22. This was associated with increased systemic levels of other proinflammatory cytokines (IL-1β, IL-6, and IL-18) and an antiinflammatory cytokine (IL-10) but not type 1 IFNs. Moreover, tuberculosis antigen-stimulated whole blood also showed increased levels of proinflammatory cytokines. Finally, type 1 and type 17 cytokines in plasma exhibit a significant positive correlation with hemoglobin A1C levels, indicating that impaired control of diabetes is associated with this proinflammatory milieu. Multivariate analysis revealed that the association of proinflammatory cytokines with diabetes mellitus was not influenced by age, sex, or other metabolic parameters., Conclusions: Our data reveal that tuberculosis with diabetes is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying type 2 diabetes potentially contributes to increased immune pathology and poor control in tuberculosis infection.

Background: Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis, although the immunological mechanisms underlying this interaction remain unexplored. The influence of poorly controlled diabetes on pathogen-specific T-helper 1 (Th1) and T-helper 17 (Th17) responses have not been examined., Methods: To identify the role of Th1 and Th17 cells in tuberculosis with coincident DM, we examined mycobacteria-specific immune responses in the whole blood of individuals who had tuberculosis with DM and compared them to those in individuals who had tuberculosis without DM., Results: Tuberculosis coincident with DM is characterized by elevated frequencies of monofunctional and dual-functional CD4(+) Th1 cells following Mycobacterium tuberculosis antigen stimulation and elevated frequencies of Th17 subsets at both baseline and following antigen stimulation. This was associated with increased systemic (plasma) levels of both Th1 and Th17 cytokines and decreased baseline frequencies of natural regulatory T cells but not interleukin 10 or transforming growth factor β., Conclusions: Therefore, our data reveal that tuberculosis in persons with DM is characterized by elevated frequencies of Th1 and Th17 cells, indicating that DM is associated with an alteration in the immune response to tuberculosis, leading to a biased induction of Th1- and Th17-mediated cellular responses and likely contributing to increased immune pathology in M. tuberculosis infection.

Background: Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India., Methods: Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens., Results: Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification., Conclusions: 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB., Trial Registration: Clinical Trials Registry of India CTRI/2012/10/003060.

Background: Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB., Methods: Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India., Results: Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α., Conclusion: These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins.

Medical college faculty, who are academicians are seldom directly involved in the implementation of national public health programmes. More than a decade ago for the first time in the global history of tuberculosis (TB) control, medical colleges of India were involved in the Revised National TB Control Programme (RNTCP) of Government of India (GOI). This report documents the unique and extraordinary course of events that led to the involvement of medical colleges in the RNTCP of GOI. It also reports the contributions made by the medical colleges to TB control in India. For more than a decade, medical colleges have been providing diagnostic services (Designated Microscopy Centres), treatment [Directly Observed Treatment (DOT) Centres] referral for treatment, recording and reporting data, carrying out advocacy for RNTCP and conducting operational research relevant to RNTCP. Medical colleges are contributing to diagnosis and treatment of human immunodeficiency virus (HIV)-TB co-infection and development of laboratory infrastructure for early diagnosis of multidrug-resistant and/or extensively drug-resistant TB (M/XDR-TB) and DOTS-Plus sites for treatment of MDR-TB cases. Overall, at a national level, medical colleges have contributed to 25 per cent of TB suspects referred for diagnosis; 23 per cent of 'new smear-positives' diagnosed; 7 per cent of DOT provision within medical college; and 86 per cent treatment success rate among new smear-positive patients. As the Programme widens its scope, future challenges include sustenance of this contribution and facilitating universal access to quality TB care; greater involvement in operational research relevant to the Programme needs; and better co-ordination mechanisms between district, state, zonal and national level to encourage their involvement.

Background: Although Type 1 cytokine responses are considered protective in pulmonary tuberculosis (PTB), their role as well as those of Type 2, 17 and immunoregulatory cytokines in tuberculous lymphadenitis (TBL) and latent tuberculosis (LTB) have not been well studied., Aim and Methods: To identify cytokine responses associated with pulmonary tuberculosis (TB), TB lymphadenitits and latent TB, we examined mycobacterial antigen-specific immune responses of PTB, TBL and LTB individuals. More specifically, we examined ESAT-6 and CFP-10 induced Type 1, Type 2 and Type 17 cytokine production and their regulation using multiplex ELISA., Results: PTB individuals exhibited a significantly lower baseline as well as antigen-specific production of Type 1 (IFNγ, TNFα and IL-2); Type 2 (IL-4) and Type 17 (IL-17A and IL-17F) cytokines in comparison to both TBL and LTB individuals. TBL individuals exhibited significantly lower antigen-specific IFNγ responses alone in comparison to LTB individuals. Although, IL-10 levels were not significantly higher, neutralization of IL-10 during antigen stimulation resulted in significantly enhanced production of IFNγ, IL-4 and IL-17A in PTB individuals, indicating that IL-10 mediates (at least partially) the suppression of cytokine responses in PTB., Conclusion: Pulmonary TB is characterized by an IL-10 dependent antigen-specific suppression of Type 1, Type 2 and Type 17 cytokines, reflecting an important association of these cytokines in the pathogenesis of active TB.

Background: Th1 and Th17 responses are known to play an important role in immunity to pulmonary tuberculosis (PTB), although little is known about their role in extrapulmonary forms of tuberculosis (TB)., Methods: To identify the role of Th1, Th17, and Th22 cells in multi-focal TB lymphadenitis (TBL), we examined mycobacteria-specific immune responses in the whole blood of individuals with PTB (n = 20) and compared them with those with TBL (n = 25)., Results: Elevated frequencies of CD4(+) T cells expressing IFN- γ, TNF-α, and IL-2 were present in individuals with TBL compared with those with PTB at baseline and in response to ESAT-6 and CFP-10. Similarly, increased frequencies of CD4(+) T cells expressing IL-17A, IL-17F, and IFN-γ were also present in individuals with TBL at baseline and following ESAT-6 and CFP-10 stimulation although no significant difference in frequency of Th22 cells was observed. Finally, frequencies of Th1 (but not Th17) cells exhibited a significantly negative correlation with natural regulatory T cell frequencies at baseline., Conclusions: Multi-focal TB lymphadenitis is therefore characterized by elevated frequencies of Th1 and Th17 cells, indicating that Th1 and Th17 responses in TB disease are probably correlates of disease severity rather than of protective immunity.

1,25 Dihydroxy vitamin D(3) (vitamin D(3)) is an immunomodulator and its deficiency has been associated with susceptibility to tuberculosis. We have studied the immunoregulatory role of vitamin D(3) on various chemokine expression in pulmonary tuberculosis. Peripheral blood mononuclear cells obtained from 21 pulmonary tuberculosis (PTB) patients and 24 healthy controls (HCs) were cultured for 48 h with culture filtrate antigen (CFA) of Mycobacterium tuberculosis with or without vitamin D(3) at a concentration 1 × 10(-7)M. The relative mRNA expression of monocyte chemoattractant protein-1 (MCP-1, CCL2), macrophage inflammatory protein-1α (MIP-1α, CCL3), macrophage inflammatory protein-1β (MIP-1β, CCL4), and regulated upon-activation, normal T cell-expressed and secreted (RANTES, CCL5) and IFN-γ inducible protein-10 (IP-10, CXCL10) chemokines were estimated from 48 h old macrophages using real-time polymerase chain reaction (RT-PCR). The culture supernatants were used to estimate the various chemokines including monokine induced by IFN-γ (MIG, CXCL9) levels using cytometric bead array. In HCs, vitamin D(3) significantly suppressed the MCP-1 mRNA expression of CFA stimulated cells (p=0.0027), while no such effect was observed in PTB patients. Vitamin D(3) showed no significant effect on MIP-1α, MIP-1β and RANTES in both the study groups. The CFA induced IP-10 mRNA and protein expression was significantly suppressed by vitamin D(3) in both the study groups (p<0.05). A similar suppressive effect of vitamin D(3) was observed with MIG protein in healthy controls (p=0.0029) and a trend towards a suppression was observed in PTB patients. The suppressive effect of vitamin D(3) is more prominent in CXC chemokines rather than CC chemokines. This suggests that vitamin D(3) may down regulate the recruitment and activation of T-cells through CXC chemokines at the site of infection and may act as a potential anti-inflammatory agent., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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 (2H(3)R(3)Z(3)E(3)/4H(3)R(3) [H isoniazid, R rifampicin, Z pyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacy andtolerability 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 (2H (3)R(3)Z(3)E(3)/4H(3)R(3)) 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., (Copyright 2012, NMJI.)

Toll-like receptors (TLRs) are pattern recognition receptors and play an important role in innate immunity. Changes in TLRs and signaling molecules that result from polymorphisms are often associated with susceptibility to various infectious diseases. In the present study, we investigated whether variants in the TLR-1 1805T/G (Ile602Ser), TLR-2 2258G/A (Arg753Gln), TLR-4 896A/G (Asp299Gly), TLR-4 1196C/T (Thr399Ile), TLR-6 745C/T (Ser249Pro), TIRAP 975C/T (Ser180Leu) genes and TLR-9 promoter region polymorphisms at positions -1237C/T and -1486C/T are associated with susceptibility or resistance to pulmonary tuberculosis (PTB). Genotyping of TLR and TIRAP gene polymorphisms was performed by polymerase chain reaction followed by restriction fragment length polymorphism method in 212 healthy control subjects (HCs) and 206 PTB patients. The allele and genotype frequencies of various TLR genes were not different between the HCs and PTB patients. However, the study is underpowered to detect minor associations. The frequency of T allele of TIRAP 975C/T (Ser180Leu) polymorphism was significantly increased among PTB patients as compared to HCs [p = 0.026; Odds ratio (OR) 1.49, 95% Confidence interval (CI) 1.049-2.22]. A trend towards an increased frequency of TT genotype of TIRAP 975C/T was also observed in PTB patients [p = 0.078, OR 3.10 95% CI (0.96-10.05)]. The present study suggests that T allele of TIRAP 975C/T polymorphism may be associated with susceptibility to pulmonary TB in south Indian population. Further study on the regulatory role of this polymorphism may be helpful to understand the innate immunity in TB., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: There is limited information on the relative proportion of reactivation and reinfection at the time of recurrence among human immunodeficiency virus (HIV)-infected and HIV-uninfected patients who are successfully treated for tuberculosis infection in India., Methods: HIV-infected and HIV-uninfected patients with sputum culture-positive pulmonary tuberculosis were treated with short-course regimens and followed up for 36 months at the Tuberculosis Research Centre, South India. Bacteriologic recurrences were documented, and typing of strains was performed using 3 different genotypic techniques: restriction fragment length polymorphism (RFLP) by IS6110, spoligotyping, and mycobacterial interspersed repeat unit (MIRU)-variable number tandem repeat (VNTR). DNA fingerprints of paired Mycobacterium tuberculosis isolates (baseline and recurrence) were compared., Results: Among 44 HIV-infected and 30 HIV-uninfected patients with recurrent tuberculosis during the period July 1999 to October 2005, 25 and 23 paired isolates, respectively, were typed using all 3 methods. Recurrence was due to exogenous reinfection in 88% of HIV-infected and 9% of HIV-uninfected patients (P<.05). Among recurrent isolates, the HIV-infected patients showed more clustering, as well as a higher proportion of drug resistance, including multidrug resistance., Conclusions: In India, a tuberculosis-endemic country, most recurrences after successful treatment of tuberculosis are due to exogenous reinfection in HIV-infected persons and endogenous reactivation in HIV-uninfected persons. Strategies for prevention and treatment of tuberculosis infection must take these findings into consideration.

Setting: TB control programmes in Bangladesh, India and Malawi., Objective: To identify and compare socio-cultural features of tuberculosis (TB) and the distribution of TB-related experiences, meanings and behaviours with reference to gender across cultures in three high-endemic low-income countries., Design: Approximately 100 patients at three sites were interviewed with in-depth semi-structured Explanatory Model Interview Catalogue (EMIC) interviews inquiring about patterns of distress, perceived causes and help-seeking behaviours in the context of illness narratives., Results: Female patients reported more diverse symptoms and men more frequently focused on financial concerns. Most patients reported psychological and emotional distress. Men emphasised smoking and drinking alcohol as causes of TB, and women in Malawi reported sexual causes associated with HIV/AIDS. In Bangladesh, exaggerated concerns about the risk of spread despite treatment contributed to social isolation of women. Public health services were preferred in Malawi, and private doctors in India and Bangladesh., Conclusion: Cross-site analysis of these studies has identified features of TB that influence the burden of disease and are likely to affect timely help seeking and adherence to treatment. Health systems benefit from sex-disaggregated epidemiological data complemented by cultural epidemiological study, which together clarify the role of gender and contribute to the knowledge base for TB control at various levels.

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.

The influence of human leukocyte antigens (HLA) on the immune response is well established. We investigated the regulatory role of HLA-DRB1 alleles on cytokine response to live M. tuberculosis and its culture filtrate antigen (CFA) in normal healthy subjects (NHS) and pulmonary tuberculosis (PTB) patients. Th1 (IFN-gamma and IL-12p40), Th2 (IL-4 and IL-5), pro-inflammatory (IL-6 and IL-8) and anti-inflammatory (TGF-beta and IL-10) cytokines were measured by ELISA in 72-h-old peripheral blood mononuclear cell culture supernatants from 58 NHS and 48 PTB patients. HLA-DRB1 genotyping was carried out by polymerase chain reaction and dot-blot hybridization with biotinylated sequence-specific oligonucleotide probes and detection by chemiluminescence. In response to live M. tuberculosis and CFA, significantly increased levels of IL-6, IL-8 and TGF-beta and decreased IFN-gamma, IL-12p40 and IL-10 were seen in PTB patients compared to NHS. We observed a significantly increased IFN-gamma response in HLA-DRB1*03-positive NHS (p=0.03) and decreased IFN-gamma response in HLA-DRB1*15-positive patients (p=0.04) than respective allele-negative individuals. An increased level of IL-12p40 in DRB1*10 (p=0.02) and IL-10 in DRB1*12- (p=0.03) positive NHS and an increased level of IL-6 in DRB1*04- (p=0.02) positive patients were observed. The study suggests that HLA-DRB1 alleles differentially modulate the various cytokine responses to M. tuberculosis antigens, which may influence the cellular and humoral immune responses to M. tuberculosis infection in a susceptible host.

1, 25 Dihydroxyvitamin D(3) (1, 25(OH)(2) D(3)) has gained significant importance in tuberculosis with regard to its immunoregulatory activities. Our aim was to evaluate the effect of 1, 25(OH)(2) D(3) on cytokine response to Mycobacterium tuberculosis antigens in pulmonary tuberculosis. Peripheral blood mononuclear cells obtained from 60 healthy controls and 52 pulmonary tuberculosis patients were cultured with culture filtrate antigen (CFA) of M. tuberculosis and live M. tuberculosis with and without 1, 25(OH)(2) D(3) (10(-9), 10(-8)and 10(-7)M concentrations). The culture supernatants were used to estimate IL-8, IL-6, TGF-beta, IL-10, IFN-gamma, IL-12p40, IL-2, IL-4 and IL-5 levels by ELISA. 1, 25 Dihydroxyvitamin D(3) significantly suppressed IL-12p40 and IFN-gamma production in response to CFA and live M. tuberculosis with a maximum suppression at 10(-7)M concentration (p<0.0001). In CFA stimulated cultures, addition of 1, 25(OH)(2) D(3) significantly suppressed IL-8, IL-6 and IL-10 whereas the IL-2 levels were significantly increased in controls. It variably influenced the Th2 cytokines, showing an increased trend for IL-4 and suppressed IL-5 levels. We report that 1, 25(OH)(2) D(3) differentially modulates production of cytokines in response to M. tuberculosis antigens by predominantly suppressing IL-12p40 and IFN-gamma production in a dose dependent manner. Our results suggest a role for vitamin D in restricting acquired immune response against tuberculosis by regulating cytokine production.

Perforin is one of the key effector molecules of cytotoxic T cells and natural killer cells. The influence of HLA-DRB1 alleles on peripheral blood perforin-positive CD4, CD8, CD16 and CD 56 cells was studied by flow cytometry. HLA-DRB1 typing was done in normal healthy subjects (NHS: n = 156) and patients with pulmonary tuberculosis (PTB: n = 102) by polymerase chain reaction-based sequence-specific oligonucleotide hybridization method. We observed a significantly decreased percentage of total perforin-positive cells (per(+)) (P = 0.0004); CD8(+)/Per(+) (P = 0.0005); CD16(+)/Per(+) (P = 0.05) and CD 56(+)/Per(+) cells (P = 0.001) in HLA-DR2-positive PTB patients compared to non-DR2 patients. Subtyping of HLA-DR2-positive subjects at the allelic level revealed that the percentage of CD8(+)/Per(+) cells did not differ among DRB1*1501 and DRB1*1502 patients while a trend towards a decreased percentage of CD16(+)/Per(+) and CD 56(+)/Per(+) cells was noticed in DRB1*1501 patients compared to DRB1*1502 patients. The present study suggests that HLA-DR2 may be associated with down-regulation of perforin-positive cytotoxic lymphocytes and natural killer cells 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.

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.

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.

Mannose-binding lectin (MBL) plays an important role in innate immunity. Functional mutant homozygotes of the MBL gene affect the serum MBL levels and have been correlated with disease susceptibility. We have studied the regulatory role of variant MBL genotypes on serum MBL level and macrophage phagocytosis with live Mycobacterium tuberculosis, and the lymphoproliferative response to M. tuberculosis culture filtrate antigen in pulmonary tuberculosis (PTB) patients (n = 48) and normal healthy subjects (NHS) (n = 58). The total serum MBL level was higher in PTB patients than in NHS (P = 0.0085). Patients and NHS with AA genotype (homozygotes of MBL - common alleles) showed a very high serum MBL level, and those with OO genotype (functional mutant homozygotes of MBL - less frequent alleles) showed a very low MBL level (AA vs. OO: NHS, P = 3.3 x 10(-9); PTB, P = 3.1 x 10(-9)). A significantly lower phagocytosis was observed in NHS with AA genotype than in NHS with AO (heterozygotes) genotype (P = 0.046). In PTB patients, no such difference was observed. A negative correlation of macrophage phagocytosis with MBL level was seen in patients and NHS (P = 0.019). Antigen-induced lymphoproliferative response was significantly decreased in PTB patients with AA genotype as compared with NHS with AA genotype (P = 0.036). The present study suggests that AA genotype with its associated higher serum MBL levels plays a regulatory role in immunity to tuberculosis than functional mutant homozygotes (OO genotype) with its associated lower level of MBL.

Objective: The currently recommended treatment for lymph node tuberculosis is 6 months of rifampicin and isoniazid plus pyrazinamide for the first 2 months, given either daily or thrice weekly. The objective of this study was to assess the efficacy of a 6-month twice-weekly regimen and a daily two-drug regimen., Methods: Patients with biopsy confirmed superficial lymph node tuberculosis were randomly allocated to receive either a daily self-administered 6-month regimen of rifampicin and isoniazid, or a twice-weekly, directly observed, 6-month regimen of rifampicin and isoniazid plus pyrazinamide for the first 2 months, in Madurai, South India, Patients were followed up for 36 months after completing treatment., Results: Of 277 enrolled patients, data was available for analysis in 268. At the end of treatment, 116 of 134 [87%; 95% confidence interval (CI) 81-93%] patients in each treatment group had a favourable clinical response; 14 (11%; 95% CI 6-16%) and 17 (13%; 95% CI 7-19%) patients had a doubtful response, and 4 (3%; 95% CI 0-6%) and 1 (1%; 95% CI 0-2%) patients had an unfavourable response among those treated with the daily and twice-weekly regimen, respectively. During 36 months after completion of treatment, five patients [2 (2%; 95% CI 1-3%) and 3 (2%; 95% CI 1-3%) patients treated with the daily and twice-weekly regimen, respectively] had relapse of lymph node tuberculosis, of 260 assessed. Adverse reactions probably attributable to the treatment regimens occurred in 1% of the patients treated daily and in 11% of those treated twice-weekly (P < 0.001). At the end of 36 months after treatment, 126 of 134 (94%; 95% CI 90-98%) and 129 of 134 (96%; 95% CI 94-98%) of the patients treated with the daily and twice-weekly regimen, respectively, had a successful outcome., Conclusion: Both the self-administered daily regimen and the fully observed twice-weekly regimen were highly efficacious for treating patients with lymph node tuberculosis and may be considered as alternative options to the recommended regimens.

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.

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.

The regulatory role of vitamin D receptor (VDR) gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on vitamin D(3)-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D(3) at a concentration of 1 x 10(-7) M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D(3) at 10(-9), 10(-8), and 10(-7) M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D(3) had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D(3) and modulate the immune functions to M. tuberculosis in NHS.

Immune responses are elicited through antigen presentation and recognition by macrophages and T-lymphocytes, respectively. The immunomodulatory effect of vitamin D(3) on macrophage phagocytic potential with live Mycobacterium tuberculosis, spontaneous and M. tuberculosis culture filtrate antigen induced lymphocyte responses were studied in pulmonary tuberculosis patients (PTBPs) ( n = 31) and normal healthy subjects (NHSs) ( n = 43). Vitamin D(3) at a concentration of 10(-7) M significantly enhanced the macrophage phagocytosis of live M. tuberculosis in normal subjects with low phagocytic potential (less than 10%) ( p = 0.015). No such increase was observed in PTBPs. Vitamin D(3) significantly decreased the spontaneous lymphoproliferative response ( p = 0.022) and increased the apoptosis of peripheral blood mononuclear cells in PTBPs ( p = 0.024). In normals, vitamin D(3) increased the spontaneous lymphoproliferative response. An inverse correlation between macrophage phagocytosis and spontaneous response was observed in NHSs, whereas a direct correlation was seen between vitamin D(3)-treated cells in normal subjects under in vitro condition. Vitamin D(3) decreased the M. tuberculosis culture filtrate antigen induced lymphocyte response significantly in normal subjects ( p = 0.0003), while it had no influence on the lymphocyte response in PTBPs. The present study suggests that exposure to vitamin D(3) increases the phagocytic potential and spontaneous lymphoproliferative response but brings down the antigen-induced response in normals. In tuberculosis, addition of vitamin D(3) has no significant effect on antigen-induced lymphoproliferative response. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) by virtue of the disease, which renders them inactive.

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 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.

Lymph node biopsy specimens, obtained from 297 paediatric and adult patients with tuberculous lymphadenitis at Madurai, were transported in selective Kirchner's liquid medium (KL-T) to the Tuberculosis Research Centre, Madras and processed for culture. Mycobacterium tuberculosis was isolated from 201 (68%) specimens. Of the 192 specimens received within 4 days of resection, 134 (69.8%) yielded M. tuberculosis on culture and of the 105 specimens received after 5 days, 67 (63.8%) were culture positive; the difference was not statistically significant. By incubating KL-T alone further, after removing the gland for processing, it was found that mere contact with the excised node during transportation was enough to retrieve 77 (38.3%) of the total of 201 positive isolates obtained, the delay did not affect the culture positivity rate. Thus, lymph node specimens for culture of tubercle bacilli can be stored in the refrigerator for up to 15 days and transported in KL-T at ambient temperature for 18-20 h without any loss in culture positivity.

Three radiologically and bacteriologically confirmed pulmonary tuberculosis patients had eosinophilic pneumonia, as demonstrated by BAL. In two patients, pulmonary eosinophilia was present only at the site of the lesion and the third had eosinophilia in both peripheral blood and lung. There was complete elimination of the eosinophilic inflammatory process in two patients who had successfully completed antituberculosis treatment.

A controlled study of three short-course regimens was undertaken in South Indian patients with newly diagnosed, sputum-positive pulmonary tuberculosis. The patients were allocated at random to one of three regimens: a) Rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (R3); b) the same regimen as above but followed by streptomycin, isoniazid and pyrazinamide twice-weekly for a further period of 2 months (R5); c) the same as R5 but without rifampicin (Z5). A bacteriological relapse requiring treatment occurred by 5 years in 16.8% of 113 R3, 5.2% of 97 R5, and 20.0% of 115 Z5 patients with organisms sensitive to streptomycin and isoniazid initially. The differences in the relapse rates between the R3 and R5 regimens and the R5 and Z5 regimens were statistically significant (p less than 0.01 for both). Considering patients with organisms initially resistant to streptomycin or isoniazid or both, 7 of 52 patients (4 R3, 2 R5, 1 Z5) had a bacteriological relapse requiring retreatment.

Objective: To assess the efficacy of a short course chemotherapy regimen for treating tuberculosis of the lymph nodes in children., Design: Open, collaborative, outpatient clinical trial., Setting: Outpatient department of the Tuberculosis Research Centre, paediatric surgery departments of the Institute of Child Health and Hospital for Children and the Government Stanley Hospital, Madras, South India., Patients: Children aged 1-12 years with extensive, multiple site, superficial tuberculous lymphadenitis confirmed by biopsy (histopathology or culture)., Interventions: Patients were treated with a fully supervised intermittent chemotherapy regimen consisting of streptomycin, rifampicin, isoniazid, and pyrazinamide three times a week for two months followed by streptomycin and isoniazid twice a week for four months on an outpatient basis. Surgery was limited to biopsy of nodes for diagnosis and assessment., Main Outcome Measures: Response to chemotherapy was assessed by regression of lymph nodes and healing of sinuses and abscesses during treatment and follow up. Compliance with treatment and frequency of adverse reactions were also estimated., Results: 197 Patients were admitted to the study and 168 into the analysis. The regimen was well tolerated and compliance was good with 101 (60%) patients receiving the prescribed chemotherapy within 15 days of the stipulated period of six months. Those whose chemotherapy extended beyond that period received the same total number of doses. Clinical response was favourable in most patients at the end of treatment. Sinuses and abscesses healed rapidly. Residual lymphadenopathy (exceeding 10 mm diameter) was present in 50 (30%) patients at the end of treatment; these nodes were biopsied. Fresh nodes, increase in size of nodes, and sinuses and abscesses occurred both during treatment and follow up. After 36 months of follow up after treatment only 5 (3%) patients required retreatment for tuberculosis., Conclusion: Tuberculous lymphadenitis in children can be successfully treated with a short course chemotherapy regimen of six months.

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.