Sub-national TB prevalence surveys in India, 2006-2012: Results of uniformly conducted data analysis.

SETTING: Community based tuberculosis (TB) prevalence surveys in ten sites across India during 2006-2012. OBJECTIVE: To re-analyze data of recent sub-national surveys using uniform statistical methods and obtain a pooled national level estimate of prevalence of TB. METHODS: Individuals ≥15 years old were screened by interview for symptoms suggestive of Pulmonary TB (PTB) and history of anti-TB treatment; additional screening by chest radiography was undertaken in five sites. Two sputum specimens were examined by smear and culture among Screen-positives. Prevalence in each site was estimated after imputing missing values to correct for bias introduced by incompleteness of data. In five sites, prevalence was corrected for non-screening by radiography. Pooled prevalence of bacteriologically positive PTB was estimated using Random Effects Model after excluding data from one site. Overall prevalence of TB (all ages, all types) was estimated by adjusting for extra-pulmonary TB and Pediatric TB. RESULTS: Of 769290 individuals registered, 715989 were screened by interview and 294532 also by radiography. Sputum specimen were examined from 50 852 individuals. Estimated prevalence of smear positive, culture positive and bacteriologically positive PTB varied between 108.4-428.1, 147.9-429.8 and 170.8-528.4 per 100000 populations in different sites. Pooled estimate of prevalence of bacteriologically positive PTB was 350.0 (260.7, 439.0). Overall prevalence of TB was estimated at 300.7 (223.7-377.5) in 2009, the mid-year of surveys. Prevalence was significantly higher in rural compared to urban areas. CONCLUSION: TB burden continues to be high in India suggesting further strengthening of TB control activities.

Sensitivity and specificity of screening tools and smear microscopy in active tuberculosis case finding.

SETTING: Community based five pulmonary tuberculosis (PTB) surveys among adults. OBJECTIVES: Estimate sensitivity and specificity of screening tools for PTB and sputum microscopy. METHODS: For each survey site, we estimated sensitivity and specificity of different screening criteria and microscopy against culture; pooled estimates were obtained using Random Effects Model. RESULTS: Sensitivity of cough alone, screening for any symptom (persistent cough ≥2 weeks, fever or chest pain ≥1 month, hemoptysis), any symptom or history of anti-TB treatment (h/o ATT) were 56.2%, 66% and 71.2% respectively; specificities were 95.3%, 93.8% and 92.7% respectively. X-ray when used alone for primary screening had sensitivity and specificity of 76.6% and 97.3% respectively. When used along with screening for cough, these figures were 94.3% and 93.1%, and 100% and 97.3% when used with any symptom and h/o ATT. When used for secondary screening, sensitivity and specificity of X-ray was 66.8% and 87.8% respectively after primary screening for cough, 65.0% and 89.8% after screening for any symptom, and 67.1% and 86.7% when used after screening for any symptom or h/o ATT. Pooled sensitivity and specificity of smear was 46.2% and 99.3% respectively. CONCLUSION: Program managers may use these estimates while evaluating algorithms for active case finding.

Tuberculosis mortality in a rural population from South India.

BACKGROUND: General mortality rate (GMR) is an essential indicator for assessing the health status of a community. Tuberculosis (TB) mortality is an indicator for the Millennium Development Goal for 2015. METHODS: This community-based retrospective survey was conducted in 2007-2008 on a sample of 114,605 rural populations living in 56 villages randomly selected from 218 villages in Tiruvallur district, South India, where the DOTS strategy was implemented in 1999. All the permanent residents of the households were registered and information on occurrence of death was recorded. All the deaths were investigated by verbal autopsy (VA) using standardized methods. RESULTS: A total of 719 deaths were registered. The GMR and tuberculosis mortality rate (TMR) were 648 (95% CI: 568-727) and 39 (95% CI: 25-52) per 100,000 p-yrs, respectively. The GMR increased with age, and was higher in males than females at all ages. The TMR was higher in males than females and the overall male:female ratio was 5:1. CONCLUSION: TB was the 6th leading cause of death overall and the 2nd leading cause among men in this area. Strategies to reduce TB death should be implemented and the impact should be monitored by repeat VA studies.

General and tuberculosis mortality in two states of India: A population-based survey.

BACKGROUND: General and cause-specific mortality data for causes of death are not available for the states of Andhra Pradesh (AP) and Orissa in India. OBJECTIVES: To estimate general mortality rate (GMR) and the tuberculosis mortality rate (TMR) among the general population in the two states. METHODS: All permanent residents in households of selected districts of AP and Orissa states were registered in the survey in 2005-2006. A sample size of 380,000 persons was selected from each state. Health workers carried out house-to-house enumeration. Demographic and occurrence of death data were collected. The cause of death was determined using the instrument of verbal autopsy. RESULTS: The GMR for AP and Orissa was 636 (95% CI: 610-662) and 616 (95% CI: 588-643) per 100,000 person years (p-ys) respectively. The TMR for AP and Orissa was 76 (95% CI: 67-85) and 41 (95% CI: 34-48) per 100,000 p-ys respectively. The difference in TMR between the states was statistically significant (P<0.0001). CONCLUSION: The GMRs are similar in AP and Orissa states. Tuberculosis accounted for 12% and 7% of deaths in AP and Orissa respectively. Focused strategies are needed to reduce mortality due to tuberculosis.

Could repeated prevalence surveys lead to decreasing tuberculosis prevalence in a community?

SETTING: Tiruvallur District, South India, where one baseline tuberculosis (TB) disease prevalence survey followed by three repeat prevalence surveys were conducted every 2.5 years between 1999 and 2008, and where the DOTS strategy was implemented in 1999. OBJECTIVE: To rule out the possibility that the observed decline in TB prevalence was influenced by conducting repeat prevalence surveys, we compared the findings from two surveys: the third repeat survey conducted in 2006-2008 and an independent single survey in a neighbouring area conducted in 2008-2009. DESIGN: An independent survey was conducted to estimate the prevalence of TB in the same district in 2008-2009 using a different set of villages and employing repeat survey methodology. The independent survey findings were compared with those of the third repeat survey. RESULTS: The estimated prevalence rate of culture- and smear-positive TB was respectively 401 per 100,000 and 186 per 100,000 population in the third repeat survey area. The corresponding rates were 340 and 184/100,000 in the independent survey area. The difference in prevalence was not significant (culture P = 0.09; smear P = 0.93). CONCLUSION: The estimated prevalence rates in the two different sample survey areas were comparable, indicating that the repeated prevalence surveys in the study area did not influence the observed decline in TB disease prevalence.

Trends in the prevalence of pulmonary tuberculosis over a period of seven and half years in a rural community in south India with DOTS.

SETTING: Tiruvallur district In Tamil Nadu where DOTS was implemented by the State Government as the tuberculosis control measure in 1999, and monitored by the National Institute for Research in Tuberculosis for over five years. OBJECTIVE: To estimate trends in TB prevalence in a rural community with DOTS. DESIGN: Surveys of pulmonary tuberculosis were undertaken in representative samples of subjects aged > or =15 years (N = 83,000 - 92,000), initially and after two and half, five and seven and half years of implementation of DOTS. Sputa were collected from those with abnormal radiograph and/or presence of chest symptoms, and examined by direct smear and culture. RESULTS: The prevalence of culture-positive tuberculosis was 607, 454, 309 and 388 per 100,000 in the four surveys, and that of smear-positive tuberculosis was 326, 259, 168 and 180. In the first five years; annual decrease was 12.4% (95% CI 10.4 - 14.4%) for culture-positive tuberculosis, and 12.2% (95% CI 8.0-16.2) for smear-positive tuberculosis. This was, however, followed by a significant increase in the next two and half years. The average new smear-positive case-notification rate was 75 per 100,000 during first four years but declined to 49 in subsequent years. There were no methodological differences during this period and information on changes in socio-economic indicators and nutritional standards was unavailable. CONCLUSION: Despite the average annual success rate (78%) in this tuberculosis unit being lower than the expected rate of 85%, the implementation of DOTS was followed by a substantial decrease in the prevalence of pulmonary tuberculosis over the seven and half year period. Our findings suggest that sustaining the high effectiveness of DOTS programme needs vigilant supervision.

Trend in tuberculosis infection prevalence in a rural area in South India after implementation of the DOTS strategy.

SETTING: Three tuberculin surveys were conducted at intervals of 5 years following the implementation of a DOTS-based programme in 1999 in Tiruvallur District, South India. OBJECTIVE: To estimate the trend in the prevalence of tuberculosis (TB) infection among children and to evaluate the impact of the DOTS strategy. METHODS: Children aged 1-9 years in the sample for each survey were registered and administered 1 tuberculin unit of purified protein derivative RT 23 with Tween 80 by intradermal injection on the volar aspect of the left forearm. The induration diameter of the reaction was measured in mm after 72 h (3 days) and the prevalence of TB infection estimated. RESULTS: The induration data of bacille Calmette-Guérin (BCG) vaccinated and non-vaccinated children were analysed using the mixture model. The estimated prevalence of TB infection among non-BCG-vaccinated children in the three tuberculin surveys were respectively 19.4%, 13.8% and 11.4%, with an average annual decline of 5.2% (95%CI 3.6-6.8). The prevalence of TB infection among BCG-vaccinated children decreased, with an average annual decline of 5.4% (95%CI 10.0-18.6). CONCLUSION: A significant declining trend in the prevalence of TB infection among children was observed following the implementation of the DOTS strategy in the area.

Attenuation of toll-like receptor expression and function in latent tuberculosis by coexistent filarial infection with restoration following antifilarial chemotherapy.

Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen-stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans.

Human type 1 and 17 responses in latent tuberculosis are modulated by coincident filarial infection through cytotoxic T lymphocyte antigen-4 and programmed death-1.

Mycobacterium tuberculosis and filarial coinfection is highly prevalent, and the presence of a tissue-invasive helminth may modulate the predominant type 1 T helper (Th1; interferon [IFN]-gamma-mediated) response needed to control M. tuberculosis infection. By analyzing the cellular responses to mycobacterial antigens in patients who had latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with M. tuberculosis infection significantly diminishes M. tuberculosis-specific Th1 (interleukin [IL]-12 and IFN-gamma) and type 17 T helper (Th17; IL-23 and IL-17) responses related to increased expression of cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1. Blockade of CTLA-4 restored production of both IFN-gamma and IL-17, whereas PD-1 blockade restored IFN-gamma production only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific Th1 and Th17 responses in latent tuberculosis, suggesting a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans.

Association between biomass fuel and pulmonary tuberculosis: a nested case-control study.

OBJECTIVE: To quantify the association between biomass fuel usage and sputum-positive pulmonary tuberculosis. METHODOLOGY: A tuberculosis prevalence survey was conducted in a random sample of 50 rural units (villages) and three urban units in the Tiruvallur district of Tamilnadu, India during the period 2001-2003. Additional data regarding exposure to tobacco smoking, alcohol consumption, biomass fuel usage and Standard of Living Index (SLI) were also collected from the study participants. A nested case-control study was carried out in this population. Cases are defined as bacteriological-positive cases diagnosed by either sputum smear or culture examination. For each case, five age- (within +/-5 years of age) and sex-matched controls were selected randomly from the non-cases residing in the same village/unit. Thus, 255 cases and 1275 controls were included in this study. RESULTS: The unadjusted OR measured from univariate analysis for biomass fuel is 2.9 (95% CI 1.8 to 4.7). The adjusted OR measured from multivariate analysis using Cox regression is 1.7 (95% CI 1.0 to 2.9). Thirty-six percent of cases are attributable to biomass fuel usage. CONCLUSION: The findings from this case-control study add to the evidence for an independent association between biomass smoke and pulmonary tuberculosis. Improvement in standards of living brought about by economic development will lead to more people using cleaner fuels for cooking than biomass fuel which in turn will lead to a reduction in the occurrence of pulmonary tuberculosis in the community.

Rapid decline in prevalence of pulmonary tuberculosis after DOTS implementation in a rural area of South India.

SETTING: Tiruvallur District in Tamilnadu, South India, where the World Health Organization-recommended DOTS strategy was implemented as a tuberculosis (TB) control measure in 1999. OBJECTIVE: To assess the epidemiological impact of the DOTS strategy on the prevalence of pulmonary tuberculosis (PTB). DESIGN: Surveys of PTB were undertaken on representative population samples aged > or =15 years (n = 83000-90000), before and at 2.5 and 5 years after the implementation of the DOTS strategy. The prevalence of PTB (smear-positive/culture-positive) was estimated. RESULTS: TB prevalence declined by about 50% in 5 years, from 609 to 311 per 100000 population for culture-positive TB and from 326 to 169/100000 for smear-positive TB. The annual rate of decline was 12.6% (95%CI 11.2-14.0) for culture-positive TB and 12.3% (95%CI 8.6-15.8) for smear-positive TB. The decline was similar at all ages and for both sexes. CONCLUSION: With an efficient case detection programme and the DOTS strategy, it is feasible to bring about a substantial reduction in the burden of TB in the community.

Excess mortality and risk factors for mortality among a cohort of TB patients from rural south India.

OBJECTIVES: To estimate the excess general mortality among tuberculosis (TB) patients in a rural area (Tiruvallur) and identify risk factors for TB-related mortality. SETTING: The study population consisted of all TB patients aged >or=15 years who were registered under the Revised National Tuberculosis Control Programme (RNTCP) during the years 2000 to 2003 at Velliyur TB unit (TU) in south India. DESIGN: This is a retrospective cohort study of 3405 patients treated under the DOTS strategy, followed up from the date of start of treatment till the date of interview (for the survivors) or the date of death (for those who died). RESULTS: There were 2710 (79.6%) survivors and 695 (20.4%) deaths. The excess general mortalities for the cohort, expressed as standardised mortality ratio (SMR), was 4.2 (95%CI 3.9-4.5). High SMR values were obtained for patients belonging to the 15-44 years age group (12.1), patients on Category II regimen (9.3), treatment failures (9.1) and defaulters (7.8). The adjusted hazards ratios (aHR) were high for patients aged 45-59 years (1.9), >or=60 years (3.1) and with incomplete treatment due to default or failure (6.4). CONCLUSION: TB is one of the main causes of mortality in the younger age group. Among TB patients, the major risk factors for mortality are old age (>or=45 years) and incomplete treatment.

Comparison of tuberculin reaction sizes at 48 and 72 hours among children in Tiruvallur district, south India.

SETTING: A rural population in Tiruvallur district, south India. OBJECTIVE: To study the variability of skin test reaction sizes between 48 and 72 hours. METHODS: A tuberculin test survey was conducted among children aged less than 10 years. The reaction sizes were read by the same reader at 48 hours and 72 hours independently. The results of the tuberculin test were compared. RESULTS: Of 957 children aged below 10 years were included in the study; the male and female ratio was 1: 1.1. There were no significant differences between the readings of reaction size at 48 and 72 hours. CONCLUSION: The tuberculin test results can be read either at 48 hours or 72 hours without compromising the validity.

Selected biological and behavioural risk factors associated with pulmonary tuberculosis.

OBJECTIVES: To measure the independent association of risk factors age, sex, smoking and alcoholism with pulmonary tuberculosis (TB) in terms of prevalence odds ratio (POR). METHOD: A community-based cross-sectional survey was conducted from June 2001 to December 2003. A total of 93945 individuals aged > or = 15 years selected from a random sample of villages in a district from South India were screened for pulmonary TB by chest symptoms and chest X-ray (MMR). Two sputum samples were collected (one spot and one early morning) from patients with chest symptoms and those with abnormal X-rays for examination by microscopy for acid-fast bacilli and by culture for Mycobacterium tuberculosis. Bacillary cases are bacteriologically positive cases diagnosed by either sputum smear or culture examination. In addition, data on exposure to tobacco smoking and alcohol consumption were collected from the male population only. All females were considered non-smokers and non-alcoholics. RESULTS: A total of 429 bacteriologically positive cases were detected during the survey. The adjusted PORs (with 95%CI) for age, sex, smoking and alcoholism were 3.3 (2.7-4.1), 2.5 (1.9-3.3), 2.1 (1.7-2.7) and 1.5 (1.2-2.0), respectively. CONCLUSION: Risk factors such as age, sex, smoking and alcoholism are independently associated with pulmonary TB. Risk factors age and sex show a stronger association than smoking and alcoholism.

Mortality of tuberculosis patients in Chennai, India.

OBJECTIVE: We aimed to measure the mortality rate and excess general mortality as well as identify groups at high risk for mortality among a cohort of tuberculosis patients treated in Chennai Corporation clinics in south India. METHODS: In this retrospective cohort study we followed up 2674 patients (1800 males and 874 females) who were registered and treated under the DOTS strategy in Chennai Corporation clinics in 2000. The follow-up period from the date of start of treatment to either the date of interview, or death was 600 days. FINDINGS: The mortality rate among this cohort of tuberculosis patients was 60/1000 person-years. The excess general mortality expressed as standardized mortality ratio (SMR) was 6.1 (95% confidence interval (CI)=5.4-6.9). Younger patients, men, patients with Category II disease, patients who defaulted on, or failed courses of treatment, and male smokers who were alcoholics, all had higher mortality ratios when compared to the rest of the cohort. CONCLUSION: The excess mortality in this cohort was six times more than that in the general population. Young age, male sex, smear-positivity, treatment default, treatment failure and the combination of smoking and alcoholism were identified as risk factors for tuberculosis mortality. We suggest that mortality rate and excess mortality be routinely used as a monitoring tool for evaluating the efficiency of the national control programme.

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence.

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.

Estimation of burden of tuberculosis in India for the year 2000.

BACKGROUND AND OBJECTIVE: Data on the burden of tuberculosis (TB) in India are vital for programme planners to plan the resource requirements and for monitoring the nation-wide TB control programme. There was a need to revise the earlier estimate on the burden of TB in India based on the increase in population and current epidemiological data. This study estimates the burden of disease for the year 2000 based on recent prevalence of TB and annual risk of tuberculosis infection (ARTI) estimates. METHODS: Data on prevalence generated among adults by the Tuberculosis Research Centre (TRC), Chennai, among children by National Tuberculosis Institute (NTI), Bangalore, and the ARTI estimates from the nation-wide sample survey by NTI and TRC were used for the estimation. The prevalence of disease corresponding to 1 per cent ARTI was extrapolated to different parts of the country using the estimates of ARTI and the population in those areas and added together to get the total cases. Abacillary cases that required treatment were estimated from X-ray abnormals. The estimates of bacillary, abacillary and extrapulmonary cases were then combined to get the national burden. RESULTS: The estimated number of bacillary cases was 3.8 million (95% CI: 2.8-4.7). The number of abacillary cases was estimated to be 3.9 million and that for extrapulmonary cases was 0.8 million giving a total burden of 8.5 million (95% CI: 6.3-10.4) for 2000. INTERPRETATION AND CONCLUSION: The present estimate differs from the earlier estimates because we have included the disease burden of X-ray cases that are likely to breakdown to bacillary cases in a one year period, and extrapulmonary TB cases. The current estimates provided baseline information for advocacy and planning resource allocation for TB control activities. Also, these estimates can be compared with that in future years to measure the long term impact of TB control activities in India.

Estimation of annual risk of tuberculosis infection (ARTI) among children aged 1-9 years in the south zone of India.

OBJECTIVE: To estimate the annual risk of tuberculosis infection (ARTI) among children aged 1-9 years in the south zone of India. SETTING: The survey was carried out in a representative sample of villages and census enumeration blocks of towns in four south Indian states, as a part of a nationwide tuberculin survey. DESIGN: Six districts were selected through systematic random sampling. Four hundred and twenty rural clusters and 180 urban clusters were selected from these districts on the basis of the rural-urban ratio in the entire zone. To obtain the required sample of 12,000 children without bacille Calmette-Guérin (BCG) vaccination, 51,000 had to be covered. Eighty-five children from each cluster were tuberculin tested and read for reaction sizes. The ARTI was computed from the estimated prevalence of TB infection among children without a BCG scar. RESULT: Among 52,951 children registered for the study, 50,846 (96%) had a tuberculin test result. The BCG coverage for the study population was about 65%. Among 17,811 children without a BCG scar, the prevalence of infection was 5.9% (95%CI 4.0-7.7%); the corresponding ARTI was 1.0% (95%CI 0.7-1.4%) [correction]. CONCLUSION: The estimated ARTI for the south zone is 1.0%, as compared to the national average of 1.7% used for programme evaluation. This baseline information should be useful for the assessment of future trends.