Structural Basis for Catalysis of a Tetrameric Class IIa Fructose 1,6-Bisphosphate Aldolase from Mycobacterium tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pegan, Scott D.; Ruskseree, Kamolchanok; Franzblau, Scott G.

2009-03-04

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), currently infects one-third of the world's population in its latent form. The emergence of multidrug-resistant and extensive drug-resistant strains has highlighted the need for new pharmacological targets within M. tuberculosis. The class IIa fructose 1,6-bisphosphate aldolase (FBA) enzyme from M. tuberculosis (MtFBA) has been proposed as one such target since it is upregulated in latent TB. Since the structure of MtFBA has not been determined and there is little information available on its reaction mechanism, we sought to determine the X-ray structure of MtFBA in complex with its substrates. By lowering themore » pH of the enzyme in the crystalline state, we were able to determine a series of high-resolution X-ray structures of MtFBA bound to dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, and fructose 1,6-bisphosphate at 1.5, 2.1, and 1.3 {angstrom}, respectively. Through these structures, it was discovered that MtFBA belongs to a novel tetrameric class of type IIa FBAs. The molecular details at the interface of the tetramer revealed important information for better predictability of the quaternary structures among the FBAs based on their primary sequences. These X-ray structures also provide interesting and new details on the reaction mechanism of class II FBAs. Substrates and products were observed in geometries poised for catalysis; in addition, unexpectedly, the hydroxyl-enolate intermediate of dihydroxyacetone phosphate was also captured and resolved structurally. These concise new details offer a better understanding of the reaction mechanisms for FBAs in general and provide a structural basis for inhibitor design efforts aimed at this class of enzymes.« less

Structural basis for catalysis of a tetrameric, class IIa fructose 1,6-bisphosphate aldolase from M. tuberculosis

PubMed Central

Pegan, Scott D.; Rukseree, Kamolchanok; Franzblau, Scott G.; Mesecar, Andrew D.

2009-01-01

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), currently infects one third of the world’s population in its latent form. The emergence of multidrug resistant strains, MDR-TB and XDR-TB has highlighted the need for new pharmacological targets within M. tuberculosis. The Class IIa fructose 1,6-bisphosphate aldolase (FBA) enzyme from M. tuberculosis (MtFBA) has been proposed as one such target since its upregulated in latent TB. Since the structure of MtFBA had not been determined and since there was little information available on its reaction mechanism, we sought to determine the X-ray structure of MtFBA in complex with its substrates. By lowering the pH of the enzyme in the crystalline state, we were able to determine a series of high-resolution X-ray structures of MtFBA bound to dihydroxyacetonephosphate (DHAP), glyceraldehyde-3-phosphate (G3P), and fructose 1,6-bisphosphate (FBP) at 1.5 Å, 2.1 Å, and 1.3 Å respectively. Through these structures it was discovered that MtFBA belongs to a novel tetrameric class of the type IIa FBAs. The molecular details at the interface of the tetramer revealed important information for being able to better predict the quaternary structures among the FBAs based on their primary sequences. These X-ray structures also provide interesting and new details on the reaction mechanism of class II FBAs. Not only were the substrates and products observed in geometries poised for catalysis, but unexpectedly the hydroxyl enolate intermediate of DHAP was also captured and resolved structurally. These concise new details provide a better understanding of the reaction mechanisms for FBAs in general and provide a structural basis for inhibitor design efforts aimed at this class of enzymes. PMID:19167403

Tackling TB in low-incidence countries: improving diagnosis and management in vulnerable populations.

PubMed

Heuvelings, C C; de Vries, S G; Grobusch, M P

2017-03-01

In low tuberculosis incidence regions, tuberculosis is mainly concentrated among hard-to-reach populations like migrants, homeless people, drug or alcohol abusers, prisoners and people living with HIV. To be able to eliminate tuberculosis from these low incidence regions tuberculosis screening and treatment programs should focus on these hard-to-reach populations. Here we discuss the barriers and facilitators of health care-seeking, interventions improving tuberculosis screening uptake and interventions improving treatment adherence in these hard-to-reach populations. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Drug Resistance and Population Structure of Mycobacterium tuberculosis Beijing Strains Isolated in Poland.

PubMed

Kozińska, Monika; Augustynowicz-Kopeć, Ewa

2015-01-01

In total, 1095 Mycobacterium tuberculosis clinical isolates from 282 patients with drug-resistant and 813 with drug-sensitive tuberculosis (TB) in Poland during 2007-2011 were analysed. Seventy-one (6.5%) patients were found to have strains of Beijing genotype as defined by spoligotyping. The majority of patients were Polish-born; among foreign-born a large proportion came from Chechnya and Vietnam. Analysis showed strong associations between Beijing genotype infection and MDR, pre-XDR and XDR resistance, with a considerable relative risk among new patients, suggesting that this is due to increased spread of drug-resistant strains rather than acquisition of resistance during treatment.

Community knowledge, attitudes and practices in relation to tuberculosis in Cameroon.

PubMed

Kwedi Nolna, S; Kammogne, I D; Ndzinga, R; Afanda, B; Ntonè, R; Boum, Y; Nolna, D

2016-09-01

With 15 080 new cases in 2013, Cameroon is a country with high tuberculosis (TB) incidence and prevalence. Understanding the community's knowledge, attitude and practice (KAP) about TB is key to TB control in such endemic settings. To assess TB-related KAP in Cameroon by describing the sociodemographics of respondents, to identify barriers to seeking care and to explore attitudes and experiences of stigma and discrimination related to TB in communities. We conducted a cross-sectional descriptive study using structured questionnaires to assess and compare TB KAP in the entire territory. The results showed that Cameroonians have insufficient understanding of TB, numerous erroneous health assumptions and beliefs concerning TB, and erroneous information about the symptoms and mode of transmission of the disease. Negative attitudes and poor practices are obstacles to elimination and control efforts. The National Tuberculosis Control Programme should generate more effective strategies to reach the populations, paying particular attention to rural populations.

Molecular epidemiology of tuberculosis in foreign-born persons living in San Francisco.

PubMed

Suwanpimolkul, Gompol; Jarlsberg, Leah G; Grinsdale, Jennifer A; Osmond, Dennis; Kawamura, L Masae; Hopewell, Philip C; Kato-Maeda, Midori

2013-05-01

In San Francisco, 70% of the tuberculosis cases occur among foreign-born persons, mainly from China, the Philippines, and Mexico. We postulate that there are differences in the characteristics and risk factors for tuberculosis among these populations. To determine the clinical, epidemiological and microbiological characteristics of tuberculosis caused by recent infection and rapid evolution in the major groups of foreign-born and the U.S.-born populations. We analyzed data from a 20-year prospective community-based study of the molecular epidemiology of tuberculosis in San Francisco. We included all culture-positive tuberculosis cases in the City during the study period. We calculated and compared incidence rates, clinical and microbiological characteristics, and risk factors for being a secondary case between the various foreign-born and U.S.-born tuberculosis populations. Between 1991 and 2010, there were 4,058 new cases of tuberculosis, of which 1,226 (30%) were U.S.-born and 2,832 (70%) were foreign-born. A total of 3,278 (81%) were culture positive, of which 2,419 (74%) had complete data for analysis. The incidence rate, including the incidence rate of tuberculosis due to recent infection and rapid evolution, decreased significantly in the U.S.-born and the major foreign-born populations. The clinical and microbiological characteristics and the risk factors for tuberculosis due to recent infection differed among the groups. There are differences in the characteristics and the risk factors for tuberculosis due to recent transmission among the major foreign-born and U.S.-born populations in San Francisco. These differences should be considered for the design of targeted tuberculosis control interventions.

The epidemic of Tuberculosis on vaccinated population

NASA Astrophysics Data System (ADS)

Syahrini, Intan; Sriwahyuni; Halfiani, Vera; Meurah Yuni, Syarifah; Iskandar, Taufiq; Rasudin; Ramli, Marwan

2017-09-01

Tuberculosis is an infectious disease which has caused a large number of mortality in Indonesia. This disease is caused by Mycrobacterium tuberculosis. Besides affecting lung, this disease also affects other organs such as lymph gland, intestine, kidneys, uterus, bone, and brain. This article discusses the epidemic of tuberculosis through employing the SEIR model. Here, the population is divided into four compartments which are susceptible, exposed, infected and recovered. The susceptible population is further grouped into two which are vaccinated group and unvaccinated group. The behavior of the epidemic is investigated through analysing the equilibrium of the model. The result shows that administering vaccine to the susceptible population contributes to the reduction of the tuberculosis epidemic rate.

Molecular Epidemiology of Tuberculosis in Foreign-Born Persons Living in San Francisco

PubMed Central

Suwanpimolkul, Gompol; Jarlsberg, Leah G.; Grinsdale, Jennifer A.; Osmond, Dennis; Kawamura, L. Masae; Hopewell, Philip C.

2013-01-01

Rationale: In San Francisco, 70% of the tuberculosis cases occur among foreign-born persons, mainly from China, the Philippines, and Mexico. We postulate that there are differences in the characteristics and risk factors for tuberculosis among these populations. Objectives: To determine the clinical, epidemiological and microbiological characteristics of tuberculosis caused by recent infection and rapid evolution in the major groups of foreign-born and the U.S.-born populations. Methods: We analyzed data from a 20-year prospective community-based study of the molecular epidemiology of tuberculosis in San Francisco. We included all culture-positive tuberculosis cases in the City during the study period. Measurements and Main Results: We calculated and compared incidence rates, clinical and microbiological characteristics, and risk factors for being a secondary case between the various foreign-born and U.S.-born tuberculosis populations. Between 1991 and 2010, there were 4,058 new cases of tuberculosis, of which 1,226 (30%) were U.S.-born and 2,832 (70%) were foreign-born. A total of 3,278 (81%) were culture positive, of which 2,419 (74%) had complete data for analysis. The incidence rate, including the incidence rate of tuberculosis due to recent infection and rapid evolution, decreased significantly in the U.S.-born and the major foreign-born populations. The clinical and microbiological characteristics and the risk factors for tuberculosis due to recent infection differed among the groups. Conclusions: There are differences in the characteristics and the risk factors for tuberculosis due to recent transmission among the major foreign-born and U.S.-born populations in San Francisco. These differences should be considered for the design of targeted tuberculosis control interventions. PMID:23471470

Genomic epidemiology of Lineage 4 Mycobacterium tuberculosis subpopulations in New York City and New Jersey, 1999-2009.

PubMed

Brown, Tyler S; Narechania, Apurva; Walker, John R; Planet, Paul J; Bifani, Pablo J; Kolokotronis, Sergios-Orestis; Kreiswirth, Barry N; Mathema, Barun

2016-11-21

Whole genome sequencing (WGS) has rapidly become an important research tool in tuberculosis epidemiology and is likely to replace many existing methods in public health microbiology in the near future. WGS-based methods may be particularly useful in areas with less diverse Mycobacterium tuberculosis populations, such as New York City, where conventional genotyping is often uninformative and field epidemiology often difficult. This study applies four candidate strategies for WGS-based identification of emerging M. tuberculosis subpopulations, employing both phylogenomic and population genetics methods. M. tuberculosis subpopulations in New York City and New Jersey can be distinguished via phylogenomic reconstruction, evidence of demographic expansion and subpopulation-specific signatures of selection, and by determination of subgroup-defining nucleotide substitutions. These methods identified known historical outbreak clusters and previously unidentified subpopulations within relatively monomorphic M. tuberculosis endemic clone groups. Neutrality statistics based on the site frequency spectrum were less useful for identifying M. tuberculosis subpopulations, likely due to the low levels of informative genetic variation in recently diverged isolate groups. In addition, we observed that isolates from New York City endemic clone groups have acquired multiple non-synonymous SNPs in virulence- and growth-associated pathways, and relatively few mutations in drug resistance-associated genes, suggesting that overall pathoadaptive fitness, rather than the acquisition of drug resistance mutations, has played a central role in the evolutionary history and epidemiology of M. tuberculosis subpopulations in New York City. Our results demonstrate that some but not all WGS-based methods are useful for detection of emerging M. tuberculosis clone groups, and support the use of phylogenomic reconstruction in routine tuberculosis laboratory surveillance, particularly in areas with relatively less diverse M. tuberculosis populations. Our study also supports the use of wider-reaching phylogenomic and population genomic methods in tuberculosis public health practice, which can support tuberculosis control activities by identifying genetic polymorphisms contributing to epidemiological success in local M. tuberculosis populations and possibly explain why certain isolate groups are apparently more successful in specific host populations.

Tea Drinking and Its Association with Active Tuberculosis Incidence among Middle-Aged and Elderly Adults: The Singapore Chinese Health Study

PubMed Central

Soh, Avril Zixin; Pan, An; Chee, Cynthia Bin Eng; Wang, Yee-Tang; Yuan, Jian-Min; Koh, Woon-Puay

2017-01-01

Experimental studies showed that tea polyphenols may inhibit growth of Mycobacterium tuberculosis. However, no prospective epidemiologic study has investigated tea drinking and the risk of active tuberculosis. We investigated this association in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese aged 45–74 years recruited between 1993 and 1998 in Singapore. Information on habitual drinking of tea (including black and green tea) and coffee was collected via structured questionnaires. Incident cases of active tuberculosis were identified via linkage with the nationwide tuberculosis registry up to 31 December 2014. Cox proportional hazard models were used to estimate the relation of tea and coffee consumption with tuberculosis risk. Over a mean 16.8 years of follow-up, we identified 1249 incident cases of active tuberculosis. Drinking either black or green tea was associated with a dose-dependent reduction in tuberculosis risk. Compared to non-drinkers, the hazard ratio (HR) (95% confidence interval (CI)) was 1.01 (0.85–1.21) in monthly tea drinkers, 0.84 (0.73–0.98) in weekly drinkers, and 0.82 (0.71–0.96) in daily drinkers (p for trend = 0.003). Coffee or caffeine intake was not significantly associated with tuberculosis risk. In conclusion, regular tea drinking was associated with a reduced risk of active tuberculosis. PMID:28587081

Tea Drinking and Its Association with Active Tuberculosis Incidence among Middle-Aged and Elderly Adults: The Singapore Chinese Health Study.

PubMed

Soh, Avril Zixin; Pan, An; Chee, Cynthia Bin Eng; Wang, Yee-Tang; Yuan, Jian-Min; Koh, Woon-Puay

2017-05-25

Experimental studies showed that tea polyphenols may inhibit growth of Mycobacterium tuberculosis . However, no prospective epidemiologic study has investigated tea drinking and the risk of active tuberculosis. We investigated this association in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese aged 45-74 years recruited between 1993 and 1998 in Singapore. Information on habitual drinking of tea (including black and green tea) and coffee was collected via structured questionnaires. Incident cases of active tuberculosis were identified via linkage with the nationwide tuberculosis registry up to 31 December 2014. Cox proportional hazard models were used to estimate the relation of tea and coffee consumption with tuberculosis risk. Over a mean 16.8 years of follow-up, we identified 1249 incident cases of active tuberculosis. Drinking either black or green tea was associated with a dose-dependent reduction in tuberculosis risk. Compared to non-drinkers, the hazard ratio (HR) (95% confidence interval (CI)) was 1.01 (0.85-1.21) in monthly tea drinkers, 0.84 (0.73-0.98) in weekly drinkers, and 0.82 (0.71-0.96) in daily drinkers ( p for trend = 0.003). Coffee or caffeine intake was not significantly associated with tuberculosis risk. In conclusion, regular tea drinking was associated with a reduced risk of active tuberculosis.

Decline in tuberculosis among Mexico-born persons in the United States, 2000-2010.

PubMed

Baker, Brian J; Jeffries, Carla D; Moonan, Patrick K

2014-05-01

In 2010, Mexico was the most common (22.9%) country of origin for foreign-born persons with tuberculosis in the United States, and overall trends in tuberculosis morbidity are substantially influenced by the Mexico-born population. To determine the risk of tuberculosis disease among Mexico-born persons living in the United States. Using data from the U.S. National Tuberculosis Surveillance System and the American Community Survey, we examined tuberculosis case counts and case rates stratified by years since entry into the United States and geographic proximity to the United States-Mexico border. We calculated trends in case rates over time measured by average annual percent change. The total tuberculosis case count (-14.5%) and annual tuberculosis case rate (average annual percent change -5.1%) declined among Mexico-born persons. Among those diagnosed with tuberculosis less than 1 year since entry into the United States (newly arrived persons), there was a decrease in tuberculosis cases (-60.4%), no change in tuberculosis case rate (average annual percent change of 0.0%), and a decrease in population (-60.7%). Among those living in the United States for more than 5 years (non-recently arrived persons), there was an increase in tuberculosis cases (+3.4%), a decrease in tuberculosis case rate (average annual percent change of -4.9%), and an increase in population (+62.7%). In 2010, 66.7% of Mexico-born cases were among non-recently arrived persons, compared with 51.1% in 2000. Although border states reported the highest proportions (>15%) of tuberculosis cases that were Mexico-born, the highest Mexico-born-specific tuberculosis case rates (>20/100,000 population) were in states in the eastern and southeastern regions of the United States. The decline in tuberculosis morbidity among Mexico-born persons may be attributed to fewer newly arrived persons from Mexico and lower tuberculosis case rates among non-recently arrived Mexico-born persons. The extent of the decline was dampened by an unchanged tuberculosis case rate among newly arrived persons from Mexico and a large increase in the non-recently arrived Mexico-born population. If current trends continue, tuberculosis morbidity among Mexico-born persons will be increasingly driven by those who have been living in the United States for more than 5 years.

Decline in Tuberculosis among Mexico-Born Persons in the United States, 2000–2010

PubMed Central

Baker, Brian J.; Jeffries, Carla D.; Moonan, Patrick K.

2016-01-01

Background In 2010, Mexico was the most common (22.9%) country of origin for foreign-born persons with tuberculosis in the United States, and overall trends in tuberculosis morbidity are substantially influenced by the Mexico-born population. Objectives To determine the risk of tuberculosis disease among Mexico-born persons living in the United States. Methods Using data from the U.S. National Tuberculosis Surveillance System and the American Community Survey, we examined tuberculosis case counts and case rates stratified by years since entry into the United States and geographic proximity to the United States–Mexico border. We calculated trends in case rates over time measured by average annual percent change. Results The total tuberculosis case count (−14.5%) and annual tuberculosis case rate (average annual percent change −5.1%) declined among Mexico-born persons. Among those diagnosed with tuberculosis less than 1 year since entry into the United States (newly arrived persons), there was a decrease in tuberculosis cases (−60.4%), no change in tuberculosis case rate (average annual percent change of 0.0%), and a decrease in population (−60.7%). Among those living in the United States for more than 5 years (non-recently arrived persons), there was an increase in tuberculosis cases (+3.4%), a decrease in tuberculosis case rate (average annual percent change of −4.9%), and an increase in population (+62.7%). In 2010, 66.7% of Mexico-born cases were among non–recently arrived persons, compared with 51.1% in 2000. Although border states reported the highest proportions (>15%) of tuberculosis cases that were Mexico-born, the highest Mexico-born–specific tuberculosis case rates (>20/100,000 population) were in states in the eastern and southeastern regions of the United States. Conclusions The decline in tuberculosis morbidity among Mexico-born persons may be attributed to fewer newly arrived persons from Mexico and lower tuberculosis case rates among non–recently arrived Mexico-born persons. The extent of the decline was dampened by an unchanged tuberculosis case rate among newly arrived persons from Mexico and a large increase in the non–recently arrived Mexico-born population. If current trends continue, tuberculosis morbidity among Mexico-born persons will be increasingly driven by those who have been living in the United States for more than 5 years. PMID:24708206

An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon

PubMed Central

Sousa, Alexandra O.; Salem, Julia I.; Lee, Francis K.; Verçosa, Maria C.; Cruaud, Philippe; Bloom, Barry R.; Lagrange, Philippe H.; David, Hugo L.

1997-01-01

A survey of an emerging tuberculosis epidemic among the Yanomami Indians of the Amazonian rain forest provided a unique opportunity to study the impact of tuberculosis on a population isolated from contact with the tubercle bacillus for millennia until the mid-1960s. Within the Yanomami population, an extraordinary high prevalence of active tuberculosis (6.4% of 625 individuals clinically examined) was observed, indicating a high susceptibility to disease, even among bacille Calmette–Guérin-vaccinated individuals. Observational studies on cell-mediated and humoral immune responses of the Yanomami Indians compared with contemporary residents of the region suggest profound differences in immunological responsiveness to Mycobacterium tuberculosis infection. Among the Yanomami, a very high prevalence of tuberculin skin test anergy was found. Of patients with active tuberculosis, 46% had purified protein derivative of tuberculosis reactions <10 mm; similarly 58% of recent bacillus Calmette–Guérin vaccines exhibited skin test reactions <5 mm. The Yanomami also had higher titers of antibodies against M. tuberculosis glycolipid antigens (>70%) than the control subjects comprised of Brazilians of European descent (14%). The antibodies were mostly of the IgM isotype. Among the tuberculosis patients who also produced IgG antibodies, the titers of IgG4 were significantly higher among the Yanomami than in the control population. Although it was not possible to analyze T-cell responses or patterns of lymphokine production in vitro because of the remoteness of the villages from laboratory facilities, the results suggest that the first encounter of the Yanomami Indian population with tuberculosis engenders a diminished cell-mediated immune response and an increased production antibody responses, relative to other populations with extensive previous contact with the pathogen. These findings suggest that tuberculosis may represent a powerful selective pressure on human evolution that over centuries has shaped the nature of human immune responses to infection. PMID:9371828

An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon.

PubMed

Sousa, A O; Salem, J I; Lee, F K; Verçosa, M C; Cruaud, P; Bloom, B R; Lagrange, P H; David, H L

1997-11-25

A survey of an emerging tuberculosis epidemic among the Yanomami Indians of the Amazonian rain forest provided a unique opportunity to study the impact of tuberculosis on a population isolated from contact with the tubercle bacillus for millennia until the mid-1960s. Within the Yanomami population, an extraordinary high prevalence of active tuberculosis (6.4% of 625 individuals clinically examined) was observed, indicating a high susceptibility to disease, even among bacille Calmette-Guérin-vaccinated individuals. Observational studies on cell-mediated and humoral immune responses of the Yanomami Indians compared with contemporary residents of the region suggest profound differences in immunological responsiveness to Mycobacterium tuberculosis infection. Among the Yanomami, a very high prevalence of tuberculin skin test anergy was found. Of patients with active tuberculosis, 46% had purified protein derivative of tuberculosis reactions <10 mm; similarly 58% of recent bacillus Calmette-Guérin vaccines exhibited skin test reactions <5 mm. The Yanomami also had higher titers of antibodies against M. tuberculosis glycolipid antigens (>70%) than the control subjects comprised of Brazilians of European descent (14%). The antibodies were mostly of the IgM isotype. Among the tuberculosis patients who also produced IgG antibodies, the titers of IgG4 were significantly higher among the Yanomami than in the control population. Although it was not possible to analyze T-cell responses or patterns of lymphokine production in vitro because of the remoteness of the villages from laboratory facilities, the results suggest that the first encounter of the Yanomami Indian population with tuberculosis engenders a diminished cell-mediated immune response and an increased production antibody responses, relative to other populations with extensive previous contact with the pathogen. These findings suggest that tuberculosis may represent a powerful selective pressure on human evolution that over centuries has shaped the nature of human immune responses to infection.

The association of hyperglycaemia with prevalent tuberculosis: a population-based cross-sectional study.

PubMed

Bailey, Sarah Lou; Ayles, Helen; Beyers, Nulda; Godfrey-Faussett, Peter; Muyoyeta, Monde; du Toit, Elizabeth; Yudkin, John S; Floyd, Sian

2016-12-05

Systematic reviews suggest that the incidence of diagnosed tuberculosis is two- to- three times higher in those with diabetes mellitus than in those without. Few studies have previously reported the association between diabetes or hyperglycaemia and the prevalence of active tuberculosis and none in a population-based study with microbiologically-defined tuberculosis. Most have instead concentrated on cases of diagnosed tuberculosis that present to health facilities. We had the opportunity to measure glycaemia alongside prevalent tuberculosis. A focus on prevalent tuberculosis enables estimation of the contribution of hyperglycaemia to the population prevalence of tuberculosis. A population-based cross-sectional study was conducted among adults in 24 communities from Zambia and the Western Cape (WC) province of South Africa. Prevalent tuberculosis was defined by the presence of a respiratory sample that was culture positive for M. tuberculosis. Glycaemia was measured by random blood glucose (RBG) concentration. Association with prevalent tuberculosis was explored across the whole spectrum of glycaemia. Among 27,800 Zambian and 11,367 Western Cape participants, 4,431 (15.9%) and 1,835 (16.1%) respectively had a RBG concentration ≥7.0 mmol/L, and 405 (1.5%) and 322 (2.8%) respectively had a RBG concentration ≥11.1 mmol/L. In Zambia, the prevalence of tuberculosis was 0 · 5% (142/27,395) among individuals with RBG concentration <11.1 mmol/L and also ≥11.1 mmol/L (2/405); corresponding figures for WC were 2 · 5% (272/11,045) and 4 · 0% (13/322). There was evidence for a positive linear association between hyperglycaemia and pulmonary prevalent tuberculosis. Taking a RBG cut-off 11.1 mmol/L, a combined analysis of data from Zambian and WC communities found evidence of association between hyperglycaemia and TB (adjusted odds ratio = 2 · 15, 95% CI [1 · 17-3 · 94]). The population attributable fraction of prevalent tuberculosis to hyperglycaemia for Zambia and WC combined was 0.99% (95% CI 0 · 12%-1.85%) for hyperglycaemia with a RBG cut-off of 11.1 mmol/L. This study demonstrates an association between hyperglycaemia and prevalent tuberculosis in a large population-based survey in Zambia and Western Cape. However, assuming causation, this association contributes little to the prevalence of TB in these populations.

Relationship between human LTA4H polymorphisms and extra-pulmonary tuberculosis in an ethnic Han Chinese population in Eastern China.

PubMed

Yang, Jinghui; Chen, Jin; Yue, Jun; Liu, Lirong; Han, Min; Wang, Hongxiu

2014-12-01

Two single nucleotide polymorphisms in Leukotriene A4 hydrolase (LTA4H) gene were reported to be associated with protection from pulmonary tuberculosis in Vietnamese population. But these associations were not found in the Russians. To investigate the association of LTA4H polymorphisms with tuberculosis in a Han Chinese population in Eastern China, we genotyped 5 SNPs of LTA4H gene in 743 of pulmonary tuberculosis patients, 372 of extra-pulmonary tuberculosis patients and 888 of healthy controls individuals. The CC and TT homozygotes of rs1978331 and rs2540474 were identified to have higher rates (P < 0.01) and be risk factors in the patients with extra-pulmonary tuberculosis (OR = 1.412; 95% CI = 1.104-1.804 and(OR = 1.380; 95% CI = 1.080-1.764). However, no significant association was found between any of the SNPs and pulmonary tuberculosis. In the extra-pulmonary tuberculosis subgroups. LTA4H gene were significantly associated with tuberculous meningitis, lymph node tuberculosis, bone tuberculosis and other extra-pulmonary tuberculosis except for pleural tuberculosis. The present findings suggest that polymorphisms in the LTA4H gene may affect susceptibility to extra-pulmonary tuberculosis and change the risk of developing the disease in the Han nationality in the East China. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lipoarabinomannan and related glycoconjugates: structure, biogenesis and role in Mycobacterium tuberculosis physiology and host–pathogen interaction

PubMed Central

Mishra, Arun K; Driessen, Nicole N; Appelmelk, Ben J; Besra, Gurdyal S

2011-01-01

Approximately one third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. This bacterium has an unusual lipid-rich cell wall containing a vast repertoire of antigens, providing a hydrophobic impermeable barrier against chemical drugs, thus representing an attractive target for vaccine and drug development. Apart from the mycolyl–arabinogalactan–peptidoglycan complex, mycobacteria possess several immunomodulatory constituents, notably lipomannan and lipoarabinomannan. The availability of whole-genome sequences of M. tuberculosis and related bacilli over the past decade has led to the identification and functional characterization of various enzymes and the potential drug targets involved in the biosynthesis of these glycoconjugates. Both lipomannan and lipoarabinomannan possess highly variable chemical structures, which interact with different receptors of the immune system during host–pathogen interactions, such as Toll-like receptors-2 and C-type lectins. Recently, the availability of mutants defective in the synthesis of these glycoconjugates in mycobacteria and the closely related bacterium, Corynebacterium glutamicum, has paved the way for host–pathogen interaction studies, as well as, providing attenuated strains of mycobacteria for the development of new vaccine candidates. This review provides a comprehensive account of the structure, biosynthesis and immunomodulatory properties of these important glycoconjugates. PMID:21521247

Genetic diversity, transmission dynamics, and drug resistance of Mycobacterium tuberculosis in Luanda, Angola.

PubMed

Perdigão, João; Clemente, Sofia; Ramos, Jorge; Masakidi, Pedro; Machado, Diana; Silva, Carla; Couto, Isabel; Viveiros, Miguel; Taveira, Nuno; Portugal, Isabel

2016-12-01

Despite the important role that the African region plays in a global tuberculosis (TB) epidemiological context, many countries in the region still lack data on the prevalence of specific Mycobacterium tuberculosis strains and drug resistance. This is the case for Angola, which presently lacks any data concerning drug-resistance rates and prevalence of specific M. tuberculosis genotypes and respective population structure. In this study, we made the first characterization of the genetic diversity and drug resistance of M. tuberculosis complex strains circulating in Luanda, Angola's most important setting concerning TB epidemiology. We have analyzed 89 M. tuberculosis isolates recovered from the same number of patients. All clinical isolates were genotyped by spoligotyping and 24-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTRs). First-line drug-susceptibility testing was performed by the standard BACTEC 960 Mycobacteria Growth Indicator Tube (MGIT) procedure. We have detected 33 different spoligotype profiles corresponding to 24 different shared international types (SITs) and nine orphan profiles. SIT 20 (LAM1) was the most prevalent (n=16, 18.2%) followed by SIT 42 (LAM9; n=15, 17.1%). Overall, the M. tuberculosis population structure in this sample was dominated by LAM (64.8%) and T (33.0%) strains. Twenty-four-loci MIRU-VNTR analysis revealed that a total of 13 isolates were grouped into five distinct clusters. Drug-susceptibility testing revealed a worrying situation concerning resistance rates. Drug-susceptibility data showed that 22 (24.7%) of the 89 clinical isolates were resistant to one or more antibacillary drugs of which four (4.5%) were multidrug resistant (MDR). Drug-resistant isolates were found across distinct clades and MIRU-VNTR clusters. This first cross-sectional study conducted in Luanda, Angola, provides a framework for future studies and programmatic management of TB in Angola. We provide sufficient evidence for cluster-based transmission with a high predominance of LAM strains, with differential geographic dispersion. The moderate rate of MDR-TB found in this sample has major public health implications and highlights the need for further studies specifically focused on MDR-TB transmission. Copyright © 2016.

Multidrug-resistant tuberculosis.

PubMed

Zager, Ellen M; McNerney, Ruth

2008-01-25

With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB) has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB) that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose that inclusion of population based statistics in global surveillance data is necessary to better inform debate on the control of drug resistant tuberculosis. Re-appraisal of global MDR-TB data to include population based statistics suggests that the problem of drug resistant tuberculosis in sub-Saharan Africa is more critical than previously perceived.

Identifying socioeconomic, epidemiological and operational scenarios for tuberculosis control in Brazil: an ecological study.

PubMed

Pelissari, Daniele Maria; Rocha, Marli Souza; Bartholomay, Patricia; Sanchez, Mauro Niskier; Duarte, Elisabeth Carmen; Arakaki-Sanchez, Denise; Dantas, Cíntia Oliveira; Jacobs, Marina Gasino; Andrade, Kleydson Bonfim; Codenotti, Stefano Barbosa; Andrade, Elaine Silva Nascimento; Araújo, Wildo Navegantes de; Costa, Fernanda Dockhorn; Ramalho, Walter Massa; Diaz-Quijano, Fredi Alexander

2018-06-06

To identify scenarios based on socioeconomic, epidemiological and operational healthcare factors associated with tuberculosis incidence in Brazil. Ecological study. The study was based on new patients with tuberculosis and epidemiological/operational variables of the disease from the Brazilian National Information System for Notifiable Diseases and the Mortality Information System. We also analysed socioeconomic and demographic variables. The units of analysis were the Brazilian municipalities, which in 2015 numbered 5570 but 5 were excluded due to the absence of socioeconomic information. Tuberculosis incidence rate in 2015. We evaluated as independent variables the socioeconomic (2010), epidemiological and operational healthcare indicators of tuberculosis (2014 or 2015) using negative binomial regression. Municipalities were clustered by the k-means method considering the variables identified in multiple regression models. We identified two clusters according to socioeconomic variables associated with the tuberculosis incidence rate (unemployment rate and household crowding): a higher socioeconomic scenario (n=3482 municipalities) with a mean tuberculosis incidence rate of 16.3/100 000 population and a lower socioeconomic scenario (2083 municipalities) with a mean tuberculosis incidence rate of 22.1/100 000 population. In a second stage of clusterisation, we defined four subgroups in each of the socioeconomic scenarios using epidemiological and operational variables such as tuberculosis mortality rate, AIDS case detection rate and proportion of vulnerable population among patients with tuberculosis. Some of the subscenarios identified were characterised by fragility in their information systems, while others were characterised by the concentration of tuberculosis cases in key populations. Clustering municipalities in scenarios allowed us to classify them according to the socioeconomic, epidemiological and operational variables associated with tuberculosis risk. This classification can support targeted evidence-based decisions such as monitoring data quality for improving the information system or establishing integrative social protective policies for key populations. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Cross-sectional studies of tuberculosis prevalence in Cambodia between 2002 and 2011.

PubMed

Mao, Tan Eang; Okada, Kosuke; Yamada, Norio; Peou, Satha; Ota, Masaki; Saint, Saly; Kouet, Pichenda; Chea, Manith; Keo, Sokonth; Pheng, Sok Heng; Tieng, Sivanna; Khun, Kim Eam; Sugamoto, Tetsuhiro; Matsumoto, Hiroko; Yoshiyama, Takashi; Ito, Kunihiko; Onozaki, Ikushi

2014-08-01

To measure trends in the pulmonary tuberculosis burden between 2002 and 2011 and to assess the impact of the DOTS (directly observed treatment, short-course) strategy in Cambodia. Cambodia's first population-based nationwide tuberculosis survey, based on multistage cluster sampling, was conducted in 2002. The second tuberculosis survey, encompassing 62 clusters, followed in 2011. Participants aged 15 years or older were screened for active pulmonary tuberculosis with chest radiography and/or for tuberculosis symptoms. For diagnostic confirmation, sputum smear and culture were conducted on those whose screening results were positive. Of the 40,423 eligible subjects, 37,417 (92.6%) participated in the survey; 103 smear-positive cases and 211 smear-negative, culture-positive cases were identified. The weighted prevalences of smear-positive tuberculosis and bacteriologically-positive tuberculosis were 271 (95% confidence interval, CI: 212-348) and 831 (95% CI: 707-977) per 100,000 population, respectively. Tuberculosis prevalence was higher in men than women and increased with age. A 38% decline in smear-positive tuberculosis (P = 0.0085) was observed with respect to the 2002 survey, after participants were matched by demographic and geographical characteristics. The prevalence of symptomatic, smear-positive tuberculosis decreased by 56% (P = 0.001), whereas the prevalence of asymptomatic, smear-positive tuberculosis decreased by only 7% (P = 0.7249). The tuberculosis burden in Cambodia has declined significantly, most probably because of the decentralization of DOTS to health centres. To further reduce the tuberculosis burden in Cambodia, tuberculosis control should be strengthened and should focus on identifying cases without symptoms and in the middle-aged and elderly population.

Tuberculosis Transmission among Immigrants and Autochthonous Populations of the Eastern Province of Saudi Arabia

PubMed Central

Varghese, Bright; Supply, Philip; Shoukri, Mohammed; Allix-Beguec, Caroline; Memish, Ziad; Abuljadayel, Naila; Al-Hakeem, Raafat; AlRabiah, Fahad; Al-Hajoj, Sahal

2013-01-01

Background Eastern province of Saudi Arabia is an industrial zone with large immigrant population and high level of tuberculosis case notification among immigrants. The impact of immigration and current trends of tuberculosis transmission among immigrants and autochthonous population in the region had not been investigated so far using molecular tools. Methodology During 2009- 2011, a total of 524 Mycobacterium tuberculosis isolates were collected from the central tuberculosis reference laboratory, representing an estimated 79.2% of the culture-positive tuberculosis cases over the study period in the province. These isolates were genotyped by using 24 locus-based MIRU-VNTR typing and spoligotyping followed by first line drug susceptibility testing. The molecular clustering profiles and phylogenetic diversity of isolates were determined and compared to the geographical origins of the patients. Principle Findings Genotyping showed an overall predominance of Delhi/CAS (29.4%), EAI (23.8%) and Ghana (13.3%) lineages, with slightly higher proportions of Delhi/CAS among autochthonous population (33.3 %) and EAI (30.9%) among immigrants. Rate of any drug resistance was 20.2% with 2.5% of multi-drug resistance. Strain cluster analysis indicated 42 clusters comprising 210 isolates, resulting in a calculated recent transmission index of 32.1%. Overall shared cluster ratio was 78.6% while 75.8% were shared between autochthonous population and immigrant population with a predominance of immigrants from South east Asia (40.7%). In contrast, cross national transmission within the immigrant population was limited (24.2%). Younger age (15-30- p value-0.043, 16-45, p value 0.030), Saudi nationality (p value-0.004) and South East Asian origin (p value-0.011) were identified as significant predisposing factors for molecular strain clustering. Conclusions The high proportion of molecular clusters shared among the autochthonous and immigrant populations suggests a high permeability of tuberculosis transmission between both populations in the province. These results prompt for the need to strengthen the current tuberculosis control strategies and surveillance programs. PMID:24147042

Mycobacterium tuberculosis population structure and molecular epidemiological analysis in Sucre municipality, Miranda state, Venezuela.

PubMed

Patiño, Margareth A; Abadía, Edgar; Solalba Gómez; Maes, Mailis; Muñoz, Mariana; Gómez, Daniela; Guzmán, Patricia; Méndez, María Victoria; Ramirez, Carmen; Mercedes, España; de Waard, Jacobus; Takiff, Howard

2014-12-01

Sucre municipality is a large, densely populated marginal area in the eastern part of Caracas, Venezuela that consistently has more cases of tuberculosis than other municipalities in the country. To identify the neighborhoods in the municipality with the highest prevalence of tuberculosis, and determine whether the Mycobacterium tuberculosis strain distribution in this municipality is different from that previously found in the western part of Caracas and the rest of Venezuela, we collected data on all tuberculosis cases in the municipality diagnosed in 2005-6. We performed two separate molecular epidemiological studies, spoligotyping 44 strains in a first study, and spoligotyping 131 strains, followed by MIRU-VNTR 15 on 21 clustered isolates in the second. With spoligotyping, the most common patterns were Shared International Type SIT17 (21%); SIT42 (15%); SIT93 (11%); SIT20 (7%); SIT53 (6%), a distribution similar to other parts of Venezuela, except that SIT42 and SIT20 were more common. MIRU-VNTR 15 showed that six of seven SIT17 strains examined belonged to a large cluster previously found circulating in Venezuela, but all of the SIT42 strains were related to a cluster centered in the neighborhoods of Unión and Maca, with a MIRU-VNTR pattern not previously seen in Venezuela. It appears that a large percentage of the tuberculosis in the Sucre municipality is caused by the active transmission of two strain families centered within distinct neighborhoods, one reflecting communication with the rest of the country, and the other suggesting the insular, isolated nature of some sectors.

First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea

PubMed Central

Ejo, Mebrat; Gehre, Florian; Barry, Mamadou Dian; Sow, Oumou; Bah, Nene Mamata; Camara, Mory; Bah, Boubacar; Uwizeye, Cecile; Nduwamahoro, Elie; Fissette, Kristina; Rijk, Pim De; Merle, Corinne; Olliaro, Piero; Burgos, Marcos; Lienhardt, Christian; Rigouts, Leen; de Jong, Bouke C.

2015-01-01

In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 “orphan” and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs. PMID:26004194

First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea.

PubMed

Ejo, Mebrat; Gehre, Florian; Barry, Mamadou Dian; Sow, Oumou; Bah, Nene Mamata; Camara, Mory; Bah, Boubacar; Uwizeye, Cecile; Nduwamahoro, Elie; Fissette, Kristina; De Rijk, Pim; Merle, Corinne; Olliaro, Piero; Burgos, Marcos; Lienhardt, Christian; Rigouts, Leen; de Jong, Bouke C

2015-07-01

In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs. Copyright © 2015. Published by Elsevier B.V.

Predominance of modern Mycobacterium tuberculosis strains and active transmission of Beijing sublineage in Jayapura, Indonesia Papua.

PubMed

Chaidir, Lidya; Sengstake, Sarah; de Beer, Jessica; Oktavian, Antonius; Krismawati, Hana; Muhapril, Erfin; Kusumadewi, Inri; Annisa, Jessi; Anthony, Richard; van Soolingen, Dick; Achmad, Tri Hanggono; Marzuki, Sangkot; Alisjahbana, Bachti; van Crevel, Reinout

2016-04-01

Mycobacterium tuberculosis genotype distribution is different between West and Central Indonesia, but there are no data on the most Eastern part, Papua. We aimed to identify the predominant genotypes of M. tuberculosis responsible for tuberculosis in coastal Papua, their transmission, and the association with patient characteristics. A total of 199 M. tuberculosis isolates were collected. Spoligotyping was applied to describe the population structure of M. tuberculosis, lineage identification was performed using a combination of lineage-specific markers, and genotypic clusters were identified using a combination of 24-locus-MIRU-VNTR and spoligotyping. A high degree of genetic diversity was observed among isolates based on their spoligopatterns. Strains from modern lineage 4 made up almost half of strains (46.9%), being more abundant than the ancient lineage 1 (33.7%), and modern lineage 2 (19.4%). Thirty-five percent of strains belonged to genotypic clusters, especially strains in the Beijing genotype. Previous TB treatment and mutations associated with drug resistance were more common in patients infected with strains of the Beijing genotype. Papua shows a different distribution of M. tuberculosis genotypes compared to other parts of Indonesia. Clustering and drug resistance of modern strains recently introduced to Papua may contribute to the high tuberculosis burden in this region. Copyright © 2016 Elsevier B.V. All rights reserved.

Cross-sectional studies of tuberculosis prevalence in Cambodia between 2002 and 2011

PubMed Central

Mao, Tan Eang; Yamada, Norio; Peou, Satha; Ota, Masaki; Saint, Saly; Kouet, Pichenda; Chea, Manith; Keo, Sokonth; Pheng, Sok Heng; Tieng, Sivanna; Khun, Kim Eam; Sugamoto, Tetsuhiro; Matsumoto, Hiroko; Yoshiyama, Takashi; Ito, Kunihiko; Onozaki, Ikushi

2014-01-01

Abstract Objective To measure trends in the pulmonary tuberculosis burden between 2002 and 2011 and to assess the impact of the DOTS (directly observed treatment, short-course) strategy in Cambodia. Methods Cambodia’s first population-based nationwide tuberculosis survey, based on multistage cluster sampling, was conducted in 2002. The second tuberculosis survey, encompassing 62 clusters, followed in 2011. Participants aged 15 years or older were screened for active pulmonary tuberculosis with chest radiography and/or for tuberculosis symptoms. For diagnostic confirmation, sputum smear and culture were conducted on those whose screening results were positive. Findings Of the 40 423 eligible subjects, 37 417 (92.6%) participated in the survey; 103 smear-positive cases and 211 smear-negative, culture-positive cases were identified. The weighted prevalences of smear-positive tuberculosis and bacteriologically-positive tuberculosis were 271 (95% confidence interval, CI: 212–348) and 831 (95% CI: 707–977) per 100 000 population, respectively. Tuberculosis prevalence was higher in men than women and increased with age. A 38% decline in smear-positive tuberculosis (P = 0.0085) was observed with respect to the 2002 survey, after participants were matched by demographic and geographical characteristics. The prevalence of symptomatic, smear-positive tuberculosis decreased by 56% (P = 0.001), whereas the prevalence of asymptomatic, smear-positive tuberculosis decreased by only 7% (P = 0.7249). Conclusion The tuberculosis burden in Cambodia has declined significantly, most probably because of the decentralization of DOTS to health centres. To further reduce the tuberculosis burden in Cambodia, tuberculosis control should be strengthened and should focus on identifying cases without symptoms and in the middle-aged and elderly population. PMID:25177072

Prevalence of Mycobacterium tuberculosis strain genotypes in Taiwan reveals a close link to ethnic and population migration.

PubMed

Dou, Horng-Yunn; Chen, Yih-Yuan; Kou, Shu-Chen; Su, Ih-Jen

2015-06-01

Taiwan is a relatively isolated island, serving as a mixing vessel for colonization by different waves of ethnic and migratory groups over the past 4 centuries. The potential transmission pattern of Mycobacterium tuberculosis in different ethnic and migratory populations remains to be elucidated. By using mycobacterial tandem repeat sequences as genetic markers, the prevalence of M. tuberculosis strains in Taiwan revealed a close link to the historical migration. Interestingly, the M. tuberculosis strain in the aborigines of Eastern and Central Taiwan had a dominance of the Haarlem (Dutch) strain while those in Southern Taiwan had a dominance of the East-African Indian (EAI) strain. The prevalence of different M. tuberculosis strains in specific ethnic populations suggests that M. tuberculosis transmission is limited and restricted to close contact. The prevalence of the Beijing modern strain in the young population causes a concern for M. tuberculosis control, because of high virulence and drug resistance. Furthermore, our data using molecular genotyping should provide valuable information on the historical study of the origin and migration of aborigines in Taiwan. Copyright © 2014. Published by Elsevier B.V.

The double burden.

PubMed

Faurholt-Jepsen, Daniel

2013-07-01

One third of the world's population is latently infected with Mycobacterium tuberculosis, and with the lifestyle changes succeeding the on-going urbanization, populations already burdened by tuberculosis are experiencing a dramatic increase in chronic diseases, with diabetes being a serious challenge. Tuberculosis and diabetes are not only becoming co-existing diseases. In fact, the diseases interact, and there is evidence to suggest that especially diabetes disease increases the susceptibility for developing active tuberculosis disease. Furthermore, it is plausible that tuberculosis leads to, either transient or permanent, impairment of the glucose metabolism, which ultimately will turn into diabetes. A number of studies from the Americas, Europe, Asia, and, most lately, from sub-Saharan Africa have reported strong association between tuberculosis and diabetes; on average, the estimated risk of active tuberculosis is thrice as high among people with diabetes. The study from sub-Saharan Africa was conducted in Tanzania and is the basis of this thesis. Based on available evidence on the association between tuberculosis and diabetes, the primary aim of the study was to assess the role of diabetes for tuberculosis risk, manifestations, treatment outcomes and survival in a Tanzanian population of tuberculosis patients and non-tuberculosis neighbourhood controls. The study was conducted in Mwanza City in northern Tanzania, with a population exceeding half a million inhabitants, with tuberculosis and HIV being common infections in the region, but with little knowledge about the prevalence of diabetes. We recruited newly diagnosed pulmonary tuberculosis patients from spring 2006 and continuously till the fall 2009, with all participating in a nutritional intervention running in parallel with the medical tuberculosis treatment. All participants underwent diabetes and HIV testing as well as a series of measurements such as anthropometric, clinical and paraclinical parameters. The population was followed up during treatment (2 and 5 months) to assess treatment outcome as well as after one year to assess their survival status. Based on data from 1,250 tuberculosis patients and 350 neighbourhood controls, we found that 38 and 21%, respectively, had impaired glycaemia, and that the prevalence of diabetes was 17 and 9% among tuberculosis patients and controls, respectively. This difference in prevalence between patients and controls was equivalent to an adjusted odds ratio of more than four, indicating a strong association between tuberculosis and diabetes. Furthermore, we found that diabetes was associated with tuberculosis among both participants with or without HIV co-infection. Despite the strong association, diabetes had only moderate clinical implications when the tuberculosis patients initiated the tuberculosis treatment; the patients with diabetes co-morbidity had a minor elevation in the immune response and more frequently reported to have fever. Furthermore, diabetes did not seem to delay time to sputum conversion during treatment. Nevertheless, diabetes co-morbidity led to impaired treatment outcome with slower recovery of weight and haemoglobin and a more than four times higher mortality rate within the initial phase of tuberculosis treatment. In conclusion, in the African region, the double burden of tuberculosis and diabetes is becoming a major health problem. Although the tuberculosis incidence has stabilized during the last decade, the increasing incidence of diabetes will possibly interfere with tuberculosis control and may, consequently, make the tuberculosis incidence increase again. Future research strategies should focus on enhanced diagnostic tools to identify tuberculosis patients with diabetes co-morbidity, and on the role of disease-disease, drug-disease and drug-drug interactions between tuberculosis and diabetes diseases and treatments.

Mathematical model for transmission of tuberculosis in badger population with vaccination

NASA Astrophysics Data System (ADS)

Tasmi, Aldila, D.; Soewono, E.; Nuraini, N.

2016-04-01

Badger was first time identified as a carrier of Bovine tuberculosis disease in England since 30 years ago. Bovine tuberculosis can be transmitted to another species through the faces, saliva, and breath. The control of tuberculosis in the badger is necessary to reduce the spread of the disease to other species. Many actions have been taken by the government to tackle the disease such as culling badgers with cyanide gas, but this way destroys the natural balance and disrupts the badger population. An alternative way to eliminate tuberculosis within badger population is by vaccination. Here in this paper a model for transmission of badger tuberculosis with vaccination is discussed. The existence of the endemic equilibrium, the stability and the basic reproduction ratio are shown analytically. Numerical simulations show that with proper vaccination level, the basic reproduction ratio could be reduced significantly. Sensitivity analysis for variation of parameters are shown numerically.

Models of Latent Tuberculosis: Their Salient Features, Limitations, and Development

PubMed Central

Patel, Kamlesh; Jhamb, Sarbjit Singh; Singh, Prati Pal

2011-01-01

Latent tuberculosis is a subclinical condition caused by Mycobacterium tuberculosis, which affects about one-third of the population across the world. To abridge the chemotherapy of tuberculosis, it is necessary to have active drugs against latent form of M. tuberculosis. Therefore, it is imperative to devise in vitro and models of latent tuberculosis to explore potential drugs. In vitro models such as hypoxia, nutrient starvation, and multiple stresses are based on adverse conditions encountered by bacilli in granuloma. Bacilli experience oxygen depletion condition in hypoxia model, whereas the nutrient starvation model is based on deprivation of total nutrients from a culture medium. In the multiple stress model dormancy is induced by more than one type of stress. In silico mathematical models have also been developed to predict the interactions of bacilli with the host immune system and to propose structures for potential anti tuberculosis compounds. Besides these in vitro and in silico models, there are a number of in vivo animal models like mouse, guinea pig, rabbit, etc. Although they simulate human latent tuberculosis up to a certain extent but do not truly replicate human infection. All these models have their inherent merits and demerits. However, there is no perfect model for latent tuberculosis. Therefore, it is imperative to upgrade and refine existing models or develop a new model. However, battery of models will always be a better alternative to any single model as they will complement each other by overcoming their limitations. PMID:22219558

Acquisition of second-line drug resistance and extensive drug resistance during recent transmission of Mycobacterium tuberculosis in rural China.

PubMed

Hu, Y; Mathema, B; Zhao, Q; Chen, L; Lu, W; Wang, W; Kreiswirth, B; Xu, B

2015-12-01

Multidrug-resistant tuberculosis (MDR-TB) is prevalent in countries with a high TB burden, like China. As little is known about the emergence and spread of second-line drug (SLD) -resistant TB, we investigate the emergence and transmission of SLD-resistant Mycobacterium tuberculosis in rural China. In a multi-centre population-based study, we described the bacterial population structure and the transmission characteristics of SLD-resistant TB using Spoligotyping in combination with genotyping based on 24-locus MIRU-VNTR (mycobacterial interspersed repetitive unit-variable-number tandem repeat) plus four highly variable loci for the Beijing family, in four rural Chinese regions with diverse geographic and socio-demographic characteristics. Transmission networks among genotypically clustered patients were constructed using social network analysis. Of 1332 M. tuberculosis patient isolates recovered, the Beijing family represented 74.8% of all isolates and an association with MDR and simultaneous resistance between first-line drugs and SLDs. The genotyping analysis revealed that 189 isolates shared MIRU-VNTR patterns in 78 clusters with clustering rate and recent transmission rate of 14.2% and 8.3%, respectively. Fifty-three SLD-resistant isolates were observed in 31 clusters, 30 of which contained the strains with different drug susceptibility profiles and genetic mutations. In conjunction with molecular data, socio-network analysis indicated a key role of Central Township in the transmission across a highly interconnected network where SLD resistance accumulation occurred during transmission. SLD-resistant M. tuberculosis has been spreading in rural China with Beijing family being the dominant strains. Primary transmission of SLD-resistant strains in the population highlights the importance of routine drug susceptibility testing and effective anti-tuberculosis regimens for drug-resistant TB. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

[Genome instability in pulmonary tuberculosis before and after treatment].

PubMed

Dzhokhadze, T A; Buadze, T Zh; Rubanov, K Dzh; Kiriia, N A; Lezhava, T A

2013-11-01

Pulmonary tuberculosis is classified as a disease with a genetic predisposition, and therefore, as with other pathologies related to this group of diseases, by pulmonary tuberculosis, special importance is given to finding those markers that enable early identification of risk groups, such as skrinnig in general population and relatives of patients with tuberculosis, which in turn can provide the basis for preventive measures. One of this markers is the level of genome stability. The aim of this study was a comparative evaluation of the functional parameters of the genome variability in patients with sensitive form of pulmonary tuberculosis before and after treatment, and the possibility of its correction with anti-stress peptide bioregulator - epitalon. The studies were conducted using short-term mitoge -stimulated cell cultures of TB patients, before and after treatment. As an indicator of genome stability has been studied the frequency of structural and numerical chromosome aberrations and fragile sites. It is shown, that in intact cultures from patients with pulmonary tuberculosis, before treatment was significantly higher level of frequency of cells with structural chromosome aberrations, that still retained after the treatment. As for epithalon, it appears that was shown a pronounced protective effect after treatment, on the test of chromosome aberrations, by reducing both overall mean frequency aberrant cells and indicators for all individuals. In the study of fragility of chromosomes in patients with primary tuberculosis was found, that in intact cultures, the proportion of cells with chromosomal fragile sites was higher than in control group of healthy individuals, befor and after treatment. High frequency of chromosome fragility persisted by treatment with peptide bioregulator in both cases - before and after treatment. It is suggested that the identified patterns can be correlated with a high incidence of re- TB.

Distinct Clinical and Epidemiological Features of Tuberculosis in New York City Caused by the RDRio Mycobacterium tuberculosis Sublineage

PubMed Central

Weisenberg, Scott A.; Gibson, Andrea L.; Huard, Richard C.; Kurepina, Natalia; Bang, Heejung; Lazzarini, Luiz C O.; Chiu, Yalin; Li, Jiehui; Ahuja, Shama; Driscoll, Jeff; Kreiswirth, Barry N.; Ho, John L.

2011-01-01

Background Genetic tracking of Mycobacterium tuberculosis is a cornerstone of tuberculosis (TB) control programs. The RDRio M. tuberculosis sublineage was previously associated with TB in Brazil. We investigated 3847 M. tuberculosis isolates and registry data from New York City (NYC) (2001–2005) to: 1) affirm the position of RDRio strains within the M. tuberculosis phylogenetic structure, 2) determine its prevalence, and 3) define transmission, demographic, and clinical characteristics associated with RDRio TB. Methods Isolates classified as RDRio or non-RDRio M. tuberculosis by multiplex PCR were further classified as clustered (≥2 isolates) or unique based primarily upon IS6110-RFLP patterns and lineage-specific cluster proportions were calculated. The secondary case rate of RDRio was compared with other prevalent M. tuberculosis lineages. Genotype data were merged with the data from the NYC TB Registry to assess demographic and clinical characteristics. Results RDRio strains were found to: 1) be restricted to the Latin American-Mediterranean family, 2) cause approximately 8% of TB cases in NYC, and 3) be associated with heightened transmission as shown by: i) a higher cluster proportion compared to other prevalent lineages, ii) a higher secondary case rate, and iii) cases in children. Furthermore, RDRio strains were significantly associated with US-born Black or Hispanic race, birth in Latin American and Caribbean countries, and isoniazid resistance. Conclusions The RDRio genotype is a single M. tuberculosis strain population that is emerging in NYC. The findings suggest that expanded RDRio case and exposure identification could be of benefit due to its association with heightened transmission. PMID:21835266

Higher Rate of Tuberculosis in Second Generation Migrants Compared to Native Residents in a Metropolitan Setting in Western Europe

PubMed Central

Marx, Florian M.; Fiebig, Lena; Hauer, Barbara; Brodhun, Bonita; Glaser-Paschke, Gisela; Haas, Walter

2015-01-01

Background In Western Europe, migrants constitute an important risk group for tuberculosis, but little is known about successive generations of migrants. We aimed to characterize migration among tuberculosis cases in Berlin and to estimate annual rates of tuberculosis in two subsequent migrant generations. We hypothesized that second generation migrants born in Germany are at higher risk of tuberculosis compared to native (non-migrant) residents. Methods A prospective cross-sectional study was conducted. All tuberculosis cases reported to health authorities in Berlin between 11/2010 and 10/2011 were eligible. Interviews were conducted using a structured questionnaire including demographic data, migration history of patients and their parents, and language use. Tuberculosis rates were estimated using 2011 census data. Results Of 314 tuberculosis cases reported, 154 (49.0%) participated. Of these, 81 (52.6%) were first-, 14 (9.1%) were second generation migrants, and 59 (38.3%) were native residents. The tuberculosis rate per 100,000 individuals was 28.3 (95CI: 24.0–32.6) in first-, 10.2 (95%CI: 6.1–16.6) in second generation migrants, and 4.6 (95%CI: 3.7–5.6) in native residents. When combining information from the standard notification variables country of birth and citizenship, the sensitivity to detect second generation migration was 28.6%. Conclusions There is a higher rate of tuberculosis among second generation migrants compared to native residents in Berlin. This may be explained by presumably frequent contact and transmission within migrant populations. Second generation migration is insufficiently captured by the surveillance variables country of birth and citizenship. Surveillance systems in Western Europe should allow for quantifying the tuberculosis burden in this important risk group. PMID:26061733

Cost-effectiveness of post-landing latent tuberculosis infection control strategies in new migrants to Canada.

PubMed

Campbell, Jonathon R; Johnston, James C; Sadatsafavi, Mohsen; Cook, Victoria J; Elwood, R Kevin; Marra, Fawziah

2017-01-01

The majority of tuberculosis in migrants to Canada occurs due to reactivation of latent TB infection. Risk of tuberculosis in those with latent tuberculosis infection can be significantly reduced with treatment. Presently, only 2.4% of new migrants are flagged for post-landing surveillance, which may include latent tuberculosis infection screening; no other migrants receive routine latent tuberculosis infection screening. To aid in reducing the tuberculosis burden in new migrants to Canada, we determined the cost-effectiveness of using different latent tuberculosis infection interventions in migrants under post-arrival surveillance and in all new migrants. A discrete event simulation model was developed that focused on a Canadian permanent resident cohort after arrival in Canada, utilizing a ten-year time horizon, healthcare system perspective, and 1.5% discount rate. Latent tuberculosis infection interventions were evaluated in the population under surveillance (N = 6100) and the total cohort (N = 260,600). In all evaluations, six different screening and treatment combinations were compared to the base case of tuberculin skin test screening followed by isoniazid treatment only in the population under surveillance. Quality adjusted life years, incident tuberculosis cases, and costs were recorded for each intervention and incremental cost-effectiveness ratios were calculated in relation to the base case. In the population under surveillance (N = 6100), using an interferon-gamma release assay followed by rifampin was dominant compared to the base case, preventing 4.90 cases of tuberculosis, a 4.9% reduction, adding 4.0 quality adjusted life years, and saving $353,013 over the ensuing ten-years. Latent tuberculosis infection screening in the total population (N = 260,600) was not cost-effective when compared to the base case, however could potentially prevent 21.8% of incident tuberculosis cases. Screening new migrants under surveillance with an interferon-gamma release assay and treating with rifampin is cost saving, but will not significantly impact TB incidence. Universal latent tuberculosis infection screening and treatment is cost-prohibitive. Research into using risk factors to target screening post-landing may provide alternate solutions.

Type 2 diabetes mellitus and its influence in the development of multidrug resistance tuberculosis in patients from southeastern Mexico.

PubMed

Pérez-Navarro, Lucia Monserrat; Fuentes-Domínguez, Francisco Javier; Zenteno-Cuevas, Roberto

2015-01-01

To determine the factors associated with the presence of pulmonary tuberculosis in patients with type 2 diabetes mellitus and the effect in the development of drug and multi-drug resistance, in a population with tuberculosis from the southeast of Mexico. This is a case-control study including 409 individuals, 146 with the binomial tuberculosis-type 2 diabetes mellitus and 263 individuals with tuberculosis. Demographic, epidemiological and outcome variables were collected. Risks were calculated. The factors associated with the presence of type 2 diabetes mellitus were age ≥35years, (OR=9.7; CI: 5.2-17.8), previous contact with a person infected with tuberculosis (OR=1.7; CI: 1.1-3.1). Body mass index ≥25 kg/m(2) (OR=2.2; CI: 1.1-4.3), and inherited family history of diabetes (OR=5.4; CI: 3.2-9.2). It was also found that patients with tuberculosis-type 2 diabetes mellitus presented a 4.7-fold (CI: 1.4-11.3) and 3.5-fold (CI: 1.1-11.1) higher risk of developing drug- and multidrug resistance tuberculosis, respectively. By last, individuals with tuberculosis-type 2 diabetes had a 2.3-fold (CI: 1.5-4.1) greater chance of persisting as tuberculosis-positive by the second month of treatment, delaying the resolution of the tuberculosis infection. Type 2 diabetes exerts a strong influence on the presentation and evolution of tuberculosis within the analyzed population and displays remarkable particularities, necessitating the development of dedicated tuberculosis-diabetes surveillance systems that consider the particular epidemiological characteristics of the population affected. Copyright © 2015 Elsevier Inc. All rights reserved.

Surgical aspects of pulmonary tuberculosis: an update.

PubMed

Dewan, Ravindra Kumar; Pezzella, A Thomas

2016-10-01

Tuberculosis remains a major global medical challenge and concern. In the world's population of over 7.4 billion people, 8.6 million are estimated to be infected with Mycobacterium tuberculosis; another 2.2 billion have latent tuberculosis. There is an annual incidence of 16,000 new cases in the USA and 7-8 million new cases worldwide, of which 440,000 are multidrug-resistant or extensively multidrug-resistant, mainly in developing countries or emerging economies. According to the World Health Organization, the incidence of tuberculosis is 133 cases per 100,000 of the population; 3.3% new cases are drug resistant and 20% are already treated cases. Of the drug-resistant cases, 9.7% are extensively drug-resistant. The annual global mortality attributable to tuberculosis is over 1.3 million people. The association with HIV/AIDS in 430,000 people has compounded the global concern and challenge. This review presents the historical indications for surgical treatment of tuberculosis, reviews the current literature and clinical experience, and collates this into increased awareness and contemporary understanding of the indications and need for surgery in primary active tuberculosis, adjuvant surgical therapy for multidrug-resistant tuberculosis, and the complications of chronic tuberculosis sequelae or previous tuberculosis surgery. © The Author(s) 2016.

Stopping tuberculosis: a biosocial model for sustainable development.

PubMed

Ortblad, Katrina F; Salomon, Joshua A; Bärnighausen, Till; Atun, Rifat

2015-12-05

Tuberculosis transmission and progression are largely driven by social factors such as poor living conditions and poor nutrition. Increased standards of living and social approaches helped to decrease the burden of tuberculosis before the introduction of chemotherapy in the 1940s. Since then, management of tuberculosis has been largely biomedical. More funding for tuberculosis since 2000, coinciding with the Millennium Development Goals, has yielded progress in tuberculosis mortality but smaller reductions in incidence, which continues to pose a risk to sustainable development, especially in poor and susceptible populations. These at-risk populations need accelerated progress to end tuberculosis as resolved by the World Health Assembly in 2015. Effectively addressing the worldwide tuberculosis burden will need not only enhancement of biomedical approaches but also rebuilding of the social approaches of the past. To combine a biosocial approach, underpinned by social, economic, and environmental actions, with new treatments, new diagnostics, and universal health coverage, will need multisectoral coordination and action involving the health and other governmental sectors, as well as participation of the civil society, and especially the poor and susceptible populations. A biosocial approach to stopping tuberculosis will not only target morbidity and mortality from disease but would also contribute substantially to poverty alleviation and sustainable development that promises to meet the needs of the present, especially the poor, and provide them and subsequent generations an opportunity for a better future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prevalence of Mycobacterium tuberculosis antibodies in a healthy population in a South-Eastern State of Nigeria.

PubMed

Chinedu, Awujo N; Seema, Bibi; Gladys, Anyanwu O

2008-01-01

To determine the seroprevalence of Mycobacterium tuberculosis in apparently healthy residents of two densely-populated and model settlement nucleated towns of Akwakuma and Orji in Owerri North Local Government Area of Imo State, South Eastern Nigeria. Antibodies to M. tuberculosis in human serum or plasma were qualitatively detected in four hundred and eighty individuals using the one step TB 1gG/1gM two sided-lateral flow chromatographic immunoassay. The prevalence of M. tuberculosis antibodies in the study population was 6.67%. However, the prevalence was significantly higher (p<0.05) in sera of inhabitants of Orji (8.33%) than in those of Akwakuma (5.56%). Generally, in both communities, the females were significantly (p<0.05) more sero-positive for M. tuberculosis antibodies (8.57%) than the males (4.0%). The antibodies were most prevalent (22.2%) in persons between the ages of 20 and 29 years. No M. tuberculosis antibody was detected in individuals that were in the 1-9, 30-39 and 50-59 year age groups. Amongst the study population, the bacterial antibodies were only detected in 25.0% of the males in Orji that were between 20 and 29 years. Comparatively, the antibodies were prevalent (16.7%) in female residents of Akwakuma that were within the 10-19 and 40-49 years age group. The high prevalence of M. tuberculosis in the study population is worrisome as the sero-positive individuals are not only at risk of having full blown tuberculosis later on, but are also a source of spreading the bacteria to the populace. Therefore, there is an urgent need for further epidemiological survey to be undertaken in the study area and, to initiate appropriate preventive and control measures.

Perceived Barriers to Adherence to Tuberculosis Infection Control Measures among Health Care Workers in the Dominican Republic.

PubMed

Chapman, Helena J; Veras-Estévez, Bienvenido A; Pomeranz, Jamie L; Pérez-Then, Eddy N; Marcelino, Belkys; Lauzardo, Michael

2017-01-01

INTRODUCTION Health care workers have an increased risk of infection due to occupational Mycobacterium tuberculosis exposure, including multidrug-resistant strains. Health care workers' risk of developing tuberculosis is greater than that of the general population, whether in low-, intermediate- or high-incidence countries. Adherence to infection control measures (administrative controls, environmental controls, and personal respiratory protection) is essential to reduce risk of disease transmission between suspected tuberculosis patients and health care workers, but for different reasons, both objective and subjective, adherence is low. Identifying the causes of low adherence is a prerequisite to effective programming to reduce risk. OBJECTIVE Identify perceived barriers to adherence to tuberculosis infection control measures among health care workers in the Dominican Republic. METHODS During August 2014, a qualitative study was conducted in two tertiary-level hospitals in different regions of the Dominican Republic. A semi-structured interview guide of nine questions was developed, based on the scientific literature and with consensus of clinical experts. Nine semi-structured interviews were conducted with a purposive sample of seven physicians (five men, two women) and two baccalaureate nurses (both women) working in the emergency medicine, internal medicine or nursing departments of those institutions. Question topics included clinical experience of M. tuberculosis infection and disease; knowledge of disease transmission and preventive practices; clinical management strategies; and perceptions of effectiveness of directly observed treatment, short-course, and disease coping strategies. RESULTS Perceived barriers were described as: 1) sense of invincibility of health care workers; 2) personal beliefs of health care workers related to direct patient communication; 3) low provider-to-patient ratios in hospitals; 4) absence of tuberculosis isolation units for patients within hospitals; and 5) limited availability of protective masks for health care workers. CONCLUSIONS Our results highlight that perceived barriers at the individual or institutional level may hinder how health care workers understand and comply with preventive strategies to reduce risk of tuberculosis transmission. Addressing these barriers by strengthening infection control program infrastructure and implementing educational interventions within institutions may reduce risk of nosocomial tuberculosis transmission to health care workers. KEYWORDS Health care providers, infection control, infectious disease transmission, health care associated infection, nosocomial infection, Mycobacterium tuberculosis occupational exposure, occupational health, qualitative research, tuberculosis, Dominican Republic.

Addressing Institutional Amplifiers in the Dynamics and Control of Tuberculosis Epidemics

PubMed Central

Basu, Sanjay; Stuckler, David; McKee, Martin

2011-01-01

Tuberculosis outbreaks originating in prisons, mines, or hospital wards can spread to the larger community. Recent proposals have targeted these high-transmission institutional amplifiers by improving case detection, treatment, or reducing the size of the exposed population. However, what effects these alternative proposals may have is unclear. We mathematically modeled these control strategies and found case detection and treatment methods insufficient in addressing epidemics involving common types of institutional amplifiers. Movement of persons in and out of amplifiers fundamentally altered the transmission dynamics of tuberculosis in a manner not effectively mitigated by detection or treatment alone. Policies increasing the population size exposed to amplifiers or the per-person duration of exposure within amplifiers potentially worsened incidence, even in settings with high rates of detection and treatment success. However, reducing the total population size entering institutional amplifiers significantly lowered tuberculosis incidence and the risk of propagating new drug-resistant tuberculosis strains. PMID:21212197

Within Host Evolution Selects for a Dominant Genotype of Mycobacterium tuberculosis while T Cells Increase Pathogen Genetic Diversity.

PubMed

Copin, Richard; Wang, Xueying; Louie, Eddie; Escuyer, Vincent; Coscolla, Mireia; Gagneux, Sebastien; Palmer, Guy H; Ernst, Joel D

2016-12-01

Molecular epidemiological assessments, drug treatment optimization, and development of immunological interventions all depend on understanding pathogen adaptation and genetic variation, which differ for specific pathogens. Mycobacterium tuberculosis is an exceptionally successful human pathogen, yet beyond knowledge that this bacterium has low overall genomic variation but acquires drug resistance mutations, little is known of the factors that drive its population genomic characteristics. Here, we compared the genetic diversity of the bacteria that established infection to the bacterial populations obtained from infected tissues during murine M. tuberculosis pulmonary infection and human disseminated M. bovis BCG infection. We found that new mutations accumulate during in vitro culture, but that in vivo, purifying selection against new mutations dominates, indicating that M. tuberculosis follows a dominant lineage model of evolution. Comparing bacterial populations passaged in T cell-deficient and immunocompetent mice, we found that the presence of T cells is associated with an increase in the diversity of the M. tuberculosis genome. Together, our findings put M. tuberculosis genetic evolution in a new perspective and clarify the impact of T cells on sequence diversity of M. tuberculosis.

Does non-central nervous system tuberculosis increase the risk of ischemic stroke? A population-based propensity score-matched follow-up study.

PubMed

Wu, Chueh-Hung; Chen, Li-Sheng; Yen, Ming-Fang; Chiu, Yueh-Hsia; Fann, Ching-Yuan; Chen, Hsiu-Hsi; Pan, Shin-Liang

2014-01-01

Previous studies on the association between tuberculosis and the risk of developing ischemic stroke have generated inconsistent results. We therefore performed a population-based, propensity score-matched longitudinal follow-up study to investigate whether contracting non-central nervous system (CNS) tuberculosis leads to an increased risk of ischemic stroke. We used a logistic regression model that includes age, sex, pre-existing comorbidities and socioeconomic status as covariates to compute the propensity score. A total of 5804 persons with at least three ambulatory visits in 2001 with the principal diagnosis of non-CNS tuberculosis were enrolled in the tuberculosis group. The non-tuberculosis group consisted of 5804, propensity score-matched subjects without tuberculosis. The three-year ischemic stroke-free survival rates for these 2 groups were estimated using the Kaplan-Meier method. The stratified Cox proportional hazards regression was used to estimate the effect of tuberculosis on the occurrence of ischemic stroke. During three-year follow-up, 176 subjects in the tuberculosis group (3.0%) and 207 in the non-tuberculosis group (3.6%) had ischemic stroke. The hazard ratio for developing ischemic stroke in the tuberculosis group was 0.92 compared to the non-tuberculosis group (95% confidence interval: 0.73-1.14, P = 0.4299). Non-CNS tuberculosis does not increase the risk of subsequent ischemic stroke.

Clinical Research and Development of Tuberculosis Diagnostics: Moving From Silos to Synergy

PubMed Central

Kim, Peter S.; Evans, Carlton A.; Alland, David; Barer, Michael; Diefenbach, Jane; Ellner, Jerrold; Hafner, Richard; Hamilton, Carol Dukes; Iademarco, Michael F.; Ireton, Gregory; Kimerling, Michael E.; Lienhardt, Christian; MacKenzie, William R.; Murray, Megan; Perkins, Mark D.; Posey, Jamie E.; Roberts, Teri; Sizemore, Christine; Stevens, Wendy S.; Via, Laura; Williams, Sharon D.; Yew, Wing W.; Swindells, Susan

2012-01-01

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations. PMID:22476718

Assessment of knowledge and practice of health workers towards tuberculosis infection control and associated factors in public health facilities of Addis Ababa, Ethiopia: A cross-sectional study.

PubMed

Demissie Gizaw, Girma; Aderaw Alemu, Zewdie; Kibret, Kelemu Tilahun

2015-01-01

Tuberculosis is the leading causes of mortality among infectious diseases worldwide. The risk of transmission from patients to health workers is doubles that of the general population. The close contact to the infectious case before diagnosis is the major risk for tuberculosis infection. The aim of the study was to assess knowledge and practice of health professionals towards tuberculosis infection control and its associated factors in health facilities of Addis Ababa, Ethiopia. A cross-sectional study was conducted from February 29 to April 15/2014 in selected health facilities in Addis Ababa. Five hundred ninety health workers were included in the study. The sample size was assigned to each health facility proportional to their number of health workers. Study subjects were selected from each stratum by simple random sampling technique. Interviewer administered structured questionnaire was used to collect information. Logistic regression was used to identify factors associated with knowledge and practice of health workers towards tuberculosis infection control. Five hundred eighty two participants with 98.6% response rate were involved in the study. Of these, 36.1% had poor knowledge and 51.7% unsatisfactory practice score towards tuberculosis infection control. Having more than six years working experience in health facility (AOR = 2.51; 95% CI: 1.5-4.1) and tuberculosis related training (AOR = 2.51 95% CI; 1.5, 4.1) were significantly associated with knowledge on tuberculosis infection control. Having experience in tuberculosis clinic (AOR =1.93; 95% CI: 1.12, 3.34) and tuberculosis related training (AOR = 1.48; 95% CI: 1.87, 2.51) were significantly associated with practice on tuberculosis infection control. One third of health workers had relatively poor knowledge and nearly half of them had unsatisfactory practice on tuberculosis infection control. Tuberculosis training and work experiences in health facility are determinant factor to knowledge. Whereas tuberculosis related training and experience in tuberculosis clinic are predictor to practice. So, training of the health professionals, on job orientations of junior health workers, and farther study including private health workers are recommended.

mosR, A Novel Transcriptional Regulator of Hypoxia and Virulence in Mycobacterium tuberculosis

USDA-ARS?s Scientific Manuscript database

Chronic tuberculosis represents a high-risk burden for one third of the world population. Previous microarray analysis of murine tuberculosis identified a novel transcriptional regulator encoded by rv0348 that could control the establishment of the chronic phase of tuberculosis. Disruption of the ...

The arms race between man and Mycobacterium tuberculosis: Time to regroup.

PubMed

Hoal, Eileen G; Dippenaar, Anzaan; Kinnear, Craig; van Helden, Paul D; Möller, Marlo

2017-08-23

An arms race is an appropriate metaphor to use for the interaction of man and Mycobacterium tuberculosis (M.tb) through the millennia. Estimates of the time of infection of modern humans with M.tb often pre-date the Out-of-Africa migration. Humans have adapted to the changing environment during the migration with respect to climate, food sources and encounters with local pathogens. More recently, there has been adaptation to the demographic changes brought about in the majority of the human population by the Neolithic revolution. By chance and/or selection, specific variants in immune defence have arisen in different population groups. These select for M.tb strains more fit to cause disease and be transmitted, sometimes by exploiting defence systems effective on other bacteria. The different selection pressures on the M.tb lineages carried by specific human groups have resulted in a worldwide M.tb population that is geographically structured according to the humans historically found there. A similar structure is seen with pathogens such as M. leprae and Helicobacter pylori. Modern M.tb strains have emerged which may be more fit, such as the Beijing lineage, leading to their rapid spread both in the areas where they arose, and into new areas after recent introduction. The speed at which this is occurring is outpacing coevolution for the time being. By using the results of genome wide and other association studies, as well as admixture mapping and 'natural experiments' in areas where both a number of populations, admixed populations, and a variety of M.tb strains occur, we can investigate the forces that have driven the coevolution of man and M.tb. The diversity of human and bacterial genetic background may be used in the future to discover and target the specific host-pathogen interactions leading to tuberculosis diseases, which suggests the potential for rational design of vaccines and host-directed therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Tuberculosis treatment outcome and health services: a comparison of displaced and settled population groups in Khartoum, Sudan.

PubMed

Bøhler, M; Mustafaa, S A; Mørkve, O

2005-01-01

The Sudan National Tuberculosis Programme serves internally displaced and settled populations in Khartoum, Sudan. To investigate whether treatment in the camps is satisfactory compared to the settled population and to World Health Organization (WHO) standards, and to map certain characteristics of the clinics that may explain differences in treatment outcome. A register analysis was done on sputum smear-positive and retreatment tuberculosis patients registered consecutively in the first and second quarters of 2000. The nine health facilities from which the patients were selected were investigated using a questionnaire. State tuberculosis officers were interviewed about regional treatment policies. Two hundred and ninety-five internally displaced and 154 settled patients from respectively five and four clinics were included. The cure and completion rates among new sputum smear-positive cases were significantly higher among displaced (65% and 9.3%) than among settled persons (43.5% and 21%). Displaced groups had better adherence to 5 and 8 month smear examinations, and the quantity of health education was higher in the camps than among the settled population. Tuberculosis treatment among the displaced population in Khartoum compares favourably with the neighbouring settled population, but both groups still face serious challenges to fulfil the WHO goals.

Diabetes mellitus in patients with pulmonary tuberculosis in an aging population in Shanghai, China: Prevalence, clinical characteristics and outcomes.

PubMed

Wu, Zheyuan; Guo, Juntao; Huang, Ying; Cai, Enmao; Zhang, Xia; Pan, Qichao; Yuan, Zheng'an; Shen, Xin

2016-03-01

To determine the prevalence of diabetes mellitus among pulmonary tuberculosis patients and the difference of clinical characteristics and outcomes between pulmonary tuberculosis patients with and without diabetes mellitus in an aging population in Shanghai, China. This is a retrospective population-based study. 201 newly diagnosed pulmonary tuberculosis patients in Changning District, Shanghai during 2007-2008 were included. Clinical characteristics and outcomes were collected. Determination of diabetes mellitus was based on the medical records before pulmonary tuberculosis was diagnosed. The prevalence of diabetes mellitus among pulmonary tuberculosis patients was 19.9% (40/201). Pulmonary tuberculosis patients with diabetes mellitus were more likely to be old (≥50, OR=5.23, 95% CI=2.07-13.25), to have pulmonary cavities (OR=3.02, 95% CI=1.31-6.98), to be sputum smear positive (OR=2.90, 95% CI=1.12-7.51), and to have extension of anti-tuberculosis treatment duration (OR=2.68, 95% CI 1.17-6.14). Besides, they had a higher 2nd month sputum smear positive proportion (OR=2.97, 95% CI 1.22-7.22) and a higher 5-year recurrence rate (OR=5.87, 95% CI 1.26-27.40). High prevalence, severe clinical characteristics and poor outcomes of pulmonary tuberculosis patients with diabetes mellitus highlight the necessity of early bi-directional screening and co-management of these two diseases in Shanghai, China. Copyright © 2016 Elsevier Inc. All rights reserved.

Common mental disorders associated with tuberculosis: a matched case-control study.

PubMed

de Araújo, Gleide Santos; Pereira, Susan Martins; dos Santos, Darci Neves; Marinho, Jamocyr Moura; Rodrigues, Laura Cunha; Barreto, Mauricio Lima

2014-01-01

Despite the availability of treatment and a vaccine, tuberculosis continues to be a public health problem worldwide. Mental disorders might contribute to the burden of the disease. The objective of this study was to investigate the association between common mental disorders and tuberculosis. A matched case-control study was conducted. The study population included symptomatic respiratory patients who attended three referral hospitals and six community clinics in the city of Salvador, Brazil. A doctor's diagnosis defined potential cases and controls. Cases were newly diagnosed tuberculosis cases, and controls were symptomatic respiratory patients for whom tuberculosis was excluded as a diagnosis by the attending physician. Cases and controls were ascertained in the same clinic. Data collection occurred between August 2008 and April 2010. The study instruments included a structured interview, a self-reporting questionnaire for the identification of common mental disorders, and a questionnaire for alcoholism. An univariate analysis included descriptive procedures (with chi-square statistics), and a multivariate analysis used conditional logistic regression. The mean age of the cases was 38 years, and 61% of the cases were males. After adjusting for potential confounders, the odds of tuberculosis were significantly higher in patients diagnosed with a common mental disorder (OR: 1.34; 95% CI 1.05-1.70). There appears to be a positive and independent association between common mental disorders and tuberculosis; further epidemiological studies are required to increase our understanding of the possible biological and social mechanisms responsible for this association. Independent of the direction of the association, this finding has implications for the provision of care for mental disorders and for tuberculosis.

The production of consumption: addressing the impact of mineral mining on tuberculosis in southern Africa

PubMed Central

Basu, Sanjay; Stuckler, David; Gonsalves, Gregg; Lurie, Mark

2009-01-01

Background Miners in southern Africa experience incident rates of tuberculosis up to ten times greater than the general population. Migration to and from mines may be amplifying tuberculosis epidemics in the general population. Discussion Migration to and from mineral mines contributes to HIV risks and associated tuberculosis incidence. Health and safety conditions within mines also promote the risk of silicosis (a tuberculosis risk factor) and transmission of tuberculosis bacilli in close quarters. In the context of migration, current tuberculosis prevention and treatment strategies often fail to provide sufficient continuity of care to ensure appropriate tuberculosis detection and treatment. Reports from Lesotho and South Africa suggest that miners pose transmission risks to other household or community members as they travel home undetected or inadequately treated, particularly with drug-resistant forms of tuberculosis. Reducing risky exposures on the mines, enhancing the continuity of primary care services, and improving the enforcement of occupational health codes may mitigate the harmful association between mineral mining activities and tuberculosis incidence among affected communities. Summary Tuberculosis incidence appears to be amplified by mineral mining operations in southern Africa. A number of immediately-available measures to improve continuity of care for miners, change recruitment and compensation practices, and reduce the primary risk of infection may critically mitigate the negative association between mineral mining and tuberculosis. PMID:19785769

Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.

PubMed

Merker, Matthias; Blin, Camille; Mona, Stefano; Duforet-Frebourg, Nicolas; Lecher, Sophie; Willery, Eve; Blum, Michael G B; Rüsch-Gerdes, Sabine; Mokrousov, Igor; Aleksic, Eman; Allix-Béguec, Caroline; Antierens, Annick; Augustynowicz-Kopeć, Ewa; Ballif, Marie; Barletta, Francesca; Beck, Hans Peter; Barry, Clifton E; Bonnet, Maryline; Borroni, Emanuele; Campos-Herrero, Isolina; Cirillo, Daniela; Cox, Helen; Crowe, Suzanne; Crudu, Valeriu; Diel, Roland; Drobniewski, Francis; Fauville-Dufaux, Maryse; Gagneux, Sébastien; Ghebremichael, Solomon; Hanekom, Madeleine; Hoffner, Sven; Jiao, Wei-wei; Kalon, Stobdan; Kohl, Thomas A; Kontsevaya, Irina; Lillebæk, Troels; Maeda, Shinji; Nikolayevskyy, Vladyslav; Rasmussen, Michael; Rastogi, Nalin; Samper, Sofia; Sanchez-Padilla, Elisabeth; Savic, Branislava; Shamputa, Isdore Chola; Shen, Adong; Sng, Li-Hwei; Stakenas, Petras; Toit, Kadri; Varaine, Francis; Vukovic, Dragana; Wahl, Céline; Warren, Robin; Supply, Philip; Niemann, Stefan; Wirth, Thierry

2015-03-01

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

Transmission of Mycobacterium tuberculosis in China: A Population-Based Molecular Epidemiologic Study

PubMed Central

Yang, Chongguang; Shen, Xin; Peng, Ying; Lan, Rushu; Zhao, Yuling; Long, Bo; Luo, Tao; Sun, Guomei; Li, Xia; Qiao, Ke; Gui, Xiaohong; Wu, Jie; Xu, Jiying; Li, Fabin; Li, Dingyue; Liu, Feiying; Shen, Mei; Hong, Jianjun; Mei, Jian; DeRiemer, Kathryn; Gao, Qian

2015-01-01

Background. Understanding the transmission of Mycobacterium tuberculosis is essential for the development of efficient tuberculosis control strategies. China has the second-largest tuberculosis burden in the world. Recent transmission and infection with M. tuberculosis, particularly drug-resistant strains, may account for many new tuberculosis cases. Methods. We performed a population-based molecular epidemiologic study of pulmonary tuberculosis in China during 1 July 2009 to 30 June 2012. We defined clusters as cases with identical variable number tandem repeat genotype patterns and identified the risk factors associated with clustering, by logistic regression. Relative transmission rates were estimated by the sputum smear status and drug susceptibility status of tuberculosis patients. Results. Among 2274 culture-positive tuberculosis patients with genotyped isolates, there were 705 (31.0%) tuberculosis patients in 287 clusters. Multidrug-resistant (MDR) tuberculosis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.25–2.63) and infection with a Beijing family strain (aOR, 1.56; 95% CI, 1.23–2.96) were associated with clustering. Eighty-four of 280 (30.0%) clusters had a putative source case that was sputum smear negative, and 30.6% of their secondary cases were attributed to transmission by sputum smear–negative patients. The relative transmission rate for sputum smear negative compared with sputum smear–positive patients was 0.89 (95% CI, .68–1.10), and was 1.51 (95% CI, 1.00–2.24) for MDR tuberculosis vs drug-susceptible tuberculosis. Conclusions. Recent transmission of M. tuberculosis, including MDR strains, contributes substantially to tuberculosis disease in China. Sputum smear–negative cases were responsible for at least 30% of the secondary cases. Interventions to reduce the transmission of M. tuberculosis should be implemented in China. PMID:25829000

Could Killing Bacterial Subpopulations Hit Tuberculosis out of the Park?

PubMed

Baranowski, Catherine; Rubin, Eric J

2016-07-14

One hurdle to treating tuberculosis could be that it is so difficult to kill nonreplicating subpopulations of the causative pathogens. This work describes two new cephalosporin derivatives that specifically target this population of Mycobacterium tuberculosis.

Tuberculosis in patients with systemic lupus erythematosus: Spain's situation.

PubMed

Arenas Miras, María del Mar; Hidalgo Tenorio, Carmen; Jimenez Alonso, Juan

2013-01-01

There has recently been an increase in the incidence of patients with systemic lupus erythematosus (SLE) due mainly to earlier diagnosis, and increased survival. Tuberculosis in our country is one of the most prevalent infectious diseases, and one of the underlying causes would be HIV infection and increased immigration from areas with high tuberculosis prevalence; this phenomenon is truly important in patients with autoimmune diseases, as clinical presentation, severity and prognosis of tuberculosis are often different to that of immunocompetent patients. Studies of tuberculosis in patients with SLE are scarce and inconclusive, with many doubts existing about the performance or non-tuberculous prophylaxis in this population and the absence of a protocol due to lack of conclusive studies. New techniques for diagnosis of tuberculosis (IGRAs) may be useful in this population due to higher sensitivity than Mantoux, helping avoid false negatives. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Tuberculosis in Far North Queensland, Australia: a retrospective clinical audit.

PubMed

Wilson, Malcolm; Weston, Jana; Mullen, Annette; Knight, Trevor; Simpson, Graham

2018-06-05

Compared with global numbers, Australia has enjoyed relatively good tuberculosis control over the last thirty years with an annual incidence of 5.7 per 100,000 population. 1 Thanks to its unique geography and proximity to high-burden countries, such as Papua New Guinea (PNG), Far North Queensland (FNQ) has previously been shown to have higher rates of tuberculosis compared with both the state and national average. 2,3 AIMS: Document tuberculosis epidemiology in FNQ with comparison to two previous audits of the region. Retrospective clinical audit of all cases of tuberculosis notified to the Cairns Tuberculosis Control Unit between 2006 and 2016. 453 cases were identified, 374 with microbiological/histological confirmation. There were 312 cases of pulmonary tuberculosis; 155 extra-pulmonary; and 21 disseminated. Three-quarters (327/453) were identified in the overseas-born population. Of the remaining 126 cases, 40 were Torres Strait Islander and 19 Aboriginal Australians. Where drug susceptibility was known, two-thirds (247/368) were fully sensitive; 42 mono-resistant; 78 multidrug-resistant; and one extensively drug resistant. Rates of HIV co-infection were less than three percent (10/362). Tuberculosis remains a significant problem in FNQ. Case numbers have increased three-fold since the 1990s. Much of the increase comes from the overseas-born population. Although PNG accounts for the majority, the number of positive notifications amongst those born elsewhere abroad has increased five-fold since 2010. Tuberculosis amongst Aboriginal Australians has decreased following policy changes in response previous audits. Tuberculosis in Torres Strait residents, however, has increased from 12 cases (1993-2002) to 40 (2006-2016). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cultural concepts of tuberculosis and gender among the general population without tuberculosis in rural Maharashtra, India.

PubMed

Atre, Sachin R; Kudale, Abhay M; Morankar, Sudhakar N; Rangan, Sheela G; Weiss, Mitchell G

2004-11-01

Gender-specific patterns of experience, meaning, and behaviour for tuberculosis (TB) require consideration to guide control programmes. To clarify concepts of gender, culture, and TB in a rural endemic population of Maharashtra, India, this study of 80 men and 80 women employed qualitative and quantitative methods of cultural epidemiology, using a locally adapted semi-structured Explanatory Model Interview Catalogue (EMIC) interviews are instruments for cultural epidemiological study of the distribution of illness-related experiences, meanings, and behaviours. This interview queried respondents without active disease about vignettes depicting a man and woman with typical features of TB. Emotional and social symptoms were frequently reported for both vignettes, but more often considered most distressing for the female vignette; specified problems included arranging marriages, social isolation, and inability to care for children and family. Job loss and reduced income were regarded most troubling for the male vignette. Men and women typically identified sexual experience as the cause of TB for opposite-sex vignettes. With wider access to information about TB, male respondents more frequently recommended allopathic doctors and specialty services. Discussion considers the practical significance of gender-specific cultural concepts of TB.

Drivers of Tuberculosis Transmission.

PubMed

Mathema, Barun; Andrews, Jason R; Cohen, Ted; Borgdorff, Martien W; Behr, Marcel; Glynn, Judith R; Rustomjee, Roxana; Silk, Benjamin J; Wood, Robin

2017-11-03

Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ-release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Association of tuberculosis with multimorbidity and social networks

PubMed Central

Valenzuela-Jiménez, Hiram; Manrique-Hernández, Edgar Fabian; Idrovo, Alvaro Javier

2017-01-01

ABSTRACT The combination of tuberculosis with other diseases can affect tuberculosis treatment within populations. In the present study, social network analysis of data retrieved from the Mexican National Epidemiological Surveillance System was used in order to explore associations between the number of contacts and multimorbidity. The node degree was calculated for each individual with tuberculosis and included information from 242 contacts without tuberculosis. Multimorbidity was identified in 49.89% of individuals. The node degrees were highest for individuals with tuberculosis + HIV infection (p < 0.04) and lowest for those with tuberculosis + pulmonary edema (p < 0.07). Social network analysis should be used as a standard method for monitoring tuberculosis and tuberculosis-related syndemics. PMID:28125153

Predictors of knowledge about tuberculosis: results from SANHANES I, a national, cross-sectional household survey in South Africa.

PubMed

Naidoo, Pamela; Simbayi, Leickness; Labadarios, Demetre; Ntsepe, Yoliswa; Bikitsha, Nwabisa; Khan, Gadija; Sewpaul, Ronel; Moyo, Sizulu; Rehle, Thomas

2016-03-18

South Africa is one of the 22 high tuberculosis burden countries that contribute 80% of the global tuberculosis cases. Tuberculosis is infectious and due to its rapid and easy transmission route poses a threat to population health. Considering the importance of social and psychological factors in influencing health outcomes, appraising knowledge and awareness of tuberculosis, remain vital for effective tuberculosis control. The main aim of this study was to investigate the factors that predict knowledge about tuberculosis among 18-64 year old adults in South Africa. A cross-sectional survey method was used. Multi-stage disproportionate, stratified cluster sampling was used to select households within enumeration areas stratified by province and locality type. Based on the Human Sciences Research Council 2007 master sample, 500 Enumerator Areas representative of the socio-demographic profile of South Africa were identified and a random sample of 20 households was randomly selected from each Enumerator Area, yielding an overall sample of 10,000 households. The tuberculosis module contained in the South African National Health And Nutrition Examination Survey I was the only module that examined the social determinants of an infectious disease. This module was questionnaire-based with no biomarkers obtained to screen for the presence of tuberculosis disease among the participants. Data was collected by administering a researcher developed individual level questionnaire. Simple and multiple linear regression was used to determine the independent variables associated with tuberculosis knowledge. Half the sample (52.6%) was female and the majority of the respondents were black African (76.5%). More than two thirds (68.0%) resided in urban areas, 56.9% did not complete high school and half were not in formal employment. Significant predictors of tuberculosis knowledge were race, sex, completion of high school, being in employment, having a diagnosis of the disease in ones' life-time and learning about tuberculosis from television, brochures, health workers, and teachers. To reduce the burden of tuberculosis in South Africa, media campaigns targeting both rural and urban communities should include conveying accurate information about the disease. Policy makers should also address structural barriers that vulnerable communities face.

Genetic Diversity and Dynamic Distribution of Mycobacterium tuberculosis Isolates Causing Pulmonary and Extrapulmonary Tuberculosis in Thailand

PubMed Central

Srilohasin, Prapaporn; Tokunaga, Katsushi; Nishida, Nao; Prammananan, Therdsak; Smittipat, Nat; Mahasirimongkol, Surakameth; Chaiyasirinroje, Boonchai; Yanai, Hideki; Palittapongarnpim, Prasit

2014-01-01

This study examined the genetic diversity and dynamicity of circulating Mycobacterium tuberculosis strains in Thailand using nearly neutral molecular markers. The single nucleotide polymorphism (SNP)-based genotypes of 1,414 culture-positive M. tuberculosis isolates from 1,282 pulmonary tuberculosis (PTB) and 132 extrapulmonary TB (EPTB) patients collected from 1995 to 2011 were characterized. Among the eight SNP cluster groups (SCG), SCG2 (44.1%), which included the Beijing (BJ) genotype, and SCG1 (39.4%), an East African Indian genotype, were dominant. Comparisons between the genotypes of M. tuberculosis isolates causing PTB and EPTB in HIV-negative cases revealed similar prevalence trends although genetic diversity was higher in the PTB patients. The identification of 10 reported sequence types (STs) and three novel STs was hypothesized to indicate preferential expansion of the SCG2 genotype, especially the modern BJ ST10 (15.6%) and ancestral BJ ST19 (13.1%). An association between SCG2 and SCG1 genotypes and particular patient age groups implies the existence of different genetic advantages among the bacterial populations. The results revealed that increasing numbers of young patients were infected with M. tuberculosis SCGs 2 and 5, which contrasts with the reduction of the SCG1 genotype. Our results indicate the selection and dissemination of potent M. tuberculosis genotypes in this population. The determination of heterogeneity and dynamic population changes of circulating M. tuberculosis strains in countries using the Mycobacterium bovis BCG (bacillus Calmette-Guérin) vaccine are beneficial for vaccine development and control strategies. PMID:25297330

Mycobacterium tuberculosis Complex Genotype Diversity and Drug Resistance Profiles in a Pediatric Population in Mexico

PubMed Central

Macías Parra, Mercedes; Kumate Rodríguez, Jesús; Arredondo García, José Luís; López-Vidal, Yolanda; Castañón-Arreola, Mauricio; Balandrano, Susana; Rastogi, Nalin; Gutiérrez Castrellón, Pedro

2011-01-01

The aim of this study was to determine the frequency of drug resistance and the clonality of genotype patterns in M. tuberculosis clinical isolates from pediatric patients in Mexico (n = 90 patients from 19 states; time period—January 2002 to December 2003). Pulmonary disease was the most frequent clinical manifestation (71%). Children with systemic tuberculosis (TB) were significantly younger compared to patients with localized TB infections (mean 7.7 ± 6.2 years versus 15 ± 3.4 years P = 0.001). Resistance to any anti-TB drug was detected in 24/90 (26.7%) of the isolates; 21/90 (23.3%) and 10/90 (11.1%) were resistant to Isoniazid and Rifampicin, respectively, and 10/90 (11.1%) strains were multidrug-resistant (MDR). Spoligotyping produced a total of 55 different patterns; 12/55 corresponded to clustered isolates (n = 47, clustering rate of 52.2%), and 43/55 to unclustered isolates (19 patterns were designated as orphan by the SITVIT2 database). Database comparison led to designation of 36 shared types (SITs); 32 SITs (n = 65 isolates) matched a preexisting shared type in SITVIT2, whereas 4 SITs (n = 6 isolates) were newly created. Lineage classification based on principal genetic groups (PGG) revealed that 10% of the strains belonged to PGG1 (Bovis and Manu lineages). Among PGG2/3 group, the most predominant clade was the Latin-American and Mediterranean (LAM) in 27.8% of isolates, followed by Haarlem and T lineages. The number of single drug-resistant (DR) and multidrug-resistant (MDR-TB) isolates in this study was similar to previously reported in studies from adult population with risk factors. No association between the spoligotype, age, region, or resistance pattern was observed. However, contrary to a study on M. tuberculosis spoligotyping in Acapulco city that characterized a single cluster of SIT19 corresponding to the EAI2-Manila lineage in 70 (26%) of patients, not a single SIT19 isolate was found in our pediatric patient population. Neither did we find any shared type belonging to the EAI family which represents ancestral PGG1 strains within the M. tuberculosis complex. We conclude that the population structure of pediatric TB in our setting is different from the one prevailing in adult TB patient population of Guerrero. PMID:22567263

Description of the population structure and genetic diversity of tuberculosis in Estado de México, a low prevalence setting from Mexico.

PubMed

Zenteno-Cuevas, Roberto; Mendoza-Damián, Fabiola; Muñoz, Irving Cansino; Enciso-Moreno, Leonor; Pérez-Navarro, Lucia Monserrat; Ramírez-Hernández, Ma Dolores; Vázquez-Medina, Karen; Widrobo-García, Lorena; Lauzardo, Michael; Enciso-Moreno, José Antonio

2015-02-01

In order to identify the genetic characteristics of the strains of mycobacteria circulating in the Estado de México, one of the states with the lowest prevalence of tuberculosis in Mexico, spoligotyping and 12-loci MIRU-VNTR typing were used to genotype tuberculosis clinical isolates. The average age of the 183 patients analyzed was 50 (± 17) years, drug resistance was noted in 57 (31%) and multidrug resistance in 22 (12%) individuals. The results from the isolates recovered showed that 80% were located in four major Euro-American lineages: Haarlem (17%), LAM (15%), T (20%) and X (29%). Other lineages found in lower proportions were: EAI, S, Beijing, West African, Turkey, Vole and Bovis. Eighteen isolates were orphans. Only 57 isolates were grouped in nine clusters and the SIT119 (X1) showed the highest number of members (23). The LAM lineage showed an increased risk for development of drug resistance (RR=4, IC: 95%: 1.05-14.2, p = 0.03). Despite the important prevalence of four major lineages found and the diversity of strains circulating in the population, we found the presence of one of the largest populations of isolates clustered to the X lineage in a setting from a Latin American country. © 2014 APMIS. Published by John Wiley & Sons Ltd.

Genotypes of Mycobacterium tuberculosis in patients at risk of drug resistance in Bolivia.

PubMed

Monteserin, Johana; Camacho, Mirtha; Barrera, Lucía; Palomino, Juan Carlos; Ritacco, Viviana; Martin, Anandi

2013-07-01

Bolivia ranks among the 10 Latin American countries with the highest rates of tuberculosis (TB) and multidrug resistant (MDR) TB. In view of this, and of the lacking information on the population structure of Mycobacterium tuberculosis in the country, we explored genotype associations with drug resistance and clustering by analyzing isolates collected in 2010 from 100 consecutive TB patients at risk of drug resistance in seven of the nine departments in which Bolivia is divided. Fourteen isolates were MDR, 29 had other drug resistance profiles, and 57 were pansusceptible. Spoligotype family distribution was: Haarlem 39.4%, LAM 26.3%, T 22.2%, S 2.0%, X 1.0%, orphan 9.1%, with very low intra-family diversity and absence of Beijing genotypes. We found 66 different MIRU-VNTR patterns; the most frequent corresponded to Multiple Locus Variable Analysis (MLVA) MtbC15 patterns 860, 372 and 873. Twelve clusters, each with identical MIRU-VNTR and spoligotypes, gathered 35 patients. We found no association of genotype with drug resistant or MDR-TB. Clustering associated with SIT 50 and the H3 subfamily to which it belongs (p<0.0001). The largest cluster involved isolates from three departments and displayed a genotype (SIT 50/MLVA 860) previously identified in Bolivian migrants into Spain and Argentina suggesting that this genotype is widespread among Bolivian patients. Our study presents a first overview of M. tuberculosis genotypes at risk of drug resistance circulating in Bolivia. However, results should be taken cautiously because the sample is small and includes a particular subset of M. tuberculosis population. Copyright © 2013 Elsevier B.V. All rights reserved.

Medical Surveillance Monthly Report. Volume 20, Number 5

DTIC Science & Technology

2013-05-01

a diagnosis of latent tuberculosis infection (LTBI). Although only pulmonary TB is reportable in the U.S. military,14 extra- pulmonary cases were...I G U R E 1 . Numbers of cases and rates of pulmonary tuberculosis (TB), active component, U.S. Armed Forces, and expected age-adjusted rates of... pulmonary tuberculosis in the general U.S. population, based on U.S. military population standard, 1998-2012a aData not available from the CDC in 2012

The burden of disease due to tuberculosis in the state of Santa Catarina, Brazil.

PubMed

Ferrer, Glênio César Nunes; da Silva, Rosemeri Maurici; Ferrer, Kelian Tenfen; Traebert, Jefferson

2014-01-01

To estimate the burden of disease due to tuberculosis in the state of Santa Catarina, Brazil, in 2009. This was an epidemiological study with an ecological design. Data on tuberculosis incidence and mortality were collected from specific Brazilian National Ministry of Health databases. The burden of disease due to tuberculosis was based on the calculation of disability-adjusted life years (DALYs). The DALYs were estimated by adding the years of life lost (YLLs) and years lived with disability (YLDs). Absolute values were transformed into rates per 100,000 population. The rates were calculated by gender, age group, and health care macroregion. The burden of disease due to tuberculosis was 5,644.27 DALYs (92.25 DALYs/100,000 population), YLLs and YLDs respectively accounting for 78.77% and 21.23% of that total. The highest rates were found in males in the 30-44 and 45-59 year age brackets, although that was not true in every health care macroregion. Overall, the highest estimated burden was in the Planalto Norte macroregion (179.56 DALYs/100,000 population), followed by the Nordeste macroregion (167.07 DALYs/100,000 population). In the majority of the health care macroregions of Santa Catarina, the burden of disease due to tuberculosis was concentrated in adult males, the level of that concentration varying among the various macroregions.

The burden of disease due to tuberculosis in the state of Santa Catarina, Brazil*, **

PubMed Central

Ferrer, Glênio César Nunes; da Silva, Rosemeri Maurici; Ferrer, Kelian Tenfen; Traebert, Jefferson

2014-01-01

OBJECTIVE: To estimate the burden of disease due to tuberculosis in the state of Santa Catarina, Brazil, in 2009. METHODS: This was an epidemiological study with an ecological design. Data on tuberculosis incidence and mortality were collected from specific Brazilian National Ministry of Health databases. The burden of disease due to tuberculosis was based on the calculation of disability-adjusted life years (DALYs). The DALYs were estimated by adding the years of life lost (YLLs) and years lived with disability (YLDs). Absolute values were transformed into rates per 100,000 population. The rates were calculated by gender, age group, and health care macroregion. RESULTS: The burden of disease due to tuberculosis was 5,644.27 DALYs (92.25 DALYs/100,000 population), YLLs and YLDs respectively accounting for 78.77% and 21.23% of that total. The highest rates were found in males in the 30-44 and 45-59 year age brackets, although that was not true in every health care macroregion. Overall, the highest estimated burden was in the Planalto Norte macroregion (179.56 DALYs/100,000 population), followed by the Nordeste macroregion (167.07 DALYs/100,000 population). CONCLUSIONS: In the majority of the health care macroregions of Santa Catarina, the burden of disease due to tuberculosis was concentrated in adult males, the level of that concentration varying among the various macroregions. PMID:24626271

Population structure and circulating genotypes of drug-sensitive and drug-resistant Mycobacterium tuberculosis clinical isolates in São Paulo state, Brazil.

PubMed

Martins, Maria Conceição; Giampaglia, Carmen M Saraiva; Oliveira, Rosângela S; Simonsen, Vera; Latrilha, Fábio Oliveira; Moniz, Letícia Lisboa; Couvin, David; Rastogi, Nalin; Ferrazoli, Lucilaine

2013-03-01

São Paulo is the most populous Brazilian state and reports the largest number of tuberculosis cases in the country annually (over 18,500). This study included 193 isolates obtained during the 2nd Nationwide Survey on Mycobacterium tuberculosis Drug Resistance that was conducted in São Paulo state and 547 isolates from a laboratory based study of drug resistance that were analyzed by the Mycobacteria Reference Laboratory at the Institute Adolfo Lutz. Both studies were conducted from 2006 to 2008 and sought to determine the genetic diversity and pattern of drug resistance of M. tuberculosis isolates (MTC) circulating in São Paulo. The patterns obtained from the spoligotyping analysis demonstrated that 51/740 (6.9%) of the isolates corresponded to orphan patterns and that 689 (93.1%) of the isolates distributed into 144 shared types, including 119 that matched a preexisting shared type in the SITVIT2 database and 25 that were new isolates. A total of 77/144 patterns corresponded to unique isolates, while the remaining 67 corresponded to clustered patterns (n=612 isolates clustered into groups of 2-84 isolates each). The evolutionarily ancient PGG1 lineages (Beijing, CAS1-DEL, EAI3-IND, and PINI2) were rarely detected in São Paulo and comprised only 13/740, or 1.76%, of the total isolates; all of the remaining 727/740, or 98.24%, of the MTC isolates from São Paulo state were from the recent PGG2/3 evolutionary isolates belonging to the LAM, T, S, X, and Haarlem lineages, i.e., the Euro-American group. This study provides the first overview of circulating genotypes of M. tuberculosis in São Paulo state and demonstrates that the clustered shared types containing seven or more M. tuberculosis isolates that are spread in São Paulo state included both resistant and susceptible isolates. Copyright © 2012 Elsevier B.V. All rights reserved.

Primary Health Care and tuberculosis: services evaluation.

PubMed

Wysocki, Anneliese Domingues; Ponce, Maria Amélia Zanon; Brunello, Maria Eugênia Firmino; Beraldo, Aline Ale; Vendramini, Silvia Helena Figueiredo; Scatena, Lúcia Marina; Ruffino, Antonio; Villa, Tereza Cristina Scatena

2017-01-01

In order to control tuberculosis, the Brazilian Ministry of Health recommends the decentralization of control actions directed to the Primary Health Care, and there are few studies on the performance of the Tuberculosis Control Program in decentralized contexts. To evaluate the performance of Primary Health Care services in tuberculosis treatment. This is an evaluative study with cross-sectional approach conducted in 2011. Two hundred and thirty-nine health professionals from Primary Health Care units were interviewed using a structured instrument based on the evaluation reference of the health services quality (structure - process - results). The performance of these services was analyzed applying techniques of descriptive statistics, validation, and construction of indicators and by determining the reduced variable "Z". The indicators "participation of professionals in tuberculosis patients' care" (structure) and "reference and counterreference" (process) had the best evaluations, whereas "professional training" (structure) and "external actions for tuberculosis control" (process) had the worst results. The decentralization of tuberculosis control actions has been taking place in a vertical manner in Primary Health Care. The challenge of controlling tuberculosis involves overcoming constraints related to the engagement, training, and turnover rates among health professionals, which is a coordination between services and monitoring of control actions in Primary Health Care.

Molecular characterisation of Mycobacterium tuberculosis isolates in the First National Survey of Anti-tuberculosis Drug Resistance from Venezuela

PubMed Central

Aristimuño, Liselotte; Armengol, Raimond; Cebollada, Alberto; España, Mercedes; Guilarte, Alexis; Lafoz, Carmen; Lezcano, María A; Revillo, María J; Martín, Carlos; Ramírez, Carmen; Rastogi, Nalin; Rojas, Janet; de Salas, Albina Vázques; Sola, Christophe; Samper, Sofía

2006-01-01

Background Molecular typing of Mycobacterium tuberculosis strains has become a valuable tool in the epidemiology of tuberculosis (TB) by allowing detection of outbreaks, tracking of epidemics, identification of genotypes and transmission events among patients who would have remained undetected by conventional contact investigation. This is the first genetic biodiversity study of M. tuberculosis in Venezuela. Thus, we investigated the genetic patterns of strains isolated in the first survey of anti-tuberculosis drug-resistance realised as part of the Global Project of Anti-tuberculosis Drug Resistance Surveillance (WHO/IUATLD). Results Clinical isolates (670/873) were genotyped by spoligotyping. The results were compared with the international spoligotyping database (SpolDB4). Multidrug resistant (MDR) strains (14/18) were also analysed by IS6110-RFLP assays, and resistance to isoniazid and rifampicin was characterised. Spoligotyping grouped 82% (548/670) of the strains into 59 clusters. Twenty new spoligotypes (SITs) specific to Venezuela were identified. Eight new inter-regional clusters were created. The Beijing genotype was not found. The genetic network shows that the Latin American and Mediterranean family constitutes the backbone of the genetic TB population-structure in Venezuela, responsible of >60% of total TB cases studied. MDR was 0.5% in never treated patients and 13.5% in previously treated patients. Mutations in rpoB gene and katG genes were detected in 64% and 43% of the MDR strains, respectively. Two clusters were found to be identical by the four different analysis methods, presumably representing cases of recent transmission of MDR tuberculosis. Conclusion This study gives a first overview of the M. tuberculosis strains circulating in Venezuela during the first survey of anti-tuberculosis drug-resistance. It may aid in the creation of a national database that will be a valuable support for further studies. PMID:17032442

The Development and Piloting of Parallel Scales Measuring External and Internal HIV and Tuberculosis Stigma Among Healthcare Workers in the Free State Province, South Africa.

PubMed

Wouters, Edwin; Rau, Asta; Engelbrecht, Michelle; Uebel, Kerry; Siegel, Jacob; Masquillier, Caroline; Kigozi, Gladys; Sommerland, Nina; Yassi, Annalee

2016-05-15

The dual burden of tuberculosis and human immunodeficiency virus (HIV) is severely impacting the South African healthcare workforce. However, the use of on-site occupational health services is hampered by stigma among the healthcare workforce. The success of stigma-reduction interventions is difficult to evaluate because of a dearth of appropriate scientific tools to measure stigma in this specific professional setting. The current pilot study aimed to develop and test a range of scales measuring different aspects of stigma-internal and external stigma toward tuberculosis as well as HIV-in a South African healthcare setting. The study employed data of a sample of 200 staff members of a large hospital in Bloemfontein, South Africa. Confirmatory factor analysis produced 7 scales, displaying internal construct validity: (1) colleagues' external HIV stigma, (2) colleagues' actions against external HIV stigma, (3) respondent's external HIV stigma, (4) respondent's internal HIV stigma, (5) colleagues' external tuberculosis stigma, (6) respondent's external tuberculosis stigma, and (7) respondent's internal tuberculosis stigma. Subsequent analyses (reliability analysis, structural equation modeling) demonstrated that the scales displayed good psychometric properties in terms of reliability and external construct validity. The study outcomes support the use of the developed scales as a valid and reliable means to measure levels of tuberculosis- and HIV-related stigma among the healthcare workforce in a resource-limited context. Future studies should build on these findings to fine-tune the instruments and apply them to larger study populations across a range of different resource-limited healthcare settings with high HIV and tuberculosis prevalence. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis.

PubMed

Francisco, Ngiambudulu M; Hsu, Nai-Jen; Keeton, Roanne; Randall, Philippa; Sebesho, Boipelo; Allie, Nasiema; Govender, Dhirendra; Quesniaux, Valerie; Ryffel, Bernhard; Kellaway, Lauriston; Jacobs, Muazzam

2015-06-26

Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. We generated neuron-specific TNF-deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.

The Development and Piloting of Parallel Scales Measuring External and Internal HIV and Tuberculosis Stigma Among Healthcare Workers in the Free State Province, South Africa

PubMed Central

Wouters, Edwin; Rau, Asta; Engelbrecht, Michelle; Uebel, Kerry; Siegel, Jacob; Masquillier, Caroline; Kigozi, Gladys; Sommerland, Nina; Yassi, Annalee

2016-01-01

Background The dual burden of tuberculosis and human immunodeficiency virus (HIV) is severely impacting the South African healthcare workforce. However, the use of on-site occupational health services is hampered by stigma among the healthcare workforce. The success of stigma-reduction interventions is difficult to evaluate because of a dearth of appropriate scientific tools to measure stigma in this specific professional setting. Methods The current pilot study aimed to develop and test a range of scales measuring different aspects of stigma—internal and external stigma toward tuberculosis as well as HIV—in a South African healthcare setting. The study employed data of a sample of 200 staff members of a large hospital in Bloemfontein, South Africa. Results Confirmatory factor analysis produced 7 scales, displaying internal construct validity: (1) colleagues’ external HIV stigma, (2) colleagues’ actions against external HIV stigma, (3) respondent’s external HIV stigma, (4) respondent’s internal HIV stigma, (5) colleagues’ external tuberculosis stigma, (6) respondent’s external tuberculosis stigma, and (7) respondent’s internal tuberculosis stigma. Subsequent analyses (reliability analysis, structural equation modeling) demonstrated that the scales displayed good psychometric properties in terms of reliability and external construct validity. Conclusions The study outcomes support the use of the developed scales as a valid and reliable means to measure levels of tuberculosis- and HIV-related stigma among the healthcare workforce in a resource-limited context. Future studies should build on these findings to fine-tune the instruments and apply them to larger study populations across a range of different resource-limited healthcare settings with high HIV and tuberculosis prevalence. PMID:27118854

Global fund financing of tuberculosis services delivery in prisons.

PubMed

Lee, Donna; Lal, S S; Komatsu, Ryuichi; Zumla, Alimuddin; Atun, Rifat

2012-05-15

Despite concerted efforts to scale up tuberculosis control with large amounts of international financing in the last 2 decades, tuberculosis continues to be a social issue affecting the world's most marginalized and disadvantaged communities. This includes prisoners, estimated at about 10 million globally, for whom tuberculosis is a leading cause of mortality and morbidity. The Global Fund to Fight AIDS, Tuberculosis and Malaria has emerged as the single largest international donor for tuberculosis control, including funding support in delivering tuberculosis treatment for the confined population. The Global Fund grants database, with an aggregate approved investment of $21.7 billion in 150 countries by the end of 2010, was reviewed to identify tuberculosis and human immunodeficiency virus/tuberculosis grants and activities that monitored the delivery of tuberculosis treatment and support activities in penitentiary settings. The distribution and trend of number of countries with tuberculosis prison support was mapped by year, geographic region, tuberculosis or multidrug-resistant tuberculosis burden, and prison population rate. We examined the types of grant recipients managing program delivery, their performance, and the nature and range of services provided. Fifty-three of the 105 countries (50%) with Global Fund-supported tuberculosis programs delivered services within prison settings. Thirty-two percent (73 of 228) of tuberculosis grants, representing $558 million of all disbursements of Global Fund tuberculosis support by the end of 2010, included output indicators related to tuberculosis services delivered in prisons. Nearly two-thirds (64%) of these grants were implemented by governments, with the remaining by civil society and other partners. In terms of services, half (36 of 73) of grants provided diagnosis and treatment and an additional 27% provided screening and monitoring of tuberculosis for prisoners. The range of services tracked was limited in scope and scale, with 69% offering only 1 type of service and less than one-fifth offering 2 types of service. This study is a preliminary attempt to examine Global Fund investments in the fight against tuberculosis in prison settings. Tuberculosis services delivered in prisons have increased in the last decade, but systematic information on funding levels and gaps, services provided, and cost-effective delivery models for delivering tuberculosis services in prisons are lacking.

Fine mapping of genetic polymorphisms of pulmonary tuberculosis within chromosome 18q11.2 in the Chinese population: a case-control study.

PubMed

Dai, Yaoyao; Zhang, Xia; Pan, Hongqiu; Tang, Shaowen; Shen, Hongbing; Wang, Jianming

2011-10-22

Recently, one genome-wide association study identified a susceptibility locus of rs4331426 on chromosome 18q11.2 for tuberculosis in the African population. To validate the significance of this susceptibility locus in other areas, we conducted a case-control study in the Chinese population. The present study consisted of 578 cases and 756 controls. The SNP rs4331426 and other six tag SNPs in the 100 Kbp up and down stream of rs4331426 on chromosome 18q11.2 were genotyped by using the Taqman-based allelic discrimination system. As compared with the findings from the African population, genetic variation of the SNP rs4331426 was rare among the Chinese. No significant differences were observed in genotypes or allele frequencies of the tag SNPs between cases and controls either before or after adjusting for age, sex, education, smoking, and drinking history. However, we observed strong linkage disequilibrium of SNPs. Constructed haplotypes within this block were linked the altered risks of tuberculosis. For example, in comparison with the common haplotype AA(rs8087945-rs12456774), haplotypes AG(rs8087945-rs12456774) and GA(rs8087945-rs12456774) were associated with a decreased risk of tuberculosis, with the adjusted odds ratio(95% confidence interval) of 0.34(0.27-0.42) and 0.22(0.16-0.29), respectively. Susceptibility locus of rs4331426 discovered in the African population could not be validated in the Chinese population. None of genetic polymorphisms we genotyped were related to tuberculosis in the single-point analysis. However, haplotypes on chromosome 18q11.2 might contribute to an individual's susceptibility. More work is necessary to identify the true causative variants of tuberculosis.

Vitamin D and solar ultraviolet radiation in the risk and treatment of tuberculosis.

PubMed

Ralph, Anna P; Ralph, Anna R; Lucas, Robyn M; Norval, Mary

2013-01-01

Improved understanding of the association between tuberculosis and vitamin D is needed to inform clinical practice. Vitamin D has both immunostimulatory and immunosuppressive effects relevant to human antimycobacterial responses. Ultraviolet radiation, the main source of vitamin D, also induces immunomodulation and could affect the relation between vitamin D and tuberculosis. Clinical trials of vitamin D supplementation in patients with tuberculosis have produced largely negative results, prompting the review of dosing regimens-an explanation for low 25-hydroxyvitamin D status in patients with active tuberculosis is also needed. The reporting of vitamin D deficiency needs to address assay inaccuracies, rising thresholds to define sufficiency, and scarce knowledge of the concentrations needed for optimum immune responses. Future research to measure the effect of the inflammatory setting on serum concentrations of 25-hydroxyvitamin D, at tuberculosis diagnosis and during recovery, could help to account for 25-hydroxyvitamin D changes in these concentrations in patients with tuberculosis. Studies into the role of vitamin D supplementation in latent tuberculosis justify clinical trials in this population, but pose methodological challenges. Vitamin D trials in patients with active tuberculosis should be done in well selected populations using adequate vitamin D doses, although such doses remain undefined. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tuberculosis control program in the municipal context: performance evaluation

PubMed Central

Arakawa, Tiemi; Magnabosco, Gabriela Tavares; Andrade, Rubia Laine de Paula; Brunello, Maria Eugenia Firmino; Monroe, Aline Aparecida; Ruffino-Netto, Antonio; Scatena, Lucia Marina; Villa, Tereza Cristina Scatena

2017-01-01

ABSTRACT OBJECTIVE The objective of this study is to evaluate the performance of the Tuberculosis Control Program in municipalities of the State of São Paulo. METHODS This is a program evaluation research, with ecological design, which uses three non-hierarchical groups of the municipalities of the State of São Paulo according to their performance in relation to operational indicators. We have selected 195 municipalities with at least five new cases of tuberculosis notified in the Notification System of the State of São Paulo and with 20,000 inhabitants or more in 2010. The multiple correspondence analysis was used to identify the association between the groups of different performances, the epidemiological and demographic characteristics, and the characteristics of the health systems of the municipalities. RESULTS The group with the worst performance showed the highest rates of abandonment (average [avg] = 10.4, standard deviation [sd] = 9.4) and the lowest rates of supervision of Directly Observed Treatment (avg = 6.1, sd = 12.9), and it was associated with low incidence of tuberculosis, high tuberculosis and HIV, small population, high coverage of the Family Health Strategy/Program of Community Health Agents, and being located on the countryside. The group with the best performance presented the highest cure rate (avg = 83.7, sd = 10.5) and the highest rate of cases in Directly Observed Treatment (avg = 83.0, sd = 12.7); the group of regular performance showed regular results for outcome (avg cure = 79.8, sd = 13.2; abandonment avg = 9.5, sd = 8.3) and supervision of the Directly Observed Treatment (avg = 42.8, sd = 18.8). Large population, low coverage of the Family Health Strategy/Program of Community Health Agents, high incidence of tuberculosis and AIDS, and being located on the coast and in metropolitan areas were associated with these groups. CONCLUSIONS The findings highlight the importance of the Directly Observed Treatment in relation to the outcome for treatment and raise reflections on the structural and managerial capacity of municipalities in the implementation of the Tuberculosis Control Program. PMID:28380207

Hyperendemic pulmonary tuberculosis in peri-urban areas of Karachi, Pakistan

PubMed Central

Akhtar, Saeed; White, Franklin; Hasan, Rumina; Rozi, Shafquat; Younus, Mohammad; Ahmed, Faiza; Husain, Sara; Khan, Bilquis Sana

2007-01-01

Background Currently there are very limited empirical data available on the prevalence of pulmonary tuberculosis among residents of marginalized settings in Pakistan. This study assessed the prevalence of pulmonary tuberculosis through active case detection and evaluated predictors of pulmonary tuberculosis among residents of two peri-urban neighbourhoods of Karachi, Pakistan. Methods A cross-sectional study was conducted in two peri-urban neighbourhoods from May 2002 to November 2002. Systematic sampling design was used to select households for inclusion in the study. Consenting subjects aged 15 years or more from selected households were interviewed and, whenever possible, sputum samples were obtained. Sputum samples were subjected to direct microscopy by Ziehl-Neelson method, bacterial culture and antibiotic sensitivity tests. Results The prevalence (per 100,000) of pulmonary tuberculosis among the subjects aged 15 years or more, who participated in the study was 329 (95% confidence interval (CI): 195 – 519). The prevalence (per 100,000) of pulmonary tuberculosis adjusted for non-sampling was 438 (95% CI: 282 – 651). Other than cough, none of the other clinical variables was significantly associated with pulmonary tuberculosis status. Analysis of drug sensitivity pattern of 15 strains of Mycobacterium tuberculosis revealed that one strain was resistant to isoniazid alone, one to streptomycin alone and one was resistant to isoniazid and streptomycin. The remaining 12 strains were susceptible to all five drugs including streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide. Conclusion This study of previously undetected tuberculosis cases in an impoverished peri-urban setting reveals the poor operational performance of Pakistan's current approach to tuberculosis control; it also demonstrates a higher prevalence of pulmonary tuberculosis than current national estimates. Public health authorities may wish to augment health education efforts aimed at prompting health-seeking behaviour to facilitate more complete and earlier case detection. Such efforts to improve passive case-finding, if combined with more accessible DOTS infra-structure for treatment of detected cases, may help to diminish the high tuberculosis-related morbidity and mortality in marginalized populations. The economics of implementing a more active approach to case finding in resource-constrained setting also deserve further study. PMID:17477870

Influence of diabetes mellitus and risk factors in activating latent tuberculosis infection: a case for targeted screening in malaysia.

PubMed

Swarna Nantha, Y

2012-10-01

A review of the epidemiology of tuberculosis, its contributing risk factors (excluding HIV) and the role of screening latent tuberculosis infection in Malaysia was done. Despite the global and domestic decrease in prevalence rates of tuberculosis in the past decade, there is an alarming increase in the trend of non communicable diseases in the country. High prevalence rates of major risk factors leading to reactivation of tuberculosis were seen within the population, with diabetes mellitus being in the forefront. The rising numbers in the ageing population of Malaysia poses a further threat of re-emergence of tuberculosis in the years to come. Economically, screening of diabetic patients with comorbidities for latent tuberculosis infection (LTBI) using two major techniques, namely tuberculin sensitivity (TST) and Interferon gamma release assay tests (IGRA) could be a viable option. The role of future research in the detection of LTBI in the Malaysian setting might be necessary to gauge the disease reservoir before implementing prophylactic measures for high risk groups involved.

Designing and Evaluating Interventions to Halt the Transmission of Tuberculosis.

PubMed

Dowdy, David W; Grant, Alison D; Dheda, Keertan; Nardell, Edward; Fielding, Katherine; Moore, David A J

2017-11-03

To reduce the incidence of tuberculosis, it is insufficient to simply understand the dynamics of tuberculosis transmission. Rather, we must design and rigorously evaluate interventions to halt transmission, prioritizing those interventions most likely to achieve population-level impact. Synergy in reducing tuberculosis transmission may be attainable by combining interventions that shrink the reservoir of latent Mycobacterium tuberculosis infection (preventive therapy), shorten the time between disease onset and treatment initiation (case finding and diagnosis), and prevent transmission in key settings, such as the built environment (infection control). In evaluating efficacy and estimating population-level impact, cluster-randomized trials and mechanistic models play particularly prominent roles. Historical and contemporary evidence suggests that effective public health interventions can halt tuberculosis transmission, but an evidence-based approach based on knowledge of local epidemiology is necessary for success. We provide a roadmap for designing, evaluating, and modeling interventions to interrupt the process of transmission that fuels a diverse array of tuberculosis epidemics worldwide. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Tuberculosis as a marker of inequities in the context of socio-spatial transformation

PubMed Central

Pedro, Alexandre San; Gibson, Gerusa; dos Santos, Jefferson Pereira Caldas; de Toledo, Luciano Medeiros; Sabroza, Paulo Chagastelles; de Oliveira, Rosely Magalhães

2017-01-01

ABSTRACT OBJECTIVE This study aims to analyze the association between the incidence of tuberculosis and different socioeconomic indicators in a territory of intense transformation of the urban space. METHODS This is an ecological study, whose analysis units were the neighborhoods of the city of Itaboraí, state of Rio de Janeiro, Brazil. The data have been analyzed by generalized linear models. The response variable was incidence of tuberculosis from 2006 to 2011. The independent variables were the socio-demographic indicators. The spatial distribution of tuberculosis was analyzed with the elaboration of thematic maps. RESULTS The results have shown a significant association between the incidence of tuberculosis and variables that reflect different dimensions of living conditions, such as consumer goods, housing conditions and its surroundings, agglomeration of population, and income distribution. CONCLUSIONS The disproportionate incidence of tuberculosis in populations with worse living conditions highlights the persistence of socioeconomic determinants in the reproduction of the disease. Different municipal public sectors need to better articulate with local tuberculosis control programs to reduce the social burden of the disease. PMID:28225909

Experience with a tuberculosis antigen test in Rhodesia.

PubMed

Cookson, J B; Cruickshank, J G; Ellis, B P

1977-10-01

Experience with a new serological method for the diagnosis of tuberculosis is reported in a predominantly black population. We have found that in only 69% of 167 patients was there agreement between serology and the presence or absence of tuberculosis. Both false positive and false negative results were common. Of 47 healthy controls, 80% were positive. These results are less satisfactory than previous studies but differences in the reading of the results seems an unlikely explanation. Differences in the populations studied may be an important factor.

Insight into the structural requirements of aminopyrimidine derivatives for good potency against both purified enzyme and whole cells of M. tuberculosis: combination of HQSAR, CoMSIA, and MD simulation studies.

PubMed

Punkvang, Auradee; Hannongbua, Supa; Saparpakorn, Patchreenart; Pungpo, Pornpan

2016-05-01

The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 < .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC > 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure-activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure-activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells.

The Influence of Host and Bacterial Genotype on the Development of Disseminated Disease with Mycobacterium tuberculosis

PubMed Central

Caws, Maxine; Thwaites, Guy; Dunstan, Sarah; Hawn, Thomas R.; Thi Ngoc Lan, Nguyen; Thuong, Nguyen Thuy Thuong; Stepniewska, Kasia; Huyen, Mai Nguyet Thu; Bang, Nguyen Duc; Huu Loc, Tran; Gagneux, Sebastien; van Soolingen, Dick; Kremer, Kristin; van der Sande, Marianne; Small, Peter; Thi Hoang Anh, Phan; Chinh, Nguyen Tran; Thi Quy, Hoang; Thi Hong Duyen, Nguyen; Quang Tho, Dau; Hieu, Nguyen T.; Torok, Estee; Hien, Tran Tinh; Dung, Nguyen Huy; Thi Quynh Nhu, Nguyen; Duy, Phan Minh; van Vinh Chau, Nguyen; Farrar, Jeremy

2008-01-01

The factors that govern the development of tuberculosis disease are incompletely understood. We hypothesized that some strains of Mycobacterium tuberculosis (M. tuberculosis) are more capable of causing disseminated disease than others and may be associated with polymorphisms in host genes responsible for the innate immune response to infection. We compared the host and bacterial genotype in 187 Vietnamese adults with tuberculous meningitis (TBM) and 237 Vietnamese adults with uncomplicated pulmonary tuberculosis. The host genotype of tuberculosis cases was also compared with the genotype of 392 cord blood controls from the same population. Isolates of M. tuberculosis were genotyped by large sequence polymorphisms. The hosts were defined by polymorphisms in genes encoding Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and Toll-like receptor-2 (TLR-2). We found a significant protective association between the Euro-American lineage of M. tuberculosis and pulmonary rather than meningeal tuberculosis (Odds ratio (OR) for causing TBM 0.395, 95% confidence intervals (C.I.) 0.193–0.806, P = 0.009), suggesting these strains are less capable of extra-pulmonary dissemination than others in the study population. We also found that individuals with the C allele of TLR-2 T597C allele were more likely to have tuberculosis caused by the East-Asian/Beijing genotype (OR = 1.57 [95% C.I. 1.15–2.15]) than other individuals. The study provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates, for the first time, a significant interaction between host and bacterial genotypes and the development of tuberculosis. PMID:18369480

A spatial analysis of social and economic determinants of tuberculosis in Brazil.

PubMed

Harling, Guy; Castro, Marcia C

2014-01-01

We investigated the spatial distribution, and social and economic correlates, of tuberculosis in Brazil between 2002 and 2009 using municipality-level age/sex-standardized tuberculosis notification data. Rates were very strongly spatially autocorrelated, being notably high in urban areas on the eastern seaboard and in the west of the country. Non-spatial ecological regression analyses found higher rates associated with urbanicity, population density, poor economic conditions, household crowding, non-white population and worse health and healthcare indicators. These associations remained in spatial conditional autoregressive models, although the effect of poverty appeared partially confounded by urbanicity, race and spatial autocorrelation, and partially mediated by household crowding. Our analysis highlights both the multiple relationships between socioeconomic factors and tuberculosis in Brazil, and the importance of accounting for spatial factors in analysing socioeconomic determinants of tuberculosis. © 2013 Published by Elsevier Ltd.

Population structure and infectious disease risk in southern Africa.

PubMed

Uren, Caitlin; Möller, Marlo; van Helden, Paul D; Henn, Brenna M; Hoal, Eileen G

2017-06-01

The KhoeSan populations are the earliest known indigenous inhabitants of southern Africa. The relatively recent expansion of Bantu-speaking agropastoralists, as well as European colonial settlement along the south-west coast, dramatically changed patterns of genetic diversity in a region which had been largely isolated for thousands of years. Owing to this unique history, population structure in southern Africa reflects both the underlying KhoeSan genetic diversity as well as differential recent admixture. This population structure has a wide range of biomedical and sociocultural implications; such as changes in disease risk profiles. Here, we consolidate information from various population genetic studies that characterize admixture patterns in southern Africa with an aim to better understand differences in adverse disease phenotypes observed among groups. Our review confirms that ancestry has a direct impact on an individual's immune response to infectious diseases. In addition, we emphasize the importance of collaborative research, especially for populations in southern Africa that have a high incidence of potentially fatal infectious diseases such as HIV and tuberculosis.

Tuberculosis, Fiji, 2002-2013.

PubMed

Pezzoli, Lorenzo; Gounder, Shakti; Tamani, Talatoka; Daulako, Mary Raori; Underwood, Frank; Mainawalala, Sakiusa; Nawadra-Taylor, Vasiti; Rafai, Eric; Gillini, Laura

2016-03-01

During 2002-2013, a total of 1,890 tuberculosis cases were recorded in Fiji. Notification rates per 100,000 population increased from 17.4 cases in 2002 to 28.4 in 2013. Older persons were most affected, but tuberculosis also increased sharply in persons 25-44 years of age.

A proposed national strategy for tuberculosis vaccine development.

PubMed

Ginsberg, A M

2000-06-01

The global tuberculosis epidemic causes approximately 5% of deaths worldwide. Despite recent concerted and largely successful tuberculosis control efforts, the incidence of tuberculosis in the United States remains 74-fold higher than the stated elimination goal of <1 case per million population by the year 2010. Current bacille Calmette-Guérin vaccines, although efficacious in preventing extrapulmonary tuberculosis in young children, have shown widely variable efficacy in preventing adult pulmonary tuberculosis, confound skin test screening, and are not recommended for use in the United States. The Advisory Council for Elimination of Tuberculosis recently stated that tuberculosis would not be eliminated from the United States without a more effective vaccine. Recent scientific advances have created unprecedented opportunity for tuberculosis vaccine development. Therefore, members of the broad tuberculosis research and control communities have recently created and proposed a national strategy, or blueprint, for tuberculosis vaccine development, which is presented here.

Tuberculosis in Sudan: a study of Mycobacterium tuberculosis strain genotype and susceptibility to anti-tuberculosis drugs

PubMed Central

2011-01-01

Background Sudan is a large country with a diverse population and history of civil conflict. Poverty levels are high with a gross national income per capita of less than two thousand dollars. The country has a high burden of tuberculosis (TB) with an estimated 50,000 incident cases during 2009, when the estimated prevalence was 209 cases per 100,000 of the population. Few studies have been undertaken on TB in Sudan and the prevalence of drug resistant disease is not known. Methods In this study Mycobacterium tuberculosis isolates from 235 patients attending three treatment centers in Sudan were screened for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin by the proportion method on Lowenstein Jensen media. 232 isolates were also genotyped by spoligotyping. Demographic details of patients were recorded using a structured questionnaire. Statistical analyses were conducted to examine the associations between drug resistance with risk ratios computed for a set of risk factors (gender, age, case status - new or relapse, geographic origin of the patient, spoligotype, number of people per room, marital status and type of housing). Results Multi drug-resistant tuberculosis (MDR-TB), being resistance to at least rifampicin and isoniazid, was found in 5% (95% CI: 2,8) of new cases and 24% (95% CI: 14,34) of previously treated patients. Drug resistance was associated with previous treatment with risk ratios of 3.51 (95% CI: 2.69-4.60; p < 0.001) for resistance to any drug and 5.23 (95% CI: 2.30-11.90; p < 0.001) for MDR-TB. Resistance was also associated with the geographic region of origin of the patient, being most frequently observed in patients from the Northern region and least in the Eastern region with risk ratios of 7.43 (95%CI:3.42,16.18; p: < 0.001) and 14.09 (95%CI:1.80,110.53; p:0.026) for resistance to any drug and MDR-TB. The major genotype observed was of the Central Asia spoligotype family (CAS1_Delhi), representing 49% of the 232 isolates examined. Conclusions We conclude that emergence of drug resistant tuberculosis has the potential to be a serious public health problem in Sudan and that strengthened tuberculosis control and improved monitoring of therapy is needed. Further surveillance is required to fully ascertain the extent of the problem. PMID:21846389

Advances in Mycobacterium tuberculosis therapeutics discovery utlizing structural biology

PubMed Central

Chim, Nicholas; Owens, Cedric P.; Contreras, Heidi; Goulding, Celia W.

2013-01-01

In 2012, tuberculosis (TB) remains a global health threat and is exacerbated both by the emergence of drug resistant Mycobacterium tuberculosis strains and its synergy with HIV infection. The waning effectiveness of current treatment regimens necessitates the development of new or repurposed anti-TB therapeutics for improved combination therapies against the disease. Exploiting atomic resolution structural information of proteins in complex with their substrates and/or inhibitors can facilitate structure-based rational drug design. Since our last review in 2009, there has been a wealth of new M. tuberculosis protein structural information. Once again, we have compiled the most promising structures with regards to potential anti-TB drug development and present them in this updated review. PMID:23167715

Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

PubMed

Suliman, Sara; Thompson, Ethan; Sutherland, Jayne; Weiner Rd, January; Ota, Martin O C; Shankar, Smitha; Penn-Nicholson, Adam; Thiel, Bonnie; Erasmus, Mzwandile; Maertzdorf, Jeroen; Duffy, Fergal J; Hill, Philip C; Hughes, E Jane; Stanley, Kim; Downing, Katrina; Fisher, Michelle L; Valvo, Joe; Parida, Shreemanta K; van der Spuy, Gian; Tromp, Gerard; Adetifa, Ifedayo M O; Donkor, Simon; Howe, Rawleigh; Mayanja-Kizza, Harriet; Boom, W Henry; Dockrell, Hazel; Ottenhoff, Tom H M; Hatherill, Mark; Aderem, Alan; Hanekom, Willem A; Scriba, Thomas J; Kaufmann, Stefan He; Zak, Daniel E; Walzl, Gerhard

2018-04-06

Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. We investigated biosignatures with predictive ability for incident tuberculosis. In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated. A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.

Developing a customised approach for strengthening tuberculosis laboratory quality management systems toward accreditation

PubMed Central

Trollip, Andre; Erni, Donatelle; Kao, Kekeletso

2017-01-01

Background Quality-assured tuberculosis laboratory services are critical to achieve global and national goals for tuberculosis prevention and care. Implementation of a quality management system (QMS) in laboratories leads to improved quality of diagnostic tests and better patient care. The Strengthening Laboratory Management Toward Accreditation (SLMTA) programme has led to measurable improvements in the QMS of clinical laboratories. However, progress in tuberculosis laboratories has been slower, which may be attributed to the need for a structured tuberculosis-specific approach to implementing QMS. We describe the development and early implementation of the Strengthening Tuberculosis Laboratory Management Toward Accreditation (TB SLMTA) programme. Development The TB SLMTA curriculum was developed by customizing the SLMTA curriculum to include specific tools, job aids and supplementary materials specific to the tuberculosis laboratory. The TB SLMTA Harmonized Checklist was developed from the World Health Organisation Regional Office for Africa Stepwise Laboratory Quality Improvement Process Towards Accreditation checklist, and incorporated tuberculosis-specific requirements from the Global Laboratory Initiative Stepwise Process Towards Tuberculosis Laboratory Accreditation online tool. Implementation Four regional training-of-trainers workshops have been conducted since 2013. The TB SLMTA programme has been rolled out in 37 tuberculosis laboratories in 10 countries using the Workshop approach in 32 laboratories in five countries and the Facility-based approach in five tuberculosis laboratories in five countries. Conclusion Lessons learnt from early implementation of TB SLMTA suggest that a structured training and mentoring programme can build a foundation towards further quality improvement in tuberculosis laboratories. Structured mentoring, and institutionalisation of QMS into country programmes, is needed to support tuberculosis laboratories to achieve accreditation. PMID:28879165

Fidaxomicin jams Mycobacterium tuberculosis RNA polymerase motions needed for initiation via RbpA contacts

PubMed Central

Lilic, Mirjana; Palka, Margaret; Mooney, Rachel Anne; Landick, Robert

2018-01-01

Fidaxomicin (Fdx) is an antimicrobial RNA polymerase (RNAP) inhibitor highly effective against Mycobacterium tuberculosis RNAP in vitro, but clinical use of Fdx is limited to treating Clostridium difficile intestinal infections due to poor absorption. To identify the structural determinants of Fdx binding to RNAP, we determined the 3.4 Å cryo-electron microscopy structure of a complete M. tuberculosis RNAP holoenzyme in complex with Fdx. We find that the actinobacteria general transcription factor RbpA contacts fidaxomycin, explaining its strong effect on M. tuberculosis. Additional structures define conformational states of M. tuberculosis RNAP between the free apo-holoenzyme and the promoter-engaged open complex ready for transcription. The results establish that Fdx acts like a doorstop to jam the enzyme in an open state, preventing the motions necessary to secure promoter DNA in the active site. Our results provide a structural platform to guide development of anti-tuberculosis antimicrobials based on the Fdx binding pocket. PMID:29480804

New indicators proposed to assess tuberculosis control and elimination in Cuba.

PubMed

González, Edilberto R; Armas, Luisa

2012-10-01

Following 48 years of successful operation of the National Tuberculosis Control Program, Cuban health authorities have placed tuberculosis elimination on the agenda. To this end some tuberculosis control processes and their indicators need redesigned and new ones introduced, related to: number and proportion of suspected tuberculosis cases among vulnerable population groups; tuberculosis suspects with sputum microscopy and culture results useful for diagnosis (interpretable); and number of identified contacts of reported tuberculosis cases who were fully investigated. Such new indicators have been validated and successfully implemented in all provinces (2011-12) and are in the approval pipeline for generalized use in the National Tuberculosis Control Program. These indicators complement existing criteria for quality of case detection and support more comprehensive program performance assessment.

Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in 1998

PubMed Central

Rose, A; Watson, J; Graham, C; Nunn, A; Drobniewski, F; Ormerod, L; Darbyshire, J; Leese, J

2001-01-01

BACKGROUND—A national survey of tuberculosis was conducted in England and Wales in 1998 to obtain detailed information on the occurrence of the disease and recent trends. This survey also piloted the methodology for enhanced tuberculosis surveillance in England and Wales and investigated the prevalence of HIV infection in adults with tuberculosis.
METHODS—Clinical and demographic data for all cases diagnosed during 1998 were obtained, together with microbiological data where available. Annual incidence rates in the population were estimated by age, sex, ethnic group, and geographical region using denominators from the 1998 Labour Force Survey. Incidence rates in different subgroups of the population were compared with the rates observed in previous surveys. The tuberculosis survey database for 1998was matched against the Communicable Disease Surveillance Centre HIV/AIDS database to estimate the prevalence of HIV co-infection in adult patients with tuberculosis.
RESULTS—A total of 5658 patients with tuberculosis were included in the survey in England and Wales (94% of all formally notified cases during the same period), giving an annual rate of 10.93per 100 000 population (95% CI 10.87 to 10.99). This represented an increase of 11% in the number of cases since the survey in 1993 and 21% since 1988. In many regions case numbers have remained little changed since 1988, but in London an increase of 71% was observed. The number of children with tuberculosis has decreased by 10% since 1993. Annual rates of tuberculosis per 100 000 population have continued to decline among the white population (4.38) and those from the Indian subcontinent, although the rate for the latter has remained high at 121 per 100 000. Annual rates per 100 000 have increased in all other ethnic groups, especially among those of black African (210) and Chinese (77.3) origin. Over 50% of all patients were born outside the UK. Recent entrants to the UK had higher rates of the disease than those who had been in the country for more than 5 years or who had been born in the UK. An estimated 3.3% of all adults with tuberculosis were co-infected with HIV.
CONCLUSIONS—The epidemiology of tuberculosis continues to change in England and Wales and the annual number of cases is rising. More than one third of cases now occur in young adults and rates are particularly high in those recently arrived from high prevalence areas of the world. The geographical distribution is uneven with urban centres having the highest rates. The increase in the number of cases in London is particularly large. Tuberculosis in patients co-infected with HIV makes a small but important contribution to the overall increase, particularly in London. To be most effective and to make the most efficient use of resources, tuberculosis prevention and control measures must be based on accurate and timely information on the occurrence of disease. A new system of continuous enhanced tuberculosis surveillance was introduced in 1999, based on the methodology developed in this national survey.

 PMID:11182007

Point prevalence and incidence of Mycobacterium tuberculosis complex in captive elephants in the United States of America.

PubMed

Feldman, Melissa; Isaza, Ramiro; Prins, Cindy; Hernandez, Jorge

2013-01-01

Captive elephants infected with tuberculosis are implicated as an occupational source of zoonotic tuberculosis. However, accurate estimates of prevalence and incidence of elephant tuberculosis from well-defined captive populations are lacking in the literature. Studies published in recent years contain a wide range of prevalence estimates calculated from summary data. Incidence estimates of elephant tuberculosis in captive elephants are not available. This study estimated the annual point prevalence, annual incidence, cumulative incidence, and incidence density of tuberculosis in captive elephants within the USA during the past 52 years. We combined existing elephant census records from captive elephants in the USA with tuberculosis culture results obtained from trunk washes or at necropsy. This data set included 15 years where each elephant was screened annually. Between 1960 and 1996, the annual point prevalence of tuberculosis complex mycobacteria for both species was 0. From 1997 through 2011, the median point prevalence within the Asian elephant population was 5.1%, with a range from 0.3% to 6.7%. The incidence density was 9.7 cases/1000 elephant years (95% CI: 7.0-13.4). In contrast, the annual point prevalence during the same time period within the African elephant population remained 0 and the incidence density was 1.5 cases/1000 elephant years (95% CI: 0.7-4.0). The apparent increase in new cases noted after 1996 resulted from a combination of both index cases and the initiation of mandatory annual tuberculosis screening in 1997 for all the elephants. This study found lower annual point prevalence estimates than previously reported in the literature. These discrepancies in prevalence estimates are primarily due to differences in terminology and calculation methods. Using the same intensive testing regime, the incidence of tuberculosis differed significantly between Asian and African elephants. Accurate and species specific knowledge of prevalence and incidence will inform our efforts to mitigate occupational risks associated with captive elephants in the USA.

Spatial analysis of pulmonary tuberculosis in Antananarivo Madagascar: tuberculosis-related knowledge, attitude and practice.

PubMed

Rakotosamimanana, Sitraka; Mandrosovololona, Vatsiharizandry; Rakotonirina, Julio; Ramamonjisoa, Joselyne; Ranjalahy, Justin Rasolofomanana; Randremanana, Rindra Vatosoa; Rakotomanana, Fanjasoa

2014-01-01

Tuberculosis infection may remain latent, but the disease is nevertheless a serious public health issue. Various epidemiological studies on pulmonary tuberculosis have considered the spatial component and taken it into account, revealing the tendency of this disease to cluster in particular locations. The aim was to assess the contribution of Knowledge Attitude and Practice (KAP) to the distribution of tuberculosis and to provide information for the improvement of the National Tuberculosis Program. We investigated the role of KAP to distribution patterns of pulmonary tuberculosis in Antananarivo. First, we performed spatial scanning of tuberculosis aggregation among permanent cases resident in Antananarivo Urban Township using the Kulldorff method, and then we carried out a quantitative study on KAP, involving TB patients. The KAP study in the population was based on qualitative methods with focus groups. The disease still clusters in the same districts identified in the previous study. The principal cluster covered 22 neighborhoods. Most of them are part of the first district. A secondary cluster was found, involving 18 neighborhoods in the sixth district and two neighborhoods in the fifth. The relative risk was respectively 1.7 (p<10-6) in the principal cluster and 1.6 (p<10-3) in the secondary cluster. Our study showed that more was known about TB symptoms than about the duration of the disease or free treatment. Knowledge about TB was limited to that acquired at school or from relatives with TB. The attitude and practices of patients and the population in general indicated that there is still a stigma attached to tuberculosis. This type of survey can be conducted in remote zones where the tuberculosis-related KAP of the TB patients and the general population is less known or not documented; the findings could be used to adapt control measures to the local particularities.

Solution Structures of Mycobacterium tuberculosis Thioredoxin C and Models of the Intact Thioredoxin System Suggest New Approaches to Inhibitor and Drug Design

PubMed Central

Olson, Andrew L.; Neumann, Terrence S.; Cai, Sheng; Sem, Daniel S.

2012-01-01

Here we report the NMR solution structures of Mycobacterium tuberculosis (M. tuberculosis) thioredoxin C in both oxidized and reduced states, with discussion of structural changes that occur in going between redox states. The NMR solution structure of the oxidized TrxC corresponds closely to that of the crystal structure, except in the C-terminal region. It appears that crystal packing effects have caused an artifactual shift in the α4 helix in the previously reported crystal structure, compared to the solution structure. Based on these TrxC structures, chemical shift mapping, a previously reported crystal structure of the M. tuberculosis thioredoxin reductase (not bound to a Trx) and structures for intermediates in the E. coli thioredoxin catalytic cycle, we have modeled the complete M. tuberculosis thioredoxin system for the various steps in the catalytic cycle. These structures and models reveal pockets at the TrxR/TrxC interface in various steps in the catalytic cycle, which can be targeted in the design of uncompetitive inhibitors as potential anti-mycobacterial agents, or as chemical genetic probes of function. PMID:23229911

Influence of migration on tuberculosis in a semi-urban area.

PubMed

Molina-Salas, Yolanda; de las Mercedes Lomas-Campos, María; Romera-Guirado, Francisco José; Romera-Guirado, María Jesús

2014-08-01

To describe the epidemiology of tuberculosis and analyzing the differences among native and immigrant patients in Area III of the Region of Murcia. Cohort study of tuberculosis cases reported to the Epidemiological Surveillance Service from 2004 to 2009. Data collection was performed through the System of Notification Diseases, reviewing clinical files and epidemiological surveys. One hundred sixty two cases were detected; 110 (67.9%) were immigrants, whose incidence rates ranged from 43.4 to 101.2 cases per 100,000 inhabitants. Ecuador (42.7%), Bolivia (30%) and Morocco (18.2%) were the main nationalities. Immigrants were younger than Spanish population (P<.001). The overall diagnostic delay was 50.5 days: 59.5 in Spanish and 47 in foreigners. Moroccans had higher proportions of extrapulmonary TB (P=.02). Mainly, immigrant population took treatment with four drugs (P<.001). Natives had better treatment adherence (P=.04). Spanish cases tuberculosis were associated with smoking (P<.001), the same as alcohol consumption (P=.01) and injection drug use (P<.001), nevertheless in the foreign-born population the most relevant risk factor was overcrowding (P<.001). The incidence tuberculosis rates are higher among immigrant population, whose the main risk factor is overcrowding. In contrast, Spanish cases are associated with toxic substances consumption and increasing age. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

L-form transformation phenomenon in Mycobacterium tuberculosis associated with drug tolerance to ethambutol.

PubMed

Slavchev, Georgi; Michailova, Lilia; Markova, Nadya

2016-12-01

Cell wall-deficient bacterial forms (L-forms) may occur along with resistance to factors that trigger their appearance. It is of interest to study the relationship between the L-form transformation of Mycobacterium tuberculosis and the exhibition of drug tolerance to ethambutol (EMB), an inhibitor of cell wall synthesis. L-form variant was produced from a sensitive EMB strain of M. tuberculosis through a cryogenic stress treatment protocol and was subsequently cultivated in Middlebrook 7H9 semisolid medium, containing EMB in a minimal inhibitory concentration of 2mg/L. Susceptibility to EMB of the parental strain and its L-form variant was evaluated phenotypically and using polymerase chain reaction-restriction fragment length polymorphism assay targeting a mutation in the embB306 gene fragment. In contrast to the sensitivity to EMB of the parental strain, its L-form variant showed phenotypic resistance to high concentrations of EMB (16mg/L), but the mutation in embB306 was not found. Electron microscopy observation of the L-form variant showed a heterogenic population of bacteria, with different degrees of cell wall deficiency, as well as cells of protoplastic type without cell walls. Of special interest were the observed capsule-like structures around the L-form cells and the biofilm-like matrix produced by the L-form population. We suggest that the expression of phenotypic resistance to EMB in M. tuberculosis can be associated with alterations or loss of cell walls in L-form bacteria, respectively, which results in a lack of a specific target for EMB action. In addition, production of capsule-like structures and biofilm matrix by L-forms could contribute to their resistance and survival in the presence of antibacterial agents. Copyright © 2016 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

First Insight into the Population Structure of Mycobacterium tuberculosis in Saudi Arabia▿ †

PubMed Central

Al-Hajoj, Sahal A. M.; Zozio, Thierry; Al-Rabiah, Fahad; Mohammad, Viquar; Al-Nasser, Maryam; Sola, Christophe; Rastogi, Nalin

2007-01-01

This study constitutes a first attempt to describe the genetic population structure and drug resistance of the tubercle bacilli circulating in Saudi Arabia. A total of 1,505 clinical isolates of M. tuberculosis, isolated between 2002 and 2005 from seven regions of Saudi Arabia, were studied. The sample studied showed a male-to-female sex ratio of 1.27, with half of the cases among foreign-born individuals and 47% within the 21- to 40-year-old age group; a total resistance rate of 19.7%; and multiple drug resistance of 4.5%. Upon spoligotyping, a total of 387 individual patterns were obtained (clustering rate, 86.4%; 182 clusters containing between 2 and 130 isolates per cluster). A total of 94% of the strains matched the spoligotype patterns in an international database. Nearly 81% of the isolates in this study belonged to established phylogeographic clades: Central Asian (CAS), 22.5%; ill-defined T clade, 19.5%; East African-Indian (EAI), 13.5%; Haarlem, 7.5%; Latin American-Mediterranean, 7.2%; Beijing, 4.4%; Manu, 2.7%; X, 0.9%; and Bovis, 0.9%. Two clonal complexes with unique spoligotyping signatures (octal codes 703777707770371 and 467777377413771) specific to Saudi Arabia were identified. These belonged to the CAS and EAI clades, respectively, as confirmed upon secondary typing using mycobacterial interspersed repetitive units (MIRUs). The results obtained underline the predominance of historic clones of principal genetic group 1, which are responsible for roughly 45% of all tuberculosis cases in Saudi Arabia. The high rate of clustering observed might be an indication of rapid ongoing transmission within certain communities and/or subpopulations in Saudi Arabia; nonetheless, spoligotyping is known to overestimate clustering, and only a systematic second-line typing, such as MIRUs, coupled with a better tuberculosis registry and epidemiological investigations would allow us to know the exact rate of ongoing transmission and associated risk factors in Saudi Arabia. PMID:17507515

Association Study of Genes Controlling IL-12-dependent IFN-γ Immunity: STAT4 Alleles Increase Risk of Pulmonary Tuberculosis in Morocco

PubMed Central

Sabri, Ayoub; Grant, Audrey V.; Cosker, Kristel; El Azbaoui, Safa; Abid, Ahmed; Abderrahmani Rhorfi, Ismail; Souhi, Hicham; Janah, Hicham; Alaoui-Tahiri, Kebir; Gharbaoui, Yasser; Benkirane, Majid; Orlova, Marianna; Boland, Anne; Deswarte, Caroline; Migaud, Melanie; Bustamante, Jacinta; Schurr, Erwin; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent; Abel, Laurent; El Baghdadi, Jamila

2014-01-01

Background. Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity. Methods. We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population. Results. Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013–.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06–2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression. Conclusions. Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression. PMID:24610875

Low-Density Granulocytes Are Elevated in Mycobacterial Infection and Associated with the Severity of Tuberculosis

PubMed Central

Luo, Qing; Huang, Zhikun; Peng, Yiping; Xiong, Guoliang; Guo, Yang; Jiang, Hong; Li, Junming

2016-01-01

Tuberculosis remains a global health problem caused by infection with Mycobacterium tuberculosis. Numerous studies have established a close correlation between the development of tuberculosis and the roles of neutrophils. Recently, a distinct population of CD15+ granulocytes was found to be present in the peripheral blood mononuclear cell (PBMC) fraction in humans. This population of granulocytes, termed low-density granulocytes (LDGs), was reported to be elevated and associated with disease activity or severity in a number of different conditions including SLE, asthma and HIV infection. However, both the frequency and clinical significance of LDGs associated with tuberculosis are unclear. Here we determined LDG levels and made comparisons between subjects with active pulmonary tuberculosis (PTB) and healthy controls, between PTB patients with mild-to-moderate disease and patients with advanced disease, and among PTB patients following anti-tuberculous therapy of varying durations. The direct correlation between M. tuberculosis infection and LDG levels was confirmed by in vitro infection of whole peripheral blood and isolated granulocytes with mycobacteria. Our results demonstrated that PBMCs in PTB patients contained significantly elevated percentages of LDGs compared with control subjects. LDGs in tuberculosis expressed higher levels of activation markers compared to normal-density granulocytes (NDGs). M. tuberculosis induced the generation of LDGs in both whole blood and isolated NDGs from control subjects, which suggests that LDGs associated with M. tuberculosis infection are likely to originate from in situ activation. Furthermore, our results revealed that the frequency of LDGs is associated with the severity of tuberculosis. PMID:27073889

Detection and Molecular Characterization of 9000-Year-Old Mycobacterium tuberculosis from a Neolithic Settlement in the Eastern Mediterranean

PubMed Central

Minnikin, David E.; Besra, Gurdyal S.; Lee, Oona Y-C.; Gernaey, Angela M.; Galili, Ehud; Eshed, Vered; Greenblatt, Charles L.; Lemma, Eshetu; Bar-Gal, Gila Kahila; Spigelman, Mark

2008-01-01

Background Mycobacterium tuberculosis is the principal etiologic agent of human tuberculosis. It has no environmental reservoir and is believed to have co-evolved with its host over millennia. This is supported by skeletal evidence of the disease in early humans, and inferred from M. tuberculosis genomic analysis. Direct examination of ancient human remains for M. tuberculosis biomarkers should aid our understanding of the nature of prehistoric tuberculosis and the host/pathogen relationship. Methodology/Principal Findings We used conventional PCR to examine bone samples with typical tuberculosis lesions from a woman and infant, who were buried together in the now submerged site of Atlit-Yam in the Eastern Mediterranean, dating from 9250-8160 years ago. Rigorous precautions were taken to prevent contamination, and independent centers were used to confirm authenticity of findings. DNA from five M tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex. Conclusions/Significance Human tuberculosis was confirmed by morphological and molecular methods in a population living in one of the first villages with evidence of agriculture and animal domestication. The widespread use of animals was not a source of infection but may have supported a denser human population that facilitated transmission of the tubercle bacillus. The similarity of the M. tuberculosis genetic signature with those of today gives support to the theory of a long-term co-existence of host and pathogen. PMID:18923677

DNA Replication Fidelity in the Mycobacterium tuberculosis Complex.

PubMed

Warner, Digby F; Rock, Jeremy M; Fortune, Sarah M; Mizrahi, Valerie

2017-01-01

Mycobacterium tuberculosis is genetically isolated, with no evidence for horizontal gene transfer or the acquisition of episomal genetic information in the modern evolution of strains of the Mycobacterium tuberculosis complex. When considered in the context of the specific features of the disease M. tuberculosis causes (e.g., transmission via cough aerosol, replication within professional phagocytes, subclinical persistence, and stimulation of a destructive immune pathology), this implies that to understand the mechanisms ensuring preservation of genomic integrity in infecting mycobacterial populations is to understand the source of genetic variation, including the emergence of microdiverse sub-populations that may be linked to the acquisition of drug resistance. In this chapter, we focus on mechanisms involved in maintaining DNA replication fidelity in M. tuberculosis, and consider the potential to target components of the DNA replication machinery as part of novel therapeutic regimens designed to curb the emerging threat of drug-resistance.

Tuberculosis, Fiji, 2002–2013

PubMed Central

Gounder, Shakti; Tamani, Talatoka; Daulako, Mary Raori; Underwood, Frank; Mainawalala, Sakiusa; Nawadra-Taylor, Vasiti; Rafai, Eric; Gillini, Laura

2016-01-01

During 2002–2013, a total of 1,890 tuberculosis cases were recorded in Fiji. Notification rates per 100,000 population increased from 17.4 cases in 2002 to 28.4 in 2013. Older persons were most affected, but tuberculosis also increased sharply in persons 25–44 years of age. PMID:26890215

Biochemical and structural investigations on phosphoribosylpyrophosphate synthetase from Mycobacterium smegmatis

PubMed Central

Donini, Stefano; Garavaglia, Silvia; Ferraris, Davide M.; Miggiano, Riccardo; Mori, Shigetarou; Shibayama, Keigo

2017-01-01

Mycobacterium smegmatis represents one model for studying the biology of its pathogenic relative Mycobacterium tuberculosis. The structural characterization of a M. tuberculosis ortholog protein can serve as a valid tool for the development of molecules active against the M. tuberculosis target. In this context, we report the biochemical and structural characterization of M. smegmatis phosphoribosylpyrophosphate synthetase (PrsA), the ortholog of M. tuberculosis PrsA, the unique enzyme responsible for the synthesis of phosphoribosylpyrophosphate (PRPP). PRPP is a key metabolite involved in several biosynthetic pathways including those for histidine, tryptophan, nucleotides and decaprenylphosphoryl-arabinose, an essential precursor for the mycobacterial cell wall biosynthesis. Since M. tuberculosis PrsA has been validated as a drug target for the development of antitubercular agents, the data presented here will add to the knowledge of the mycobacterial enzyme and could contribute to the development of M. tuberculosis PrsA inhibitors of potential pharmacological interest. PMID:28419153

Biochemical and structural investigations on phosphoribosylpyrophosphate synthetase from Mycobacterium smegmatis.

PubMed

Donini, Stefano; Garavaglia, Silvia; Ferraris, Davide M; Miggiano, Riccardo; Mori, Shigetarou; Shibayama, Keigo; Rizzi, Menico

2017-01-01

Mycobacterium smegmatis represents one model for studying the biology of its pathogenic relative Mycobacterium tuberculosis. The structural characterization of a M. tuberculosis ortholog protein can serve as a valid tool for the development of molecules active against the M. tuberculosis target. In this context, we report the biochemical and structural characterization of M. smegmatis phosphoribosylpyrophosphate synthetase (PrsA), the ortholog of M. tuberculosis PrsA, the unique enzyme responsible for the synthesis of phosphoribosylpyrophosphate (PRPP). PRPP is a key metabolite involved in several biosynthetic pathways including those for histidine, tryptophan, nucleotides and decaprenylphosphoryl-arabinose, an essential precursor for the mycobacterial cell wall biosynthesis. Since M. tuberculosis PrsA has been validated as a drug target for the development of antitubercular agents, the data presented here will add to the knowledge of the mycobacterial enzyme and could contribute to the development of M. tuberculosis PrsA inhibitors of potential pharmacological interest.

Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing

PubMed Central

Sadsad, Rosemarie; Martinez, Elena; Jelfs, Peter; Hill-Cawthorne, Grant A.; Gilbert, Gwendolyn L.; Marais, Ben J.; Sintchenko, Vitali

2016-01-01

Background Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways. Methods We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants. Results Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade. Conclusion Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster. PMID:26938641

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

PubMed Central

Pienaar, Elsje; Matern, William M.; Linderman, Jennifer J.

2016-01-01

Granulomas are a hallmark of tuberculosis. Inside granulomas, the pathogen Mycobacterium tuberculosis may enter a metabolically inactive state that is less susceptible to antibiotics. Understanding M. tuberculosis metabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. Two key adaptations of M. tuberculosis are a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic conditions. To explore how these adaptations influence granuloma-scale outcomes in vivo, we present a multiscale in silico model of granuloma formation in tuberculosis. The model comprises host immunity, M. tuberculosis metabolism, M. tuberculosis growth adaptation to hypoxia, and nutrient diffusion. We calibrated our model to in vivo data from nonhuman primates and rabbits and apply the model to predict M. tuberculosis population dynamics and heterogeneity within granulomas. We found that bacterial populations are highly dynamic throughout infection in response to changing oxygen levels and host immunity pressures. Our results indicate that a nonreplicating phenotype, but not lipid inclusion formation, is important for long-term M. tuberculosis survival in granulomas. We used virtual M. tuberculosis knockouts to predict the impact of both metabolic enzyme inhibitors and metabolic pathways exploited to overcome inhibition. Results indicate that knockouts whose growth rates are below ∼66% of the wild-type growth rate in a culture medium featuring lipid as the only carbon source are unable to sustain infections in granulomas. By mapping metabolite- and gene-scale perturbations to granuloma-scale outcomes and predicting mechanisms of sterilization, our method provides a powerful tool for hypothesis testing and guiding experimental searches for novel antituberculosis interventions. PMID:26975995

First insight into the molecular epidemiology of Mycobacterium tuberculosis in Santa Catarina, southern Brazil.

PubMed

Nogueira, Christiane Lourenço; Prim, Rodrigo Ivan; Senna, Simone Gonçalves; Rovaris, Darcita Büerger; Maurici, Rosemeri; Rossetti, Maria Lúcia; Couvin, David; Rastogi, Nalin; Bazzo, Maria Luiza

2016-03-01

Molecular epidemiology of Mycobacterium tuberculosis is useful for understanding disease transmission dynamics, and to establish strategic measures for TB control and prevention. The aim of this study was to analyze clinical, epidemiological and molecular characteristics of MTBC clinical isolates from Santa Catarina state, southern Brazil. During one-year period, 406 clinical isolates of MTBC were collected from Central Laboratory of Public Health and typed by spoligotyping. Demographic and clinical data were collected from the Brazilian National Mandatory Disease Reporting System. The majority of cases occurred in highest population densities regions and about 50% had some condition associated with TB. Among all isolates, 5.7% were MDR, which showed association with drug addiction. LAM was the most predominant lineage with 47.5%, followed by the T superfamily with 25.9% and Haarlem with 12.3%. The MST showed two major groups: the first was formed mainly by the LAM lineage and the second was mainly formed by the T and Haarlem lineages. Others lineages were distributed in peripheral positions. This study provides the first insight into the population structure of M. tuberculosis in SC State. Spoligotyping and other genotyping analyses are important to establish strategic measures for TB control and prevention. Copyright © 2015 Elsevier Ltd. All rights reserved.

Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis

PubMed Central

Williamson, Benjamin H.; Kerns, Robert J.; Berger, James M.

2016-01-01

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone–gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone–enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance. PMID:26792525

Clustured regularly interspersed short palindromic repeats (CRISPR) genetic diversity studies as a mean to reconstruct the evolution of the Mycobacterium tuberculosis complex.

PubMed

Sola, Christophe

2015-06-01

The natural history of tuberculosis may be tackled by various means, among which the record of molecular scars that have been registered by the Mycobacterium tuberculosis complex (MTBC) genomes transmitted from patient to patient for tens of thousands years and possibly more. Recently discovered polymorphic loci, the CRISPR sequences, are indirect witnesses of the historical phage-bacteria struggle, and may be related to the time when the ancestor of today's tubercle bacilli were environmental bacteria, i.e. before becoming intracellular parasites. In this article, we present what are CRISPRs and try to summarize almost 20 years of research results obtained using the genetic diversity of the CRISPR loci in MTBC as a perspective for studying new models. We show that the study of the diversity of CRISPR sequences, thanks to «spoligotyping», has played a great role in our global understanding of the population structure of MTBC. Copyright © 2015 Elsevier Ltd. All rights reserved.

An application of forward-backward difference approximation method on the optimal control problem in the transmission of tuberculosis model

NASA Astrophysics Data System (ADS)

Rahmah, Z.; Subartini, B.; Djauhari, E.; Anggriani, N.; Supriatna, A. K.

2017-03-01

Tuberculosis (TB) is a disease that is infected by the bacteria Mycobacterium tuberculosis. The World Health Organization (WHO) recommends to implement the Baccilus Calmete Guerin (BCG) vaccine in toddler aged two to three months to be protected from the infection. This research explores the numerical simulation of forward-backward difference approximation method on the model of TB transmission considering this vaccination program. The model considers five compartments of sub-populations, i.e. susceptible, vaccinated, exposed, infected, and recovered human sub-populations. We consider here the vaccination as a control variable. The results of the simulation showed that vaccination can indeed reduce the number of infected human population.

HLA-A and -B phenotypes associated with tuberculosis in population from north-eastern Romania.

PubMed

Vasilca, Venera; Oana, Raluca; Munteanu, Dorina; Zugun, F; Constantinescu, Daniela; Carasevici, E

2004-01-01

HLA antigens are involved in inducing either susceptibility or resistance to different diseases. Many studies reported various associations between HLA antigens and tuberculosis, depending on race, ethnic group and geographic area. Our purpose was to identify HLA class I antigens inducing susceptibility to tuberculosis in population from North-Eastern Romania. The study group consisted of 50 tuberculosis patients and the control group included 90 healthy people. HLA-A and HLA-B antigens were determined using the CDC-NIH (complement-dependent-cytotoxicity-National Institute of Health) assay. A comparison was made between the frequency of HLA antigens expression in the two studied groups. HLA-B18 and HLA-A29(19) were expressed more frequently in tuberculosis patients. The difference was statistically significant only for HLA-B18 antigen. HLA-B7 and -B61(40) antigens were expressed with statistically significant higher frequency in controls compared to tuberculosis patients. The frequency of other HLA-A and HLA-B antigens was either comparable in the two groups or without statistical significance. CONCLUSIONS We found a positive association between HLA-B18 antigen and tuberculosis, while HLA-B7 and HLA-B61(40) antigens seem to protect against the disease.

Enriching the annotation of Mycobacterium tuberculosis H37Rv proteome using remote homology detection approaches: insights into structure and function.

PubMed

Ramakrishnan, Gayatri; Ochoa-Montaño, Bernardo; Raghavender, Upadhyayula S; Mudgal, Richa; Joshi, Adwait G; Chandra, Nagasuma R; Sowdhamini, Ramanathan; Blundell, Tom L; Srinivasan, Narayanaswamy

2015-01-01

The availability of the genome sequence of Mycobacterium tuberculosis H37Rv has encouraged determination of large numbers of protein structures and detailed definition of the biological information encoded therein; yet, the functions of many proteins in M. tuberculosis remain unknown. The emergence of multidrug resistant strains makes it a priority to exploit recent advances in homology recognition and structure prediction to re-analyse its gene products. Here we report the structural and functional characterization of gene products encoded in the M. tuberculosis genome, with the help of sensitive profile-based remote homology search and fold recognition algorithms resulting in an enhanced annotation of the proteome where 95% of the M. tuberculosis proteins were identified wholly or partly with information on structure or function. New information includes association of 244 proteins with 205 domain families and a separate set of new association of folds to 64 proteins. Extending structural information across uncharacterized protein families represented in the M. tuberculosis proteome, by determining superfamily relationships between families of known and unknown structures, has contributed to an enhancement in the knowledge of structural content. In retrospect, such superfamily relationships have facilitated recognition of probable structure and/or function for several uncharacterized protein families, eventually aiding recognition of probable functions for homologous proteins corresponding to such families. Gene products unique to mycobacteria for which no functions could be identified are 183. Of these 18 were determined to be M. tuberculosis specific. Such pathogen-specific proteins are speculated to harbour virulence factors required for pathogenesis. A re-annotated proteome of M. tuberculosis, with greater completeness of annotated proteins and domain assigned regions, provides a valuable basis for experimental endeavours designed to obtain a better understanding of pathogenesis and to accelerate the process of drug target discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mycobacterium tuberculosis Population in Northwestern Russia: An Update from Russian-EU/Latvian Border Region

PubMed Central

Mokrousov, Igor; Vyazovaya, Anna; Otten, Tatiana; Zhuravlev, Viacheslav; Pavlova, Elena; Tarashkevich, Larisa; Krishevich, Valery; Vishnevsky, Boris; Narvskaya, Olga

2012-01-01

This study aimed to characterize the population structure of Mycobacterium tuberculosis in Pskov oblast in northwestern Russia, to view it in the geographical context, to compare drug resistance properties across major genetic families. Ninety M. tuberculosis strains from tuberculosis (TB) patients, permanent residents in Pskov oblast were subjected to LAM-specific IS6110-PCR and spoligotyping, followed by comparison with SITVITWEB and MIRU-VNTRplus databases. The Beijing genotype (n = 40) was found the most prevalent followed by LAM (n = 18), T (n = 13), Haarlem (n = 10), Ural (n = 5), and Manu2 (n = 1); the family status remained unknown for 3 isolates. The high rate of Beijing genotype and prevalence of LAM family are similar to those in the other Russian settings. A feature specific for M. tuberculosis population in Pskov is a relatively higher rate of Haarlem and T types. Beijing strains were further typed with 12-MIRU (followed by comparison with proprietary global database) and 3 hypervariable loci QUB-3232, VNTR-3820, VNTR-4120. The 12-MIRU typing differentiated 40 Beijing strains into 14 types (HGI = 0.82) while two largest types were M2 (223325153533) prevalent throughout former USSR and M11 (223325173533) prevalent in Russia and East Asia. The use of 3 hypervariable loci increased a discrimination of the Beijing strains (18 profiles, HGI = 0.89). Both major families Beijing and LAM had similar rate of MDR strains (62.5 and 55.6%, respectively) that was significantly higher than in other strains (21.9%; P = 0.001 and 0.03, respectively). The rpoB531 mutations were more frequently found in Beijing strains while LAM drug resistant strains mainly harbored rpoB516 and inhA −15 mutations. Taken together with a high rate of multidrug resistance among Beijing strains from new TB cases (79.3% versus 44.4% in LAM), these findings suggest the critical impact of the Beijing genotype on the current situation with MDR-TB in the Pskov region in northwestern Russia. PMID:22844457

Educational intervention and the health seeking attitude and adherence to therapy by tuberculosis patients from an urban slum in lagos Nigeria.

PubMed

Olayemi, S O; Oreagba, I A; Akinyede, A; Adepoju, G E

2009-12-01

Community based participation has been advocated by a number of international health organisations including the World Health Organization (WHO) as a solution to the problems of poor patient adherence and default from Directly Observed Treatment Short course [DOTs] programmes for tuberculosis control. To determine the impact of a health educational intervention on the management of tuberculosis in relation to the outcome and adherence to therapy by Tuberculosis patients residing in a densely populated urban slum in Lagos, Nigeria. The study was conducted using forty tuberculosis patients (confirmed by acid fast bacilli positive sputum), and selected randomly from those who attend the Mainland Hospital in Lagos. They were divided into two groups of twenty each made up of those to be provided with education intervention at the community level and the control groups followed up at the hospital level only. An initial assessment of the knowledge about tuberculosis management was done through a structured questionnaire for both groups. This was followed by continuous health talks for intervention group in form of neighbourhood self help approach. The results showed that the intervention had a significant impact on the understanding of disease and its management (X(2) =11.842 p<0.05), DOTS and increased awareness (X(2) =17.289 p<0.05, X(2) =10.461 p<0.05), knowing the side effects of anti-TB drugs (X(2) =10.157 p<0.05), the meaning of resistance to anti-Tuberculosis drugs (X(2) =19.798 p<0.05, X(2) =11.192 p<0.05) and importance of contact tracing (X(2) =32.4 p<0.05, X(2) =3.360 p<0.05). An effective health education is therefore beneficial for TB control in Nigeria.

Factors determining ethnic differences in the incidence of bacteriologically confirmed genitourinary tuberculosis in south east England.

PubMed

Grange, J M; Yates, M D; Ormerod, L P

1995-01-01

In South East England, genitourinary (GU) tuberculosis is a much less common manifestation of non-respiratory tuberculosis in patients of Indian subcontinent (ISC) ethnic origin than in those of European ethnic origin. When considered in relation to all bacteriologically confirmed cases of tuberculosis, both respiratory and non-respiratory, the ethnic difference in the occurrence of GU tuberculosis is much less evident, while there is a highly significant excess of other forms of non-respiratory tuberculosis among the ethnic ISC patients. Unlike other forms of non-respiratory tuberculosis, GU disease tends to occur in an older age range in the ethnic ISC population and, when stratified for age, the ethnic difference in the occurrence of this form of tuberculosis is not significant while that of lymph node tuberculosis remains significantly high. Thus, after elimination of the confounding factor of age, the occurrence of GU tuberculosis is very similar in the two ethnic groups while other forms of non-respiratory tuberculosis differ considerably.

The within-host population dynamics of Mycobacterium tuberculosis vary with treatment efficacy.

PubMed

Trauner, Andrej; Liu, Qingyun; Via, Laura E; Liu, Xin; Ruan, Xianglin; Liang, Lili; Shi, Huimin; Chen, Ying; Wang, Ziling; Liang, Ruixia; Zhang, Wei; Wei, Wang; Gao, Jingcai; Sun, Gang; Brites, Daniela; England, Kathleen; Zhang, Guolong; Gagneux, Sebastien; Barry, Clifton E; Gao, Qian

2017-04-19

Combination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics. By combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance. Our findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.

Insights from the docking and molecular dynamics simulation of the Phosphopantetheinyl transferase (PptT) structural model from Mycobacterium tuberculosis.

PubMed

Rohini, Karunakaran; Srikumar, Padmalayam Sadanandan

2013-01-01

A great challenge is posed to the treatment of tuberculosis due to the evolution of multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis in recent times. The complex cell envelope of the bacterium contains unusual structures of lipids which protects the bacterium from host enzymes and escape immune response. To overcome the drug resistance, targeting "drug targets" which have a critical role in growth and virulence factor is a novel approach for better tuberculosis treatment. The enzyme Phosphopantetheinyl transferase (PptT) is an attractive drug target as it is primarily involved in post translational modification of various types-I polyketide synthases and assembly of mycobactin, which is required for lipid virulence factors. Our in silico studies reported that the structural model of M.tuberculosis PptT characterizes the structure-function activity. The refinement of the model was carried out with molecular dynamics simulations and was analyzed with root mean square deviation (RMSD), and radius of gyration (Rg). This confirmed the structural behavior of PptT in dynamic system. Molecular docking with substrate coenzyme A (CoA) identified the binding pocket and key residues His93, Asp114 and Arg169 involved in PptT-CoA binding. In conclusion, our results show that the M.tuberculosis PptT model and critical CoA binding pocket initiate the inhibitor design of PptT towards tuberculosis treatment.

Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning.

PubMed

Nishikiori, Nobuyuki; Van Weezenbeek, Catharina

2013-02-02

Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. The prioritization of appropriate target populations and careful selection of cost-effective diagnostic strategies are critical prerequisites for rational active case-finding activities. A decision to conduct such activities should be based on the setting-specific cost-effectiveness analysis and programmatic assessment. A web-based tool was developed and is available to support national tuberculosis programmes and partners in the formulation of cost-effective active case-finding activities at the national and subnational levels.

Association study of genes controlling IL-12-dependent IFN-γ immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco.

PubMed

Sabri, Ayoub; Grant, Audrey V; Cosker, Kristel; El Azbaoui, Safa; Abid, Ahmed; Abderrahmani Rhorfi, Ismail; Souhi, Hicham; Janah, Hicham; Alaoui-Tahiri, Kebir; Gharbaoui, Yasser; Benkirane, Majid; Orlova, Marianna; Boland, Anne; Deswarte, Caroline; Migaud, Melanie; Bustamante, Jacinta; Schurr, Erwin; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent; Abel, Laurent; El Baghdadi, Jamila

2014-08-15

Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity. We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population. Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013-.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06-2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression. Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Tuberculosis Incidence in Elderly in Serbia: Key Trends in Socioeconomic Transition

PubMed Central

Pešut, Dragica P.; Gledović, Zorana B.; Grgurević, Anita D.; Nagorni-Obradović, Ljudmila M.; Adžić, Tatjana N.

2008-01-01

Aim To examine tuberculosis incidence rates among the elderly in Central Serbia in 1992-2006 period, which was characterized by socioeconomic crisis and migration of population. Methods We analyzed all reported active tuberculosis cases in a 15-year period, especially among patients aged ≥65, according to the Annual Reports of the Institute of Lung Diseases and Tuberculosis in Belgrade and Central Tuberculosis Register. Population estimates with extrapolations were based on 1991 and 2002 census data. Results Total tuberculosis incidence rates showed a slight but non-significant decreasing trend (P = 0.535), and no significant increase was found in patients aged ≥65 years (P = 0.064), with an average age-specific incidence rate for the elderly of 64.0 (95% confidence interval, 60.7-67.4). The increase was significant in patients aged ≥70 years (y = 49.3549 + 2.1186x; P = 0.001), both in men (y = 62.8666 + 2.3977x; P = 0.005) and even more prominently in women (y = 39.8240 + 1.9150x; P < 0.001). The proportion of tuberculosis cases in the elderly peaked in 2005, with 35% of all tuberculosis cases. Conclusion High incidence rates and increasing time trend of tuberculosis in the elderly in Central Serbia is a serious problem, especially among those aged 70 years and over, who might present a target group for active case-finding of the disease. PMID:19090606

Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study.

PubMed

Gao, Lei; Li, Xiangwei; Liu, Jianmin; Wang, Xinhua; Lu, Wei; Bai, Liqiong; Xin, Henan; Zhang, Haoran; Li, Hengjing; Zhang, Zongde; Ma, Yu; Li, Mufei; Feng, Boxuan; Du, Jiang; Sui, Hongtao; Zhao, Rong; Su, Haoxiang; Pan, Shouguo; Guan, Ling; Shen, Fei; He, Jian; Yang, Shumin; Si, Hongyan; Cheng, Xu; Xu, Zuhui; Tan, Yunhong; Chen, Tianzhu; Xu, Weiguo; Peng, Hong; Wang, Zhijian; Zhu, Tao; Chen, Xiaoyou; Zhou, Xinhua; Guan, Xueling; Jin, Qi

2017-10-01

The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014-15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of ≥10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration ≥10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0·87 (95% CI 0·68-1·07) per 100 person-years was observed for individuals who tested positive with QFT, 0·50 (0·38-0·63) per 100 person-years for those who tested positive with TST (p<0·0001), and 0·82 (0·60-1·04) per 100 person-years for those who tested positive with both tests. Male sex and a history of tuberculosis were significantly associated with increased risk of disease development with adjusted hazard ratios of 2·36 (95% CI 1·30-4·30) for male sex and 5·40 (3·34-8·71) for a history of tuberculosis. Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-γ releasing assay rather than a TST. National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Immigrants treated for tuberculosis in Mazovian Center for Treatment of Lung Diseases and Tuberculosis in Otwock].

PubMed

Jagodziński, Jacek; Zielonka, Tadeusz M

2010-01-01

Migration of population contributes to the transmission of tuberculosis (TB), particularly multidrug-resistant tuberculosis. In the countries of Western Europe, the immigrants' inflow contributes to the deterioration of the epidemiological situation. Majority of newly detected TB cases in some countries were affirmed among immigrant and foreign born population. In Poland, this problem has not been investigated up to 2005. The aim of the study was the assessment of the occurrence of tuberculosis in foreigners treated in the Mazovian Centre for Treatment of Lung Diseases and Tuberculosis in Otwock. This work had a retrospective character. The number of cases of tuberculosis in foreigners admitted between 2002 and 2007 was calculated from the data base of the Mazovian Centre for Treatment of Lung Diseases and Tuberculosis; 125 patients, whose basic demographic data, bacteriological status and the radiological changes suggested TB, were included in the study. The foreigners made up to 0.5-1.7% all tuberculosis cases treated in Mazovian Centre for Treatment of Lung Diseases and Tuberculosis. Among confirmed cases, twenty four nationalities were seen. Nationals of the Russian Federation (coming from the Republic of Chechnya) formed the biggest group (24%), followed by the Vietnamese (21%) and the Ukrainians (12%). Most of all cases were young men (77%; average age - 34 years). Children made up to 12% of all cases. Tuberculosis of lungs was predominating, and there were culture confirmed extrapulmonary locations in 13.6% of cases. Bacteriological confirmation was achieved in 53% of cases, but up to 22.7% cases were resistant to one of the antituberculosis medicines and 13.6% was multidrug-resistant. Despite the fact, that foreigners made up a small proportion among all the patient treated for tuberculosis in Mazovia, their number systematically increases. High proportion of multidrug-resistant tuberculosis reported in foreign-born cases is a concern.

Polymorphisms in the prostaglandin receptor EP2 gene confers susceptibility to tuberculosis.

PubMed

Liang, Li; Zhang, Qing; Luo, Liu-Lin; Yue, Jun; Zhao, Yan-Lin; Han, Min; Liu, Li-Rong; Xiao, He-Ping

2016-12-01

Prostaglandin E2 (PGE2) is an important lipid mediator of the inflammatory immune response during acute and chronic infections. PGE2 modulates a variety of immune functions via four receptors (EP1-EP4), which mediate distinct PGE2 effects. Mice lacking EP2 are more susceptible to infection by Mycobacterium tuberculosis (M.tb), have a higher bacterial load, and increase size and number of granulomatous lesions. Our aim was to assess whether single nucleotide polymorphisms (SNPs) in EP2 increase the risk of tuberculosis. DNA re-sequencing revealed five common EP2 variants in the Chinese Han population. We sequenced the EP2 gene from 600 patients and 572 healthy controls to measure SNP frequencies in association with tuberculosis infections (TB) within the population. The rs937337 polymorphism is associated with increased risk to tuberculosis (p=0.0044, odds ratio [OR], 1.67; 95% confidential interval,1.22-2.27). The rs937337 AA genotype and the rs1042618 CC genotype were significantly associated with TB. An estimation of the frequencies of haplotypes revealed a single protective haplotype GACGC for tuberculosis (p=0.00096, odds ratio [OR], 0.56; 95% confidential interval, 0.41-0.77). Furthermore, we determined that the remaining SNPs of EP2 were nominally associated with clinical patterns of disease. We identified genetic polymorphisms in EP2 associated with susceptibility to tuberculosis within a Chinese population. Our data support that EP2 SNPs are genetic predispositions of increased susceptibility to TB and to different clinical patterns of disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Origin, Spread and Demography of the Mycobacterium tuberculosis Complex

PubMed Central

Wirth, Thierry; Hildebrand, Falk; Allix-Béguec, Caroline; Wölbeling, Florian; Kubica, Tanja; Kremer, Kristin; van Soolingen, Dick; Rüsch-Gerdes, Sabine; Locht, Camille; Brisse, Sylvain; Meyer, Axel

2008-01-01

The evolutionary timing and spread of the Mycobacterium tuberculosis complex (MTBC), one of the most successful groups of bacterial pathogens, remains largely unknown. Here, using mycobacterial tandem repeat sequences as genetic markers, we show that the MTBC consists of two independent clades, one composed exclusively of M. tuberculosis lineages from humans and the other composed of both animal and human isolates. The latter also likely derived from a human pathogenic lineage, supporting the hypothesis of an original human host. Using Bayesian statistics and experimental data on the variability of the mycobacterial markers in infected patients, we estimated the age of the MTBC at 40,000 years, coinciding with the expansion of “modern” human populations out of Africa. Furthermore, coalescence analysis revealed a strong and recent demographic expansion in almost all M. tuberculosis lineages, which coincides with the human population explosion over the last two centuries. These findings thus unveil the dynamic dimension of the association between human host and pathogen populations. PMID:18802459

Worldwide Report, Epidemiology, No. 327.

DTIC Science & Technology

1983-08-10

20 Briefs Dengue Fever in Michoacan 21 Tuberculosis in Chiapas 21 PAKISTAN 20-Year Program To Eradicate Tuberculosis (DAWN, 6 Jul 83) 22...EXCELSIOR in Spanish 23 Jun 83 p 6] 8255 TUBERCULOSIS IN CHIAPAS —Tuxtla Gutierrez, Chis., June 18—It is very diffi- cult to confirm that 40 per cent of...actual tuberculosis figure for the Chiapas area fluctuates between 15 and 20 per cent of the population, but that the utmost has been done to

High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia.

PubMed

Muchemwa, Levy; Shabir, Lakhi; Andrews, Ben; Bwalya, Mwango

2017-05-01

Tuberculosis is recognised as one of the leading causes of severe sepsis among HIV-infected patients. Most patients with Mycobacterium tuberculosis bacteraemia have advanced HIV disease with CD4 counts less than 100 cells/μl and its presentation is non-specific in most instances. This was a cross-sectional study which was done by analyzing data from 201 adult HIV-infected patients who met the inclusion criteria for severe sepsis. The prevalence of Mycobacterium tuberculosis bactraemia in the study population was 34.8%. Severe sepsis caused by other etiologies was observed in 33 (16.4%) of the participants. Concomitant infection of Mycobacterium tuberculosis bactraemia with other organisms is not uncommon in patients with severe sepsis. This cohort of HIV-infected patients had severe immunosuppression with a median CD4 count of 51 (20-136) cells/μl with moderate anaemia, mean haemoglobin 8.0 (3.0) g/dl, and were generally underweight with a mean mid upper arm circumference (MUAC) of 21.0 (3.4) cm. Mycobacterium tuberculosis bacteraemia is very common in HIV-infected patients with advanced HIV disease who present with severe sepsis. Mycobacterium tuberculosis bacteraemia co-infection with aerobic organisms is not uncommon. Factors that were independently associated with Mycobacterium tuberculosis bacteraemia in our study population were MUAC and sodium level.

Dynamics of a stochastic tuberculosis model with constant recruitment and varying total population size

NASA Astrophysics Data System (ADS)

Liu, Qun; Jiang, Daqing; Shi, Ningzhong; Hayat, Tasawar; Alsaedi, Ahmed

2017-03-01

In this paper, we develop a mathematical model for a tuberculosis model with constant recruitment and varying total population size by incorporating stochastic perturbations. By constructing suitable stochastic Lyapunov functions, we establish sufficient conditions for the existence of an ergodic stationary distribution as well as extinction of the disease to the stochastic system.

Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents.

PubMed

Ma, Junying; Huang, Hongbo; Xie, Yunchang; Liu, Zhiyong; Zhao, Jin; Zhang, Chunyan; Jia, Yanxi; Zhang, Yun; Zhang, Hua; Zhang, Tianyu; Ju, Jianhua

2017-08-30

Tuberculosis remains one of the world's deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1-6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6-8) from the respective mutants. Most impressively, ilamycins E 1 /E 2 , which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.Tuberculosis (TB) remains one of the world's deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.

Structure of Rv1848 (UreA), the Mycobacterium tuberculosis urease γ subunit

PubMed Central

Habel, Jeff E.; Bursey, Evan H.; Rho, Beom-Seop; Kim, Chang-Yub; Segelke, Brent W.; Rupp, Bernhard; Park, Min S.; Terwilliger, Thomas C.; Hung, Li-Wei

2010-01-01

The crystal structure of the urease γ subunit (UreA) from Mycobacterium tuberculosis, Rv1848, has been determined at 1.8 Å resolution. The asymmetric unit contains three copies of Rv1848 arranged into a homotrimer that is similar to the UreA trimer in the structure of urease from Klebsiella aerogenes. Small-angle X-ray scattering experiments indicate that the Rv1848 protein also forms trimers in solution. The observed homotrimer and the organization of urease genes within the M. tuberculosis genome suggest that M. tuberculosis urease has the (αβγ)3 composition observed for other bacterial ureases. The γ subunit may be of primary importance for the formation of the urease quaternary structure. PMID:20606272

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel

PubMed Central

Gupta, Amita; Mathad, Jyoti S.; Abdel-Rahman, Susan M.; Albano, Jessica D.; Botgros, Radu; Brown, Vikki; Browning, Renee S.; Dawson, Liza; Dooley, Kelly E.; Gnanashanmugam, Devasena; Grinsztejn, Beatriz; Hernandez-Diaz, Sonia; Jean-Philippe, Patrick; Kim, Peter; Lyerly, Anne D.; Mirochnick, Mark; Mofenson, Lynne M.; Montepiedra, Grace; Piper, Jeanna; Sahin, Leyla; Savic, Radojka; Smith, Betsy; Spiegel, Hans; Swaminathan, Soumya; Watts, D. Heather; White, Amina

2016-01-01

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15–44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population. PMID:26658057

Tuberculosis in Southern Brazilian wild boars (Sus scrofa): First epidemiological findings.

PubMed

Maciel, A L G; Loiko, M R; Bueno, T S; Moreira, J G; Coppola, M; Dalla Costa, E R; Schmid, K B; Rodrigues, R O; Cibulski, S P; Bertagnolli, A C; Mayer, F Q

2018-04-01

Bovine tuberculosis (bTB) is a zoonosis caused mainly by Mycobacterium bovis that affects domestic and wild animals. In Brazil, there are no epidemiological studies on tuberculosis in wild animal populations and their possible role in the disease maintenance in cattle herds; thus, the aim of this study was to evaluate the occurrence of tuberculosis in wild boars in Rio Grande do Sul, southern Brazil. Tissue samples of animals hunted under government consent were submitted to histopathology and M. bovis polymerase chain reaction (PCR) as screening tests; the positive samples were subsequently submitted to bacterial isolation, the gold standard diagnosis. Eighty animals were evaluated, of which 27.9% and 31.3% showed histopathological changes and M. bovis genome presence, respectively. Moreover, 23.8% of the animals had at least one organ with isolates classified as Mycobacterium tuberculosis complex (MTC). Three hunting points were risk factors for positive results on screening tests. This study shows the occurrence of tuberculosis in a wild boars' population, and raise the possibility of these animals to play a role as disease reservoirs in southern Brazil. These results may help to improve the Brazilian tuberculosis control programme, as well as elucidate the circulation of mycobacteria in this country. © 2017 Blackwell Verlag GmbH.

Evaluation of a tuberculosis education video among immigrants and refugees at an adult education center: a community-based participatory approach.

PubMed

Wieland, Mark L; Nelson, Jonathan; Palmer, Tiffany; O'Hara, Connie; Weis, Jennifer A; Nigon, Julie A; Sia, Irene G

2013-01-01

Tuberculosis disproportionately affects immigrants and refugees to the United States. Upon arrival to the United States, many of these individuals attend adult education centers, but little is known about how to deliver tuberculosis health information at these venues. Therefore, the authors used a participatory approach to design and evaluate a tuberculosis education video in this setting. The authors used focus group data to inform the content of the video that was produced and delivered by adult learners and their teachers. The video was evaluated by learners for acceptability through 3 items with a 3-point Likert scale. Knowledge (4 items) and self-efficacy (2 items) about tuberculosis were evaluated before and after viewing the video. A total of 159 learners (94%) rated the video as highly acceptable. Knowledge about tuberculosis improved after viewing the video (56% correct vs. 82% correct; p <.001), as did tuberculosis-related self-efficacy (77% vs. 90%; p <.001). Adult education centers that serve large immigrant and refugee populations may be excellent venues for health education, and a video may be an effective tool to educate these populations. Furthermore, a participatory approach in designing health education materials may enhance the efficacy of these tools.

Modelling the social and structural determinants of tuberculosis: opportunities and challenges

PubMed Central

Boccia, D.; Dodd, P. J.; Lönnroth, K.; Dowdy, D. W.; Siroka, A.; Kimerling, M. E.; White, R. G.; Houben, R. M. G. J.

2017-01-01

INTRODUCTION: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants. OBJECTIVE: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB. METHODS: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting. RESULTS: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socioeconomic and nutritional status), and one focused on macro-economic influences. CONCLUSIONS: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes. PMID:28826444

Genetic diversity of Mycobacterium tuberculosis strains isolated in Algeria: Results of spoligotyping.

PubMed

Ifticene, Malika; Kaïdi, Saïd; Khechiba, Mesbah-Mounir; Yala, Djamel; Boulahbal, Fadila

2015-12-01

Molecular typing tools, including spoligotyping, are currently widely used in the monitoring and study of the dynamics of tuberculosis epidemics. A study of the molecular profile of a sample of 129 Myobacterium tuberculosis strains isolated during 2011 was carried out in the National Reference Laboratory for Tuberculosis and Mycobacteria at the Pasteur Institute of Algeria. This sample was selected at random from a set of 350 strains isolated from tuberculosis patients from central and eastern areas of the country. Genotypic analysis helped to clarify the frequencies of the different genotypes in the current study population: H family, 29%; LAM family, 26%; T family, 25%; S family, 5%, and other genomic families, including orphan strains, 15%. The study of strains isolated between January and December 2011 has allowed insight into the frequency of different genomic families and the importance of existing clusters in the population of central and eastern Algeria. Copyright © 2015 Asian African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

The ancient city of Rome, its empire, and the spread of tuberculosis in Europe.

PubMed

Eddy, Jared J

2015-06-01

The formation of the Roman Empire constituted an unprecedented joining of Mediterranean and European lands and peoples, centering on the capital of Rome. During the late Roman Republic and early Roman Empire (ca. 200B.C.-ca. 200 A.D.) urbanization and population growth led to conditions favorable to the spread of tuberculosis throughout Italy and especially within Rome itself. Trade and military expansion would have acted as vehicles for the further extension of tuberculosis to the provinces via direct transmission from Italian-born Romans to the native populations. However, an alternative explanation may better explain the increase in the number of archeological cases of tuberculosis with the start of the Roman era. A literature review of Roman-era cases and their locations suggests that the development of an urban, Roman way of life resulted in significant increases in prevalence in regions where tuberculosis had previously been endemic only at a low level. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Knowledge of the Bamako general population of tuberculosis].

PubMed

Diallo, S; Diarra, B; Diop, S; Toloba, Y; Berthé, F; Sissoko, B; Gomez, P; M'Baye, O; Keita, B

2009-01-01

The hope of the World Health Organization (WHO) in the fight against tuberculosis rests today on the implementation of the strategy DOTS. The success of this strategy passes obligatorily by an implication of the parents, neighbors in one word of the population living with the patient; this is why we fixed our objective to study knowledge on the tuberculosis of the people of more than 18 years of the district of Bamako. We carried out a cross-sectional study supplemented by focus-groups in 3 districts of Bamako near the general population (socio-medical personnel, old tuberculous, and helping natural) for the period from the 1st of June to July 15, 2004. Our sample was composed of 246 people for the individual questionnaires and of 47 per 8 meetings of focus group: the sex ratio was 2,5 in favour of the men and 60,2% of our subjects had less than 30 years. In the general population of Bamako 24,8% had a good knowledge, 49,0% an average knowledge and 26,2% a bad knowledge. 48,8 % of those which had a good knowledge were the pupils, students and civils servant. So in general the population had a good knowledge on symptomatology (90,2 %), it on the other hand had the knowledge very limited on the etiology (only 10,6% of the subject knew that tuberculosis is caused by a mycobactery) or on the modes of transmission (cigarettes, soap, meat). The population of Bamako has a very passable level of knowledge on tuberculosis. If this level is good with regard to symptomatology, it is very insufficient on the etiology or on the transmission of the disease. To improve this knowledge one needs a sensitizing supported for television and the radio in the dialects and national languages.

The Socioeconomic Factors and the Indigenous Component of Tuberculosis in Amazonas

PubMed Central

2016-01-01

Despite the availability of tuberculosis prevention and control services throughout Amazonas, high rates of morbidity and mortality from tuberculosis remain in the region. Knowledge of the social determinants of tuberculosis in Amazonas is important for the establishment of public policies and the planning of effective preventive and control measures for the disease. To analyze the relationship of the spatial distribution of the incidence of tuberculosis in municipalities and regions of Amazonas to the socioeconomic factors and indigenous tuberculosis component, from 2007 to 2013. An ecological study was conducted based on secondary data from the epidemiological surveillance of tuberculosis. A linear regression model was used to analyze the relationship of the annual incidence of tuberculosis to the socioeconomic factors, performance indicators of health services, and indigenous tuberculosis component. The distribution of the incidence of tuberculosis in the municipalities of Amazonas was positively associated with the Gini index and the population attributable fraction of tuberculosis in the indigenous peoples, but negatively associated with the proportion of the poor and the unemployment rate. The spatial distribution of tuberculosis in the different regions of Amazonas was heterogeneous and closely related with the socioeconomic factors and indigenous component of tuberculosis. PMID:27362428

Assessment of the probability of introducing Mycobacterium tuberculosis into Danish cattle herds.

PubMed

Foddai, Alessandro; Nielsen, Liza Rosenbaum; Krogh, Kaspar; Alban, Lis

2015-11-01

Tuberculosis is a zoonosis caused by Mycobacterium spp. International trade in cattle is regulated with respect to Mycobacterium bovis (M. bovis) but not Mycobacterium tuberculosis (M. tuberculosis), despite that cattle can become infected with both species. In this study we estimated the annual probability (PIntro) of introducing M. tuberculosis into the Danish cattle population, by the import of cattle and/or by immigrants working in Danish cattle herds. Data from 2013 with date, number, and origin of imported live cattle were obtained from the Danish cattle database. Information on immigrants working in Danish cattle herds was obtained through a questionnaire sent to Danish cattle farmers. The gained inputs were fed into three stochastic scenario trees to assess the PIntro for the current and alternative test-and-manage strategies, such as testing of imported animals and/or testing immigrant workers with the tuberculin skin test. We considered the population of Danish farmers and practitioners free of tuberculosis, because in Denmark, the incidence of the disease in humans is low and primarily related to immigrants and socially disadvantaged people. The median annual probability of introducing M. tuberculosis into the Danish cattle population due to imported live cattle was 0.008% (90% P.I.: 0.0007%; 0.03%), while the probability due to immigrant workers was 4.1% (90% P.I.: 0.8%; 12.1%). The median combined probability (PIntro) due to imported cattle plus workers was 4.1% (90% P.I.: 0.8%; 12.6%). Hence, on average at least one introduction each 24 (90% P.I.: 8; 125) years could be expected. Imported live cattle appeared to play a marginal role on the overall annual PIntro, because they represented only approximately 0.2% of the median annual probability. By testing immigrant workers the overall annual PIntro could be reduced to 0.2% (90% P.I.: 0.04%; 0.7%). Thus, testing of immigrant workers could be considered as a risk mitigation strategy to markedly reduce the likelihood of introducing M. tuberculosis into the Danish cattle population, if the risk is considered unacceptable by the veterinary public health authorities. Copyright © 2015 Elsevier B.V. All rights reserved.

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1.

PubMed

Ilin, Aleksandr I; Kulmanov, Murat E; Korotetskiy, Ilya S; Islamov, Rinat A; Akhmetova, Gulshara K; Lankina, Marina V; Reva, Oleg N

2017-01-01

Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain Mycobacterium tuberculosis SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of M. tuberculosis isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of M. tuberculosis . Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.

Gender-related factors influencing tuberculosis control in shantytowns: a qualitative study.

PubMed

Onifade, Dami A; Bayer, Angela M; Montoya, Rosario; Haro, Marie; Alva, Jessica; Franco, Jessica; Sosa, Rosario; Valiente, Betty; Valera, Enit; Ford, Carolyn M; Acosta, Colleen D; Evans, Carlton A

2010-06-29

There is evidence that female gender is associated with reduced likelihood of tuberculosis diagnosis and successful treatment. This study aimed to characterize gender-related barriers to tuberculosis control in Peruvian shantytowns. We investigated attitudes and experiences relating gender to tuberculosis using the grounded theory approach to describe beliefs amongst key tuberculosis control stakeholders. These issues were explored in 22 semi-structured interviews and in four focus group discussions with 26 tuberculosis patients and 17 healthcare workers. We found that the tuberculosis program was perceived not to be gender discriminatory and provided equal tuberculosis diagnostic and treatment care to men and women. This contrasted with stereotypical gender roles in the broader community context and a commonly expressed belief amongst patients and healthcare workers that female health inherently has a lower priority than male health. This belief was principally associated with men's predominant role in the household economy and limited employment for women in this setting. Women were also generally reported to experience the adverse psychosocial and economic consequences of tuberculosis diagnosis more than men. There was a common perception that women's tuberculosis care was of secondary importance to that of men. This reflected societal gender values and occurred despite apparent gender equality in care provision. The greatest opportunities for improving women's access to tuberculosis care appear to be in improving social, political and economic structures, more than tuberculosis program modification.

Gender-related factors influencing tuberculosis control in shantytowns: a qualitative study

PubMed Central

2010-01-01

Background There is evidence that female gender is associated with reduced likelihood of tuberculosis diagnosis and successful treatment. This study aimed to characterize gender-related barriers to tuberculosis control in Peruvian shantytowns. Methods We investigated attitudes and experiences relating gender to tuberculosis using the grounded theory approach to describe beliefs amongst key tuberculosis control stakeholders. These issues were explored in 22 semi-structured interviews and in four focus group discussions with 26 tuberculosis patients and 17 healthcare workers. Results We found that the tuberculosis program was perceived not to be gender discriminatory and provided equal tuberculosis diagnostic and treatment care to men and women. This contrasted with stereotypical gender roles in the broader community context and a commonly expressed belief amongst patients and healthcare workers that female health inherently has a lower priority than male health. This belief was principally associated with men's predominant role in the household economy and limited employment for women in this setting. Women were also generally reported to experience the adverse psychosocial and economic consequences of tuberculosis diagnosis more than men. Conclusions There was a common perception that women's tuberculosis care was of secondary importance to that of men. This reflected societal gender values and occurred despite apparent gender equality in care provision. The greatest opportunities for improving women's access to tuberculosis care appear to be in improving social, political and economic structures, more than tuberculosis program modification. PMID:20587044

[Factors associated to pulmonary tuberculosis in patients with diabetes mellitus from Veracruz, México].

PubMed

Pérez-Navarro, Lucía Montserrat; Fuentes-Domínguez, Francisco; Morales-Romero, Jaime; Zenteno-Cuevas, Roberto

2011-01-01

In Mexico, 20% of cases of tuberculosis (TB) are associated with diabetes mellitus (DM). However, the behavior of the factors related to this comorbidity is unknown, so the aim of this study was to estimate the risk factors and outcome for TB-DM in a population from the state of Veracruz, Mexico. We developed a double-design study: cases and controls for the estimation of risk factors, and a retrospective cohort for the outcome factors. The populations surveyed were 67 patients with the comorbidity TB-DB and 109 with TB. The risk factors for tuberculosis in the diabetic population studied were: age ≥ 35 with an OR of 2.5 (95% CI: 1.4-4.3) and IMC ≥ 25 with an OR of 8.5 (95% CI: 3.1-23.3). According to the outcome variables, the patients with TB-DM showed an increased risk of 2.8 (95% CI: 2.2-3.4) for the development of drug resistance against tuberculosis. In conclusion, age and overweight are important risk factors, and drug resistance is an important outcome factor for the binomial TB-DM in the population from Veracruz. This information will have important effects on the development of surveillance programs against TB, with emphasis on the characteristics of the diabetic population.

[Preventive measures against tuberculosis in working facilities and companies].

PubMed

Suzuki, Kiminori; Satou, Ken

2007-03-01

The health care program in working facilities and companies have played a significant part in prevention of tuberculosis. However, the ordinary national tuberculosis survey policy was abolished in April, 2005 and the tuberculosis survey for salary-earners is on the brink of drastic change. In this symposium the current status of the prevailing survey of tuberculosis in working facilities and companies was reviewed and the future direction of the tuberculosis survey in comparison to that in lung cancer survey was discussed. 1. Epidemiological trends of tuberculosis from the tuberculosis surveillance data: Masako OHMORI (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association). The estimated rate of tuberculosis case discovery by periodical mass screening in the working facilities was 0.033% and it was higher than that in general adult population. The detection rate of tuberculosis in nurses who suffered from tuberculosis reached 40.4% by an aid of mass X-ray screening and 8.7% by contact tracing. The risk of onset of the disease was 4.3 times higher nurses than in general at the same years of age. The importance of infection control measures in the medical facilities was emphasized. 2. Current status and problems in tuberculosis control in a large-sized company: Yusuke NAKAOKA (Department of Occupational Health, Osaka Railway Hospital, West Japan Railway Company). Some preventive modalities against TB such as periodical medical check-up and awareness programs have been done for the purpose of prevention in our company. The prevalence of the disease has significantly reduced in number. The specific circumstances in large-sized company should be taken into consideration, and it is important for company workers and health professionals to recognize their roles in preventing the infectious disease. 3. Are there any differences between clinical cases and control people working for small-sized companies in the onset of tuberculosis?: Osamu NAKASHIMA, Kohei IMOTO (Taito Health Center, Tokyo) and Toru MORI (Research Institute of Tuberculosis, JATA). We surveyed environmental conditions in working places and domestic conditions of employees who were working for small-sized companies located in Taito ward, based on written questionnaires. The companies were selected as those which had the patients of tuberculosis in the past one-year period, and the number of employees was less than ten. Compared with control people, TB patients had more frequent smoking habit (p < 0.05), and tended to have been less exposed to the sunshine at their residency and to have nutritionally poor meals and deficits of their meals. These results suggest that these factors alone or in combination may contribute to accelerated onset of tuberculosis. 4. Current status and problems in tuberculosis management among high prevalence population and in health check-up for personnel with unspecified and high occupational contact with tuberculosis patients: Hidetoshi IGARI (Division of Control and Treatment of Infectious Diseases, Chiba University Hospital), Kiminori SUZUKI (Chiba Foundation for Health Promotion and Disease Prevention). Tuberculosis prevalence is as high as 500-1500 per 100,000 peoples among the homeless and construction workers living in "Hanba", a bunkhouse. We surveyed their medical conditions through periodical or extraperiodical health check-up. We retrospectively analyzed some medical factors contributing to successful treatment of the disease. Hospital admission and enhancement of counseling opportunities were two factors leading to the success of the treatment. The ambulance attendants have a significant possibility to contact patients with TB and are high at risk of acquiring the infection. As there are often limited information on TB in patients in an emergency condition, it is difficult to protect themselves from its contagion properly. Periodical and extraperiodical health check-up is important for these personnel and application of QuantiFERON-TB 2nd generation to the personnel is new and useful for diagnosis of the latent tuberculosis infection. 5. A role of chest X-ray examination for lung cancer detection among company workers: Takeo TESHIMA (Koseikan Clinic, Miyagi Branch, Japan Anti-Tuberculosis Association). Detection rates of lung cancer in company workers and in general population under the age of 60 years were compared. Chest X-ray survey was done using 10 cm x 10 cm indirect chest X-ray films of the chest. The detection rates of lung cancer in patients with definite or suspicious diagnosis in 265,620 company workers were 2.3 and 2.6 per 100,000, respectively. On the other hand the rates were 9.9 and 8.8 per 100,000 in a general population of 811,391. Twenty-four percent of patients with suspicious diagnosis were eventually made a definite diagnosis. The corrected detection rate reached to 21.0 for male patients and 8.3 for female patients and 12.1 totally. The detection rates of lung cancer in company workers and in general population under the age of 60 years exceeded the rate of pulmonary tuberculosis. Chest X-ray examination for the detection of lung cancer and pulmonary tuberculosis is still recommended under various working and social circumstances.

CE: Tuberculosis: A New Screening Recommendation and an Expanded Approach to Elimination in the United States.

PubMed

Parmer, John; Allen, Leeanna; Walton, Wanda

2017-08-01

: Nurses play a critical role in the diagnosis and treatment of tuberculosis and in the prevention of tuberculosis transmission through infection control practices. To eliminate tuberculosis in the United States, however, an expanded approach to testing and treating people with latent tuberculosis infection must be implemented. Recently, the U.S. Preventive Services Task Force (USPSTF) issued a new recommendation statement on latent tuberculosis infection testing that expands nurses' opportunities to identify at-risk populations for tuberculosis prevention. In combination with newer testing methodologies and shorter treatment regimens, implementation of the USPSTF recommendation has the potential to remove previously existing barriers to screening and treatment of both patients and health care providers. This article provides a general overview of tuberculosis transmission, pathogenesis, and epidemiology; presents preventive care recommendations for targeted testing among high-risk groups; and discusses the USPSTF recommendation's applicability to public health and primary care practice in the United States.

Tuberculosis and mental health in the Asia-Pacific.

PubMed

Mason, Paul H; Sweetland, Annika C; Fox, Greg J; Halovic, Shaun; Nguyen, Thu Anh; Marks, Guy B

2016-12-01

This opinion piece encourages mental health researchers and clinicians to engage with mental health issues among tuberculosis patients in the Asia-Pacific region in a culturally appropriate and ethical manner. The diversity of cultural contexts and the high burden of tuberculosis throughout the Asia-Pacific presents significant challenges. Research into tuberculosis and mental illness in this region is an opportunity to develop more nuanced models of mental illness and treatment, while simultaneously contributing meaningfully to regional tuberculosis care and prevention. We overview key issues in tuberculosis and mental illness co-morbidity, highlight ethical concerns and advocate for a regional approach to tuberculosis and mental health that is consistent with the transnational challenges presented by this airborne infectious disease. Integrating tuberculosis and mental health services will go a long way to addressing the needs of vulnerable populations and stopping the transmission of one of the world's biggest infectious killers. © The Royal Australian and New Zealand College of Psychiatrists 2016.

De Novo Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells Formed against Antituberculosis Drugs In Vitro

PubMed Central

Sebastian, Jees; Swaminath, Sharmada; Nair, Rashmi Ravindran; Jakkala, Kishor; Pradhan, Atul

2016-01-01

ABSTRACT Bacterial persisters are a subpopulation of cells that can tolerate lethal concentrations of antibiotics. However, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell populations, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. In the present study, we found that Mycobacterium tuberculosis cells exposed continuously to lethal concentrations of rifampin (RIF) or moxifloxacin (MXF) for prolonged durations showed killing, RIF/MXF persistence, and regrowth phases. RIF-resistant or MXF-resistant mutants carrying clinically relevant mutations in the rpoB or gyrA gene, respectively, were found to emerge at high frequency from the RIF persistence phase population. A Luria-Delbruck fluctuation experiment using RIF-exposed M. tuberculosis cells showed that the rpoB mutants were not preexistent in the population but were formed de novo from the RIF persistence phase population. The RIF persistence phase M. tuberculosis cells carried elevated levels of hydroxyl radical that inflicted extensive genome-wide mutations, generating RIF-resistant mutants. Consistent with the elevated levels of hydroxyl radical-mediated genome-wide random mutagenesis, MXF-resistant M. tuberculosis gyrA de novo mutants could be selected from the RIF persistence phase cells. Thus, unlike previous studies, which showed emergence of genetically resistant mutants upon exposure of bacteria for short durations to sublethal concentrations of antibiotics, our study demonstrates that continuous prolonged exposure of M. tuberculosis cells to lethal concentrations of an antibiotic generates antibiotic persistence phase cells that form a reservoir for the generation of genetically resistant mutants to the same antibiotic or another antibiotic. These findings may have clinical significance in the emergence of drug-resistant tubercle bacilli. PMID:27895008

Sugar cane manufacturing is associated with tuberculosis in an indigenous population in Brazil.

PubMed

Sacchi, Flávia Patussi Correia; Croda, Mariana Garcia; Estevan, Anderson Oliveira; Ko, Albert I; Croda, Julio

2013-03-01

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality among indigenous peoples in Brazil, and identifying the risk factors for TB in this population secondary to specific epidemiological conditions is essential for recommending interventions aimed at disease control. This case-control study was conducted with an indigenous population between June 2009 and August 2011 in Dourados, Brazil. Tuberculosis cases reported to the national disease surveillance programme were paired with two control cases matched by age and geographic location. There were 63 cases included in this study, and the annual incidence of TB in the indigenous communities examined was 222 (95% CI, 148-321) per 100 000 inhabitants. The multivariate analysis demonstrated that the variables associated with TB infection included male gender (OR 2.6; 95% CI 1.3-5.3), not owning a home (OR 3.4; 95% CI 1.2-10.1), illiteracy (OR 2.4; 95% CI 1.1-5.0), TB contact (OR 2.4; 95% CI 1.2-4.8) and work performed in a sugar cane factory (OR 6.8; 95% CI 1.2-36.9). There is a potential relationship between exposure to sugar cane manufacturing processes and tuberculosis infection among indigenous populations.

Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance.

PubMed

Filippova, Ekaterina V; Kieser, Karen J; Luan, Chi-Hao; Wawrzak, Zdzislaw; Kiryukhina, Olga; Rubin, Eric J; Anderson, Wayne F

2016-06-01

Mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic-resistant M. tuberculosis makes tuberculosis infections difficult to treat. To overcome this problem new effective antimicrobial strategies are urgently needed. One promising target for new therapeutic approaches is PonA1, a class A penicillin-binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth in mycobacteria. Here, crystal structures of the transpeptidase domain, the enzymatic domain responsible for penicillin binding, of PonA1 from M. tuberculosis in the inhibitor-free form and in complex with penicillin V are reported. We used site-directed mutagenesis, antibiotic profiling experiments, and fluorescence thermal shift assays to measure PonA1's sensitivity to different classes of β-lactams. Structural comparison of the PonA1 apo-form and the antibiotic-bound form shows that binding of penicillin V induces conformational changes in the position of the loop β4'-α3 surrounding the penicillin-binding site. We have also found that binding of different antibiotics including penicillin V positively impacts protein stability, while other tested β-lactams such as clavulanate or meropenem resulted in destabilization of PonA1. Our antibiotic profiling experiments indicate that the transpeptidase activity of PonA1 in both M. tuberculosis and M. smegmatis mediates tolerance to specific cell wall-targeting antibiotics, particularly to penicillin V and meropenem. Because M. tuberculosis is an important human pathogen, these structural data provide a template to design novel transpeptidase inhibitors to treat tuberculosis infections. Structural data are available in the PDB database under the accession numbers 5CRF and 5CXW. © 2016 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Challenges in the Estimation of the Annual Risk of Mycobacterium tuberculosis Infection in Children Aged Less Than 5 Years.

PubMed

Khan, P Y; Glynn, Judith R; Mzembe, T; Mulawa, D; Chiumya, R; Crampin, Amelia C; Kranzer, Katharina; Fielding, Katherine L

2017-10-15

Accurate estimates of Mycobacterium tuberculosis infection in young children provide a critical indicator of ongoing community transmission of M. tuberculosis. Cross-reactions due to infection with environmental mycobacteria and/or bacille Calmette-Guérin (BCG) vaccination compromise the estimates derived from population-level tuberculin skin-test surveys using traditional cutoff methods. Newer statistical approaches are prone to failure of model convergence, especially in settings where the prevalence of M. tuberculosis infection is low and environmental sensitization is high. We conducted a tuberculin skin-test survey in 5,119 preschool children in the general population and among household contacts of tuberculosis cases in 2012-2014 in a district in northern Malawi where sensitization to environmental mycobacteria is common and almost all children are BCG-vaccinated. We compared different proposed methods of estimating M. tuberculosis prevalence, including a method described by Rust and Thomas more than 40 years ago. With the different methods, estimated prevalence in the general population was 0.7%-11.5% at ages <2 years and 0.8%-3.3% at ages 2-4 years. The Rust and Thomas method was the only method to give a lower estimate in the younger age group (0.7% vs 0.8%), suggesting that it was the only method that adjusted appropriately for the marked effect of BCG-attributable induration in the very young. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

TUBERCULOSIS BURDEN IN LEBANON: EVOLUTION AND CURRENT STATUS.

PubMed

Araj, George F; Saade, Antoine; Itani, Lina Y; Avedissian, Aline Z

2016-01-01

In the absence of surveillance data and consolidated information about tuberculosis (TB) and its drug resistance burden in Lebanon, this retrospective study was conducted to shed light on TB and its other relevant aspects over the last 15 years in this country. To generate the TB data for this retrospective study, two main sources were used: 1) the records of patients in the National Tuberculosis Program (NTP); 2) the results of the Clinical Microbiology Laboratory (CML) at the American University of Beirut Medical Center (AUBMC). The TB data review pertained to its epidemiological aspect, implementation of the directly observed therapy strategy (DOTS) all over, the gender distribution, the impact of high risk groups (non-national population, Syrian refugees, patients with multi-drug resistance-TB [MDR-TB] and the inmate population) on the trend of TB in Lebanon between 1999 and 2013. Reviewed also are TB in children, extrapulmonary tuberculosis and the mycobacterium other than tuberculosis (MOTT). During the last 15 years, 7548 TB cases were diagnosed and evaluated at the NTP. After the decreasing of TB incidence from 13/100 000 population in 2001 to 9/100 000 in 2006, the incidence started to increase in 2007, reaching 20/100 000 in 2013, mostly due to increased cases among non-national population. Fluctuations in TB rates over the years were seen among children, inmates, MDR-TB, and HIV patients. MOTT isolates recovery rates also fluctuated during the study period, M. simiae being the most common. After the decreasing trends of TB incidence between 1999 and 2006, Lebanon has been experiencing an increasing incidence in tuberculosis population since 2007. This is mainly attributed to the dramatic increase of TB patients among non-nationals and the influx of Syrian refugees. The ongoing collaboration between the public and private sectors, improvements of the surveillance system and TB control are important factors for successful elimination of TB in this country.

Strengthening tuberculosis control overseas: who benefits?

PubMed

Nguyen, Hoa Thi Minh; Hickson, Roslyn I; Kompas, Tom; Mercer, Geoffry N; Lokuge, Kamalini M

2015-03-01

Although tuberculosis is a major cause of morbidity and mortality worldwide, available funding falls far short of that required for effective control. Economic and spillover consequences of investments in the treatment of tuberculosis are unclear, particularly when steep gradients in the disease and response are linked by population movements, such as that between Papua New Guinea (PNG) and the Australian cross-border region. To undertake an economic evaluation of Australian support for the expansion of basic Directly Observed Treatment, Short Course in the PNG border area of the South Fly from the current level of 14% coverage. Both cost-utility analysis and cost-benefit analysis were applied to models that allow for population movement across regions with different characteristics of tuberculosis burden, transmission, and access to treatment. Cost-benefit data were drawn primarily from estimates published by the World Health Organization, and disease transmission data were drawn from a previously published model. Investing $16 million to increase basic Directly Observed Treatment, Short Course coverage in the South Fly generates a net present value of roughly $74 million for Australia (discounted 2005 dollars). The cost per disability-adjusted life-year averted and quality-adjusted life-year saved for PNG is $7 and $4.6, respectively. Where regions with major disparities in tuberculosis burden and health system resourcing are connected through population movements, investments in tuberculosis control are of mutual benefit, resulting in net health and economic gains on both sides of the border. These findings are likely to inform the case for appropriate investment in tuberculosis control globally. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Tuberculosis and nutrition

PubMed Central

Gupta, Krishna Bihari; Gupta, Rajesh; Atreja, Atulya; Verma, Manish; Vishvkarma, Suman

2009-01-01

Malnutrition and tuberculosis are both problems of considerable magnitude in most of the underdeveloped regions of the world. These two problems tend to interact with each other. Tuberculosis mortality rates in different economic groups in a community tend to vary inversely with their economic levels. Similarly, nutritional status is significantly lower in patients with active tuberculosis compared with healthy controls. Malnutrition can lead to secondary immunodeficiency that increases the host's susceptibility to infection. In patients with tuberculosis, it leads to reduction in appetite, nutrient malabsorption, micronutrient malabsorption, and altered metabolism leading to wasting. Both, protein-energy malnutrition and micronutrients deficiencies increase the risk of tuberculosis. It has been found that malnourished tuberculosis patients have delayed recovery and higher mortality rates than well-nourished patients. Nutritional status of patients improves during tuberculosis chemotherapy. High prevalence of human immunodeficiency (HIV) infection in the underdeveloped countries further aggravates the problem of malnutrition and tuberculosis. Effect of malnutrition on childhood tuberculosis and tuberculin skin test are other important considerations. Nutritional supplementation may represent a novel approach for fast recovery in tuberculosis patients. In addition, raising nutritional status of population may prove to be an effective measure to control tuberculosis in underdeveloped areas of world. PMID:20165588

Updates on Knowledge, Attitude and Preventive Practices on Tuberculosis among Healthcare Workers.

PubMed

Wahab, Farhanah Abd; Abdullah, Sarimah; Abdullah, Jafri Malin; Jaafar, Hasnan; Noor, Siti Suraiya Md; Mohammad, Wan Mohd Zahiruddin Wan; Yusoff, Abdul Aziz Mohamed; Tharakan, John; Bhaskar, Shalini; Sangu, Muthuraju; Mahmood, Mohd Shah; Kassim, Fauziah; Rafia, Md Hanip; Haspani, Mohammed Safari Mohammed; Alias, Azmi; Pando, Rogelio Hernández

2016-11-01

Ranking as the most communicable disease killer worldwide, tuberculosis, has accounted with a total of 9.6 million new tuberculosis cases with 1.5 million tuberculosis-related deaths reported globally in 2014. Tuberculosis has remain as an occupational hazard for healthcare workers since 1920s and due to several tuberculosis outbreaks in healthcare settings in the early 1990s, the concern about the transmission to both patients and healthcare workers has been raised. Healthcare workers have two to three folds greater the risk of active tuberculosis than the general population. Several studies on knowledge, attitude and practices on tuberculosis among healthcare workers worldwide have revealed that majority of the participated healthcare workers had good knowledge on tuberculosis. Most of the healthcare workers from South India and South Africa also reported to have positive attitude whereas a study in Thailand reported that most of the healthcare providers have negative attitude towards tuberculosis patients. Nevertheless, majority of the healthcare workers have low level of practice on tuberculosis prevention. An improved communication between healthcare workers and the patients as well as their families is the key to better therapeutic outcomes with good knowledge, attitude and preventive practice towards tuberculosis.

Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement.

PubMed

van Hest, N A; Aldridge, R W; de Vries, G; Sandgren, A; Hauer, B; Hayward, A; Arrazola de Oñate, W; Haas, W; Codecasa, L R; Caylà, J A; Story, A; Antoine, D; Gori, A; Quabeck, L; Jonsson, J; Wanlin, M; Orcau, Å; Rodes, A; Dedicoat, M; Antoun, F; van Deutekom, H; Keizer, St; Abubakar, I

2014-03-06

In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective. Lessons can be learnt from across the EU and this consensus statement on TB control in big cities and urban risk groups was prepared by a working group representing various EU big cities, brought together on the initiative of the European Centre for Disease Prevention and Control. The consensus statement describes general and specific social, educational, operational, organisational, legal and monitoring TB control interventions in EU big cities, as well as providing recommendations for big city TB control, based upon a conceptual TB transmission and control model.

[RISK FACTORS FOR TUBERCULOSIS IN REPRODUCTIVE-AGED WOMEN].

PubMed

2010-01-01

The sociohygienic risk factors of tuberculosis were assessed in 253 reproductive-aged women from Izhevsk to develop social and medical prophylactic measures. There is evidence that living conditions, income and education levels, nutrition quality, marital and employment status are of particular importance among the social risk factors of tuberculosis. The low levels of medical activity and hygienic literacy, poor awareness of prophylactic measures against tuberculosis largely favors the untimely detection and spread of tuberculosis infection among the population, including women of reproductive age. In this connection, healthcare workers should activate work on the publicity of health-saving lifestyle and on the prevention of tuberculosis. The analysis indicated that 83.5% of the female patients with tuberculosis were detected from the disease risk groups, prophylactic work with this group will therefore prevent the occurrence of new cases and reduce morbidity of this pathology.

[An inventory of knowledge on tuberculosis among dentists in the Netherlands].

PubMed

Burger, M S; Abraham-Inpijn, L; Vissink, A

2012-03-01

By the nature of his work, a dentist has a higher risk of tuberculosis infection than the average Dutch population. Thus, the question arises whether dentists do have sufficient knowledge on tuberculosis. In order to determine their knowledge, an inventory was conducted among a sample of dentists in the Netherlands. Analysis of the dentists' response to 19 correct or incorrect statements revealed that their knowledge level on tuberculosis was rather low, did not vary with regard to gender, and was independent of the region where they were practising and of their explicit medical interest. The dentists indicated a desire for education on tuberculosis.

Drug development against tuberculosis: Impact of alkaloids.

PubMed

Mishra, Shardendu K; Tripathi, Garima; Kishore, Navneet; Singh, Rakesh K; Singh, Archana; Tiwari, Vinod K

2017-09-08

Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Barriers to sustainable tuberculosis control in the Russian Federation health system.

PubMed Central

Atun, R. A.; Samyshkin, Y. A.; Drobniewski, F.; Skuratova, N. M.; Gusarova, G.; Kuznetsov, S. I.; Fedorin, I. M.; Coker, R. J.

2005-01-01

The Russian Federation has the eleventh highest tuberculosis burden in the world in terms of the total estimated number of new cases that occur each year. In 2003, 26% of the population was covered by the internationally recommended control strategy known as directly observed treatment (DOT) compared to an overall average of 61% among the 22 countries with the highest burden of tuberculosis. The Director-General of WHO has identified two necessary starting points for the scaling-up of interventions to control emerging infectious diseases. These are a comprehensive engagement with the health system and a strengthening of the health system. The success of programmes aimed at controlling infectious diseases is often determined by constraints posed by the health system. We analyse and evaluate the impact of the arrangements for delivering tuberculosis services in the Russian Federation, drawing on detailed analyses of barriers and incentives created by the organizational structures, and financing and provider-payment systems. We demonstrate that the systems offer few incentives to improve the efficiency of services or the effectiveness of tuberculosis control. Instead, the system encourages prolonged supervision through specialized outpatient departments in hospitals (known as dispensaries), multiple admissions to hospital and lengthy hospitalization. The implementation, and expansion and sustainability of WHO-approved methods of tuberculosis control in the Russian Federation are unlikely to be realized under the prevailing system of service delivery. This is because implementation does not take into account the wider context of the health system. In order for the control programme to be sustainable, the health system will need to be changed to enable services to be reconfigured so that incentives are created to reward improvements in efficiency and outcomes. PMID:15798846

Genotypic diversity of Mycobacterium tuberculosis in Buenos Aires, Argentina.

PubMed

Monteserin, Johana; Paul, Roxana; Gravina, Elida; Reniero, Ana; Hernandez, Teresa; Mazzeo, Eduardo; Togneri, Ana; Simboli, Norberto; López, Beatriz; Couvin, David; Rastogi, Nalin; Ritacco, Viviana

2018-04-06

Buenos Aires is an overpopulated port city historically inhabited by people of European descent. Together with its broader metropolitan area, the city exhibits medium tuberculosis rates, and receives migrants, mainly from tuberculosis highly endemic areas of Argentina and neighboring countries. This work was aimed to gain insight into the Mycobacterium tuberculosis population structure in two suburban districts of Buenos Aires which are illustrative of the overall situation of tuberculosis in Argentina. The Lineage 4 Euro-American accounted for >99% of the 816 isolates analyzed (one per patient). Frequencies of spoligotype families were T 35.9%, LAM 33.2%, Haarlem 19.5%, S 3.2%, X 1.5%, Ural 0.7%, BOV 0.2%, Beijing 0.2%, and Cameroon 0.2%. Unknown signatures accounted for 5.3% isolates. Of 55 spoligotypes not matching any extant shared international type (SIT) in SITVIT database, 22 fitted into 15 newly-issued SITs. Certain autochthonous South American genotypes were found to be actively evolving. LAM3, which is wild type for RD rio , was the predominant LAM subfamily in both districts and the RD rio signature was rare among autochthonous, newly created, SITs and orphan patterns. Two genotypes that are rarely observed in neighboring countries ̶ SIT2/H2 and SIT159/T1 Tuscany ̶ were conspicuously represented in Argentina. The infrequent Beijing patterns belonged to Peruvian patients. We conclude that the genotype diversity observed reflects the influence of the Hispanic colonization and more recent immigration waves from Mediterranean and neighboring countries. Unlike in Brazil, the RD rio type does not play a major role in the tuberculosis epidemic in Buenos Aires. Copyright © 2018 Elsevier B.V. All rights reserved.

An ethnography of nonadherence: culture, poverty, and tuberculosis in urban Bolivia.

PubMed

Greene, Jeremy A

2004-09-01

The author conducted a focused descriptive ethnographic study of nonadherence with tuberculosis (TB) therapy among Aymara-speaking residents of the city of La Paz, Bolivia. A cohort of patient-informants was identified from the District III TB Control Registry of La Paz as having been nonadherent with their TB medication protocol. From June to August 1998, ethnographic material was collected through participant-observation and repeated interviews and visits in homes, workplaces, clinics, and the community. Ethnographic analysis revealed structural barriers to be more important than cultural differences in the production of nonadherence. Though informants maintained a variety of beliefs and practices related to Aymara medicine, the majority of patients were comfortable with a biomedical model of tuberculosis and maintained belief in the efficacy of antituberculosis chemotherapy and desire to finish treatment. Patients overwhelmingly cited hidden costs of treatments, poor access to care, ethnic discrimination, and prior maltreatment by the health system as reasons for abandoning treatment. These data suggest that overemphasis of cultural difference without exploration of other social dimensions of health care delivery can obscure a more practical understanding of nonadherence in marginalized populations.

Drug-resistant tuberculosis: time for visionary political leadership.

PubMed

Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin

2013-06-01

Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans. Copyright © 2013 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd. All rights reserved.

Validity and reliability of a health care service evaluation instrument for tuberculosis

PubMed Central

Scatena, Lucia Marina; Wysocki, Anneliese Domingues; Beraldo, Aline Ale; Magnabosco, Gabriela Tavares; Brunello, Maria Eugênia Firmino; Netto, Antonio Ruffino; Nogueira, Jordana de Almeida; Silva, Reinaldo Antonio; Brito, Ewerton William Gomes; Alexandre, Patricia Borges Dias; Monroe, Aline Aparecida; Villa, Tereza Cristina Scatena

2015-01-01

OBJECTIVE To evaluate the validity and reliability of an instrument that evaluates the structure of primary health care units for the treatment of tuberculosis. METHODS This cross-sectional study used simple random sampling and evaluated 1,037 health care professionals from five Brazilian municipalities (Natal, state of Rio Grande do Norte; Cabedelo, state of Paraíba; Foz do Iguaçu, state of Parana; Sao José do Rio Preto, state of Sao Paulo, and Uberaba, state of Minas Gerais) in 2011. Structural indicators were identified and validated, considering different methods of organization of the health care system in the municipalities of different population sizes. Each structure represented the organization of health care services and contained the resources available for the execution of health care services: physical resources (equipment, consumables, and facilities); human resources (number and qualification); and resources for maintenance of the existing infrastructure and technology (deemed as the organization of health care services). The statistical analyses used in the validation process included reliability analysis, exploratory factor analysis, and confirmatory factor analysis. RESULTS The validation process indicated the retention of five factors, with 85.9% of the total variance explained, internal consistency between 0.6460 and 0.7802, and quality of fit of the confirmatory factor analysis of 0.995 using the goodness-of-fit index. The retained factors comprised five structural indicators: professionals involved in the care of tuberculosis patients, training, access to recording instruments, availability of supplies, and coordination of health care services with other levels of care. Availability of supplies had the best performance and the lowest coefficient of variation among the services evaluated. The indicators of assessment of human resources and coordination with other levels of care had satisfactory performance, but the latter showed the highest coefficient of variation. The performance of the indicators “training” and “access to recording instruments” was inferior to that of other indicators. CONCLUSIONS The instrument showed feasibility of application and potential to assess the structure of primary health care units for the treatment of tuberculosis. PMID:25741651

Is Knowledge Regarding Tuberculosis Associated with Stigmatising and Discriminating Attitudes of General Population towards Tuberculosis Patients? Findings from a Community Based Survey in 30 Districts of India.

PubMed

Sagili, Karuna D; Satyanarayana, Srinath; Chadha, Sarabjit S

2016-01-01

Stigmatising and discriminating attitudes may discourage tuberculosis (TB) patients from actively seeking medical care, hide their disease status, and discontinue treatment. It is expected that appropriate knowledge regarding TB should remove stigmatising and discriminating attitudes. In this study we assessed the prevalence of stigmatising and discriminating attitudes towards TB patients among general population and their association with knowledge regarding TB. A cross-sectional knowledge, attitude and practice survey was conducted in 30 districts of India in January-March 2011. A total of 4562 respondents from general population were interviewed using semi-structured questionnaires which contained items to measure stigma, discrimination and knowledge on TB. Of the 4562 interviewed, 3823 were eligible for the current analysis. Of these, 73% (95% CI 71.4-74.2) had stigmatising and 98% (95% CI 97.4-98.3) had discriminating attitude towards TB patients. Only 17% (95% CI 15.6-18.0) of the respondents had appropriate knowledge regarding TB with even lower levels observed amongst females, rural areas and respondents from low income groups. Surprisingly stigmatising (adjusted OR 1.31 (0.78-2.18) and discriminating (adjusted OR 0.79 (0.43-1.44) attitudes were independent of knowledge regarding TB. Stigmatising and discriminating attitudes towards TB patients remain high among the general population in India. Since these attitudes were independent of the knowledge regarding TB, it is possible that the current disseminated knowledge regarding TB which is mainly from a medical perspective may not be adequately addressing the factors that lead to stigma and discrimination towards TB patients. Therefore, there is an urgent need to review the messages and strategies currently used for disseminating knowledge regarding TB among general population and revise them appropriately. The disseminated knowledge should include medical, psycho-social and economic aspects of TB that not only informs people about medical aspects of TB disease, but also removes stigma and discrimination.

Moving new vaccines for tuberculosis through the regulatory process.

PubMed

Brennan, M J

2000-06-01

The development of novel vaccines for the prevention of tuberculosis is an area of intense interest for scientific researchers, public health agencies, and pharmaceutical manufacturers. Development of effective new vaccines directed against tuberculosis for use in target populations will require close cooperation among several different international organizations, including regulatory agencies responsible for evaluating the safety and effectiveness of new biologics for human use.

The Epidemiological Characteristics of Beijing Lineage Mycobacterium tuberculosis from a National Referral Center in China.

PubMed

Li, Xiao Ying; Li, Ying; Zhang, Yao; Kang, Wan Li; Zhao, Li Ping; Ding, Peng Ju; Dai, Wen Tao; Huang, Hai Rong; Huang, Yan Feng; Li, Wei Min

2015-07-01

Our study was to investigate the epidemiological characteristics of M.tuberculosis from a national tuberculosis referral center in China. All strains isolated from TB patients, were genotyped by the RD105 deletion, 8 and 51 SNP loci and VNTR. The high differentiation SNPs of modern Beijing strains were analyzed for protein function and structure. 413 M. tuberculosis were included. Of 379 Beijing lineage M. tuberculosis, 'modern' and 'ancient' strains respectively represented 85.5% (324/379) and 14.5% (55/379). Rv2494 (V48A) and Rv0245 (S103F) were confirmed as high differentiation SNPs associated with modern strains. In a word, Modern Beijing lineage M.tuberculosis was dominant and the structural models suggested that modern sub-lineage may more easily survive in 'extreme' host condition. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Co-evolution of Mycobacterium tuberculosis and Homo sapiens

PubMed Central

Brites, Daniela; Gagneux, Sebastien

2015-01-01

The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M. tuberculosis to transmit from person to person, it has to cause pulmonary disease. Therefore, M. tuberculosis virulence has likely been a significant determinant of the association between M. tuberculosis and humans. Indeed, the evolutionary success of some M. tuberculosis genotypes seems at least partially attributable to their increased virulence. The latter possibly evolved as a consequence of human demographic expansions. If co-evolution occurred, humans would have counteracted to minimize the deleterious effects of M. tuberculosis virulence. The fact that human resistance to infection has a strong genetic basis is a likely consequence of such a counter-response. The genetic architecture underlying human resistance to M. tuberculosis remains largely elusive. However, interactions between human genetic polymorphisms and M. tuberculosis genotypes have been reported. Such interactions are consistent with local adaptation and allow for a better understanding of protective immunity in TB. Future ‘genome-to-genome’ studies, in which locally associated human and M. tuberculosis genotypes are interrogated in conjunction, will help identify new protective antigens for the development of better TB vaccines. PMID:25703549

[Tuberculosis and immigration].

PubMed

Salas-Coronas, Joaquín; Rogado-González, M Cruz; Lozano-Serrano, Ana Belén; Cabezas-Fernández, M Teresa

2016-04-01

The incidence of tuberculosis worldwide is declining. However, in Western countries this decline is slower due to the impact of immigration. Tuberculosis in the immigrant population is related to health status in the country of origin and with overcrowding and poverty conditions in the host country. Immigrants with tuberculosis are younger, have a higher prevalence of extrapulmonary forms, greater proportion of drug resistance and higher treatment default rates than those of natives. New molecular techniques not only reduce diagnostic delay time but also allow the rapid identification of resistances and improve knowledge of transmission patterns. It is necessary to implement measures to improve treatment compliance in this population group like facilitating access to health card, the use of fixed-dose combination drugs, the participation of cultural mediators and community health workers and gratuity of drugs. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

PubMed Central

Moraes, Gleiciane Leal; Gomes, Guelber Cardoso; de Sousa, Paulo Robson Monteiro; Alves, Cláudio Nahum; Govender, Thavendran; Kruger, Hendrik G.; Maguire, Glenn E.M.; Lamichhane, Gyanu; Lameira, Jerônimo

2015-01-01

SUMMARY Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB. PMID:25701501

Structural basis of DNA sequence recognition by the response regulator PhoP in Mycobacterium tuberculosis.

PubMed

He, Xiaoyuan; Wang, Liqin; Wang, Shuishu

2016-04-15

The transcriptional regulator PhoP is an essential virulence factor in Mycobacterium tuberculosis, and it presents a target for the development of new anti-tuberculosis drugs and attenuated tuberculosis vaccine strains. PhoP binds to DNA as a highly cooperative dimer by recognizing direct repeats of 7-bp motifs with a 4-bp spacer. To elucidate the PhoP-DNA binding mechanism, we determined the crystal structure of the PhoP-DNA complex. The structure revealed a tandem PhoP dimer that bound to the direct repeat. The surprising tandem arrangement of the receiver domains allowed the four domains of the PhoP dimer to form a compact structure, accounting for the strict requirement of a 4-bp spacer and the highly cooperative binding of the dimer. The PhoP-DNA interactions exclusively involved the effector domain. The sequence-recognition helix made contact with the bases of the 7-bp motif in the major groove, and the wing interacted with the adjacent minor groove. The structure provides a starting point for the elucidation of the mechanism by which PhoP regulates the virulence of M. tuberculosis and guides the design of screening platforms for PhoP inhibitors.

Genetic polymorphism and immune response to tuberculosis in indigenous populations: a brief review.

PubMed

Longhi, Renata Maronna Praça; Zembrzuski, Verônica Marques; Basta, Paulo Cesar; Croda, Julio

2013-01-01

We systematically reviewed studies of the immune response to tuberculosis and the genetic polymorphisms associated with Th1- or Th2-mediated cytokine expression in indigenous populations. A bibliographic search was performed on the Medline and ISI databases and included studies published between January 1980 and October 2011. The search terms were tuberculosis, American Indians, Amerindian, indigenous, Indians, native people, aboriginal, immun*, host immune, immune response, cytokine*, polymorphism*, and gene. Regardless of their design, studies that evaluated immunoglobulin, cytokine levels and genetic polymorphisms that altered cytokine expression were included. Thirteen studies met the inclusion criteria. The majority of studies were performed in Latin America, and five investigated the Warao ethnic group of Venezuela. Most of the investigations indirectly evaluated the immune response. Higher anergy to the tuberculin skin test, higher IgG4 and IgM levels, higher IL-5 production and lower TNF-α, IL-12p40 and IFN-γ production were found in the indigenous populations. The studies also reported a predominantly Th2-type response in these populations and a possibly higher susceptibility to tuberculosis. A better understanding of the relevant genetic polymorphisms and their role in immune regulation would help to clarify the immunogenetic mechanisms of TB infection in these populations. This information would be useful for identifying new treatments and preventing infection and progression to active disease. Copyright © 2013 Elsevier Editora Ltda. All rights reserved.

Immigrants and tuberculosis in Hong Kong.

PubMed

Leung, C C; Chan, C K; Chang, K C; Law, W S; Lee, S N; Tai, L B; Leung, Eric C C; Tam, C M

2015-08-01

To examine the impact of immigrant populations on the epidemiology of tuberculosis in Hong Kong. Longitudinal cohort study. Hong Kong. Socio-demographic and disease characteristics of all tuberculosis notifications in 2006 were captured from the statutory tuberculosis registry and central tuberculosis reference laboratory. Using 2006 By-census population data, indirect sex- and age-standardised incidence ratios by place of birth were calculated. Treatment outcome at 12 months was ascertained from government tuberculosis programme record forms, and tuberculosis relapse was tracked through the notification registry and death registry up to 30 June 2013. Moderately higher sex- and age-standardised incidence ratios were observed among various immigrant groups: 1.06 (Mainland China), 2.02 (India, Pakistan, Bangladesh), 1.59 (Philippines, Thailand, Indonesia, Nepal), and 3.11 (Vietnam). Recent Mainland migrants had a lower sex- and age-standardised incidence ratio (0.51 vs 1.09) than those who immigrated 7 years ago or earlier. Age younger than 65 years, birth in the Mainland or the above Asian countries, and previous treatment were independently associated with resistance to isoniazid and/or rifampicin. Older age, birth in the above Asian countries, non-permanent residents, previous history of treatment, and resistance to isoniazid and/or rifampicin were independently associated with poor treatment outcome (other than cure/treatment completion) at 1 year. Birth outside Hong Kong was an independent predictor of relapse following successful completion of treatment (adjusted hazard ratio=1.76; 95% confidence interval, 1.07-2.89; P=0.025). Immigrants carry with them a higher tuberculosis incidence and/or drug resistance rate from their place of origin. The higher drug resistance rate, poorer treatment outcome, and excess relapse risk raise concern over secondary transmission of drug-resistant tuberculosis within the local community.

Household crowding as a potential mediator of socioeconomic determinants of tuberculosis incidence in Brazil

PubMed Central

Pelissari, Daniele Maria; Diaz-Quijano, Fredi Alexander

2017-01-01

Although many studies have identified social conditions associated with tuberculosis, contextual and individual factors have rarely been analysed simultaneously. Consequently, we aimed to identify contextual and individual factors associated with tuberculosis incidence in general population in Brazil in 2010. We also assessed whether household crowding mediates the association between socioeconomic determinants and tuberculosis incidence. Individual data of tuberculosis cases were obtained from 5,565 municipalities in Brazil in 2010 (last year of national census), and merged with contextual variables. The associations were evaluated in a multilevel analysis using negative binomial regression. After adjusting for individual factors (age, sex and race) and geographic region, the following contextual factors were associated with tuberculosis incidence rate: AIDS incidence rate [incidence rate ratio (IRR), 1.21; 95% confidence interval (CI), 1.18–1.24], unemployment rate (IRR, 1.16; 95% CI, 1.13–1.19), Gini coefficient (IRR, 1.05; 95% CI, 1.02–1.08), proportion of inmates (IRR, 1.11; 95% CI, 1.09–1.14), mean per capita household income (IRR, 0.94; 95% CI, 0.91–0.97) and primary care coverage (IRR, 0.94; 95% CI, 0.92–0.96). Inclusion of household crowding in the multivariate model led to a loss of the associations of both Gini coefficient and mean per capita household income. In conclusion, our findings suggest that income inequality and poverty, as determinants of tuberculosis incidence, can be mediated by household crowding. Moreover, prison population can represent a potential social reservoir of tuberculosis in Brazil and should be addressed as a priority for disease control. Finally, the negative association between primary health coverage and tuberculosis incidence highlights the importance of this level of care as a strategy to control this disease. PMID:28419146

The brucellosis and tuberculosis status of wood bison in the Mackenzie Bison Sanctuary, Northwest Territories, Canada.

PubMed Central

Tessaro, S V; Gates, C C; Forbes, L B

1993-01-01

Postmortem examinations were done on 51 wood bison (Bison bison athabascae) killed as part of a multidisciplinary research project in the Mackenzie Bison Sanctuary, Northwest Territories, Canada, between 1986 and 1988. There was no gross, histological or bacteriological evidence of brucellosis or tuberculosis in these bison. Traumatic lesions were seen in one calf that had been attacked by wolves and a second calf that had been gored. Antibody titers to Brucella abortus were not found in sera from these 51 animals or an additional 112 wood bison that were chemically-immobilized or killed in the Sanctuary between 1986 and 1990. The combined prevalence of the diseases in the population could not have exceeded 5.95% for the necropsy survey to have missed finding at least one infected animal, and the prevalence of brucellosis in the population would have had to be less than 1.95% for the broader serological survey to have failed to find at least one reactor animal on the battery of tests. These results, and the cumulative epidemiological information on brucellosis and tuberculosis in bison, indicate that bovine brucellosis and tuberculosis are not enzootic in the wood bison population in and around the Mackenzie Bison Sanctuary, and suggest that the population is free of these diseases. However, this expanding population is at risk of contracting both diseases from the infected bison population in and around nearby Wood Buffalo National Park. PMID:8269360

Mycobacterium tuberculosis Genotypes Determined by Spoligotyping to Be Circulating in Colombia between 1999 and 2012 and Their Possible Associations with Transmission and Susceptibility to First-Line Drugs

PubMed Central

Puerto, Gloria; Erazo, Lina; Wintaco, Maira; Castro, Claudia; Ribón, Wellman; Guerrero, Martha Inírida

2015-01-01

Introduction Tuberculosis (TB) remains a primary public health problem worldwide. The number of multidrug-resistant tuberculosis (MDR TB) cases has increased in recent years in Colombia. Knowledge of M. tuberculosis genotypes defined by spoligotyping can help determine the circulation of genotypes that must be controlled to prevent the spread of TB. Objective To describe the genotypes of M. tuberculosis using spoligotyping in resistant and drug-sensitive isolates and their possible associations with susceptibility to first-line drugs. Methods An analytical observational study was conducted that included 741 isolates of M. tuberculosis from patients. The isolates originated from 31 departments and were obtained by systematic surveillance between 1999 and 2012. Results In total 61.94% of the isolates were resistant to 1 or more drugs, and 147 isolates were MDR. In total, 170 genotypes were found in the population structure of Colombian M. tuberculosis isolates. The isolates were mainly represented by four families: LAM (39.9%), Haarlem (19%), Orphan (17%) and T (9%). The SIT42 (LAM 9) was the most common genotype and contained 24.7% of the isolates, followed by the genotypes SIT62 (Haarlem1), SIT53 (T1), and SIT50 (H3). A high clustering of isolates was evident with 79.8% of the isolates classified into 32 groups. The Beijing family was associated with resistant isolates, whereas the Haarlem and T families were associated with sensitive isolates. The Haarlem family was also associated with grouped isolates (p = 0.031). Conclusions A high proportion (approximately 80%) of isolates was found in clusters; these clusters were not associated with resistance to first-line drugs. The Beijing family was associated with drug resistance, whereas the T and Haarlem families were associated with susceptibility in the Colombian isolates studied. PMID:26066494

Extensively drug-resistant tuberculosis in a young child after travel to India.

PubMed

Salazar-Austin, Nicole; Ordonez, Alvaro A; Hsu, Alice Jenh; Benson, Jane E; Mahesh, Mahadevappa; Menachery, Elizabeth; Razeq, Jafar H; Salfinger, Max; Starke, Jeffrey R; Milstone, Aaron M; Parrish, Nicole; Nuermberger, Eric L; Jain, Sanjay K

2015-12-01

Extensively drug-resistant (XDR) tuberculosis is becoming increasingly prevalent worldwide, but little is known about XDR tuberculosis in young children. In this Grand Round we describe a 2-year-old child from the USA who developed pneumonia after a 3 month visit to India. Symptoms resolved with empirical first-line tuberculosis treatment; however, a XDR strain of Mycobacterium tuberculosis grew in culture. In the absence of clinical or microbiological markers, low-radiation exposure pulmonary CT imaging was used to monitor treatment response, and guide an individualised drug regimen. Management was complicated by delays in diagnosis, uncertainties about drug selection, and a scarcity of child-friendly formulations. Treatment has been successful so far, and the child is in remission. This report of XDR tuberculosis in a young child in the USA highlights the risks of acquiring drug-resistant tuberculosis overseas, and the unique challenges in management of tuberculosis in this susceptible population. Copyright © 2015 Elsevier Ltd. All rights reserved.

Population Genomics of Mycobacterium tuberculosis in Ethiopia Contradicts the Virgin Soil Hypothesis for Human Tuberculosis in Sub-Saharan Africa

PubMed Central

Comas, Iñaki; Hailu, Elena; Kiros, Teklu; Bekele, Shiferaw; Mekonnen, Wondale; Gumi, Balako; Tschopp, Rea; Ameni, Gobena; Hewinson, R. Glyn; Robertson, Brian D.; Goig, Galo A.; Stucki, David; Gagneux, Sebastien; Aseffa, Abraham; Young, Douglas; Berg, Stefan

2015-01-01

Summary Colonial medical reports claimed that tuberculosis (TB) was largely unknown in Africa prior to European contact, providing a “virgin soil” for spread of TB in highly susceptible populations previously unexposed to the disease [1, 2]. This is in direct contrast to recent phylogenetic models which support an African origin for TB [3, 4, 5, 6]. To address this apparent contradiction, we performed a broad genomic sampling of Mycobacterium tuberculosis in Ethiopia. All members of the M. tuberculosis complex (MTBC) arose from clonal expansion of a single common ancestor [7] with a proposed origin in East Africa [3, 4, 8]. Consistent with this proposal, MTBC lineage 7 is almost exclusively found in that region [9, 10, 11]. Although a detailed medical history of Ethiopia supports the view that TB was rare until the 20th century [12], over the last century Ethiopia has become a high-burden TB country [13]. Our results provide further support for an African origin for TB, with some genotypes already present on the continent well before European contact. Phylogenetic analyses reveal a pattern of serial introductions of multiple genotypes into Ethiopia in association with human migration and trade. In place of a “virgin soil” fostering the spread of TB in a previously naive population, we propose that increased TB mortality in Africa was driven by the introduction of European strains of M. tuberculosis alongside expansion of selected indigenous strains having biological characteristics that carry a fitness benefit in the urbanized settings of post-colonial Africa. PMID:26687624

Population Genomics of Mycobacterium tuberculosis in Ethiopia Contradicts the Virgin Soil Hypothesis for Human Tuberculosis in Sub-Saharan Africa.

PubMed

Comas, Iñaki; Hailu, Elena; Kiros, Teklu; Bekele, Shiferaw; Mekonnen, Wondale; Gumi, Balako; Tschopp, Rea; Ameni, Gobena; Hewinson, R Glyn; Robertson, Brian D; Goig, Galo A; Stucki, David; Gagneux, Sebastien; Aseffa, Abraham; Young, Douglas; Berg, Stefan

2015-12-21

Colonial medical reports claimed that tuberculosis (TB) was largely unknown in Africa prior to European contact, providing a "virgin soil" for spread of TB in highly susceptible populations previously unexposed to the disease [1, 2]. This is in direct contrast to recent phylogenetic models which support an African origin for TB [3-6]. To address this apparent contradiction, we performed a broad genomic sampling of Mycobacterium tuberculosis in Ethiopia. All members of the M. tuberculosis complex (MTBC) arose from clonal expansion of a single common ancestor [7] with a proposed origin in East Africa [3, 4, 8]. Consistent with this proposal, MTBC lineage 7 is almost exclusively found in that region [9-11]. Although a detailed medical history of Ethiopia supports the view that TB was rare until the 20(th) century [12], over the last century Ethiopia has become a high-burden TB country [13]. Our results provide further support for an African origin for TB, with some genotypes already present on the continent well before European contact. Phylogenetic analyses reveal a pattern of serial introductions of multiple genotypes into Ethiopia in association with human migration and trade. In place of a "virgin soil" fostering the spread of TB in a previously naive population, we propose that increased TB mortality in Africa was driven by the introduction of European strains of M. tuberculosis alongside expansion of selected indigenous strains having biological characteristics that carry a fitness benefit in the urbanized settings of post-colonial Africa. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Tuberculosis and malaria global prophylaxis in the light of decisions of the Big Eight].

PubMed

Onishchenko, G G

2008-01-01

At the present time about two million people, one third of the Earth's population, are carriers of tuberculosis agent. Though tuberculosis is curable disease, it continues to take away lives of about 4400 persons; most of them are young and are in the most productive age. The most active incidence rate of tuberculosis occurs in the countries of Africa to the south of Sahara (29% of all cases of tuberculosis per head); half of new cases of tuberculosis fall on Asian countries: Bangladesh, China, India, Indonesia, Pakistan, Philippines. The governments of Big Eight maintain activities that have stabilized morbidity of tuberculosis on a world scale. Over 11 years (1995 - 2006) World Health Organization (WHO) implemented the DOTS strategy (Directly Observed Treatment with Short course of chemotherapy) in 183 countries and tested it on 26 millions patients with tuberculosis. Global data acquisition in 2005 found out morbidity of tuberculosis in 59% (the aim is 70%) and successful cure in 84% cases (the aim is 85 %). In 2006 WHO started realization of the Global Plan "Stop tuberculosis" (2006 - 2012). At the present time Global Fund use about 17% its resources to finance programs against tuberculosis. These funds help to reveal 5 millions extra cases of tuberculosis and cure 3 millions patients in the network of DOTS.

Recurrent tuberculosis in an urban area in China: Relapse or exogenous reinfection?

PubMed

Shen, Xin; Yang, Chongguang; Wu, Jie; Lin, Senlin; Gao, Xu; Wu, Zheyuan; Tian, Jiyun; Gan, Mingyu; Luo, Tao; Wang, Lili; Yu, Chenlei; Mei, Jian; Pan, Qichao; DeRiemer, Kathryn; Yuan, ZhengAn; Gao, Qian

2017-03-01

Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01-8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30-59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recurrent tuberculosis in an urban area in China: relapse or exogenous reinfection?

PubMed Central

Shen, Xin; Yang, Chongguang; Wu, Jie; Lin, Senlin; Gao, Xu; Wu, Zheyuan; Tian, Jiyun; Gan, Mingyu; Luo, Tao; Wang, Lili; Yu, Chenlei; Mei, Jian; Pan, Qichao; DeRiemer, Kathryn; Yuan, ZhengAn; Gao, Qian

2017-01-01

Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01–8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30–59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting. PMID:28237039

A multi-scale approach to designing therapeutics for tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Linderman, Jennifer J.; Cilfone, Nicholas A.; Pienaar, Elsje

Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis. Lastly, we describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oralmore » and inhaled antibiotics, and (c) the effect of vaccination.« less

A multi-scale approach to designing therapeutics for tuberculosis

DOE PAGES

Linderman, Jennifer J.; Cilfone, Nicholas A.; Pienaar, Elsje; ...

2015-04-20

Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis. Lastly, we describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oralmore » and inhaled antibiotics, and (c) the effect of vaccination.« less

Genetic Heterogeneity in Mycobacterium tuberculosis Isolates Reflected in IS6110 Restriction Fragment Length Polymorphism Patterns as Low-Intensity Bands

PubMed Central

de Boer, Annette S.; Kremer, Kristin; Borgdorff, Martien W.; de Haas, Petra E. W.; Heersma, Herre F.; van Soolingen, Dick

2000-01-01

Mycobacterium tuberculosis isolates with identical IS6110 restriction fragment length polymorphism (RFLP) patterns are considered to originate from the same ancestral strain and thus to reflect ongoing transmission. In this study, we investigated 1,277 IS6110 RFLP patterns for the presence of multiple low-intensity bands (LIBs), which may indicate infections with multiple M. tuberculosis strains. We did not find any multiple LIBs, suggesting that multiple infections are rare in the Netherlands. However, we did observe a few LIBs in 94 patterns (7.4%) and examined the nature of this phenomenon. With single-colony cultures it was found that LIBs mostly represent mixed bacterial populations with slightly different RFLP patterns. Mixtures were expressed in RFLP patterns as LIBs when 10 to 30% of the DNA analyzed originated from a bacterial population with another RFLP pattern. Presumably, a part of the LIBs did not represent mixed bacterial populations, as in some clusters all strains exhibited LIBs in their RFLP patterns. The occurrence of LIBs was associated with increased age in patients. This may reflect either a gradual change of the bacterial population in the human body over time or IS6110-mediated genetic adaptation of M. tuberculosis to changes in the environmental conditions during the dormant state or reactivation thereafter. PMID:11101583

[Estimating the year of eradication of tuberculosis in Japan].

PubMed

Ohmori, M

1991-12-01

The time of eradication of tuberculosis has been discussed for several countries, and based on those results, a new strategic plan and goals have been elaborated. Considering such developments, and in order to make a new tuberculosis control strategy, it is important to determine the point at which eradication of tuberculosis would be achieved in Japan. Styblo proposed the two conventional definitions of eradication of tuberculosis, namely that the incidence of smear-positive tuberculosis has fallen below 1 per million population or that the prevalence of tuberculosis infection in the general population has fallen below 1% and continues to decrease. The bacteriological results of new cases have been reported since 1975 in Japan. However, those results are still of doubtful validity and reliability. Therefore, the author estimated the year of eradication of tuberculosis, according to the criterion that tuberculosis is eradicated when the proportion of the population infected with tubercle bacilli is less than 1%. If the risk of infection is changing at a regular rate, it is possible to estimate the risk of infection at any time in the past and in the future. Once the risk of infection is determined, it is also possible to calculate the age-specific prevalence of infection and the proportion of the population infected with tubercle bacilli at various times in the past and in the future. In Japan, the risk of infection before World War II was assumed to be around 4% and not to vary with calendar year. And based on the data from the prevalence surveys in Okinawa in 1968 and 1973, the risk of infection was estimated 0.3% in 1968 and has declined on average, by 10 to 11% annually. At that time, Okinawa was the only area free from BCG vaccination in Japan. The incidence rate in Japan also has declined, on average, by 10% annually. However, since late 1970s, the annual speed of decline of the incidence rate has been slowed down. Therefore, I assumed that the recent trend of the infection risk is the same as the trend of the recent incidence rate among the 0-29 year age-group. The size of the effect of age on the risk of infection has been discussed. The author also considered age-effects in the model. The weight applied to the risk of infection by age was determined by examining the age-specific positive rate in the 1930s before the era when BCG vaccination was widely used.(ABSTRACT TRUNCATED AT 400 WORDS)

DNA Replication in Mycobacterium tuberculosis

PubMed Central

DITSE, ZANELE; LAMERS, MEINDERT H.; WARNER, DIGBY F.

2017-01-01

Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as Mycobacterium tuberculosis that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable M. tuberculosis to adapt to these stresses: the emergence of drug-resistant isolates provides direct evidence of this capacity, so too the well-documented genetic diversity among M. tuberculosis lineages across geographic loci, as well as the microvariation within individual patients that is increasingly observed as whole-genome sequencing methodologies are applied to clinical samples and tuberculosis (TB) disease models. However, the precise mutagenic mechanisms responsible for M. tuberculosis evolution and adaptation are poorly understood. Here, we summarize current knowledge of the machinery responsible for DNA replication in M. tuberculosis, and discuss the potential contribution of the expanded complement of mycobacterial DNA polymerases to mutagenesis. We also consider briefly the possible role of DNA replication—in particular, its regulation and coordination with cell division—in the ability of M. tuberculosis to withstand antibacterial stresses, including host immune effectors and antibiotics, through the generation at the population level of a tolerant state, or through the formation of a subpopulation of persister bacilli—both of which might be relevant to the emergence and fixation of genetic drug resistance. PMID:28361736

Phenotypic and genotypic characteristics of drug resistance in Mycobacterium tuberculosis isolates from pediatric population of Chennai, India.

PubMed

Therese, K Lily; Gayathri, R; Balasubramanian, S; Natrajan, S; Madhavan, H N

2012-01-01

Multidrug-resistant TB (MDR-TB) has been reported in almost all parts of the world. Childhood TB is accorded low priority by national TB control programs. Probable reasons include diagnostic difficulties, limited resources, misplaced faith in BCG and lack of data on treatment. Good data on the burden of all forms of TB among children in India are not available. To study the drug sensitivity pattern of tuberculosis in children aged from 3 months to 18 years and the outcome of drug-resistant tuberculosis by BACTEC culture system and PCR-based DNA sequencing technique. This is a retrospective study. One hundred and fifty-nine clinical specimens were processed for Ziehl-Neelsen stain, Mycobacterial culture by BACTEC method, phenotypic DST for first-line drugs for Mycobacterium tuberculosis (M. tuberculosis) isolates and PCR-based DNA sequencing was performed for the M. tuberculosis isolates targeting rpoB, katG, inhA, oxyR-ahpC, rpsL, rrs and pncA. Out of the 159 Mycobacterial cultures performed during the study period, 17 clinical specimens (10.7%) were culture positive for M. tuberculosis. Among the 17 M. tuberculosis isolates, 2 were multidrug-resistant TB. PCR-based DNA sequencing revealed the presence of many novel mutations targeting katG, inhA, oxyR-ahpC and pncA and the most commonly reported mutation Ser531Leu in the rpoB gene. This study underlines the urgent need to take efforts to develop methods for rapid detection and drug susceptibility of tubercle bacilli in the pediatric population.

'A scandal which must be corrected'. Reconsidering the success of the Australian Tuberculosis Campaign.

PubMed

Stylianou, Marianna

2009-01-01

Operating from 1948 to 1976, the Australian Tuberculosis Campaign was successful in almost eliminating the incidence of tuberculosis in Victoria, which until the late 1940s had been the leading cause of death for the state's young adults. Yet despite claims that the campaign was inclusive of all citizens, this dramatic fall in morbidity and mortality was not replicated in Victoria's Indigenous population. By examining contemporary discourses relating to citizenship and civic responsibility, this article seeks to understand policymakers' rationale and methodology for the public health campaign, and then analyse them to explore the reasons for the striking disparity in outcomes between Victoria's white and Indigenous populations.

Controlling the Seedbeds of Tuberculosis: Diagnosis and Treatment of Tuberculosis Infection

PubMed Central

Rangaka, Molebogeng X.; Cavalcante, Solange C.; Marais, Ben J.; Thim, Sok; Martinson, Neil A.; Swaminathan, Soumya; Chaisson, Richard E.

2015-01-01

The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a critical opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programs focusing on single strategies rather than comprehensive programs that deliver an integrated arsenal for tuberculosis control may continue to struggle. Tuberculosis preventive therapy is a poorly utilized tool that is essential for controlling the reservoirs of disease that drive the current epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. This paper outlines challenges to implementation of preventive therapy and provides pragmatic suggestions for overcoming them. It further advocates for tuberculosis preventive therapy as the core of a renewed global focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics, and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems, community engagement, and enhance sustainable large scale implementation of preventive therapy programs. PMID:26515679

Molecular study on human tuberculosis in three geographically distinct and time delineated populations from ancient Egypt.

PubMed Central

Zink, A. R.; Grabner, W.; Reischl, U.; Wolf, H.; Nerlich, A. G.

2003-01-01

We describe the molecular identification of human tuberculosis (TB) from vertebral bone tissue samples from three different populations of ancient Egypt. The specimens were obtained from the predynastic to early dynastic necropolis of Abydos (7 individuals, c. 3500-2650 B.C.), from a Middle Kingdom to Second Intermediate Period tomb of the necropolis of Thebes-West (37. c. 2100-1550 B.C.) and from five further Theban tombs used in the New Kingdom and the Late Period (39, c. 1450-500 B.C.). A total of 18 cases tested positive for the presence of ancient DNA (aDNA) of the M. tuberculosis complex. Out of the 9 cases with typical macromorphological signs of tuberculous spondylitis, 6 were positive for mycobacterial aDNA (66.7%). Of 24 cases with non-specific pathological alterations, 5 provided a positive result (20.8%). In 50 cases of normally appearing vertebral bones 7 tested positive (14.0%). There were only minor differences in the frequencies between the three populations. These data strongly support the notion that tuberculosis was present and prevalent in ancient Egypt since very early periods of this civilization. The unexpectedly high rate of mycobacterial aDNA in normal bone samples is presumably due to a pre- to perimortal systemic spread of the bacteria and indicates a generalized infection by M. tuberculosis. PMID:12729192

Tuberculosis Control in South African Gold Mines: Mathematical Modeling of a Trial of Community-Wide Isoniazid Preventive Therapy

PubMed Central

Vynnycky, Emilia; Sumner, Tom; Fielding, Katherine L.; Lewis, James J.; Cox, Andrew P.; Hayes, Richard J.; Corbett, Elizabeth L.; Churchyard, Gavin J.; Grant, Alison D.; White, Richard G.

2015-01-01

A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006–2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial (“optimized intervention”), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus–positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus–positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens. PMID:25792607

Tuberculin reactivity and tuberculosis epidemiology in the Pakaanóva (Wari') Indians of Rondônia, south-western Brazilian Amazon.

PubMed

Escobar, A L; Coimbra, C E A; Camacho, L A B; Santos, R V

2004-01-01

To investigate the characteristics of tuberculin skin test reactivity in the Pakaanóva Indians, in Amazonia, Brazil, after revaccination of all study participants with bacille Calmette-Guerin (BCG). The investigation was designed as a post-BCG vaccination purified protein derivative (PPD) survey. Data included PPD readings, age, sex, nutritional status, place of residence, previous tuberculosis, physical examinations and BCG status. Bivariate and multivariate logistic regression analyses were conducted. About 90% (n = 505) of the total population participated. One third (32.1%) of the subjects presented induration > or = 10 mm at 72 h. Induration sizes showed weak linear correlation with age; differences between sexes were not observed. Skin reaction was not associated with nutritional status. Individuals with a history of tuberculosis were six times more likely to test positive. History of tuberculosis, age, and previous BCG vaccination were significantly associated with PPD reactivity in the multivariate analyses. The Pakaanóva showed a high proportion (58.4%) of non-reactors, even with a recent BCG booster. Sex differences in PPD reactivity were either not present or could not be demonstrated. The association between age and PPD reactivity resembles that observed in other Amazonian populations. The authors discuss the potential of PPD testing as a screening tool to enhance tuberculosis detection, especially in indigenous populations in Amazonia with limited access to health services.

Development of a culturally sensitive educational intervention program to reduce the high incidence of tuberculosis among foreign-born Vietnamese.

PubMed

Houston, H Rika; Harada, Nancy; Makinodan, Takashi

2002-11-01

In Los Angeles County and Orange County, 98% of Asians with tuberculosis (TB) were foreign born; newly arrived Vietnamese immigrants had the highest TB risk: i.e. > 100 times higher than that of the USA. The study objective was to find ways to reduce the high incidence of tuberculosis among the Vietnamese by: (1) identifying and understanding the cultural health beliefs and barriers among the Vietnamese population of Orange County, California; and (2) developing a partnership between UCLA/VA/RAND MEDTEP, key Vietnamese community-based organizations, and community leaders in Orange County to develop and implement a comprehensive, culturally sensitive educational intervention program. Vietnamese residing in Orange County were recruited to obtain qualitative and quantitative data in 1998 and 1999, respectively. The study design included focus groups, in-depth interviews, and community surveys. Data were collected via qualitative reports, computer-assisted random telephone interviews, and self-administered questionnaires. A conceptual schema was identified within the Vietnamese health belief system that recognized two different forms of tuberculosis: non-infectious psychological and infectious physical tuberculosis. It was possible to engage community organizations in developing programs to combat TB in the Vietnamese population. The Health beliefs of Vietnamese will be important considerations in developing a culturally sensitive educational intervention program to service this at-risk population.

Structure-based screening and molecular dynamics simulations offer novel natural compounds as potential inhibitors of Mycobacterium tuberculosis isocitrate lyase.

PubMed

Shukla, Rohit; Shukla, Harish; Sonkar, Amit; Pandey, Tripti; Tripathi, Timir

2018-06-01

Mycobacterium tuberculosis is the etiological agent of tuberculosis in humans and is responsible for more than two million deaths annually. M. tuberculosis isocitrate lyase (MtbICL) catalyzes the first step in the glyoxylate cycle, plays a pivotal role in the persistence of M. tuberculosis, which acts as a potential target for an anti-tubercular drug. To identify the potential anti-tuberculosis compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,748) against the MtbICL structure. The ligands were docked against MtbICL in three sequential docking modes that resulted in 340 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 27 compounds were found to fit well with re-docking studies. After refinement by molecular docking and drug-likeness analyses, three potential inhibitors (ZINC1306071, ZINC2111081, and ZINC2134917) were identified. These three ligands and the reference compounds were further subjected to molecular dynamics simulation and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the MtbICL and bound complexes. The binding free energy analyses were calculated to validate and capture the intermolecular interactions. The results suggested that the three compounds had a negative binding energy with -96.462, -143.549, and -122.526 kJ mol -1 for compounds with IDs ZINC1306071, ZINC2111081, and ZINC2134917, respectively. These lead compounds displayed substantial pharmacological and structural properties to be drug candidates. We concluded that ZINC2111081 has a great potential to inhibit MtbICL and would add to the drug discovery process against tuberculosis.

Role of the Health Department in Tuberculosis Prevention and Control-Legal and Public Health Considerations.

PubMed

Jeffries, Carla; Lobue, Phil; Chorba, Terence; Metchock, Beverly; Kashef, Ijaz

2017-03-01

Because tuberculosis is caused by an infectious organism that is spread from person to person through the air, public health measures are essential to control the disease. There are three priority strategies for tuberculosis prevention and control in the United States: (i) identifying and treating persons who have tuberculosis disease; (ii) finding persons exposed to infectious tuberculosis patients, evaluating them for Mycobacterium tuberculosis infection and disease, and providing subsequent treatment, if appropriate; and (iii) testing populations at high risk for latent tuberculosis infection (LTBI) and treating those persons who are infected to prevent progression to disease. These strategies for prevention and control of tuberculosis are discussed in a framework containing the following important topics: historical and epidemiological context of tuberculosis control, organization of public health tuberculosis control programs, legal basis for public health authority, conducting overall planning and development of policy, identifying persons who have clinically active tuberculosis, evaluation of immigrants, managing persons who have or who are suspected of having disease, medical consultation, interjurisdictional referrals, identifying and managing persons infected with Mycobacterium tuberculosis, providing laboratory and diagnostic services, collecting and analyzing data, and providing training and education. This chapter describes the role of the health department in the context of these components. This discussion is primarily applicable to tuberculosis prevention and control programs in the United States.

Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel.

PubMed

Graham, Stephen M; Ahmed, Tahmeed; Amanullah, Farhana; Browning, Renee; Cardenas, Vicky; Casenghi, Martina; Cuevas, Luis E; Gale, Marianne; Gie, Robert P; Grzemska, Malgosia; Handelsman, Ed; Hatherill, Mark; Hesseling, Anneke C; Jean-Philippe, Patrick; Kampmann, Beate; Kabra, Sushil Kumar; Lienhardt, Christian; Lighter-Fisher, Jennifer; Madhi, Shabir; Makhene, Mamodikoe; Marais, Ben J; McNeeley, David F; Menzies, Heather; Mitchell, Charles; Modi, Surbhi; Mofenson, Lynne; Musoke, Philippa; Nachman, Sharon; Powell, Clydette; Rigaud, Mona; Rouzier, Vanessa; Starke, Jeffrey R; Swaminathan, Soumya; Wingfield, Claire

2012-05-15

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

[Tuberculosis and HIV infection: experience of the national tuberculosis prevention program in Djibouti: 1990-1996].

PubMed

Renoux, E; Matan, A Barreh; Sevre, J P; Mohamed Ali, I; Chami, D; Vincent, V

2002-01-01

Based on analysis of data collected from the national tuberculosis prevention program in Djibouti between 1990 and 1996, the authors analyzed the relationship between HIV infection and tuberculosis. The study cohort comprised a total of 22,000 patients including 14,000 with documented HIV infection. Although HIV infection probably worsened the situation, it was neither the only nor the main factor involved in the resurgence of tuberculosis. Demographic growth, higher population density, and increasing poverty as well as the quality of the national tuberculosis prevention program must be taken into account. The incidence of smear-negative tuberculosis was not significantly higher in HIV-infected patients (incidence of smear positive cases, > 92%). Extrapulmonary tuberculosis especially of pleural involvement was more common (15% versus 9.4%). Treatment was effective in HIV-infected patients. If directly observed (DOT) therapy was used, there was no risk of emergence of multidrug-resistant tuberculosis strains. Drug side-effects associated with the protocols used in Djibouti were not greater in HIV-infected patients. Most additional mortality observed in HIV-infected tuberculosis patients (10.5% versus 2%) was due to progression of HIV infection.

Tuberculosis among the homeless, United States, 1994-2010.

PubMed

Bamrah, S; Yelk Woodruff, R S; Powell, K; Ghosh, S; Kammerer, J S; Haddad, M B

2013-11-01

1) To describe homeless persons diagnosed with tuberculosis (TB) during the period 1994-2010, and 2) to estimate a TB incidence rate among homeless persons in the United States. TB cases reported to the National Tuberculosis Surveillance System were analyzed by origin of birth. Incidence rates were calculated using the US Department of Housing and Urban Development homeless population estimates. Analysis of genotyping results identified clustering as a marker for transmission among homeless TB patients. Of 270,948 reported TB cases, 16,527 (6%) were homeless. The TB incidence rate among homeless persons ranged from 36 to 47 cases per 100,000 population in 2006-2010. Homeless TB patients had over twice the odds of not completing treatment and of belonging to a genotype cluster. US- and foreign-born homeless TB patients had respectively 8 and 12 times the odds of substance abuse. Compared to the general population, homeless persons had an approximately 10-fold increase in TB incidence, were less likely to complete treatment and more likely to abuse substances. Public health outreach should target homeless populations to reduce the excess burden of TB in this population.

Peritoneal tuberculosis with elevated serum Ca-125 level mimicking advanced stage ovarian cancer: a case report.

PubMed

Tan, Orkun; Luchansky, Edward; Rosenman, Stephen; Pua, Tarah; Azodi, Masoud

2009-08-01

Tuberculosis is still a common problem in immigrant population with peritoneal tuberculosis as the most common presentation of extrapulmonary disease. A 36-year-old woman presented with abdominal distention, night sweats and weight loss. Physical examination and radiologic studies revealed ascites, omental caking and bilateral enlarged ovaries with an elevated serum Ca-125 of 353 U/mL. Acid-fast stain and culture were negative for Mycobacterium tuberculosis. Diagnostic laparoscopy and biopsy revealed multiple granulomas with epithelioid cells and caseification necrosis confirming tuberculosis. Treatment with anti-tuberculin drugs resulted in resolution of symptoms with a reduction in Ca-125 to normal. Laparoscopic biopsy with frozen section evaluation would spare patients with peritoneal tuberculosis from unnecessary extensive surgery. Serum Ca-125 level may be useful in monitoring treatment response.

Identification of new benzamide inhibitor against α-subunit of tryptophan synthase from Mycobacterium tuberculosis through structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations.

PubMed

Naz, Sadia; Farooq, Umar; Ali, Sajid; Sarwar, Rizwana; Khan, Sara; Abagyan, Ruben

2018-03-13

Multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis has emerged as global health threat, causing millions of deaths worldwide. Identification of new drug candidates for tuberculosis (TB) by targeting novel and less explored protein targets will be invaluable for antituberculosis drug discovery. We performed structure-based virtual screening of eMolecules database against a homology model of relatively unexplored protein target: the α-subunit of tryptophan synthase (α-TRPS) from Mycobacterium tuberculosis essential for bacterial survival. Based on physiochemical properties analysis and molecular docking, the seven candidate compounds were selected and evaluated through whole cell-based activity against the H37Rv strain of M. tuberculosis. A new Benzamide inhibitor against α-subunit of tryptophan synthase (α-TRPS) from M. tuberculosis has been identified causing 100% growth inhibition at 25 μg/ml and visible bactericidal activity at 6 μg/ml. This benzamide inhibitor displayed a good predicted binding score (-48.24 kcal/mol) with the α-TRPS binding pocket and has logP value (2.95) comparable to Rifampicin. Further refinement of docking results and evaluation of inhibitor-protein complex stability were investigated through Molecular dynamic (MD) simulations studies. Following MD simulations, Root mean square deviation, Root mean square fluctuation and secondary structure analysis confirmed that protein did not unfold and ligand stayed inside the active pocket of protein during the explored time scale. This identified benzamide inhibitor against the α-subunit of TRPS from M. tuberculosis could be considered as candidate for drug discovery against TB and will be further evaluated for enzyme-based inhibition in future studies.

Genetic diversity of drug and multidrug-resistant Mycobacterium tuberculosis circulating in Veracruz, Mexico

PubMed Central

Munro-Rojas, Daniela; Fernandez-Morales, Esdras; Zarrabal-Meza, José; Martínez-Cazares, Ma. Teresa; Parissi-Crivelli, Aurora; Fuentes-Domínguez, Javier; Séraphin, Marie Nancy; Lauzardo, Michael; González-y-Merchand, Jorge Alberto; Rivera-Gutierrez, Sandra

2018-01-01

Background Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of drug-resistant tuberculosis isolates is limited. Methods In this study, the genetic structure of 112 Mycobacterium tuberculosis strains from the southeastern Mexico was determined by spoligotyping and 24-loci MIRU-VNTRs. Findings The results show eight major lineages, the most of which was T1 (24%), followed by LAM (16%) and H (15%). A total of 29 (25%) isolates were identified as orphan. The most abundant SITs were SIT53/T1 and SIT42/LAM9 with 10 isolates each and SIT50/H3 with eight isolates. Fifty-two spoligotype patterns, twenty-seven clusters and ten clonal complexes were observed, demonstrating an important genetic diversity of drug and multidrug-resistant tuberculosis isolates in circulation and transmission level of these aggravated forms of tuberculosis. Being defined as orphan or as part of an orphan cluster, was a risk factor for multidrug resistant-tuberculosis (OR 2.5, IC 1.05–5.86 and OR 3.3, IC 1–11.03, respectively). Multiple correspondence analyses showed association of some clusters and SITs with specific geographical locations. Conclusions Our study provides one of the most detailed description of the genetic structure of drug and multidrug-resistant tuberculosis strains in southeast Mexico, establishing for the first time a baseline of the genotypes observed in resistant isolates circulating, however further studies are required to better elucidate the genetic structure of tuberculosis in region and the factors that could be participating in their dispersion. PMID:29543819

[Knowledge and perception about tuberculosis among public transport workers in Lima, Peru].

PubMed

Lukac, Danitza; Garaycochea, Octavio; Taype-Rondan, Alvaro; Luque Bustamante, Laura; Mujica-Vasquez, André; Zamora, Dario

2016-11-23

To describe the level of knowledge and perception of tuberculosis among public transport workers attending Road Safety Education courses in Lima, Peru. An observational, cross-sectional, analytic study was conducted between July and August 2014 in public transport workers attending the courses of Road Safety education. In Lima, such courses are mandatory for workers in the public transport area. An anonymous and voluntary survey was applied to obtain the following variables: sociodemographic characteristics, history of tuberculosis, tuberculosis knowledge and attitudes towards the disease. The factors associated to the risk perception of Tuberculosis infection were analysed using Poisson regression. From 309 attendees, 216 surveys were analysed (69.9%). Of these, 88.4% were males, 3.2% had a history of tuberculosis. The most widely known symptom was cough with phlegm (44.4%), the most popular source of information was television (39.8%), and only 9.7% had any training about tuberculosis. A 41.2% of respondents believed that working in the public transport sector was an occupation with a high risk of tuberculosis infection. No significant association between risk perception of tuberculosis and sociodemographic characteristics was found. A considerable lack of knowledge about tuberculosis symptoms and a low perception of risk for tuberculosis exists among public transport workers in Lima. Education strategies directed to this population need to be implemented.

Mycobacterium tuberculosis complex transmission is not associated with recent immigration (≤5 years) in Florida.

PubMed

Séraphin, Marie Nancy; Lauzardo, Michael

2015-12-01

As tuberculosis (TB) incidence decreases in the US, foreign-born persons continue to account for a larger proportion of the burden. In these cross-sectional analyses of 1149 culture-confirmed TB cases genotyped using spoligotyping and 24-locus MIRU, we show that over a quarter of cases among the foreign-born population in Florida resulted from recent transmission of the Mycobacterium tuberculosis complex. In addition, over a third of these cases occurred among persons who had immigrated 5 years or less prior to their diagnosis. Although recent immigration was not a significant predictor of TB transmission, younger age, birthplace in the Americas, homelessness, drug use and TB lineage are risk factors for TB transmission among the foreign-born population in Florida. These data provide actionable insights into TB transmission among the foreign-born population in Florida. Copyright © 2015 Elsevier B.V. All rights reserved.

Achievements in and Challenges of Tuberculosis Control in South Korea.

PubMed

Kim, Ji Han; Yim, Jae-Joon

2015-11-01

After the Korean War (1950-1953), nearly 6.5% of South Korea's population had active tuberculosis (TB). In response, South Korea implemented the National Tuberculosis Program in 1962. From 1965 to 1995, the prevalence of bacteriologically confirmed pulmonary TB in South Korea decreased from 940 to 219 cases per 100,000 population. Astounding economic growth might have contributed to this result; however, TB incidence in South Korea remains the highest among high-income countries. The rate of decrease in TB incidence seems to have slowed over the past 15 years. A demographic shift toward an older population, many of whom have latent TB and various concurrent conditions, is challenging TB control efforts in South Korea. The increasing number of immigrants also plays a part in the prolonged battle against TB. A historical review of TB in South Korea provides an opportunity to understand national TB control efforts that are applicable to other parts of the world.

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development.

PubMed

Moraes, Gleiciane Leal; Gomes, Guelber Cardoso; Monteiro de Sousa, Paulo Robson; Alves, Cláudio Nahum; Govender, Thavendran; Kruger, Hendrik G; Maguire, Glenn E M; Lamichhane, Gyanu; Lameira, Jerônimo

2015-03-01

Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB. Copyright © 2015. Published by Elsevier Ltd.

From Mosques to Classrooms: Mobilizing the Community to Enhance Case Detection of Tuberculosis

PubMed Central

Rifat, Mahfuza; Rusen, I. D.; Mahmud, Mohammad Hasan; Nayer, Israt; Islam, Akramul; Ahmed, Faruque

2008-01-01

In response to the global challenge of inadequate case detection of tuberculosis (TB), the Fund for Innovative DOTS Expansion through Local Initiatives to Stop Tuberculosis (FIDELIS) was developed in 2003 to rapidly assess and implement innovative approaches to increase the detection of new smear-positive TB cases. As previously reported, a wide range of target populations and interventions has been incorporated into successful FIDELIS projects. PMID:18633095

Environmental aspects related to tuberculosis and intestinal parasites in a low-income community of the Brazilian Amazon

PubMed Central

Cardoso, Biatriz Araújo; Fonseca, Fabio de Oliveira; de Moraes, Antonio Henrique Almeida; Martins, Ana Caroline Guedes Souza; Oliveira, Nissa Vilhena da Silva; Lima, Luana Nepomuceno Gondim Costa; Dias, George Alberto da Silva; Saad, Maria Helena Féres

2017-01-01

ABSTRACT We carried out a cross-sectional study from January to December 2015 on 1,425 inhabitants from a floating population in the Brazilian Amazon (Murinin district, Pará State) to describe the population-based prevalence of tuberculosis (TB) from 2011 to 2014, recent TB contacts (rCts) latently infected with Mycobacterium tuberculosis (LTBI) , the coverage of the local health network, socio-environmental factors, and frequency of intestinal parasitic infection (IPI). We found that the sanitary structure was inadequate, with latrines being shared with other rooms within the same accommodation; well water was the main source of water, and 48% of families had low incomes. The average rate of TB was 105/100, 000 inhabitants per year; one third of TB patients had been household contacts of infected individuals in the past, and 23% of rCts were LTBI. More than half (65%) of 44% of the stools examined (representing 76% of the housing) had IPIs; the highest prevalence was of fecal-oral transmitted protozoa (40%, Giardia intestinalis ), followed by soil-transmitted helminths (23%). TB transmission may be related to insufficient disease control of rCts, frequent relocation, and underreporting. Education, adopting hygienic habits, improving sanitation, provision of a treated water supply and efficient sewage system, further comprehensive epidemiological surveillance of those who enter and leave the community and resources for basic treatment of IPIs are crucial in combating the transmission of these neglected diseases. PMID:28793025

Environmental aspects related to tuberculosis and intestinal parasites in a low-income community of the Brazilian Amazon.

PubMed

Cardoso, Biatriz Araújo; Fonseca, Fabio de Oliveira; Moraes, Antonio Henrique Almeida de; Martins, Ana Caroline Guedes Souza; Oliveira, Nissa Vilhena da Silva; Lima, Luana Nepomuceno Gondim Costa; Dias, George Alberto da Silva; Saad, Maria Helena Féres

2017-08-07

We carried out a cross-sectional study from January to December 2015 on 1,425 inhabitants from a floating population in the Brazilian Amazon (Murinin district, Pará State) to describe the population-based prevalence of tuberculosis (TB) from 2011 to 2014, recent TB contacts (rCts) latently infected with Mycobacterium tuberculosis (LTBI) , the coverage of the local health network, socio-environmental factors, and frequency of intestinal parasitic infection (IPI). We found that the sanitary structure was inadequate, with latrines being shared with other rooms within the same accommodation; well water was the main source of water, and 48% of families had low incomes. The average rate of TB was 105/100, 000 inhabitants per year; one third of TB patients had been household contacts of infected individuals in the past, and 23% of rCts were LTBI. More than half (65%) of 44% of the stools examined (representing 76% of the housing) had IPIs; the highest prevalence was of fecal-oral transmitted protozoa (40%, Giardia intestinalis ), followed by soil-transmitted helminths (23%). TB transmission may be related to insufficient disease control of rCts, frequent relocation, and underreporting. Education, adopting hygienic habits, improving sanitation, provision of a treated water supply and efficient sewage system, further comprehensive epidemiological surveillance of those who enter and leave the community and resources for basic treatment of IPIs are crucial in combating the transmission of these neglected diseases.

Prevalence, incidence, and associated risk factors of tuberculosis in children with HIV living in the UK and Ireland (CHIPS): a cohort study.

PubMed

Turkova, Anna; Chappell, Elizabeth; Judd, Ali; Goodall, Ruth L; Welch, Steven B; Foster, Caroline; Riordan, Andrew; Shingadia, Delane; Shackley, Fiona; Doerholt, Katja; Gibb, Diana M; Collins, Intira J

2015-12-01

Tuberculosis is the most common serious co-infection in people living with HIV worldwide, but little is known about its incidence in HIV-infected children living in high-resource settings with low tuberculosis prevalence. We aimed to assess the incidence and prevalence of tuberculosis in children with HIV living in the UK and Ireland to understand rates, risk factors, and outcomes of the disease in this group. We did an analysis of children enrolled in CHIPS, an observational multicentre cohort of children receiving HIV care in the UK and Ireland. We assessed characteristics and prevalence of tuberculosis at baseline, measured incidence of disease through the follow-up period using the CHIPS database, and calculated associated risk factors in these children with multivariable logistic and Cox regression models. Between Jan 1, 1996, to Sept 18, 2014, data for 1848 children with 14 761 years of follow-up were reported to CHIPS. 57 (3%) children were diagnosed with tuberculosis: 29 children had tuberculosis at presentation (prevalent tuberculosis) and 29 had the disease diagnosed during follow-up (incident tuberculosis), including one child with recurrent tuberculosis events. Median age at diagnosis was 9 years (IQR 5-12). 25 (43%) children had pulmonary tuberculosis, 24 (41%) had extrapulmonary tuberculosis with or without pulmonary involvement, and the remainder (n=9; 16%) had unspecified-site tuberculosis. The overall incidence rate for the follow-up period was 196 cases per 100 000 person-years (95% CI 137-283). In our multivariable model, tuberculosis at presentation was associated with more severe WHO immunological stage at baseline (odds ratio 0·25, 95% CI 0·08-0·74; p=0·0331; for none vs severe) and being born abroad (odds ratio 0·28, 0·10-0·73; p=0·0036; for UK and Ireland vs abroad). Incident tuberculosis was associated with time-updated more severe WHO immunological stage (hazard ratio 0·15, 95% CI 0·06-0·41; p=0·0056; for none vs severe) and older age at baseline (1·11, 0·47-2·63; p=0·0027; for age >10 years vs 5-9 years). Tuberculosis rates in HIV-infected children in the UK and Ireland were higher than those reported in the general paediatric population. Further study is warranted of tuberculosis screening and preventive treatment for children at high-risk of this disease to avoid morbidity and mortality in this population. NHS England, PENTA Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effects of poverty and ageing on the increase in tuberculosis.

PubMed

Davies, P D

1999-04-01

Among the causes of the current increase in tuberculosis worldwide are poverty and ageing. It has been widely accepted that tuberculosis and poverty have been closely linked since the scientific study of the disease began. The decline of tuberculosis in developed countries before the arrival of specific chemotherapy was largely attributed to improvement in social conditions. With the rapidly increasing world population and the wider disparity of income, more and more people are falling into poverty, whichever way it is defined. Studies in the developed world show that the close association between tuberculosis and poverty remains. Some workers in the field even suggest that tuberculosis cannot be controlled until the issue of global poverty has been addressed. This may be too pessimistic. It may be possible to define accurately which aspects of poverty are most closely associated with tuberculosis and to deal with those specifically. Within developed countries longevity is increasing. The population now in their seventies, or older, even in developed countries, will have been alive when the disease was highly prevalent in the communities in which they lived. The majority will, therefore, have acquired infection, and in a substantial minority of these infection may reactivate to cause disease as the ageing process weakens host immunity. In the indigenous Caucasian population of Western Europe, rates of disease are highest in elderly males. Previous research showed that beyond the age of forty, the incidence of disease declined with increasing age. The higher rates in the elderly were a result of the residue of higher rates from birth cohorts born earlier. Data presented in this article suggest that this pattern may be altering such that the incidence of disease actually increases after a certain age is reached. This could have important repercussions for disease incidence in the emerging economies of the Pacific Rim, where longevity is increasing most rapidly.

Mobile phone interventions for tuberculosis should ensure access to mobile phones to enhance equity - A prospective, observational cohort study in Peruvian shantytowns.

PubMed

Saunders, Matthew J; Wingfield, Tom; Tovar, Marco A; Herlihy, Niamh; Rocha, Claudio; Zevallos, Karine; Montoya, Rosario; Ramos, Eric; Datta, Sumona; Evans, Carlton A

2018-06-04

Mobile phone interventions have been advocated for tuberculosis care, but little is known about access of target populations to mobile phones. We studied mobile phone access amongst patients with tuberculosis, focusing on vulnerable patients and patients who later had adverse treatment outcomes. In a prospective cohort study in Callao, Peru, we recruited and interviewed 2,584 patients with tuberculosis between 2007-2013 and followed them until 2016 for adverse treatment outcomes using national treatment registers. Subsequently, we recruited a further 622 patients between 2016-2017. Data were analysed using logistic regression and by calculating relative risks (RR). Between 2007-2013, the proportion of the general population of Peru without mobile phone access averaged 7.8% but for patients with tuberculosis was 18% (p<0.001). Patients without access were more likely to hold a lower socioeconomic position, suffer from food insecurity and be older than 50 years (all p<0.01). Compared to patients with mobile phone access, patients without access at recruitment were more likely to subsequently have incomplete treatment (20% versus 13%, RR=1.5; p=0.001) or an adverse treatment outcome (29% versus 23% RR=1.3; p=0.006). Between 2016 and 2017, the proportion of patients without access dropped to 8.9% overall, but remained the same (18%) as in 2012 among the poorest third. Access to mobile phones among patients with tuberculosis is insufficient, and rarest in patients who are poorer and later have adverse treatment outcomes. Thus, mobile phone interventions to improve tuberculosis care may be least accessed by the priority populations for whom they are intended. Such interventions should ensure access to mobile phones to enhance equity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Transmission of Mycobacterium Tuberculosis in Households and the Community: A Systematic Review and Meta-Analysis.

PubMed

Martinez, Leonardo; Shen, Ye; Mupere, Ezekiel; Kizza, Allan; Hill, Philip C; Whalen, Christopher C

2017-06-15

The individual- and population-level impact of household tuberculosis exposure on transmission is unclear but may have implications for the effectiveness and implementation of control interventions. We systematically searched for and included studies in which latent tuberculosis infection was assessed in 2 groups: children exposed and unexposed to a household member with tuberculosis. We also extracted data on the smear and culture status of index cases, the age and bacillus Calmette-Guérin vaccination status of contacts, and study design characteristics. Of 6,176 citations identified from our search strategy, 26 studies (13,999 children with household exposure to tuberculosis and 174,097 children without) from 1929-2015 met inclusion criteria. Exposed children were 3.79 (95% confidence interval (CI): 3.01, 4.78) times more likely to be infected than were their community counterparts. Metaregression demonstrated higher infection among children aged 0-4 years of age compared with children aged 10-14 years (ratio of odds ratios = 2.24, 95% CI: 1.43, 3.51) and among smear-positive versus smear-negative index cases (ratio of odds ratios = 5.45, 95% CI: 3.43, 8.64). At the population level, we estimated that a small proportion (<20%) of transmission was attributable to household exposure. Our results suggest that targeting tuberculosis prevention efforts to household contacts is highly effective. However, a large proportion of transmission at the population level may occur outside the household. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Individual-Based Modeling of Tuberculosis in a User-Friendly Interface: Understanding the Epidemiological Role of Population Heterogeneity in a City

PubMed Central

Prats, Clara; Montañola-Sales, Cristina; Gilabert-Navarro, Joan F.; Valls, Joaquim; Casanovas-Garcia, Josep; Vilaplana, Cristina; Cardona, Pere-Joan; López, Daniel

2016-01-01

For millennia tuberculosis (TB) has shown a successful strategy to survive, making it one of the world’s deadliest infectious diseases. This resilient behavior is based not only on remaining hidden in most of the infected population, but also by showing slow evolution in most sick people. The course of the disease within a population is highly related to its heterogeneity. Thus, classic epidemiological approaches with a top-down perspective have not succeeded in understanding its dynamics. In the past decade a few individual-based models were built, but most of them preserved a top-down view that makes it difficult to study a heterogeneous population. We propose an individual-based model developed with a bottom-up approach to studying the dynamics of pulmonary TB in a certain population, considered constant. Individuals may belong to the following classes: healthy, infected, sick, under treatment, and treated with a probability of relapse. Several variables and parameters account for their age, origin (native or immigrant), immunodeficiency, diabetes, and other risk factors (smoking and alcoholism). The time within each infection state is controlled, and sick individuals may show a cavitated disease or not that conditions infectiousness. It was implemented in NetLogo because it allows non-modelers to perform virtual experiments with a user-friendly interface. The simulation was conducted with data from Ciutat Vella, a district of Barcelona with an incidence of 67 TB cases per 100,000 inhabitants in 2013. Several virtual experiments were performed to relate the disease dynamics with the structure of the infected subpopulation (e.g., the distribution of infected times). Moreover, the short-term effect of health control policies on modifying that structure was studied. Results show that the characteristics of the population are crucial for the local epidemiology of TB. The developed user-friendly tool is ready to test control strategies of disease in any city in the short-term. PMID:26793189

Individual-Based Modeling of Tuberculosis in a User-Friendly Interface: Understanding the Epidemiological Role of Population Heterogeneity in a City.

PubMed

Prats, Clara; Montañola-Sales, Cristina; Gilabert-Navarro, Joan F; Valls, Joaquim; Casanovas-Garcia, Josep; Vilaplana, Cristina; Cardona, Pere-Joan; López, Daniel

2015-01-01

For millennia tuberculosis (TB) has shown a successful strategy to survive, making it one of the world's deadliest infectious diseases. This resilient behavior is based not only on remaining hidden in most of the infected population, but also by showing slow evolution in most sick people. The course of the disease within a population is highly related to its heterogeneity. Thus, classic epidemiological approaches with a top-down perspective have not succeeded in understanding its dynamics. In the past decade a few individual-based models were built, but most of them preserved a top-down view that makes it difficult to study a heterogeneous population. We propose an individual-based model developed with a bottom-up approach to studying the dynamics of pulmonary TB in a certain population, considered constant. Individuals may belong to the following classes: healthy, infected, sick, under treatment, and treated with a probability of relapse. Several variables and parameters account for their age, origin (native or immigrant), immunodeficiency, diabetes, and other risk factors (smoking and alcoholism). The time within each infection state is controlled, and sick individuals may show a cavitated disease or not that conditions infectiousness. It was implemented in NetLogo because it allows non-modelers to perform virtual experiments with a user-friendly interface. The simulation was conducted with data from Ciutat Vella, a district of Barcelona with an incidence of 67 TB cases per 100,000 inhabitants in 2013. Several virtual experiments were performed to relate the disease dynamics with the structure of the infected subpopulation (e.g., the distribution of infected times). Moreover, the short-term effect of health control policies on modifying that structure was studied. Results show that the characteristics of the population are crucial for the local epidemiology of TB. The developed user-friendly tool is ready to test control strategies of disease in any city in the short-term.

Contact investigation outcomes of Canadian-born adults with tuberculosis in Indigenous and non-Indigenous populations in Alberta.

PubMed

Eisenbeis, Lisa; Gao, Zhiwei; Heffernan, Courtney; Yacoub, Wadieh; Long, Richard; Verma, Geetika

2016-06-27

Contact investigations are a critical component of tuberculosis control in high-income countries. However, the relative success of conventional methods by population group and place of residence is unknown. This study compares outcomes of contact investigations of Canadian-born Indigenous tuberculosis cases living on- and off-reserve with other Canadian-born cases. In a retrospective analysis, Canadian-born adult culture-positive pulmonary TB cases (2001-2010) were identified. Characteristics of source cases and their contacts were compared by population group. Outcomes of contact investigations, including completion of recommended investigations and preventive therapy, were compared in multivariable analysis. Of 171 cases of tuberculosis identified, 49 (29%) were Indigenous on-reserve, 62 (36%) Indigenous off-reserve, and 60 (35%) non-Indigenous or Canadian-born, "other". Indigenous people had more contacts identified per case compared to non-Indigenous patients. Case population group and smear status were the main predictors of the success of contact investigations. Of those recommended preventive therapy, close contacts of Indigenous cases on-reserve had the highest rate of completion, at 54%, vs. 41% and 37% for close contacts of Indigenous living off-reserve and Canadian-born "other" respectively (p = 0.02). Contacts of Indigenous cases living off-reserve had the greatest delay in assessment and the lowest rates of completion of assessment and preventive therapy. In multivariable analysis, population group, smear status of source case and proximity of contact were predictors of preventive therapy acceptance and/or completion. Significant differences in outcomes of contact investigations were observed between population groups. The higher priority of contacts of smear-positive cases appears to influence efficiency of service delivery, regardless of population group. Jurisdictional differences in program delivery, resource availability and perceived risk of transmission likely influence outcomes of contact investigations.

BCG protects toddlers during a tuberculosis outbreak.

PubMed

Gaensbauer, J T; Vandaleur, M; O'Neil, M; Altaf, A; Ní Chróinín, M

2009-05-01

In 2007, an outbreak of tuberculosis occurred in a toddler population attending two child care centres in Cork, Ireland. Of 268 children exposed, 18 were eventually diagnosed with active tuberculosis. We present the initial clinical and radiographic characteristics of the active disease group. Mantoux testing was positive in only 66% of cases. All cases were either pulmonary or involved hilar adenopathy on chest radiograph; there were no cases of disseminated disease or meningitis. 24% of the exposed children had been previously vaccinated with BCG, and no case of active disease was found in this group (p = 0.016), suggesting a profound protective effect of BCG in this population. Our experience provides evidence supporting a protective effect of BCG against pulmonary disease in young children.

The disease profile of poverty: morbidity and mortality in northern Uganda in the context of war, population displacement and HIV/AIDS.

PubMed

Accorsi, S; Fabiani, M; Nattabi, B; Corrado, B; Iriso, R; Ayella, E O; Pido, B; Onek, P A; Ogwang, M; Declich, S

2005-03-01

The population of Gulu District (northern Uganda) has been severely incapacitated by war, epidemics and social disruption. This study is aimed at describing disease patterns and trends in this area through a retrospective analysis of discharge records for 155205 in-patients of Lacor Hospital in the period 1992-2002. The burden of infectious diseases in childhood is overwhelming, with malaria accounting for the steepest increase in admissions. Admissions for war-related injuries and malnutrition fluctuated with the intensity of the war and the severity of famine. Emerging and re-emerging infections, such as HIV/AIDS, tuberculosis and Ebola, accounted for a heavy disease burden; however, there has been a trend for admissions related to HIV/AIDS and tuberculosis to decrease since the implementation of community-based services. Vulnerable groups (infants, children and women) accounted for 79.8% of admissions. Long-term war, population displacement, the collapse of social structures and the breakdown of the health system place people at a much greater risk of persistent, emerging and re-emerging infectious diseases, malnutrition and war-related injuries, shaping the 'disease profile of poverty'. Most of the disease burden results from infectious diseases of childhood, whose occurrence could be dramatically reduced by low-cost and effective preventive and curative interventions.

Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.

PubMed

Gao, Lei; Lu, Wei; Bai, Liqiong; Wang, Xinhua; Xu, Jinsheng; Catanzaro, Antonino; Cárdenas, Vicky; Li, Xiangwei; Yang, Yu; Du, Jiang; Sui, Hongtao; Xia, Yinyin; Li, Mufei; Feng, Boxuan; Li, Zhen; Xin, Henan; Zhao, Rong; Liu, Jianmin; Pan, Shouguo; Shen, Fei; He, Jian; Yang, Shumin; Si, Hongyan; Wang, Yi; Xu, Zuhui; Tan, Yunhong; Chen, Tianzhu; Xu, Weiguo; Peng, Hong; Wang, Zhijian; Zhu, Tao; Zhou, Feng; Liu, Haiying; Zhao, Yanlin; Cheng, Shiming; Jin, Qi

2015-03-01

Prophylactic treatment of individuals with latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control in some settings. In China, the prevalence of latent tuberculosis infection, and preventive interventions against this disease, have not been systematically studied. We aimed to assess the prevalence of latent tuberculosis and its associated risk factors in rural populations in China. Between July 1, and Sept 30, 2013, we undertook a baseline survey of a population-based, multicentre, prospective cohort study of registered residents (≥5 years old) at four study sites in rural China. Eligible participants were identified by door-to-door survey with a household sampling design. We screened participants for active tuberculosis and history of tuberculosis then used a tuberculin skin test and an interferon-γ release assay (QuantiFERON [QFT]) to test for latent infection. We used odds ratios (ORs) and 95% CIs to assess variables associated with positivity of QFT and tuberculin skin tests. 21,022 (90%) of 23,483 eligible participants completed a baseline survey. Age-standardised and sex-standardised rates of skin-test positivity (≥10 mm) ranged from 15% to 42%, and QFT positivity rates ranged from 13% to 20%. Rates of positivity for the tuberculin skin test and the QFT test were low in study participants younger than 20 years and gradually increased with age (p for trend <0·0001). Rates of latent tuberculosis infection were higher for men than women (p<0·0001). Overall agreement between the tuberculin skin test and the QFT test was moderate (81·06%; kappa coefficient 0·485), with skin-test-only positive results associated with the presence of BCG scar, male sex, and ages of 60 years and older, and QFT-only positive results associated with male sex and ages of 60 years and older. On the basis of findings showing that the performance of the tuberculin skin test might be affected by various factors including BCG vaccination and age, our results suggest that the prevalence of latent tuberculosis in China might be overestimated by skin tests compared with interferon-γ release assays. The National Science and Technology Major Project of China, the Program for Changjiang Scholars and Innovative Research Team in University of China. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Tuberculous gumma or metastatic tuberculous abscess as initial diagnosis of tuberculosis in an immunocompetent patient: an unusual presentation].

PubMed

Marco, A; Solé, R; Raguer, E; Aranda, M

2014-01-01

Tuberculous cold abscesses or gumma are an unusual form of tuberculosis. We report a case of gumma as initial diagnosis of disseminated tuberculosis. This case was studied in 2012 in Barcelona ( Spain). Source data was compiled from the electronic clinical records, hospital reports and additional diagnostic testing. Immunocompetent inmate, born in Cape Verde, living in Spain since the age of four. Positive tuberculin skin test. Initial examination without interest, but a palpable mass in lower back. Fine needle aspiration of the abscess was positive (PCR and Lowenstein) for M. tuberculosis. Computed tomography showed lung cavitary nodes in apical part and lung upper right side. After respiratory isolation, antituberculous therapy and an excellent evolution, the patient was discharged from hospital with disseminated tuberculosis diagnosis. It is advisable to monitor the injuries since, although rare, it may be secondary to Mycobacterium tuberculosis infection, mainly in inmuno-compromised populations and in immigrants coming from hyper-endemic tuberculosis areas.

A complex scenario of tuberculosis transmission is revealed through genetic and epidemiological surveys in Porto.

PubMed

Rito, Teresa; Matos, Carlos; Carvalho, Carlos; Machado, Henrique; Rodrigues, Gabriela; Oliveira, Olena; Ferreira, Eduarda; Gonçalves, Jorge; Maio, Lurdes; Morais, Clara; Ramos, Helena; Guimarães, João Tiago; Santos, Catarina L; Duarte, Raquel; Correia-Neves, Margarida

2018-01-25

Tuberculosis (TB) incidence is decreasing worldwide and eradication is becoming plausible. In low-incidence countries, intervention on migrant populations is considered one of the most important strategies for elimination. However, such measures are inappropriate in European areas where TB is largely endemic, such as Porto in Portugal. We aim to understand transmission chains in Porto through a genetic characterization of Mycobacterium tuberculosis strains and through a detailed epidemiological evaluation of cases. We genotyped the M. tuberculosis strains using the MIRU-VNTR system. We performed an evolutionary reconstruction of the genotypes with median networks, used in this context for the first time. TB cases from a period of two years were evaluated combining genetic, epidemiological and georeferencing information. The data reveal a unique complex scenario in Porto where the autochthonous population acts as a genetic reservoir of M. tuberculosis diversity with discreet episodes of transmission, mostly undetected using classical epidemiology alone. Although control policies have been successful in decreasing incidence in Porto, the discerned complexity suggests that, for elimination to be a realistic goal, strategies need to be adjusted and coupled with a continuous genetic characterization of strains and detailed epidemiological evaluation, in order to successfully identify and interrupt transmission chains.

Impact of an effective multidrug-resistant tuberculosis control programme in the setting of an immature HIV epidemic: system dynamics simulation model.

PubMed

Atun, Rifat A; Lebcir, Reda; Drobniewski, Francis; Coker, Richard J

2005-08-01

This study sought to determine the impact of an effective programme of multidrug resistant tuberculosis control (MDRTB) on a population that is witnessing an explosive HIV epidemic among injecting drug users (IDUs), where the prevalence of MDRTB is already high. A transmission model was constructed that represents the dynamics of the drug-susceptible tuberculosis (DSTB), MDRTB and HIV spread among the adult population of Samara Oblast, Russia: from official notifications of tuberculosis and of HIV infection, estimates of MDRTB derived from surveillance studies, population data from official regional statistics, data on transmission probabilities from peer-reviewed publications and informed estimates, and policy-makers' estimates of IDU populations. Two scenarios of programme effectiveness for MDRTB were modelled and run over a period of 10 years to predict cumulative deaths. In a population of 3.3 million with a high prevalence of MDRTB, an emerging epidemic of HIV among IDUs, and a functioning directly observed therapy-short course (DOTS) programme, the model predicts that under low cure rates for MDRTB the expected cumulative deaths from tuberculosis will reach 6303 deaths including 1900 deaths from MDRTB at 10 years. Under high cure rate for MDRTB 4465 deaths will occur including 134 deaths from MDRTB. At 10 years there is little impact on HIV-infected populations from the MDRTB epidemic, but as the HIV epidemic matures the impact becomes substantial. When the model is extended to 20 years cumulative deaths from MDRTB become very high if cure rates for MDRTB are low and cumulative deaths in the HIV-infected population, likewise, are profoundly affected. In the presence of an immature HIV epidemic failure to actively control MDRTB may result in approximately a third more deaths than if effective treatment is given. As the HIV epidemic matures then the impact of MDRTB grows substantially if MDRTB control strategies are ineffective. The epidemiological starting point for these scenarios is present in many regions within the former Soviet Union and this analysis suggests control of MDRTB should be an urgent priority.

The 1.25 Å resolution structure of phosphoribosyl-ATP pyrophosphohydrolase from Mycobacterium tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Javid-Majd, Farah; Yang, Dong; Ioerger, Thomas R.

2008-06-01

The crystal structure of M. tuberculosis phosphoribosyl-ATP pyrophosphohydrolase, the second enzyme in the histidine-biosynthetic pathway, is presented. The structural and inferred functional relationships between M. tuberculosis phosphoribosyl-ATP pyrophosphohydrolase and other members of the nucleoside-triphosphate pyrophosphatase-fold family are described. Phosphoribosyl-ATP pyrophosphohydrolase is the second enzyme in the histidine-biosynthetic pathway, irreversibly hydrolyzing phosphoribosyl-ATP to phosphoribosyl-AMP and pyrophosphate. It is encoded by the hisE gene, which is present as a separate gene in many bacteria and archaea but is fused to hisI in other bacteria, fungi and plants. Because of its essentiality for growth in vitro, HisE is a potential drug target formore » tuberculosis. The crystal structures of two native (uncomplexed) forms of HisE from Mycobacterium tuberculosis have been determined to resolutions of 1.25 and 1.79 Å. The structure of the apoenzyme reveals that the protein is composed of five α-helices with connecting loops and is a member of the α-helical nucleoside-triphosphate pyrophosphatase superfamily. The biological unit of the protein is a homodimer, with an active site on each subunit composed of residues exclusively from that subunit. A comparison with the Campylobacter jejuni dUTPase active site allowed the identification of putative metal- and substrate-binding sites in HisE, including four conserved glutamate and glutamine residues in the sequence that are consistent with a motif for pyrophosphohydrolase activity. However, significant differences between family members are observed in the loop region between α-helices H1 and H3. The crystal structure of M. tuberculosis HisE provides insights into possible mechanisms of substrate binding and the diversity of the nucleoside-triphosphate pyrophosphatase superfamily.« less

The Republic of Korea: Intercultural Education and the Nevada Air National Guard (Team Spirit 󈨖).

DTIC Science & Technology

1982-07-01

GOVERNMENT STRUCTURE written de-.rep whi, li bans the dissemi- pendents, many of whom had con- nation of false rumors , criticism of tended...medicine. - Hanvak system of treatment -- herbs and acupuncture - Tuberculosis - No. I disease. Also cholera , typhoid and VD. 80% of 119 A population has...ated and the false foisted as truth, especially when reforms because they brought with them American their effect was to fan anti-Americanism and nat

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

PubMed Central

Graham, Stephen M.; Ahmed, Tahmeed; Amanullah, Farhana; Browning, Renee; Cardenas, Vicky; Casenghi, Martina; Cuevas, Luis E.; Gale, Marianne; Gie, Robert P.; Grzemska, Malgosia; Handelsman, Ed; Hatherill, Mark; Hesseling, Anneke C.; Jean-Philippe, Patrick; Kampmann, Beate; Kabra, Sushil Kumar; Lienhardt, Christian; Lighter-Fisher, Jennifer; Madhi, Shabir; Makhene, Mamodikoe; Marais, Ben J.; McNeeley, David F.; Menzies, Heather; Mitchell, Charles; Modi, Surbhi; Mofenson, Lynne; Musoke, Philippa; Nachman, Sharon; Powell, Clydette; Rigaud, Mona; Rouzier, Vanessa; Starke, Jeffrey R.; Swaminathan, Soumya; Wingfield, Claire

2012-01-01

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis. PMID:22448023

Epidemiological situation of tuberculosis in Poland: part II. What are the causes of the different epidemiological situation in various regions of Poland?

PubMed

Rowińska-Zakrzewska, Ewa; Korzeniewska-Koseła, Maria; Roszkowski-Śliż, Kazimierz

2014-01-01

The different epidemiological situation of tuberculosis in various regions of Poland (higher and lower notification rates) was described previously by our group. The patients diagnosed with tuberculosis in the higher notification rate areas were younger and there were more cases of primary tuberculosis (tuberculous pleurisy and tuberculosis of chest lymph nodes) than in the patients diagnosed in the lower notification areas. The aim of the present study was to assess the possible causes of the different epidemiological situation of tuberculosis in various regions of Poland. Analysis was done at the same regions as in the previous paper. A comparison was made between two groups: Group I, which included three voivodeships with higher rates of notification, from 23.7 to 32.3/100,000 (mean rates in the analysed period of time); and Group II, which included five voivodeships with lower notification rates (mean rates from 12.2 to 18.6/100,000). The wealth of the regions (GDP, gross domestic product per capita), the level of unemployment, and social status of the patients were analysed. We compared the population density in both regions. The results of treatment in both regions were also analysed. We did not find any differences in GDP and unemployment rates between the compared regions. The results of treatment were different in particular regions, but there was no clear tendency for worse results in voivodeships in Group I compared to voivodeships in Group II. However, the number of patients lost from observation was significantly higher in the regions from Group I than in those from Group II. There was also a significantly higher death rate from tuberculosis in younger patients (£ 59 years) from Group I than from Group II. This is additional proof that the epidemiological situation in the two regions was different. Finally, we found that the mean density of population in the regions from Group I was higher than that from Group II. The density of population may influence transmission of tuberculosis. There is also the possibility that the differences in the epidemiological situation in various regions of Poland are caused by historical events. In the past the epidemiological situation of tuberculosis was much worse in the east of Europe than in the west. Just after the Second World War, according to the changes of the Polish territory, many Polish citizens (mainly ancestors of those from Group I) were displaced from the east to the west. In conclusion, the greater number of patients lost from observation, together with the higher density of population in the regions from Group I in comparison with those from Group II, seems to be partly responsible for the difference in the epidemiological situation in the two regions. It is also possible that some patients from Group I are more susceptible to infection and disease caused by Mycobacterium tuberculosis due to their ancestors, who lived in the east of Europe.

The strategies of Japanese public health nurses in medication support for high-risk tuberculosis patients.

PubMed

Shimamura, Tamae; Taguchi, Atsuko; Kobayashi, Sayuri; Nagata, Satoko; Magilvy, Joan Kathy; Murashima, Sachiyo

2013-07-01

The purpose of this study was to describe the support provided by Japanese public health nurses (PHNs) to high-risk tuberculosis (TB) patients, focusing specifically on the support aimed at preventing interruptions in treatment. A qualitative descriptive approach was used with a convenience sample of 11 PHNs in Japan who cared for TB patients at highest risk for medication adherence problems. Semi-structured interviews were conducted to learn the scope and practice of PHNs with high-risk TB patients. Data were analyzed using a qualitative descriptive analysis process. One main theme was identified: "Supporting the patients in overcoming tuberculosis, regaining health, and living a healthier life." Three categories with five subcategories described the nurses' activities: (1) empathetic and reliable support, (2) motivational strategies for medication adherence, and (3) developing a foundation for healthier life. The nurses interviewed described creative and extraordinary strategies used to promote medication adherence and facilitate development of a healthy posttreatment lifestyle. Their approach was patient-centered and culturally congruent. Findings may be transferrable to PHN practice in other regions as care for this economically disadvantaged and marginalized population is a critical need. © 2012 Wiley Periodicals, Inc.

Women and tuberculosis.

PubMed

Connolly, M; Nunn, P

1996-01-01

Tuberculosis is the leading infectious cause of death in women worldwide. The disease poses a major threat to women's health security. Population growth, the HIV epidemic, increasing poverty and rising levels of drug resistance will inevitably increase the burden of this disease in women. Women are at increased risk of progression to disease during their reproductive years. However, in most low-income countries, twice as many men are notified with tuberculosis as women. Biological mechanisms may account for most of this difference but socioeconomic and cultural factors leading to barriers in accessing health care may cause under-notification in women. Tuberculosis control programmes should be sensitive to the constraints faced by women in accessing health care, in order to empower women to commence and complete treatment. The fear and stigma associated with tuberculosis have a greater impact on women than on men, often leaving them in a more precarious social and economic position. Tuberculosis in women creates orphans, impoverished families and reduces the economic development of society. Tuberculosis is a major cause of preventable suffering and death in women. WHO's recommended tuberculosis control strategy, DOTS, represents a cost-effective response to the problem of tuberculosis in women. Tuberculosis is a major women's health issue. It is a global health priority that tuberculosis treatment be made available to women, particularly to those in low-income countries who are bearing the brunt of this epidemic.

Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA-E during active tuberculosis and express type 2 cytokines.

PubMed

Caccamo, Nadia; Pietra, Gabriella; Sullivan, Lucy C; Brooks, Andrew G; Prezzemolo, Teresa; La Manna, Marco P; Di Liberto, Diana; Joosten, Simone A; van Meijgaarden, Krista E; Di Carlo, Paola; Titone, Lucina; Moretta, Lorenzo; Mingari, Maria C; Ottenhoff, Tom H M; Dieli, Francesco

2015-04-01

CD8 T cells contribute to protective immunity against Mycobacterium tuberculosis. In humans, M. tuberculosis reactive CD8 T cells typically recognize peptides associated to classical MHC class Ia molecules, but little information is available on CD8 T cells recognizing M. tuberculosis Ags presented by nonclassical MHC class Ib molecules. We show here that CD8 T cells from tuberculosis (TB) patients recognize HLA-E-binding M. tuberculosis peptides in a CD3/TCR αβ mediated and CD8-dependent manner, and represent an additional type of effector cells playing a role in immune response to M. tuberculosis during active infection. HLA-E-restricted recognition of M. tuberculosis peptides is detectable by a significant enhanced ex vivo frequency of tetramer-specific circulating CD8 T cells during active TB. These CD8 T cells produce type 2 cytokines upon antigenic in vitro stimulation, help B cells for Ab production, and mediate limited TRAIL-dependent cytolytic and microbicidal activity toward M. tuberculosis infected target cells. Our results, together with the finding that HLA-E/M. tuberculosis peptide specific CD8 T cells are detected in TB patients with or without HIV coinfection, suggest that this is a new human T-cell population that participates in immune response in TB. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Spatial Analysis of Tuberculosis Cases in Migrants and Permanent Residents, Beijing, 2000–2006

PubMed Central

Jia, Zhong-Wei; Jia, Xiao-Wei; Dye, Christopher; Chen, Feng; Chen, Chang-Sheng; Zhang, Wen-Yi; Li, Xiao-Wen

2008-01-01

To determine the role of the migrant population in the transmission of tuberculosis (TB), we investigated the distribution and magnitude of TB in permanent residents and migrant populations of Beijing, People’s Republic of China, from 2000 through 2006. An exploratory spatial data analysis was applied to detect the “hot spots” of TB among the 2 populations. Results, using the data obtained from 2004–2006, showed that people who migrated from the western, middle, and eastern zones of China had a significantly higher risk of having TB than did permanent residents. These findings indicate that population fluctuations have affected the rate of TB prevalence in Beijing, and interventions to control TB should include the migrant population. PMID:18760008

A brief history of tuberculosis in the Czech Lands.

PubMed

Vargová, Lenka; Vymazalová, Kateřina; Horáčková, Ladislava

2017-07-01

Tuberculosis currently remains a serious medical problem, therefore increased attention is being paid to this disease. Paleopathological studies focused on the monitoring of morbid changes in skeletal remains of historical populations facilitate a detailed study of the development of this disease. They provide direct evidence of the existence of tuberculosis and its past forms. In addition to literary and iconographic sources, the present study is focused on recording the findings of bone tuberculosis in historical osteological sets from the Czech Lands and is the starting point for their detailed review. Approximately 76 cases of bone tuberculosis from the Czech Lands have been published and more or less reliably documented from 20 archeological sites dated back from the Eneolithic to the modern period. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diversity and Evolution of Mycobacterium tuberculosis: Moving to Whole-Genome-Based Approaches

PubMed Central

Niemann, Stefan; Supply, Philip

2014-01-01

Genotyping of clinical Mycobacterium tuberculosis complex (MTBC) strains has become a standard tool for epidemiological tracing and for the investigation of the local and global strain population structure. Of special importance is the analysis of the expansion of multidrug (MDR) and extensively drug-resistant (XDR) strains. Classical genotyping and, more recently, whole-genome sequencing have revealed that the strains of the MTBC are more diverse than previously anticipated. Globally, several phylogenetic lineages can be distinguished whose geographical distribution is markedly variable. Strains of particular (sub)lineages, such as Beijing, seem to be more virulent and associated with enhanced resistance levels and fitness, likely fueling their spread in certain world regions. The upcoming generalization of whole-genome sequencing approaches will expectedly provide more comprehensive insights into the molecular and epidemiological mechanisms involved and lead to better diagnostic and therapeutic tools. PMID:25190252

The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2.

PubMed

Gilleron, Martine; Nigou, Jérôme; Nicolle, Delphine; Quesniaux, Valérie; Puzo, Germain

2006-01-01

Detection of Mycobacterium tuberculosis antigens by professional phagocytes via toll-like receptors (TLR) contributes to controlling chronic M. tuberculosis infection. Lipomannans (LM), which are major lipoglycans of the mycobacterial envelope, were recently described as agonists of TLR2 with potent activity on proinflammatory cytokine regulation. LM correspond to a heterogeneous population of acyl- and glyco-forms. We report here the purification and the complete structural characterization of four LM acyl-forms from Mycobacterium bovis BCG using MALDI MS and 2D (1)H-(31)P NMR analyses. All this biochemical work provided the tools to investigate the implication of LM acylation degree on its proinflammatory activity. The latter was ascribed to the triacylated LM form, essentially an agonist of TLR2, using TLR2/TLR1 heterodimers for signaling. Altogether, these findings shed more light on the molecular basis of LM recognition by TLR.

Pathway to care for drug resistant tuberculosis cases identified during a retrospective study conducted in high TB burden wards in Mumbai

PubMed Central

Lobo, Eunice; Shah, Shimoni; Rangan, Sheela; Dholakia, Yatin; Mistry, Nerges

2018-01-01

Background: Mumbai is witnessing a rising incidence of all forms of drug resistant tuberculosis (DR-TB). Methods: A population-based, retrospective study was conducted between April and July 2014, in 15 high TB burden wards in Mumbai, to capture the patient pathways to TB care. A total of 23 DR-TB patients were identified and their pathways to access DR-TB care were recorded using semi-structured interviews. Results: The total DR-TB pathway time of new patients (who did not report any past episode of TB) (180 days; IQR 123,346) was found to be more than twice that of retreatment patients (who reported a past episode of TB) (69 days; IQR 42,128). Conclusions: The unacceptable delay for diagnosis and treatment of DR-TB in Mumbai advocates for consistent implementation of early screening of patients using rapid gene-based technologies. PMID:29863175

Pathway to care for drug resistant tuberculosis cases identified during a retrospective study conducted in high TB burden wards in Mumbai.

PubMed

Lobo, Eunice; Shah, Shimoni; Rangan, Sheela; Dholakia, Yatin; Mistry, Nerges

2018-05-10

Background: Mumbai is witnessing a rising incidence of all forms of drug resistant tuberculosis (DR-TB). Methods: A population-based, retrospective study was conducted between April and July 2014, in 15 high TB burden wards in Mumbai, to capture the patient pathways to TB care. A total of 23 DR-TB patients were identified and their pathways to access DR-TB care were recorded using semi-structured interviews. Results: The total DR-TB pathway time of new patients (who did not report any past episode of TB) (180 days; IQR 123,346) was found to be more than twice that of retreatment patients (who reported a past episode of TB) (69 days; IQR 42,128). Conclusions: The unacceptable delay for diagnosis and treatment of DR-TB in Mumbai advocates for consistent implementation of early screening of patients using rapid gene-based technologies.

A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography.

PubMed

Bunker, Richard D; Mandal, Kalyaneswar; Bashiri, Ghader; Chaston, Jessica J; Pentelute, Bradley L; Lott, J Shaun; Kent, Stephen B H; Baker, Edward N

2015-04-07

Protein 3D structure can be a powerful predictor of function, but it often faces a critical roadblock at the crystallization step. Rv1738, a protein from Mycobacterium tuberculosis that is strongly implicated in the onset of nonreplicating persistence, and thereby latent tuberculosis, resisted extensive attempts at crystallization. Chemical synthesis of the L- and D-enantiomeric forms of Rv1738 enabled facile crystallization of the D/L-racemic mixture. The structure was solved by an ab initio approach that took advantage of the quantized phases characteristic of diffraction by centrosymmetric crystals. The structure, containing L- and D-dimers in a centrosymmetric space group, revealed unexpected homology with bacterial hibernation-promoting factors that bind to ribosomes and suppress translation. This suggests that the functional role of Rv1738 is to contribute to the shutdown of ribosomal protein synthesis during the onset of nonreplicating persistence of M. tuberculosis.

Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

PubMed Central

Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.

2013-01-01

Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2–53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17–0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17–50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease. PMID:23223591

Tuberculosis among the homeless, United States, 1994–2010

PubMed Central

Bamrah, S.; Yelk Woodruff, R. S.; Powell, K.; Ghosh, S.; Kammerer, J. S.; Haddad, M. B.

2016-01-01

SUMMARY OBJECTIVES 1) To describe homeless persons diagnosed with tuberculosis (TB) during the period 1994–2010, and 2) to estimate a TB incidence rate among homeless persons in the United States. METHODS TB cases reported to the National Tuberculosis Surveillance System were analyzed by origin of birth. Incidence rates were calculated using the US Department of Housing and Urban Development homeless population estimates. Analysis of genotyping results identified clustering as a marker for transmission among homeless TB patients. RESULTS Of 270 948 reported TB cases, 16 527 (6%) were homeless. The TB incidence rate among homeless persons ranged from 36 to 47 cases per 100 000 population in 2006–2010. Homeless TB patients had over twice the odds of not completing treatment and of belonging to a genotype cluster. US- and foreign-born homeless TB patients had respectively 8 and 12 times the odds of substance abuse. CONCLUSIONS Compared to the general population, homeless persons had an approximately 10-fold increase in TB incidence, were less likely to complete treatment and more likely to abuse substances. Public health outreach should target homeless populations to reduce the excess burden of TB in this population. PMID:24125444

TB Anywhere Is TB Everywhere: The Intersection of U.S. Immigration Enforcement Policy and TB

DTIC Science & Technology

2016-09-01

born population.40 One region of special concern in the United States is the area along the border with Mexico . Tuberculosis rates in the border ...Controlling Tuberculosis along the US- Mexico Border ,” Morbidity and Mortality Weekly Report 50, no. RR1 (2001): 1–2, http://www.cdc.gov/mmwr/ preview/mmwrhtml...Ramirez, “Health Departments Fight Tuberculosis on both Sides of the U.S. Border with Mexico : Mexican Immigrants Often Contract the Disease before

Cigarette smoking and health-promoting behaviours among tuberculosis patients in rural areas.

PubMed

Tsai, Shu-Lan; Lai, Chun-Liang; Chi, Miao-Ching; Chen, Mei-Yen

2016-09-01

To explore cigarette smoking and health-promoting behaviours among disadvantaged adults before their tuberculosis diagnosis and after their tuberculosis treatment. Although tuberculosis infection is associated with impaired immune function, healthy lifestyle habits can play a role in improving the immune system. However, limited research has explored the health-promoting behaviours and cigarette smoking habits among tuberculosis patients in Taiwan. A cross-sectional retrospective study with a convenience sample. This study was conducted between May 2013-June 2014 with 123 patients at a rural district hospital in Chiayi County, Taiwan. Statistical analyses included descriptive statistics, univariate analysis and stepwise regression analysis. Tuberculosis tended to be associated with less education, male sex, malnutrition, cigarette smoking and unhealthy lifestyle habits before the tuberculosis diagnosis. The percentage of smoking decreased from 46·9% before to 30·2% after the tuberculosis diagnosis. Body mass index and health-promoting behaviours also significantly improved after tuberculosis treatment. After controlling for potential confounding factors, multivariate analysis identified chronic disease and completed treatment as significant factors that were associated with current health-promoting behaviours. A high prevalence of cigarette smoking and low levels of health-promoting behaviours were observed before the diagnosis and during or after completing tuberculosis treatment. This study's findings indicate the importance of promoting healthy lifestyle changes among tuberculosis patients; aggressive measures should be implemented immediately after the first diagnosis of tuberculosis. Furthermore, health promotion and smoking cessation programmes should be initiated in the general population to prevent activation of latent tuberculosis infection, and these programmes should specifically target men and rural residents. © 2016 John Wiley & Sons Ltd.

[Health examination in future at the era of low tuberculosis incidence--from contacts examination toward active epidemiological studies].

PubMed

Maeda, Hideo; Shirai, Chika

2013-03-01

Japan is still "intermediate burden" country as medium-incidence of tuberculosis (TB). But the incidence of TB varies by public health units. The priority for TB control would be lowering in the areas where the incidence of TB is relatively low. In addition, younger age groups get low prevalence of TB infection than elderly persons. As a result, fewer experiences for TB diagnosis and treatment in the hospital and the medical facility would cause the delay in the detection of TB patients which eventually cause outbreaks. Although there are differences in population density and population mobility between urban and rural areas, the socially economic vulnerable patients and foreign patients are the common risks. Any public health units' policies of TB should correspond to the individual situation. At the era of low tuberculosis incidence, the infection risk is to be "From ubiquitous to the uneven distribution". This makes TB detection much more difficult. At this symposium, each speaker presented the case for actually experienced with QFT test and/or VNTR analysis. They mainly focused on the paradigm shift in TB control which is indispensable for resolving the gaps in regional differences and the differences in diagnostic capability. Although the cases in this symposium were not for the low incidence situation, the pioneering approaches presented here would boost the future application of QFT and VNTR analysis nationwide. The discussions also partially covered the technical infrastructure for molecular epidemiology which covers the whole country. By making full use of QFT test and VNTR analysis as a contact screening tool, we can appropriately understand the risk of TB infection in the region from a buildup of bacteria and patient information. Now is the time to prepare for. Active surveillance of TB by this way would clarify the risk of the disease and lead to the advocacy essential for the resolution. 1. Current situation and challenge of contact survey by using QFT test in Tokyo: Hideo MAEDA (Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government). 2. Contact investigation of a tuberculosis outbreak: Kenichi MIYAMOTO (Takaido Community Health Center). We have experienced a TB outbreak in integrated junior and senior high school in Tokyo. Index patient was a student with persistent respiratory symptoms for six months before diagnosis of sputum smear-positive TB. Public health center started contact investigation immediately. QFT-positive rates were high in close contacts, especially in classmates. Additionally, a student outside of contact investigation was diagnosed as TB and considered to be infected from the first patient by VNTR analysis. Therefore, public health center expanded QFT-tests to all students and teachers in this school. Finally, 9 students and 2 teachers in this school were diagnosed as sputum smear-negative TB by contact investigation. 3. Utilization of molecular epidemiological procedure in contact investigation in Kyoto City: Masahiro ITO (Public Health Center of Kyoto City) Molecular epidemiological procedure using VNTR analysis has been used for contact investigation of tuberculosis since January 2011 in Kyoto City. One hundred forty four strains of Mycobacterium tuberculosis from patients with tuberculosis were investigated and 130 strains were fully analyzed. Fourteen clusters were found and the number of strains included in the cluster was ranged from two to 11. Epidemiological relationship between patients in one cluster was found, however, significant relationship in another clusters was not demonstrated. It was suggested that VNTR analysis is useful for molecular epidemiological analysis of tuberculosis. 4. The population based molecular epidemiological studies and QFT test in a contact examination: Riyo FUJIYAMA, Keisuke MATSUBAYASHI, Setsuko MIZUSHIRI, Junko HIGUCHIL Chika SHIRAI, Yuko KATAGAMI, Mieko CHIHARA, Akihiro IJICHI (Kobe City Public Health Center), Kentaro ARIKAWA, Noriko NAKANISHI, Tomotada IWAMOTO (Kobe Institute of Health). The population based molecular epidemiological studies should be made good use of contacts examination. In future, we expect the tuberculosis molecular epdimiological study improve search for the process of tuberculosis infection. The QFT positive rates correlated well with closeness of contact. QFT test is considered useful for diagnosing tuberculosis infection. However, in the judgment of tuberculosis infection, we should consider the total result of contact investigation not only QFT test but also the contact situation. 5. Insights into the TB epidemiology through population based molecular epidemiological studies: Tomotada IWAMOTO (Kobe Institute of Health) The population based molecular epidemiological studies unveiled the transmission dynamics of tuberculosis at bacterial clone level. This provides scientific evidences for achieving better TB control programs. In the advanced stage of the tuberculosis molecular epidemiological study, we expect to change the current geno-typing based molecular epidemiology to whole genome-typing based molecular epidemiology on the basis of the rapid innovation of next-generation sequencing technology.

CD8 T cells and Mycobacterium tuberculosis infection

PubMed Central

Lin, Philana Ling; Flynn, JoAnne L.

2015-01-01

Tuberculosis is primarily a respiratory disease that is caused by Mycobacterium tuberculosis. M. tuberculosis can persist and replicate in macrophages in vivo, usually in organized cellular structures called granulomas. There is substantial evidence for the importance of CD4 T cells in control of tuberculosis, but the evidence for a requirement for CD8 T cells in this infection has not been proven in humans. However, animal model data support a non-redundant role for CD8 T cells in control of M. tuberculosis infection, and in humans, infection with this pathogen leads to generation of specific CD8 T cell responses. These responses include classical (MHC Class I restricted) and non-classical CD8 T cells. Here, we discuss the potential roles of CD8 T cells in defense against tuberculosis, and our current understanding of the wide range of CD8 T cell types seen in M. tuberculosis infection. PMID:25917388

BCG and New Preventive Tuberculosis Vaccines: Implications for Healthcare Workers

PubMed Central

Hatherill, Mark; Scriba, Thomas J.; Udwadia, Zarir F.; Mullerpattan, Jai B.; Hawkridge, Anthony; Mahomed, Hassan; Dye, Christopher

2016-01-01

Healthcare workers (HCWs) are at high risk of Mycobacterium tuberculosis (Mtb) infection and tuberculosis disease, but also play a crucial role in implementing healthcare. Preexposure tuberculosis vaccination, including revaccination with BCG, might benefit Mtb-uninfected HCWs, but most HCWs in tuberculosis-endemic countries are already sensitized to mycobacteria. A new postexposure tuberculosis vaccine offers greatest potential for protection, in the setting of repeated occupational Mtb exposure. Novel strategies for induction of mycobacteria-specific resident memory T cells in the lung by aerosol administration, or induction of T cells with inherent propensity for residing in mucosal sites, such as CD1-restricted T cells and mucosa-associated innate T cells, should be explored. The need for improved protection of HCWs against tuberculosis disease is clear. However, health systems in tuberculosis-endemic countries would need significantly improved occupational health structures to implement a screening and vaccination strategy for HCWs. PMID:27118856

Pili of Mycobacterium tuberculosis: current knowledge and future prospects.

PubMed

Ramsugit, Saiyur; Pillay, Manormoney

2015-08-01

Many pathogenic bacteria express filamentous appendages, termed pili, on their surface. These organelles function in several important bacterial processes, including mediating bacterial interaction with, and colonization of the host, signalling events, locomotion, DNA uptake, electric conductance, and biofilm formation. In the last decade, it has been established that the tuberculosis-causing bacterium, Mycobacterium tuberculosis, produces two pili types: curli and type IV pili. In this paper, we review studies on M. tuberculosis pili, highlighting their structure and biological significance to M. tuberculosis pathogenesis, and discuss their potential as targets for therapeutic intervention and diagnostic test development.

A systematic review of economic models used to assess the cost-effectiveness of strategies for identifying latent tuberculosis in high-risk groups.

PubMed

Auguste, Peter; Tsertsvadze, Alexander; Court, Rachel; Pink, Joshua

2016-07-01

Timely diagnosis and treatment of latent tuberculosis infection (LTBI) through screening remains a key public health priority. Although globally it is recommended to screen people at high risk of developing TB, the economic evidence underpinning these recommendations is limited. This review critically appraised studies that had used a decision-analytical modelling framework to estimate the cost-effectiveness of interferon gamma release assays (IGRAs) compared to tuberculin skin test (TST) for detecting LTBI in high risk populations. A comprehensive search of MEDLINE, EMBASE, NHS-EED was undertaken from 2009 up to June 2015. Studies were screened and extracted by independent reviewers. The study quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and the Philips' checklist, respectively. A narrative synthesis of the included studies was undertaken. Ten studies were included in this review. Two economic evaluations were conducted in a child population, six in an immunocompromised population and two in a recently arrived population from a country with a high incidence of TB. Most studies (n = 7) used a decision tree structure with Markov nodes. In general, all models were clearly described in terms of reporting quality, but were subject to limitations to structure and model inputs. Models have not elaborated on their setting or the perspective of the studies was not consistent with their analyses. Other concerns were related to derivation of prevalence, test accuracy and transition probabilities. Current methods available highlight limitations in the clinical effectiveness literature, model structures and assumptions, which impact on the robustness of the cost-effectiveness results. These models available are useful, but limited on the information that can be used to inform on future cost-effectiveness analysis. Until consideration is given on deriving the performance of tests used to identify LTBI that progresses to active TB, and the development of more comprehensive models, the economic benefit of LTBI testing with TST/IGRAs in high risk populations will remain unanswered. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Tuberculosis in subjects under 15 years of age in the population of Warao in Venezuela].

PubMed

Fernández de Larrea, Carlos; Fandiño, Cecil; López, Diana; del Nogal, Berenice; Rodríguez, Nilia; Convit, Jacinto; Araujo, Zaida; de Waard, Jacobus H

2002-03-01

It is difficult to establish a definitive diagnosis of tuberculosis in rural areas where there is no access to a large hospital. The Warao people of the Delta Amacuro State in Venezuela, have a very high prevalence of adult TB, and we suspected that the Warao children would also have a high prevalence of the disease, almost entirely undiagnosed. We applied a simple methodology to select children suspicious for tuberculosis that is based on a rating system using clinical criteria, reactivity to tuberculin and intradomicilliary contacts. Of the 502 children under the age of 15 that were evaluated with this rating system, 27 were determined to be suspicious of TB and were further evaluated by a chest X-ray. Radiologic confirmation of TB was found in 16 (60%) of the 27 suspicious children. Of these 16 patients, 13 (81%) were PPD positive and 3 were PPD negative. Additionally, 7 of the 16 children with pathologic x-ray changes had one or more confirmatory findings: 3 were positive by culture or smear examination and 5 had a positive serologic B diagnostic test. In conclusion this methodology proved to be highly efficient in diagnosing childhood tuberculosis in this population, and should also be useful in other rural populations with a high prevalence of adult TB.

Tuberculosis testing among populations with high HIV risk in Tijuana, Baja California, Mexico.

PubMed

Velasquez, Michele G; Laniado-Laborin, Rafael; Rodwell, Timothy C; Cerecer, Paris; Lozada, Remedios; Cuevas-Mota, Jazmine; Burgos, Jose Luis; Garfein, Richard S

2012-07-01

To assess the prevalence of prior tuberculin skin testing (TST) among populations at risk for HIV infection in Tijuana, Mexico, and to identify factors associated with TST. Sex workers, injection drug users, noninjecting drug users, and homeless persons > 18 years old were recruited by using targeted sampling for risk assessment interviews and serologic testing for HIV and Mycobacterium tuberculosis infection. Univariate and multivariate logistic regression were used to identify correlates of self-reported TST history. Of 502 participants, 38.0% reported prior TST, which was associated with previous incarceration in the United States of America [odds ratio (OR) = 13.38; 95% confidence interval (CI) = 7.37-24.33] and injection drug use (OR = 1.99; 95% CI = 1.27- 3.11). Positive results on serologic tests for M. tuberculosis infection (57%) and HIV (4.2%) were not associated with a prior TST. A history of TST was lower in HIV-positive participants even though TST is indicated for persons with HIV in Mexico. Fewer than half the individuals at high risk for HIV in this study had a history of TST; however, TST was fairly common among those individuals with a prior history of incarceration. Increased tuberculosis screening is needed for populations at risk of contracting HIV in Tijuana, particularly those outside of criminal justice settings.

Is Knowledge Regarding Tuberculosis Associated with Stigmatising and Discriminating Attitudes of General Population towards Tuberculosis Patients? Findings from a Community Based Survey in 30 Districts of India

PubMed Central

Sagili, Karuna D.; Satyanarayana, Srinath; Chadha, Sarabjit S.

2016-01-01

Background Stigmatising and discriminating attitudes may discourage tuberculosis (TB) patients from actively seeking medical care, hide their disease status, and discontinue treatment. It is expected that appropriate knowledge regarding TB should remove stigmatising and discriminating attitudes. In this study we assessed the prevalence of stigmatising and discriminating attitudes towards TB patients among general population and their association with knowledge regarding TB. Method A cross-sectional knowledge, attitude and practice survey was conducted in 30 districts of India in January-March 2011. A total of 4562 respondents from general population were interviewed using semi-structured questionnaires which contained items to measure stigma, discrimination and knowledge on TB. Result Of the 4562 interviewed, 3823 were eligible for the current analysis. Of these, 73% (95% CI 71.4–74.2) had stigmatising and 98% (95% CI 97.4–98.3) had discriminating attitude towards TB patients. Only 17% (95% CI 15.6–18.0) of the respondents had appropriate knowledge regarding TB with even lower levels observed amongst females, rural areas and respondents from low income groups. Surprisingly stigmatising (adjusted OR 1.31 (0.78–2.18) and discriminating (adjusted OR 0.79 (0.43–1.44) attitudes were independent of knowledge regarding TB. Conclusion Stigmatising and discriminating attitudes towards TB patients remain high among the general population in India. Since these attitudes were independent of the knowledge regarding TB, it is possible that the current disseminated knowledge regarding TB which is mainly from a medical perspective may not be adequately addressing the factors that lead to stigma and discrimination towards TB patients. Therefore, there is an urgent need to review the messages and strategies currently used for disseminating knowledge regarding TB among general population and revise them appropriately. The disseminated knowledge should include medical, psycho-social and economic aspects of TB that not only informs people about medical aspects of TB disease, but also removes stigma and discrimination. PMID:26829713

European framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group.

PubMed

Broekmans, J F; Migliori, G B; Rieder, H L; Lees, J; Ruutu, P; Loddenkemper, R; Raviglione, M C

2002-04-01

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas.

PubMed

Kurthkoti, Krishna; Amin, Hamel; Marakalala, Mohlopheni J; Ghanny, Saleena; Subbian, Selvakumar; Sakatos, Alexandra; Livny, Jonathan; Fortune, Sarah M; Berney, Michael; Rodriguez, G Marcela

2017-08-15

This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies. IMPORTANCE One-third of the world population may harbor persistent M. tuberculosis , causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis , which can be exploited for the design of new antitubercular therapies. Copyright © 2017 Kurthkoti et al.

Achievements in and Challenges of Tuberculosis Control in South Korea

PubMed Central

Kim, Ji Han

2015-01-01

After the Korean War (1950–1953), nearly 6.5% of South Korea’s population had active tuberculosis (TB). In response, South Korea implemented the National Tuberculosis Program in 1962. From 1965 to 1995, the prevalence of bacteriologically confirmed pulmonary TB in South Korea decreased from 940 to 219 cases per 100,000 population. Astounding economic growth might have contributed to this result; however, TB incidence in South Korea remains the highest among high-income countries. The rate of decrease in TB incidence seems to have slowed over the past 15 years. A demographic shift toward an older population, many of whom have latent TB and various concurrent conditions, is challenging TB control efforts in South Korea. The increasing number of immigrants also plays a part in the prolonged battle against TB. A historical review of TB in South Korea provides an opportunity to understand national TB control efforts that are applicable to other parts of the world. PMID:26485188

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis.

PubMed

Eldholm, Vegard; Pettersson, John H-O; Brynildsrud, Ola B; Kitchen, Andrew; Rasmussen, Erik Michael; Lillebaek, Troels; Rønning, Janne O; Crudu, Valeriu; Mengshoel, Anne Torunn; Debech, Nadia; Alfsnes, Kristian; Bohlin, Jon; Pepperell, Caitlin S; Balloux, Francois

2016-11-29

The "Beijing" Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979-1989 Soviet-Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time.

Modulation of the phenotype and function of Mycobacterium tuberculosis-stimulated dendritic cells by adrenal steroids.

PubMed

Angerami, Matias; Suarez, Guadalupe; Pascutti, Maria Fernanda; Salomon, Horacio; Bottasso, Oscar; Quiroga, Maria Florencia

2013-07-01

Cell-mediated immunity, cytokines induced during the specific immune response and T-cell populations are crucial factors for containing Mycobacterium tuberculosis infection. Recent reports suggest a cross-regulation between adrenal steroids (glucocorticoids and dehydroepiandrosterone, DHEA) and the function of antigen-presenting cells (APCs). Therefore, we investigated the role of adrenal hormones on the functional capacity of M. tuberculosis-induced dendritic cells (DCs). Cortisol significantly inhibited the functions of M. tuberculosis-induced DCs. Interestingly, the presence of DHEA enhanced the M. tuberculosis-induced expression of MHC I, MHC II and CD86 and also increased ERK1/2 phosphorylation. Moreover, DHEA improved the production of IL-12 in response to M. tuberculosis stimulation, diminished IL-10 secretion and could not modify TNF-α synthesis. Importantly, we observed that DHEA enhanced the antigen-specific T-cell proliferation and IFN-γ production induced by M. tuberculosis-stimulated DC. These data show for the first time the relevance of the adrenal axis (especially of DHEA) in the modulation of DC function in the context of tuberculosis, a disease where the induction of a Th1 environment by APCs is crucial for the development of an effective immune response to the mycobacteria.

Socioeconomic Factors Associated with Knowledge on Tuberculosis among Adults in Ethiopia.

PubMed

Gelaw, Sifrash Meseret

2016-01-01

Background. Ethiopia is among highly tuberculosis affected countries. This might be related to low level of awareness on the disease in the population. The objective of the study was to determine the level of tuberculosis knowledge and socioeconomic factors associated with it. Methods. The 2011 Ethiopia health and demographic survey data were used. Overall tuberculosis knowledge score was computed to evaluate the outcome variable. Multivariable logistic regression was employed to identify independent socioeconomic factors associated with low tuberculosis knowledge. Results. The overall tuberculosis knowledge was low, 44.05% (95% CI: 42.05-46.24%) among women and 32.3% (95% CI: 30.34-34.32%) among men. Rural women (AOR = 1.22) and youth, no formal education (women: AOR = 3.28, men: AOR = 7.42), attending only primary education (women: AOR = 1.95, men: AOR = 3.49), lowest wealth quintiles (women: AOR = 1.4, Men: AOR = 1.28), unskilled female manual workers (AOR = 4.15), female agricultural employee (AOR = 2.28), and lack of access to media (women: AOR = 1.52, men: AOR = 1.71) are significantly associated with low tuberculosis knowledge. Conclusion. The level of tuberculosis knowledge among adults in Ethiopia is low and varied by socioeconomic groups. Tuberculosis control programs should consider appropriate strategies for tuberculosis education, promotion, communication, and social mobilization to address the rural women, youths, the poor, less educated people, and unskilled workers.

Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence

PubMed Central

Poquet, Yannick; Levillain, Florence; Botanch, Catherine; Bardou, Fabienne; Daffé, Mamadou; Emile, Jean-François; Marchou, Bruno; Cardona, Pere-Joan; de Chastellier, Chantal; Altare, Frédéric

2008-01-01

Tuberculosis (TB) is characterized by a tight interplay between Mycobacterium tuberculosis and host cells within granulomas. These cellular aggregates restrict bacterial spreading, but do not kill all the bacilli, which can persist for years. In-depth investigation of M. tuberculosis interactions with granuloma-specific cell populations are needed to gain insight into mycobacterial persistence, and to better understand the physiopathology of the disease. We have analyzed the formation of foamy macrophages (FMs), a granuloma-specific cell population characterized by its high lipid content, and studied their interaction with the tubercle bacillus. Within our in vitro human granuloma model, M. tuberculosis long chain fatty acids, namely oxygenated mycolic acids (MA), triggered the differentiation of human monocyte-derived macrophages into FMs. In these cells, mycobacteria no longer replicated and switched to a dormant non-replicative state. Electron microscopy observation of M. tuberculosis–infected FMs showed that the mycobacteria-containing phagosomes migrate towards host cell lipid bodies (LB), a process which culminates with the engulfment of the bacillus into the lipid droplets and with the accumulation of lipids within the microbe. Altogether, our results suggest that oxygenated mycolic acids from M. tuberculosis play a crucial role in the differentiation of macrophages into FMs. These cells might constitute a reservoir used by the tubercle bacillus for long-term persistence within its human host, and could provide a relevant model for the screening of new antimicrobials against non-replicating persistent mycobacteria. PMID:19002241

Modern laboratory diagnosis of tuberculosis.

PubMed

Drobniewski, F A; Caws, M; Gibson, A; Young, D

2003-03-01

One-third of the global population is believed to be infected with bacteria of the Mycobacterium tuberculosis complex, the causative agent of tuberculosis. More than 8 million new cases of tuberculosis occur annually leading to 2 million deaths. Mortality is particularly high in those coinfected with HIV and where the bacteria are multiple-drug-resistant strains--ie, strains resistant to at least isoniazid and rifampicin. Early diagnosis of tuberculosis and drug resistance improves survival and by identifying infectious cases promotes contact tracing, implementation of institutional cross-infection procedures, and other public-health actions. This review addresses significant advances made in the diagnosis of infection, clinical disease, and drug resistance over the past decade. It proposes operational criteria for a modern diagnostic service in the UK (as a model of a low-incidence country) and explores some of the economic issues surrounding the use of these techniques.

Florida's tuberculosis epidemic. Public health response.

PubMed

Witte, J J; Bigler, W J

1994-03-01

Florida ranked fourth in the nation with 1,707 tuberculosis cases reported in 1992 for a rate of 12.7 per 100,000 population. Thirteen percent of these patients had AIDS. Recent cases in prisons, shelters, hospitals and schools have stimulated interest and media coverage. Resurgence of strains of multiple-drug resistant tuberculosis is a serious concern. The Florida Department of Health and Rehabilitative Services, in collaboration with allied agencies, has utilized several initiatives in response. The most significant, Tuberculosis Epidemic Containment Plan, details intervention strategies needed to eliminate TB in the state by the year 2010. Successful implementation depends upon local TB prevention and control coalitions that include private and public sector providers.

Characteristics of childhood tuberculosis patients registered under RNTCP in Varanasi, Uttar Pradesh.

PubMed

Thakur, Harshad P

2013-01-01

Childhood tuberculosis (TB) reflects on-going transmission. Data on childhood TB from TB registers under Revised National Tuberculosis Control Program of 2008 and 2009 in Varanasi district was analyzed. Proportion of childhood TB was 8.3% of total registered cases 12,242. It was lower than estimated 10-20% in endemic areas. In rural Tuberculosis Units childhood case detection was poor. Case detection in ≤5 years was very less. The childhood cases were detected mainly in adolescent age group. Thus, childhood TB is remaining a under diagnosed/under reported disease in India. It needs attention to increase the detection of childhood TB cases to control TB in general population.

Propelling novel vaccines directed against tuberculosis through the regulatory process.

PubMed

Brennan, M J; Collins, F M; Morris, S L

1999-01-01

The development of novel vaccines for use in the prevention and immunotherapy of tuberculosis is an area of intense interest for scientific researchers, public health agencies and pharmaceutical manufacturers. Development of effective anti-tuberculosis vaccines for use in specific target populations will require close cooperation among several different international organizations including agencies responsible for evaluating the safety and effectiveness of new biologics for human use. In this review, the major issues that are addressed by regulatory agencies to ensure that vaccines are pure, potent, safe, and effective are discussed. It is hoped that the comments provided here will help accelerate the development of new effective vaccines for the prevention and treatment of tuberculosis.

Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers.

PubMed

Bloom, Chloe I; Graham, Christine M; Berry, Matthew P R; Rozakeas, Fotini; Redford, Paul S; Wang, Yuanyuan; Xu, Zhaohui; Wilkinson, Katalin A; Wilkinson, Robert J; Kendrick, Yvonne; Devouassoux, Gilles; Ferry, Tristan; Miyara, Makoto; Bouvry, Diane; Valeyre, Dominique; Dominique, Valeyre; Gorochov, Guy; Blankenship, Derek; Saadatian, Mitra; Vanhems, Phillip; Beynon, Huw; Vancheeswaran, Rama; Wickremasinghe, Melissa; Chaussabel, Damien; Banchereau, Jacques; Pascual, Virginia; Ho, Ling-Pei; Lipman, Marc; O'Garra, Anne

2013-01-01

New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

Bovine tuberculosis: a retrospective study at Jos abattoir, Plateau State, Nigeria.

PubMed

Okeke, Lilian Akudo; Fawole, Olufunmilayo; Muhammad, Maryam; Okeke, Ikenna Osemeka; Nguku, Patrick; Wasswa, Peter; Dairo, David; Cadmus, Simeon

2016-01-01

Nigeria has the thirteenth highest burden of human tuberculosis. The current increasing incidence of tuberculosis in humans, particularly in immune-compromised persons, has given interest in the zoonotic importance of Mycobacterium bovis in developing countries like Nigeria. This study determined the prevalence of bovine tuberculosis as a background information for effective control measures in Plateau State in cattle population. We reviewed surveillance records on cattle slaughtered and suggestive tuberculosis lesions from cattle slaughtered annually from 2007-2012 in Jos abattoir, Plateau State. Bovine tuberculosis cases at post mortem were based on examination of characteristics TB lesion on organs by Veterinary officers. We performed descriptive analysis using Epi info version 3.5.3 and Microsoft Excel 2007. A total of 52, 262 cattle were slaughtered from 2007-2012, out of which 4, 658 (11.2%) had evidence of tuberculosis lesion at post mortem. The average yearly prevalence was 9.1% but varied from a high of 16.3% in 2007 to a low of 3.1% in 2012. Trend analysis showed that bovine tuberculosis had a seasonal variation and peaked mostly in July and August. The number of suggestive Tb lesion cases was highest in the month of August and lowest in the month of January, 2007-2012. This study shows that bovine tuberculosis is endemic in Plateau State. Trend analysis showed that bovine tuberculosis is seasonal and peaked mostly in July and August. Continuous surveillance through meat inspection is required to prevent zoonotic transmission of bovine tuberculosis.

TNF neutralization results in disseminated disease during acute and latent M. tuberculosis infection with normal granuloma structure

PubMed Central

Lin, Philana Ling; Myers, Amy; Smith, Le’Kneitah; Bigbee, Carolyn; Bigbee, Matthew; Fuhrman, Carl; Grieser, Heather; Chiosea, Ion; Voitenek, Nikolai N.; Capuano, Saverio V.; Klein, Edwin; Flynn, JoAnne L.

2010-01-01

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor alpha (TNF) neutralizing agents. In murine models, impaired signaling by TNF caused exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. The non-human primate model of tuberculosis provides an opportunity to study immune modulation in the setting of TNF neutralization during primary and latent tuberculosis. Administration of TNF neutralizing agents prior to M. tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks post-infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathology and bacterial burden. A spectrum of dissemination was noted including extrapulmonary disease. Surprisingly, monkeys who developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition compared to active control monkeys. TNF neutralization was associated with increased IL-12, decreased CCL4, increased chemokine receptor expression and reduced mycobacteria-specific IFN-γ production in blood but not to the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes. These findings have important clinical implications for determining the mechanism of TNF-neutralization-related tuberculosis. PMID:20112395

Delivering Patient-Centered Care in a Fragile State: Using Patient-Pathway Analysis to Understand Tuberculosis-Related Care Seeking in Pakistan.

PubMed

Fatima, Razia; Haq, Mahboob Ul; Yaqoob, Aashifa; Mahmood, Nasir; Ahmad, Khawaja Laeeq; Osberg, Mike; Makayova, Julia; Hymoff, Aaron; Hanson, Christy

2017-11-06

Pakistan has the sixth largest population in the world and boasts the fifth greatest burden of tuberculosis. The Government of Pakistan has set the ambitious goal of zero deaths due to tuberculosis and universal access to tuberculosis care by 2020. Successfully reaching these goals is dependent on the country's capacity to diagnose and successfully treat an estimated 200000 unnotified or missing patients with tuberculosis. A patient-pathway analysis (PPA) was conducted at the national level, as well as for each of the 4 provinces, to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services. Almost 90% of patients initiated care in the private sector, which accounts for only 15% of facilities with the capacity for tuberculosis diagnosis and treatment. Across the country, nearly 50% of tuberculosis microscopy laboratories were located in public-sector-basic health units and regional health centers. However, very few patients initiated care in these facilities. Overall, tuberculosis case detection was high given the low likelihood of patients reaching facilities with the capacity for tuberculosis service delivery during their first visit. Improving the engagement of the informal sector and lower-level clinicians will improve the efficiency and timeliness of tuberculosis diagnosis for patients in Pakistan. Concurrently, the apparent strength of the referral networks connecting community-level workers and private clinicians to the public sector for tuberculosis diagnosis and treatment suggests that strengthening the capacity of the public sector could be valuable. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Delivering Patient-Centered Care in a Fragile State: Using Patient-Pathway Analysis to Understand Tuberculosis-Related Care Seeking in Pakistan

PubMed Central

Fatima, Razia; Haq, Mahboob Ul; Yaqoob, Aashifa; Mahmood, Nasir; Ahmad, Khawaja Laeeq; Osberg, Mike; Makayova, Julia; Hymoff, Aaron; Hanson, Christy

2017-01-01

Abstract Background Pakistan has the sixth largest population in the world and boasts the fifth greatest burden of tuberculosis. The Government of Pakistan has set the ambitious goal of zero deaths due to tuberculosis and universal access to tuberculosis care by 2020. Successfully reaching these goals is dependent on the country’s capacity to diagnose and successfully treat an estimated 200000 unnotified or missing patients with tuberculosis. Methods A patient-pathway analysis (PPA) was conducted at the national level, as well as for each of the 4 provinces, to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services. Results Almost 90% of patients initiated care in the private sector, which accounts for only 15% of facilities with the capacity for tuberculosis diagnosis and treatment. Across the country, nearly 50% of tuberculosis microscopy laboratories were located in public-sector–basic health units and regional health centers. However, very few patients initiated care in these facilities. Overall, tuberculosis case detection was high given the low likelihood of patients reaching facilities with the capacity for tuberculosis service delivery during their first visit. Discussion Improving the engagement of the informal sector and lower-level clinicians will improve the efficiency and timeliness of tuberculosis diagnosis for patients in Pakistan. Concurrently, the apparent strength of the referral networks connecting community-level workers and private clinicians to the public sector for tuberculosis diagnosis and treatment suggests that strengthening the capacity of the public sector could be valuable. PMID:29117348

The C-Terminal Domain of the Virulence Factor MgtC Is a Divergent ACT Domain

PubMed Central

Yang, Yinshan; Labesse, Gilles; Carrère-Kremer, Séverine; Esteves, Kevin; Kremer, Laurent

2012-01-01

MgtC is a virulence factor of unknown function important for survival inside macrophages in several intracellular bacterial pathogens, including Mycobacterium tuberculosis. It is also involved in adaptation to Mg2+ deprivation, but previous work suggested that MgtC is not a Mg2+ transporter. In this study, we demonstrated that the amount of the M. tuberculosis MgtC protein is not significantly increased by Mg2+ deprivation. Members of the MgtC protein family share a conserved membrane N-terminal domain and a more divergent cytoplasmic C-terminal domain. To get insights into MgtC functional and structural organization, we have determined the nuclear magnetic resonance (NMR) structure of the C-terminal domain of M. tuberculosis MgtC. This structure is not affected by the Mg2+ concentration, indicating that it does not bind Mg2+. The structure of the C-terminal domain forms a βαββαβ fold found in small molecule binding domains called ACT domains. However, the M. tuberculosis MgtC ACT domain differs from canonical ACT domains because it appears to lack the ability to dimerize and to bind small molecules. We have shown, using a bacterial two-hybrid system, that the M. tuberculosis MgtC protein can dimerize and that the C-terminal domain somehow facilitates this dimerization. Taken together, these results indicate that M. tuberculosis MgtC does not have an intrinsic function related to Mg2+ uptake or binding but could act as a regulatory factor based on protein-protein interaction that could be facilitated by its ACT domain. PMID:22984256

The crystal structure of MCAT from Mycobacterium tuberculosis reveals three new catalytic models.

PubMed

Li, Zexuan; Huang, Yishu; Ge, Jing; Fan, Hang; Zhou, Xiaohong; Li, Shentao; Bartlam, Mark; Wang, Honghai; Rao, Zihe

2007-08-24

The malonyl coenzyme A (CoA)-acyl carrier protein (ACP) transacylase (MCAT) plays a key role in cell wall biosynthesis in Mycobacterium tuberculosis and other bacteria. The M. tuberculosis MCAT (MtMCAT) is encoded by the FabD gene and catalyzes the transacylation of malonate from malonyl-CoA to holo-ACP. Malonyl-ACP is the substrate in fatty acid biosynthesis and is a by-product of the transacylation reaction. This ability for fatty acid biosynthesis enables M. tuberculosis to survive in hostile environments, and thus understanding the mechanism of biosynthesis is important for the design of new anti-tuberculosis drugs. The 2.3 A crystal structure of MtMCAT reported here shows that its catalytic mechanism differs from those of ScMCAT and EcMCAT, whose structures have previously been determined. In MtMCAT, the C(beta)-O(gamma) bond of Ser91 turns upwards, resulting in a different orientation and thus an overall change of the active pocket compared to other known MCAT enzymes. We identify three new nucleophilic attack chains from the MtMCAT structure: His90-Ser91, Asn155-Wat6-Ser91 and Asn155-His90-Ser91. Enzyme activity assays show that His90A, Asn155A and His90A-Asn155A mutants all have substantially reduced MCAT activity, indicating that M. tuberculosis MCAT supports a unique means of proton transfer. Furthermore, His194 cannot form part of a His-Ser catalytic dyad and only stabilizes the substrate. This new discovery should provide a deeper insight into the catalytic mechanisms of MCATs.

Chest X-ray and chest CT findings in patients diagnosed with pulmonary tuberculosis following solid organ transplantation: a systematic review.

PubMed

Giacomelli, Irai Luis; Schuhmacher Neto, Roberto; Marchiori, Edson; Pereira, Marisa; Hochhegger, Bruno

2018-04-01

The objective of this systematic review was to select articles including chest X-ray or chest CT findings in patients who developed pulmonary tuberculosis following solid organ transplantation (lung, kidney, or liver). The following search terms were used: "tuberculosis"; "transplants"; "transplantation"; "mycobacterium"; and "lung". The databases used in this review were PubMed and the Brazilian Biblioteca Virtual em Saúde (Virtual Health Library). We selected articles in English, Portuguese, or Spanish, regardless of the year of publication, that met the selection criteria in their title, abstract, or body of text. Articles with no data on chest CT or chest X-ray findings were excluded, as were those not related to solid organ transplantation or pulmonary tuberculosis. We selected 29 articles involving a collective total of 219 patients. The largest samples were in studies conducted in Brazil and South Korea (78 and 35 patients, respectively). The imaging findings were subdivided into five common patterns. The imaging findings varied depending on the transplanted organ in these patients. In liver and lung transplant recipients, the most common pattern was the classic one for pulmonary tuberculosis (cavitation and "tree-in-bud" nodules), which is similar to the findings for pulmonary tuberculosis in the general population. The proportion of cases showing a miliary pattern and lymph node enlargement, which is most similar to the pattern seen in patients coinfected with tuberculosis and HIV, was highest among the kidney transplant recipients. Further studies evaluating clinical data, such as immunosuppression regimens, are needed in order to improve understanding of the distribution of these imaging patterns in this population.

[Tuberculosis among immigrants in Scandinavian medical journals].

PubMed

Steen, M

2001-06-30

The decline in incidence of tuberculosis in Scandinavia has stagnated in the last decades because of a growing number of immigrants from high incidence countries. The aim of this study was to find out what has been published on tuberculosis among immigrants in Denmark, Norway and Sweden in the main medical journals in these countries from 1995 to 2000. 23 papers on the topic were identified through PubMed searches. Eight papers were selected for a more detailed description of their content. The main medical journals in Denmark, Norway and Sweden have published papers on epidemiological aspects and clinical traits as well as the challenge for the health services of controlling tuberculosis in immigrants. The majority of patients are under the age of 40 and of African origin. They seldom infect the population of the host country. Extrapulmonary tuberculosis is relatively common. Control on arrival could be improved in all three countries. Considerable doctor's and patient's delay is not uncommon. Medical journals are an important source for knowledge on tuberculosis among immigrants from high incidence countries.

Testing the influenza–tuberculosis selective mortality hypothesis with Union Army data⋆

PubMed Central

Noymer, Andrew

2009-01-01

Using Cox regression, this paper shows a weak association between having tuberculosis and dying from influenza among Union Army veterans in late nineteenth-century America. It has been suggested elsewhere [Noymer, A. and M. Garenne (2000). The 1918 influenza epidemic’s effects on sex differentials in mortality in the United States. Population and Development Review 26(3), 565–581.] that the 1918 influenza pandemic accelerated the decline of tuberculosis, by killing many people with tuberculosis. The question remains whether individuals with tuberculosis were at greater risk of influenza death, or if the 1918/post-1918 phenomenon arose from the sheer number of deaths in the influenza pandemic. The present findings, from microdata, cautiously point toward an explanation of Noymer and Garenne’s selection effect in terms of age-overlap of the 1918 pandemic mortality and tuberculosis morbidity, a phenomenon I term “passive selection”. Another way to think of this is selection at the cohort, as opposed to individual, level. PMID:19304361

Models to understand the population-level impact of mixed strain M. tuberculosis infections.

PubMed

Sergeev, Rinat; Colijn, Caroline; Cohen, Ted

2011-07-07

Over the past decade, numerous studies have identified tuberculosis patients in whom more than one distinct strain of Mycobacterium tuberculosis is present. While it has been shown that these mixed strain infections can reduce the probability of treatment success for individuals simultaneously harboring both drug-sensitive and drug-resistant strains, it is not yet known if and how this phenomenon impacts the long-term dynamics for tuberculosis within communities. Strain-specific differences in immunogenicity and associations with drug resistance suggest that a better understanding of how strains compete within hosts will be necessary to project the effects of mixed strain infections on the future burden of drug-sensitive and drug-resistant tuberculosis. In this paper, we develop a modeling framework that allows us to investigate mechanisms of strain competition within hosts and to assess the long-term effects of such competition on the ecology of strains in a population. These models permit us to systematically evaluate the importance of unknown parameters and to suggest priority areas for future experimental research. Despite the current scarcity of data to inform the values of several model parameters, we are able to draw important qualitative conclusions from this work. We find that mixed strain infections may promote the coexistence of drug-sensitive and drug-resistant strains in two ways. First, mixed strain infections allow a strain with a lower basic reproductive number to persist in a population where it would otherwise be outcompeted if has competitive advantages within a co-infected host. Second, some individuals progressing to phenotypically drug-sensitive tuberculosis from a state of mixed drug-sensitive and drug-resistant infection may retain small subpopulations of drug-resistant bacteria that can flourish once the host is treated with antibiotics. We propose that these types of mixed infections, by increasing the ability of low fitness drug-resistant strains to persist, may provide opportunities for compensatory mutations to accumulate and for relatively fit, highly drug-resistant strains of M. tuberculosis to emerge. Published by Elsevier Ltd.

Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis.

PubMed

Kaur, Divneet; Mathew, Shalu; Nair, Chinchu G S; Begum, Azitha; Jainanarayan, Ashwin K; Sharma, Mukta; Brahmachari, Samir K

2017-12-21

The problem of drug resistance and bacterial persistence in tuberculosis is a cause of global alarm. Although, the UN's Sustainable Development Goals for 2030 has targeted a Tb free world, the treatment gap exists and only a few new drug candidates are in the pipeline. In spite of large information from medicinal chemistry to 'omics' data, there has been a little effort from pharmaceutical companies to generate pipelines for the development of novel drug candidates against the multi drug resistant Mycobacterium tuberculosis. In the present study, we describe an integrated methodology; utilizing systems level information to optimize ligand selection to lower the failure rates at the pre-clinical and clinical levels. In the present study, metabolic targets (Rv2763c, Rv3247c, Rv1094, Rv3607c, Rv3048c, Rv2965c, Rv2361c, Rv0865, Rv0321, Rv0098, Rv0390, Rv3588c, Rv2244, Rv2465c and Rv2607) in M. tuberculosis, identified using our previous Systems Biology and data-intensive genome level analysis, have been used to design potential lead molecules, which are likely to be non-toxic. Various in silico drug discovery tools have been utilized to generate small molecular leads for each of the 15 targets with available crystal structures. The present study resulted in identification of 20 novel lead molecules including 4 FDA approved drugs (droxidropa, tetroxoprim, domperidone and nemonapride) which can be further taken for drug repurposing. This comprehensive integrated methodology, with both experimental and in silico approaches, has the potential to not only tackle the MDR form of Mtb but also the most important persister population of the bacterium, with a potential to reduce the failures in the Tb drug discovery. We propose an integrated approach of systems and structural biology for identifying targets that address the high attrition rate issue in lead identification and drug development We expect that this system level analysis will be applicable for identification of drug candidates to other pathogenic organisms as well.

[Tuberculosis: steady dynamics between past and present to imagine the future].

PubMed

Cabello C, Felipe

2011-07-01

Progress in understanding the biological processes that allow Mycobacterium tuberculosis to be a successful parasite have accelerated in the last twenty years. This progress has been stimulated by the return of tuberculosis (TB) as an important disease in industrialized countries, by its increase in emergent nations in the tail of population increases and poverty and by the spread of multiple drug resistant (MDR) and extensively drug resistant (XDR) M. tuberculosis as a result of treatment failures. Progress on M. tuberculosis biology has also been fueled by advances in microbiology and molecular biology, including molecular genetics, genomics, proteomics and in vitro and in vivo models of infection. The study of latency or dormancy, a phenomenon central to understanding the persistence of M. tuberculosis and the development of TB in individuals, its spread in human populations and the emergence of antibiotic-resistant/tolerant organisms, has been preferred targets for investigators in this area. In this manner, factors that trigger M. tuberculosis latency (e. g, hypoxia, nutrient starvation, NO exposure) have been characterized and the metabolic shifts to host lipid utilization, tolerance to antimicrobials and resistance to host immune mechanisms involved in latency have been determined. Similarly, genetic changes and the resulting antimicrobial mechanisms mediating the MDR and XDR states have been characterized and potential new vaccines that avoid reactivation from latency and infection are being developed. Despite this progress, and given the fact that effective anti tuberculosis therapy was developed and first introduced clinically at the end of the 1940s, there are now more cases of latent and active TB worldwide than ever before. This reinforces the concept of TB as a bacterial disease with strong social and economical! determinants which are presently stimulating increased transmission in many human groups, undermining diagnostics, treatment and prevention. It suggests that in a scenario of global economical crisis the struggle against TB will be weakened, unless efforts are included to alleviate poverty, decrease economic inequality, improve public health and allow democracy and political organization.

[Tuberculosis in indigenous peoples in the Brazilian Amazon: an epidemiological study in the Upper Rio Negro region].

PubMed

Rios, Diana Patrícia Giraldo; Malacarne, Jocieli; Alves, Luiz Carlos Corrêa; Sant'Anna, Clemax Couto; Camacho, Luiz Antonio Bastos; Basta, Paulo Cesar

2013-01-01

To describe the sociodemographic, clinical, and epidemiological characteristics of reported tuberculosis cases among indigenous individuals of São Gabriel de Cachoeira, State of Amazonas, Brazil, and to identify the factors associated with mortality during treatment; and to estimate the prevalence of latent tuberculosis infection (LTBI) and associated factors and obtain information on the therapeutic course and the individual perceptions regarding acquistion of tuberculosis in the district of Iauaretê. Firstly, a retrospective epidemiological study (1997 to 2007) was conducted using data from the Brazilian Notifiable Diseases Surveillance System (SINAN). Next, a cross-sectional study (2010) was conducted with respiratory symptomatic subjects and contacts of Iauaretê. Seven hundred and twenty-three new cases were reported, with incidence of 273.4/100 000 and mortality of 13.2/100 000. There was a predominance of males (57%), aged > 45 years (37.6%), people with no schooling (42.7%), and cases from rural areas (76.9%). Patients aged 0 to 20 years were at lower risk of death when compared to those aged > 45 years (OR = 0.3; IC95%: 0.1 a 0.9). In Iauaretê, with 15.3% of the reported cases, 184 people were interviewed. A prevalence of LTB of 76.1% was reported. Tuberculin skin test > 5 mm was associated with the > 15-year old age group, history of active tuberculosis, and radiological alterations. A previous history of tuberculosis was cited by 54 people (29.3%). The main explanation for the disease was "puffing/poisoning" (24.1%). The therapeutic course included industrialized drugs (42.6%), medicinal plants/roots, shamanism, and prayer (42.7%). The risk of tuberculosis infection and disease in this population was high. Despite the reduced incidence resulting from recent efforts, tuberculosis control requires closer surveillance of contacts and improvement in communication strategies between health teams and indigenous populations.

Anti-Tuberculosis Policy of the Government General of Korea during Japanese-Colonial Period (1910-1945): From Simple Restriction to Active Enlightenment.

PubMed

Choi, Eun Kyung

2013-12-01

In this paper, I tried to examine the characteristic of anti-tuberculosis policy in colonial Korea and find out internal constraint of hygienic administration by Japanese government during Japanese-Colonial Period. Despite of high prevalence of tuberculosis among Japanese in Korea, the Japanese Government General of Korea had done almost nothing until 1936. Japan's hygienic administration was highly dependent upon hygienic police, and mainly with compulsory isolation and disinfection. It was inefficient in tuberculosis problem. In 1918, Japanese Government General enacted 'Ordinance of Prevention of Tuberculosis', solely based upon naive tuberculosis etiology in sputum; consisted of simple crackdown and isolation and had no effect due to the limit of anti-tuberculosis and health budget. Also the ordinance actually set limitation upon the tuberculosis facilities, only a few health care facilities could be affordable for tuberculosis patients. Since 1936, the Japanese Government General of Korea began tuberculosis prevention measures in earnest. Due to the Second Sino- Japanese War and World War II, there was urgent need to make Korean society and population as "safe, and healthy rear area". The Government organized 'Chosen Anti-tuberculosis Association' and highly pursued enlightment campaign. It was almost temporary measures of enlightenment and publicity. Also various types of health screening and tuberculosis prevalence research were introduced to Korean people. But it was not so effective to identify tuberculosis problem in Korea. Mass tuberculin test and X-ray test was introduced, but it was not well organized and scientifically designed. Besides, tuberculosis treatment facility was extremely rare because of strict isolation and high standard policy. Japanese Governemtn set numerous tuberculosis-counseling centers and mobilized public doctor for consulting tuberculosis, but the accessibility of centers was very low. Moreover, there was no source to establish facilities like sanatorium. The Japanese Government General of Korea was constantly suffered from limit of budget and a lot of Japanese in Korea had no inherent motive for installing sanatorium and anti-tuberculosis measures. As the result, the effort made by Japanese Government General of Korea to diminish tuberculosis in Korea failed during the wartime.

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

PubMed Central

Reece, Stephen T.; Loddenkemper, Christoph; Askew, David J.; Zedler, Ulrike; Schommer-Leitner, Sandra; Stein, Maik; Mir, Fayaz Ahmad; Dorhoi, Anca; Mollenkopf, Hans-Joachim; Silverman, Gary A.; Kaufmann, Stefan H.E.

2010-01-01

The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2–/– mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2–/– mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis. PMID:20679732

T7 Phage Display Library a Promising Strategy to Detect Tuberculosis Specific Biomarkers.

PubMed

Talwar, Harvinder; Talreja, Jaya; Samavati, Lobelia

2016-06-01

One-third of the world's population is infected with tuberculosis, only 10% will develop active disease and the remaining 90% is considered to have latent TB (LTB). While active TB is contagious and can be lethal, the LTB can evolve to active TB. The diagnosis of TB can be challenging, especially in the early stages, due to the variability in presentation and nonspecific signs and symptoms. Currently, we have limited tools available to diagnose active TB, predict treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses through vaccination. Therefore, the identification of robust and accurate tuberculosis-specific biomarkers is crucial for the successful eradication of TB. In this commentary, we summarized the available methods for diagnosis and differentiation of active TB from LTB and their limitations. Additionally, we present a novel peptide microarray platform as promising strategy to identify TB biomarkers.

Tuberculosis in the immigrant population in Italy: state-of-the-art review.

PubMed

Scotto, Gaetano; Fazio, Vincenzina; Lo Muzio, Lorenzo

2017-09-01

Although the incidence of tuberculosis (TB) has been decreasing in the European Union/European Economic Area (EU/EEA) in recent decades, specific subgroups of the population, such as immigrants, remain at high risk of the disease. Immigration from areas of high incidence is thought to have fuelled the resurgence of TB in areas of low incidence. Indeed, while immigrants have a high risk of acquiring TB prior to migration, after migration they are exposed to additional risk factors for acquiring or reactivating TB infection, such as poverty, stressful living conditions, social inequalities, overcrowded housing, malnutrition, substance abuse and limited access to health care. In Italy as well, TB has increasingly become a disease for specific population subgroups such as immigrants and in urban settings often driven by reactivation of imported latent TB infection (LTBI). In this paper we present an analysis of the national scientific literature from recent years in order to estimate the burden of TB in foreign-born populations, to establish the burden of TB in migrants by gender, age group and country of origin as well as other relevant subgroups, and evaluate the clinical manifestations of latent or active tuberculosis and treatment response.

Common Polymorphisms in the PKP3-SIGIRR-TMEM16J Gene Region Are Associated With Susceptibility to Tuberculosis

PubMed Central

Randhawa, April K.; Chau, Tran T. H.; Bang, Nguyen D.; Yen, Nguyen T. B.; Farrar, Jeremy J.; Dunstan, Sarah J.; Hawn, Thomas R.

2012-01-01

(See the editorial commentary by Wilkinson, on pages 525–7.) Background. Tuberculosis has been associated with genetic variation in host immunity. We hypothesized that single-nucleotide polymorphisms (SNPs) in SIGIRR, a negative regulator of Toll-like receptor/IL-1R signaling, are associated with susceptibility to tuberculosis. Methods. We used a case-population study design in Vietnam with cases that had either tuberculous meningitis or pulmonary tuberculosis. We genotyped 6 SNPs in the SIGIRR gene region (including the adjacent genes PKP3 and TMEM16J) in a discovery cohort of 352 patients with tuberculosis and 382 controls. Significant associations were genotyped in a validation cohort (339 patients with tuberculosis, 376 controls). Results. Three SNPs (rs10902158, rs7105848, rs7111432) were associated with tuberculosis in discovery and validation cohorts. The polymorphisms were associated with both tuberculous meningitis and pulmonary tuberculosis and were strongest with a recessive genetic model (odds ratios, 1.5–1.6; P = .0006–.001). Coinheritance of these polymorphisms with previously identified risk alleles in Toll-like receptor 2 and TIRAP was associated with an additive risk of tuberculosis susceptibility. Conclusions. These results demonstrate a strong association of SNPs in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. To our knowledge, these are the first associations of polymorphisms in this region with any disease. PMID:22223854

Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis.

PubMed

Sterling, Timothy R; Lehmann, Harold P; Frieden, Thomas R

2003-03-15

This study sought to determine the impact of the World Health Organization's directly observed treatment strategy (DOTS) compared with that of DOTS-plus on tuberculosis deaths, mainly in the developing world. Decision analysis with Monte Carlo simulation of a Markov decision tree. People with smear positive pulmonary tuberculosis. Analyses modelled different levels of programme effectiveness of DOTS and DOTS-plus, and high (10%) and intermediate (3%) proportions of primary multidrug resistant tuberculosis, while accounting for exogenous reinfection. The cumulative number of tuberculosis deaths per 100 000 population over 10 years. The model predicted that under DOTS, 276 people would die from tuberculosis (24 multidrug resistant and 252 not multidrug resistant) over 10 years under optimal implementation in an area with 3% primary multidrug resistant tuberculosis. Optimal implementation of DOTS-plus would result in four (1.5%) fewer deaths. If implementation of DOTS-plus were to result in a decrease of just 5% in the effectiveness of DOTS, 16% more people would die with tuberculosis than under DOTS alone. In an area with 10% primary multidrug resistant tuberculosis, 10% fewer deaths would occur under optimal DOTS-plus than under optimal DOTS, but 16% more deaths would occur if implementation of DOTS-plus were to result in a 5% decrease in the effectiveness of DOTS CONCLUSIONS: Under optimal implementation, fewer tuberculosis deaths would occur under DOTS-plus than under DOTS. If, however, implementation of DOTS-plus were associated with even minimal decreases in the effectiveness of treatment, substantially more patients would die than under DOTS.

Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983-1998.

PubMed

2001-02-01

In Tanzania, a national tuberculosis programme (NTP) was established in 1979 based on the principles currently known as the World Health Organization DOTS strategy. From the period 1983-1987 to 1994-1998, notification rates of smear-positive tuberculosis increased from 32 to 69 per 100,000 population, mainly due to the human immunodeficiency virus (HIV) epidemic. To estimate the trend in the annual risk of tuberculosis infection and to establish to what extent the opposing forces of improved tuberculosis control and HIV have had an impact on tuberculosis transmission. Three national surveys were conducted in Tanzania among primary school children at 5-year intervals. The annual risk of tuberculosis infection and its trend were determined by tuberculin skin testing. The annual risk of infection in children without BCG scar using the criterion '17 mm + 2 x 18 mm' or more was estimated at 1.1% in 1983-1987, 1.0 in 1988-1992, and 0.9% in 1993-1998. There appears to have been little change in the annual risk of infection over the study period, either when using other criteria to define infection or in children with a BCG scar. The estimated number of infections per notified case decreased over time from 36 to 19. Despite strongly increased tuberculosis notification rates in adults, associated with the HIV epidemic, the risk of tuberculosis infection in children appears to have been stable over the past 15 years in Tanzania. This remarkable achievement is probably due to the impact of the NTP on tuberculosis transmission.

Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung Cancers

PubMed Central

Bloom, Chloe I.; Graham, Christine M.; Berry, Matthew P. R.; Rozakeas, Fotini; Redford, Paul S.; Wang, Yuanyuan; Xu, Zhaohui; Wilkinson, Katalin A.; Wilkinson, Robert J.; Kendrick, Yvonne; Devouassoux, Gilles; Ferry, Tristan; Miyara, Makoto; Bouvry, Diane; Dominique, Valeyre; Gorochov, Guy; Blankenship, Derek; Saadatian, Mitra; Vanhems, Phillip; Beynon, Huw; Vancheeswaran, Rama; Wickremasinghe, Melissa; Chaussabel, Damien; Banchereau, Jacques; Pascual, Virginia; Ho, Ling-pei; Lipman, Marc; O’Garra, Anne

2013-01-01

Rationale New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. Objectives To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. Methods We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. Measurements and Main Results An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. Conclusions Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment. PMID:23940611

Whole genome sequencing of the monomorphic pathogen Mycobacterium bovis reveals local differentiation of cattle clinical isolates.

PubMed

Lasserre, Moira; Fresia, Pablo; Greif, Gonzalo; Iraola, Gregorio; Castro-Ramos, Miguel; Juambeltz, Arturo; Nuñez, Álvaro; Naya, Hugo; Robello, Carlos; Berná, Luisa

2018-01-02

Bovine tuberculosis (bTB) poses serious risks to animal welfare and economy, as well as to public health as a zoonosis. Its etiological agent, Mycobacterium bovis, belongs to the Mycobacterium tuberculosis complex (MTBC), a group of genetically monomorphic organisms featured by a remarkably high overall nucleotide identity (99.9%). Indeed, this characteristic is of major concern for correct typing and determination of strain-specific traits based on sequence diversity. Due to its historical economic dependence on cattle production, Uruguay is deeply affected by the prevailing incidence of Mycobacterium bovis. With the world's highest number of cattle per human, and its intensive cattle production, Uruguay represents a particularly suited setting to evaluate genomic variability among isolates, and the diversity traits associated to this pathogen. We compared 186 genomes from MTBC strains isolated worldwide, and found a highly structured population in M. bovis. The analysis of 23 new M. bovis genomes, belonging to strains isolated in Uruguay evidenced three groups present in the country. Despite presenting an expected highly conserved genomic structure and sequence, these strains segregate into a clustered manner within the worldwide phylogeny. Analysis of the non-pe/ppe differential areas against a reference genome defined four main sources of variability, namely: regions of difference (RD), variable genes, duplications and novel genes. RDs and variant analysis segregated the strains into clusters that are concordant with their spoligotype identities. Due to its high homoplasy rate, spoligotyping failed to reflect the true genomic diversity among worldwide representative strains, however, it remains a good indicator for closely related populations. This study introduces a comprehensive population structure analysis of worldwide M. bovis isolates. The incorporation and analysis of 23 novel Uruguayan M. bovis genomes, sheds light onto the genomic diversity of this pathogen, evidencing the existence of greater genetic variability among strains than previously contemplated.

Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives.

PubMed

Abel, Laurent; Fellay, Jacques; Haas, David W; Schurr, Erwin; Srikrishna, Geetha; Urbanowski, Michael; Chaturvedi, Nimisha; Srinivasan, Sudha; Johnson, Daniel H; Bishai, William R

2018-03-01

Tuberculosis is an ancient human disease, estimated to have originated and evolved over thousands of years alongside modern human populations. Despite considerable advances in disease control, tuberculosis remains one of the world's deadliest communicable diseases with 10 million incident cases and 1·8 million deaths in 2015 alone based on the annual WHO report, due to inadequate health service resources in less-developed regions of the world, and exacerbated by the HIV/AIDS pandemic and emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Recent findings from studies of tuberculosis infection and of patients with Mendelian predisposition to severe tuberculosis have started to reveal human loci influencing tuberculosis outcomes. In this Review, we assess the current understanding of the contribution of host genetics to disease susceptibility and to drug treatment. Despite remarkable progress in technology, only a few associated genetic variants have so far been identified, strongly indicating the need for larger global studies that investigate both common and under-represented rare variants to develop new approaches to combat the disease. Pharmacogenomic discoveries are also likely to lead to more efficient drug design and development, and ultimately safer and more effective therapies for tuberculosis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tuberculosis associates with both airflow obstruction and low lung function: BOLD results.

PubMed

Amaral, André F S; Coton, Sonia; Kato, Bernet; Tan, Wan C; Studnicka, Michael; Janson, Christer; Gislason, Thorarinn; Mannino, David; Bateman, Eric D; Buist, Sonia; Burney, Peter G J

2015-10-01

In small studies and cases series, a history of tuberculosis has been associated with both airflow obstruction, which is characteristic of chronic obstructive pulmonary disease, and restrictive patterns on spirometry. The objective of the present study was to assess the association between a history of tuberculosis and airflow obstruction and spirometric abnormalities in adults.The study was performed in adults, aged 40 years and above, who took part in the multicentre, cross-sectional, general population-based Burden of Obstructive Lung Disease study, and had provided acceptable post-bronchodilator spirometry measurements and information on a history of tuberculosis. The associations between a history of tuberculosis and airflow obstruction and spirometric restriction were assessed within each participating centre, and estimates combined using meta-analysis. These estimates were stratified by high- and low/middle-income countries, according to gross national income.A self-reported history of tuberculosis was associated with airflow obstruction (adjusted odds ratio 2.51, 95% CI 1.83-3.42) and spirometric restriction (adjusted odds ratio 2.13, 95% CI 1.42-3.19).A history of tuberculosis was associated with both airflow obstruction and spirometric restriction, and should be considered as a potentially important cause of obstructive disease and low lung function, particularly where tuberculosis is common. Copyright ©ERS 2015.

Tuberculosis associates with both airflow obstruction and low lung function: BOLD results

PubMed Central

Amaral, André F. S.; Coton, Sonia; Kato, Bernet; Tan, Wan C.; Studnicka, Michael; Janson, Christer; Gislason, Thorarinn; Mannino, David; Bateman, Eric D.; Buist, Sonia; Burney, Peter G. J.

2015-01-01

Background In small studies and cases series, a history of tuberculosis has been associated with both airflow obstruction, which is characteristic of chronic obstructive pulmonary disease, and restrictive patterns on spirometry. Objective To assess the association between a history of tuberculosis and airflow obstruction and spirometric abnormalities in adults. Methods The study was performed in adults, aged 40 and above, who took part in the multicentre cross-sectional, general population-based, Burden of Obstructive Lung Disease study, had provided acceptable post-bronchodilator spirometry measurements and information on a history of tuberculosis. The associations between a history of tuberculosis and airflow obstruction and spirometric restriction were assessed within each participating centre, and estimates combined using meta-analysis. These estimates were stratified by high and low/middle income countries, according to gross national income. Results A self-reported history of tuberculosis was associated with airflow obstruction (adjusted odds ratio = 2.51, 95% confidence interval 1.83-3.42) and spirometric restriction (adjusted odds ratio = 2.13, 95% confidence interval 1.42-3.19). Conclusion A history of tuberculosis was associated with both airflow obstruction and spirometric restriction, and should be considered as a potentially important cause of obstructive disease and low lung function, particularly where tuberculosis is common. PMID:26113680

CsoR Is Essential for Maintaining Copper Homeostasis in Mycobacterium tuberculosis

PubMed Central

Marcus, Sarah A.; Sidiropoulos, Sarah W.; Steinberg, Howard; Talaat, Adel M.

2016-01-01

Mycobacterium tuberculosis, a pathogen infecting one third of the world population, faces numerous challenges within the host, including high levels of copper. We have previously shown that M. tuberculosis CsoR is a copper inducible transcriptional regulator. Here we examined the hypothesis that csoR is necessary for maintaining copper homeostasis and surviving under various stress conditions. With an unmarked csoR knockout strain, we were able to characterize the role of csoR in M. tuberculosis as it faced copper and host stress. Growth under high levels of copper demonstrated that M. tuberculosis survives copper stress significantly better in the absence of csoR. Yet under minimal levels of copper, differential expression analysis revealed that the loss of csoR results in a cell wide hypoxia-type stress response with the induction of the DosR regulon. Despite the stress placed on M. tuberculosis by the loss of csoR, survival of the knockout strain was increased compared to wild type during the early chronic stages of mouse infection, suggesting that csoR could play an active role in modulating M. tuberculosis fitness within the host. Overall, analysis of CsoR provided an increased understanding of the M. tuberculosis copper response with implications for other intracellular pathogens harboring CsoR. PMID:26999439

Associations between national tuberculosis program budgets and tuberculosis outcomes: an ecological study.

PubMed

Chapple, Will; Katz, Alan Roy; Li, Dongmei

2012-01-01

The objective of this study is to explore the associations between national tuberculosis program (NTP) budget allocation and tuberculosis related outcomes in the World Health Organization's 22 high burden countries from 2007-2009. This ecological study used mixed effects and generalized estimating equation models to identify independent associations between NTP budget allocations and various tuberculosis related outcomes. Models were adjusted for a number of independent variables previously noted to be associated with tuberculosis incidence. Increasing the percent of the NTP budget for advocacy, communication and social mobilization was associated with an increase in the case detection rate. Increasing TB-HIV funding was associated with an increase in HIV testing among TB patients. Increasing the percent of the population covered by the Directly Observed Therapy (DOT) program was associated with an increase in drug susceptibility testing. Laboratory funding was positively associated with tuberculosis notification. Increasing the budgets for first line drugs, management and multi-drug resistant tuberculosis (MDR-TB) was associated with a decrease in smear positive deaths. Effective TB control is a complex and multifaceted challenge. This study revealed a number of budget allocation related factors associated with improved TB outcome parameters. If confirmed with future longitudinal studies, these findings could help guide NTP managers with allocation decisions.

Associations between national tuberculosis program budgets and tuberculosis outcomes: an ecological study

PubMed Central

Chapple, Will; Katz, Alan Roy; Li, Dongmei

2012-01-01

Introduction The objective of this study is to explore the associations between national tuberculosis program (NTP) budget allocation and tuberculosis related outcomes in the World Health Organization's 22 high burden countries from 2007–2009. Methods This ecological study used mixed effects and generalized estimating equation models to identify independent associations between NTP budget allocations and various tuberculosis related outcomes. Models were adjusted for a number of independent variables previously noted to be associated with tuberculosis incidence. Results Increasing the percent of the NTP budget for advocacy, communication and social mobilization was associated with an increase in the case detection rate. Increasing TB-HIV funding was associated with an increase in HIV testing among TB patients. Increasing the percent of the population covered by the Directly Observed Therapy (DOT) program was associated with an increase in drug susceptibility testing. Laboratory funding was positively associated with tuberculosis notification. Increasing the budgets for first line drugs, management and multi-drug resistant tuberculosis (MDR-TB) was associated with a decrease in smear positive deaths. Conclusion Effective TB control is a complex and multifaceted challenge. This study revealed a number of budget allocation related factors associated with improved TB outcome parameters. If confirmed with future longitudinal studies, these findings could help guide NTP managers with allocation decisions. PMID:23024825

The Granuloma in Tuberculosis: Dynamics of a Host–Pathogen Collusion

PubMed Central

Ehlers, Stefan; Schaible, Ulrich E.

2012-01-01

A granuloma is defined as an inflammatory mononuclear cell infiltrate that, while capable of limiting growth of Mycobacterium tuberculosis, also provides a survival niche from which the bacteria may disseminate. The tuberculosis lesion is highly dynamic and shaped by both, immune response elements and the pathogen. In the granuloma, M. tuberculosis switches to a non-replicating but energy-generating life style whose detailed molecular characterization can identify novel targets for chemotherapy. To secure transmission to a new host, M. tuberculosis has evolved to drive T cell immunity to the point that necrotizing granulomas leak into bronchial cavities to facilitate expectoration of bacilli. From an evolutionary perspective it is therefore questionable whether vaccination and immunity enhancing strategies that merely mimic the natural immune response directed against M. tuberculosis infection can overcome pulmonary tuberculosis in the adult population. Juxtaposition of molecular pathology and immunology with microbial physiology and the use of novel imaging approaches afford an integrative view of the granuloma’s contribution to the life cycle of M. tuberculosis. This review revisits the different input of innate and adaptive immunity in granuloma biogenesis, with a focus on the co-evolutionary forces that redirect immune responses also to the benefit of the pathogen, i.e., its survival, propagation, and transmission. PMID:23308075

Occupational Risk Factors for Tuberculosis Among Healthcare Workers in KwaZulu-Natal, South Africa

PubMed Central

Tudor, Carrie; Van der Walt, Martie L.; Margot, Bruce; Dorman, Susan E.; Pan, William K.; Yenokyan, Gayane; Farley, Jason E.

2016-01-01

Background. Tuberculosis is a known occupational hazard for healthcare workers (HCWs), especially in countries with a high burden of tuberculosis. It is estimated that HCWs have a 2- to 3-fold increased risk of developing tuberculosis compared with the general population. The objective of this study was to identify occupational risk factors for tuberculosis among HCWs in 3 district hospitals with specialized multidrug-resistant tuberculosis wards in KwaZulu-Natal, South Africa. Methods. We conducted a case-control study of HCWs diagnosed with tuberculosis between January 2006 and December 2010. Cases and controls were asked to complete a self-administered questionnaire regarding potential risk factors for tuberculosis. Results. Of 307 subjects selected, 145 (47%) HCWs responded to the questionnaire; 54 (37%) tuberculosis cases and 91 (63%) controls. Cases occurred more frequently among clinical staff 46% (n = 25) and support staff 35% (n = 19). Thirty-two (26% [32/125]) HCWs were known to be infected with human immunodeficiency virus (HIV), including 45% (21/54) of cases. HCWs living with HIV (odds ratio [OR], 6.35; 95% confidence interval [CI], 3.54–11.37) and those who spent time working in areas with patients (OR, 2.24; 95% CI, 1.40–3.59) had significantly greater odds of developing tuberculosis, controlling for occupation, number of wards worked in, and household crowding. Conclusions. HIV was the major independent risk factor for tuberculosis among HCWs in this sample. These findings support the need for HCWs to know their HIV status, and for HIV-infected HCWs to be offered antiretroviral therapy and isoniazid preventive therapy. Infection prevention and control should also be improved to prevent transmission of tuberculosis in healthcare settings to protect both HCWs and patients. PMID:27118855

Mycobacterium tuberculosis Complex and HIV Co-Infection among Extrapulmonary Tuberculosis Suspected Cases at the University of Gondar Hospital, Northwestern Ethiopia.

PubMed

Fanosie, Alemu; Gelaw, Baye; Tessema, Belay; Tesfay, Wogahta; Admasu, Aschalew; Yitayew, Gashaw

2016-01-01

Extrapulmonary Tuberculosis (EPTB) and Human Immunodeficiency Virus (HIV) infection are interrelated as a result of immune depression. The aim of this study was to determine the prevalence of Mycobacterium tuberculosis complex isolates and the burden of HIV co-infection among EPTB suspected patients. An institution based cross-sectional study was conducted among EPTB suspected patients at the University of Gondar Hospital. Socio-demographic characteristics and other clinical data were collected using a pretested questionnaire. GeneXpert MTB/RIF assay was performed to diagnosis Mycobacterium tuberculosis complex and Rifampicin resistance. All samples were also investigated by cytology and culture. The HIV statuses of all patients were screened initially by KHB, and all positive cases were further re-tested by STAT-pack. Data was analyzed using SPSS version 20 computer software and a P-value of < 0.05 was taken as statistically significant. A total of 141 extrapulmonary suspected patients were enrolled in this study. The overall prevalence of culture confirmed extrapulmonary tuberculosis infection was 29.8%, but the GeneXpert result showed a 26.2% prevalence of Mycobacterium tuberculosis complex infection. The 78.4% prevalence of extrapulmonary tuberculosis infection was found to be higher among the adult population. The prevalence of HIV infection among EPTB suspected patients was 14.1%, while it was 32.4% among GeneXpert-confirmed extrapulmonary TB cases (12/37). Tuberculosis lymphadenitis was the predominant (78.4%) type of EPTB infection followed by tuberculosis cold abscess (10.7%). Adult hood, previous history of contact with known pulmonary tuberculosis patients, and HIV co-infection showed a statistically significant association with extrapulmonary tuberculosis infection (P<0.013). The prevalence of culture confirmed-EPTB infection was high, and a higher EPTB-HIV co-infection was also observed.

Vitamin D, serum 25(OH)D, LL-37 and polymorphisms in a Canadian First Nation population with endemic tuberculosis

PubMed Central

Larcombe, Linda; Mookherjee, Neeloffer; Slater, Joyce; Slivinski, Caroline; Dantouze, Joe; Singer, Matthew; Whaley, Chris; Denechezhe, Lizette; Matyas, Sara; Decter, Kate; Turner-Brannen, Emily; Ramsey, Clare; Nickerson, Peter; Orr, Pamela

2015-01-01

Background Canadian First Nation populations have experienced endemic and epidemic tuberculosis (TB) for decades. Vitamin D–mediated induction of the host defence peptide LL-37 is known to enhance control of pathogens such as Mycobacterium tuberculosis. Objective Evaluate associations between serum levels of 25-hydroxy vitamin D (25(OH)D) and LL-37, in adult Dene First Nation participants (N = 34) and assess correlations with single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP). Design Venous blood was collected from all participants at baseline (winter and summer) and in conjunction with taking vitamin D supplements (1,000 IU/day) (winter and summer). Samples were analysed using ELISA for concentrations of vitamin D and LL-37, and SNPs in the VDR and VDBP regions were genotyped. Results Circulating levels of 25(OH)D were not altered by vitamin D supplementation, but LL-37 levels were significantly decreased. VDBP and VDR SNPs did not correlate with serum concentrations of 25(OH)D, but LL-37 levels significantly decreased in individuals with VDBP D432E T/G and T/T, and with VDR SNP Bsm1 T/T genotypes. Conclusions Our findings suggest that vitamin D supplementation may not be beneficial as an intervention to boost innate immune resistance to M. tuberculosis in the Dene population. PMID:26294193

Tuberculosis testing among populations with high HIV risk in Tijuana, Baja California, Mexico

PubMed Central

Velasquez, Michele G.; Laniado-Laborin, Rafael; Rodwell, Timothy C.; Cerecer, Paris; Lozada, Remedios; Cuevas-Mota, Jazmine; Burgos, Jose Luis; Garfein, Richard S.

2013-01-01

Objective To assess the prevalence of prior tuberculin skin testing (TST) among populations at risk for HIV infection in Tijuana, Mexico, and to identify factors associated with TST. Methods Sex workers, injection drug users, noninjecting drug users, and homeless persons ≥ 18 years old were recruited by using targeted sampling for risk assessment interviews and serologic testing for HIV and Mycobacterium tuberculosis infection. Univariate and multivariate logistic regression were used to identify correlates of self-reported TST history. Results Of 502 participants, 38.0% reported prior TST, which was associated with previous incarceration in the United States of America [odds ratio (OR) = 13.38; 95% confidence interval (CI) = 7.37–24.33] and injection drug use (OR = 1.99; 95% CI = 1.27–3.11). Positive results on serologic tests for M. tuberculosis infection (57%) and HIV (4.2%) were not associated with a prior TST. Conclusions A history of TST was lower in HIV-positive participants even though TST is indicated for persons with HIV in Mexico. Fewer than half the individuals at high risk for HIV in this study had a history of TST; however, TST was fairly common among those individuals with a prior history of incarceration. Increased tuberculosis screening is needed for populations at risk of contracting HIV in Tijuana, particularly those outside of criminal justice settings. PMID:22910722

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

PubMed Central

Kurtz, Sherry L.

2015-01-01

A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses. PMID:26269537

Tuberculosis Screening on a Health Science Campus: Use of QuantiFERON-TB Gold Test for Students and Employees

ERIC Educational Resources Information Center

Veeser, Peggy Ingram; Smith, Phillip Karl; Handy, Barry; Martin, Sharon R.

2007-01-01

Detecting and managing "Mycobacterium tuberculosis" (TB) infection in a health-science center population is a clinical dilemma. Tuberculin skin tests are still the preferred method for detecting present or past infection of TB. The authors discuss the performance of whole blood interferon gamma release assay test commercially known as…

Fragment-Based Drug Discovery in Academia: Experiences From a Tuberculosis Programme

NASA Astrophysics Data System (ADS)

Heikkila, Timo J.; Surade, Sachin; Silvestre, Hernani L.; Dias, Marcio V. B.; Ciulli, Alessio; Bromfield, Karen; Scott, Duncan; Howard, Nigel; Wen, Shijun; Wei, Alvin Hung; Osborne, David; Abell, Chris; Blundell, Tom L.

The problems associated with neglected diseases are often compounded by increasing incidence of antibiotic resistance. Patient negligence and abuse of antibiotics has lead to explosive growth in cases of tuberculosis, with some M. tuberculosis strains becoming virtually untreatable. Structure-based drug development is viewed as cost-effective and time-consuming method for discovery and development of hits to lead compounds. In this review we will discuss the suitability of fragment-based methods for developing new chemotherapeutics against neglected diseases, providing examples from our tuberculosis programme.

A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis.

PubMed

Fakhar, Zeynab; Naiker, Suhashni; Alves, Claudio N; Govender, Thavendran; Maguire, Glenn E M; Lameira, Jeronimo; Lamichhane, Gyanu; Kruger, Hendrik G; Honarparvar, Bahareh

2016-11-01

An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

PubMed Central

Myers, Amy J.; Jarvela, Jessica; Flynn, JoAnne; Rutledge, Tara; Bonfield, Tracey

2016-01-01

Immune cells of the distal airways serve as “first responders” of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD4+cells but more CD8+ and CD4+CD8+ double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease). Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung. PMID:27509488

Risk factors for pulmonary tuberculosis in Estonia.

PubMed

Tekkel, M; Rahu, M; Loit, H M; Baburin, A

2002-10-01

To determine the risk factors for pulmonary tuberculosis incidence in Estonia. In a case-control study, the cases were 248 adult tuberculosis patients treated in a hospital in Tallinn between January 1999 and June 2000, and the controls were 248 persons sampled from the Population Registry and matched to cases by sex, year of birth and county of residence. A questionnaire was administered to collect information on potential risk factors. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The main risk factors for tuberculosis were marital status other than married, educational level less than higher, low income, having been in prison, not having own place of residence, current unemployment, current smoking, alcohol consumption, shortage of food, and contact with tuberculosis patients. Place of birth was not a risk factor. Risk of tuberculosis decreased for overweight persons whose individual economic situation had improved during the last year. The pattern of risk factors for pulmonary tuberculosis in Estonia was somewhat different from that in Western European countries; a large percentage of the patients were men, but were not elderly, and immigration and drug abuse did not increase the risk. Major risk factors were related to poverty and low socio-economic status.

Modeling socio-demography to capture tuberculosis transmission dynamics in a low burden setting

PubMed Central

Ajelli, Marco; Yang, Zhenhua; Merler, Stefano; Furlanello, Cesare; Kirschner, Denise

2011-01-01

Evidence of preferential mixing through selected social routes has been suggested for the transmission of tuberculosis (TB) infection in low burden settings. A realistic modelization of these contact routes is needed to appropriately assess the impact of individually targeted control strategies, such as contact network investigation of index cases and treatment of latent TB infection (LTBI). We propose an age-structured, socio-demographic individual based model (IBM) with a realistic, time-evolving structure of preferential contacts in a population. In particular, transmission within households, schools and work-places, together with a component of casual, distance-dependent contacts are considered. We also compared the model against two other formulations having no social structure of contacts (homogeneous mixing transmission): a baseline deterministic model without age structure and an age-structured IBM. The socio-demographic IBM better fitted recent longitudinal data on TB epidemiology in Arkansas, USA, which serves as an example of a low burden setting. Inclusion of age structure in the model proved fundamental to capturing actual proportions of reactivated TB cases (as opposed to recently transmitted) as well as profiling age-group specific incidence. The socio-demographic structure additionally provides a prediction of TB transmission rates (the rate of infection in household contacts and the rate of secondary cases in household and workplace contacts). These results suggest that the socio-demographic IBM is an optimal choice for evaluating current control strategies, including contact network investigation of index cases, and the simulation of alternative scenarios, particularly for TB eradication targets. PMID:21906603

Latent tuberculosis infections in hard-to-reach drug using population-detection, prevention and control.

PubMed

Hwang, Lu-Yu; Grimes, Carolyn Z; Beasley, R Palmer; Graviss, Edward A

2009-12-01

Interferon-gamma release assays (IGRAs) need be evaluated for effectiveness as screening tests for tuberculosis (TB) infection in drug users. These tests have demonstrated improved sensitivity and specificity, but have not been studied in drug users. These one step blood tests are intended to replace the tuberculin skin test (TST), which is difficult to use and requires 48 hour follow-up, so they are expected to be particularly suitable for risk groups, like drug users, in whom follow-up is problematic. Drug users have traditionally been identified as being at increased risk for acquiring TB disease. The results of our pilot study using the TST and simpler and more sensitive interferon-gamma release assays showed that about 45% of current drug users in Houston tested have at least one test positive for latent tuberculosis infection (LTBI). These preliminary data suggest that there is an important reservoir of LTBI in drug using populations, and the risk of progression to active TB disease with other infections is great. However, LTBI in drug using populations has not been studied in depth and deserves further investigation. We need to evaluate the validity of IGRAs for detection of latent TB infection, the factors associated with LTBI, the incidence and risk for developing active TB disease in drug users and the effectiveness of early treatment of LTBI. We believe that using better tuberculosis screening tools will allow us to more accurately measure the prevalence of latent TB infection and incidence of active TB disease in drug using populations and develop more effective TB prevention and treatment interventions in the community.

Strains of Mycobacterium tuberculosis transmitting infection in Brazilian households and those associated with community transmission of tuberculosis.

PubMed

Vinhas, Solange Alves; Jones-López, Edward C; Ribeiro Rodrigues, Rodrigo; Gaeddert, Mary; Peres, Renata Lyrio; Marques-Rodrigues, Patricia; de Aguiar, Paola Poloni Lobo; White, Laura Forsberg; Alland, David; Salgame, Padmini; Hom, David; Ellner, Jerrold J; Dietze, Reynaldo; Collins, Lauren F; Shashkina, Elena; Kreiswirth, Barry; Palaci, Moisés

2017-05-01

Molecular epidemiologic studies have shown that the dynamics of tuberculosis transmission varies geographically. We sought to determine which strains of Mycobacterium tuberculosis (MTB) were infecting household contacts (HHC), and which were causing clusters of tuberculosis (TB) disease in Vitoria-ES, Brazil. A total of 741 households contacts (445 TST +) and 139 index cases were characterized according to the proportion of contacts in each household that had a tuberculin skin test positive: low (LT) (≤40% TST+), high (HT) (≥70% TST+) and (40-70% TST+) intermediate (IT) transmission. IS6110-RFLP and spoligotyping analysis were performed only 139 MTB isolates from index cases and 841 community isolates. Clustering occurred in 45% of the entire study population. There was no statistically significant association between MTB household transmission category and clustering. Within the household study population, the proportion of clusters in HT and LT groups was similar (31% and 36%, respectively; p = 0.82). Among index cases isolates associated with households demonstrating TST conversion, the frequency of unique pattern genotypes was higher for index cases of the LT compared to HT households (p = 0.03). We concluded that clusters and lineages associated with MTB infection in HT households had no proclivity for increased transmission of TB in the community. Copyright © 2017 Elsevier Ltd. All rights reserved.

Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism

PubMed Central

Adams, Kristin N.; Takaki, Kevin; Connolly, Lynn E.; Wiedenhoft, Heather; Winglee, Kathryn; Humbert, Olivier; Edelstein, Paul H.; Cosma, Christine L.; Ramakrishnan, Lalita

2011-01-01

SUMMARY Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multi-drug tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This newly discovered tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug, or more specific inhibitors, to standard antitubercular therapy may shorten the duration of curative treatment. PMID:21376383

Infection of the Invisible: Impressions of a Tuberculosis Intervention Program for Migrants in Istanbul.

PubMed

Yasin, Yesim; Biehl, Kristen; Erol, Maral

2015-10-01

This paper reviews the experience of the Istanbul Tuberculosis Aid Program, which targeted tuberculosis (TB) disease in the growing irregular migrant populations of Istanbul. This experience illustrated the importance of community-based public health interventions when dealing with an infectious disease like TB among vulnerable groups. Our data is derived primarily from a qualitative study carried out with program stakeholders. We summarize lessons for success of ITAP as: (1) Strengthening impact and outreach of TB intervention among irregular migrant communities through involvement of multiple stakeholders (2) Increasing TB awareness through a community targeted approach (3) Increasing TB contact tracing and treatment success among infected irregular migrants, and, (4) Improving overall health seeking behavior of irregular migrants through empowerment and trust. Given these particularities we list our policy suggestions for revision of regulations regarding TB control and healthcare needs of irregular migrant populations.

1.55 Å resolution X-ray crystal structure of Rv3902c from Mycobacterium tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reddy, Bharat G.; Moates, Derek B.; Kim, Heung-Bok

The 1.55 Å resolution X-ray crystal structure of Rv3902c from M. tuberculosis reveals a novel fold. The crystallographic structure of the Mycobacterium tuberculosis (TB) protein Rv3902c (176 residues; molecular mass of 19.8 kDa) was determined at 1.55 Å resolution. The function of Rv3902c is unknown, although several TB genes involved in bacterial pathogenesis are expressed from the operon containing the Rv3902c gene. The unique structural fold of Rv3902c contains two domains, each consisting of antiparallel β-sheets and α-helices, creating a hand-like binding motif with a small binding pocket in the palm. Structural homology searches reveal that Rv3902c has an overallmore » structure similar to that of the Salmonella virulence-factor chaperone InvB, with an r.m.s.d. for main-chain atoms of 2.3 Å along an aligned domain.« less

Inbreeding depression increases susceptibility to bovine tuberculosis in lions: an experimental test using an inbred-outbred contrast through translocation.

PubMed

Trinkel, Martina; Cooper, Dave; Packer, Craig; Slotow, Rob

2011-07-01

Disease can dramatically influence the dynamics of endangered wildlife populations, especially when they are small and isolated, with increased risk of inbreeding. In Hluhluwe-iMfolozi Park (HiP), a small, enclosed reserve in South Africa, a large lion (Panthera leo) population arose from a small founder group in the 1960s and started showing conspicuous signs of inbreeding. To restore the health status of the HiP lion population, outbred lions were translocated into the existing population. In this study, we determined the susceptibility to bovine tuberculosis (bTB), and the prevalence of antibody to feline viruses of native lions, and compared the findings with those from translocated outbred lions and their offspring. Antibodies to feline herpesvirus, feline calicivirus, feline parvovirus, and feline coronavirus were present in the lion population, but there was no significant difference in antibody prevalence between native and translocated lions and their offspring, and these feline viruses did not appear to have an effect on the clinical health of HiP lions. However, feline immunodeficiency virus (FIV), which was previously absent from HiP, appears to have been introduced into the lion population through translocation. Within 7 yr, the prevalence of antibody to FIV increased up to 42%. Bovine tuberculosis posed a major threat to the inbred native lion population, but not to translocated lions and their offspring. More than 30% of the native lion population died from bTB or malnutrition compared with <2% of the translocated lions and their offspring. We have demonstrated that management of population genetics through supplementation can successfully combat a disease that threatens population persistence. However, great care must be taken not to introduce new diseases into populations through translocation.

Spatial patterns of multidrug resistant tuberculosis and relationships to socio-economic, demographic and household factors in northwest Ethiopia.

PubMed

Alene, Kefyalew Addis; Viney, Kerri; McBryde, Emma S; Clements, Archie C A

2017-01-01

Understanding the geographical distribution of multidrug-resistant tuberculosis (MDR-TB) in high TB burden countries such as Ethiopia is crucial for effective control of TB epidemics in these countries, and thus globally. We present the first spatial analysis of multidrug resistant tuberculosis, and its relationship to socio-economic, demographic and household factors in northwest Ethiopia. An ecological study was conducted using data on patients diagnosed with MDR-TB at the University of Gondar Hospital MDR-TB treatment centre, for the period 2010 to 2015. District level population data were extracted from the Ethiopia National and Regional Census Report. Spatial autocorrelation was explored using Moran's I statistic, Local Indicators of Spatial Association (LISA), and the Getis-Ord statistics. A multivariate Poisson regression model was developed with a conditional autoregressive (CAR) prior structure, and with posterior parameters estimated using a Bayesian Markov chain Monte Carlo (MCMC) simulation approach with Gibbs sampling, in WinBUGS. A total of 264 MDR-TB patients were included in the analysis. The overall crude incidence rate of MDR-TB for the six-year period was 3.0 cases per 100,000 population. The highest incidence rate was observed in Metema (21 cases per 100,000 population) and Humera (18 cases per 100,000 population) districts; whereas nine districts had zero cases. Spatial clustering of MDR-TB was observed in districts located in the Ethiopia-Sudan and Ethiopia-Eritrea border regions, where large numbers of seasonal migrants live. Spatial clustering of MDR-TB was positively associated with urbanization (RR: 1.02; 95%CI: 1.01, 1.04) and the percentage of men (RR: 1.58; 95% CI: 1.26, 1.99) in the districts; after accounting for these factors there was no residual spatial clustering. Spatial clustering of MDR-TB, fully explained by demographic factors (urbanization and percent male), was detected in the border regions of northwest Ethiopia, in locations where seasonal migrants live and work. Cross-border initiatives including options for mobile TB treatment and follow up are important for the effective control of MDR-TB in the region.

IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

PubMed Central

Marín, Nancy D.; Marín, Diana M.; López, Lucelly; Henao, Hanna M.; Martínez, Teresita; Villa, Liliana; Barrera, Luis F.; Ortiz, Blanca L.; Ramírez, María E.; Montes, Carlos J.; Oquendo, María C.; Arango, Lisandra M.; Riaño, Felipe; Aguirre, Carlos; Bustamante, Alberto; Belisle, John T.; Dobos, Karen; Mejía, Gloria I.; Giraldo, Margarita R.; Brennan, Patrick J.; Robledo, Jaime; Arbeláez, María P.; Rojas, Carlos A.; García, Luis F.

2009-01-01

Objectives Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNγ produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNγ levels in HHCs correlate with tuberculosis development. Methods A cohort of 2060 HHCs was followed for 2–3 years after exposure to a tuberculosis case. Besides TST, IFNγ responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. Results Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNγ response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNγ responders to CFP-10 (HR 1.82 95% CI 0.79–4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNγ producers was observed (trend Log rank p = 0.007). Discussion CFP-10-induced IFNγ production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprohylaxis to child contacts regardless of BCG vaccination. PMID:20011589

Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells.

PubMed

Sakai, Shunsuke; Kauffman, Keith D; Schenkel, Jason M; McBerry, Cortez C; Mayer-Barber, Katrin D; Masopust, David; Barber, Daniel L

2014-04-01

Th1 cells are critical for containment of Mycobacterium tuberculosis infection, but little else is known about the properties of protective CD4 T cell responses. In this study, we show that the pulmonary Th1 response against M. tuberculosis is composed of two populations that are either CXCR3(hi) and localize to lung parenchyma or are CX3CR1(hi)KLRG1(hi) and are retained within lung blood vasculature. M. tuberculosis-specific parenchymal CD4 T cells migrate rapidly back into the lung parenchyma upon adoptive transfer, whereas the intravascular effectors produce the highest levels of IFN-γ in vivo. Importantly, parenchymal T cells displayed greater control of infection compared with the intravascular counterparts upon transfer into susceptible T cell-deficient hosts. Thus, we identified a subset of naturally generated M. tuberculosis-specific CD4 T cells with enhanced protective capacity and showed that control of M. tuberculosis correlates with the ability of CD4 T cells to efficiently enter the lung parenchyma rather than produce high levels of IFN-γ.

Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection.

PubMed Central

Segueni, Noria; Benmerzoug, Sulayman; Rose, Stéphanie; Gauthier, Amandine; Bourigault, Marie-Laure; Reverchon, Flora; Philippeau, Amandine; Erard, François; Le Bert, Marc; Bouscayrol, Hélène; Wachter, Thierry; Garcia, Irène; Kollias, George; Jacobs, Muazzam; Ryffel, Bernhard; Quesniaux, Valerie F.J.

2016-01-01

TNF is crucial for controlling Mycobacterium tuberculosis infection and understanding how will help immunomodulating the host response. Here we assessed the contribution of TNFR1 pathway from innate myeloid versus T cells. We first established the prominent role of TNFR1 in haematopoietic cells for controlling M. tuberculosis in TNFR1 KO chimera mice. Further, absence of TNFR1 specifically on myeloid cells (M-TNFR1 KO) recapitulated the uncontrolled M. tuberculosis infection seen in fully TNFR1 deficient mice, with increased bacterial burden, exacerbated lung inflammation, and rapid death. Pulmonary IL-12p40 over-expression was attributed to a prominent CD11b+ Gr1high cell population in infected M-TNFR1 KO mice. By contrast, absence of TNFR1 on T-cells did not compromise the control of M. tuberculosis infection over 6-months. Thus, the protective TNF/TNFR1 pathway essential for controlling primary M. tuberculosis infection depends on innate macrophage and neutrophil myeloid cells, while TNFR1 pathway in T cells is dispensable. PMID:26931771

Capturing CD4 cells using a functionalized circular microfluidic device and glutaraldehyde as biolinker for tuberculosis detection and diagnosis

NASA Astrophysics Data System (ADS)

Shih, Yeu-Farn; Huang, Nien-Tsu; Lee, Chih-Kung

2015-03-01

It is estimated that about one-third of the world's population has already been infected by tuberculosis. Mycobacterium tuberculosis, in general, can result in an active case of tuberculosis in approximately 5%-10% of those who suffer from latent tuberculosis and the chance of becoming ill is the highest within one of year of getting the disease. Although a newly developed methods called interferon gamma release assay (IGRA) can monitor CD4 cells secreted cytokine to diagnose tuberculosis (TB) condition. However, it is difficult to count total numbers of cytokine secreted CD4 cells, which make the diagnosis less accurate. Therefore, we develop a functionalized polydimethylsiloxane (PDMS) device using glutaraldehyde to capture CD4 cells. To enhance the capture efficiency, we use COMSOL simulation to optimize the arrangement of PDMS micro pillars to make cells uniformly distributed in the device. Our preliminary data showed the microfluidic configuration in a circular shape with HCP patterned micro pillars turned 30 degrees offers the highest cell capture rate.

Tuberculosis incidence in prisons: a systematic review.

PubMed

Baussano, Iacopo; Williams, Brian G; Nunn, Paul; Beggiato, Marta; Fedeli, Ugo; Scano, Fabio

2010-12-21

Transmission of tuberculosis (TB) in prisons has been reported worldwide to be much higher than that reported for the corresponding general population. A systematic review has been performed to assess the risk of incident latent tuberculosis infection (LTBI) and TB disease in prisons, as compared to the incidence in the corresponding local general population, and to estimate the fraction of TB in the general population attributable (PAF%) to transmission within prisons. Primary peer-reviewed studies have been searched to assess the incidence of LTBI and/or TB within prisons published until June 2010; both inmates and prison staff were considered. Studies, which were independently screened by two reviewers, were eligible for inclusion if they reported the incidence of LTBI and TB disease in prisons. Available data were collected from 23 studies out of 582 potentially relevant unique citations. Five studies from the US and one from Brazil were available to assess the incidence of LTBI in prisons, while 19 studies were available to assess the incidence of TB. The median estimated annual incidence rate ratio (IRR) for LTBI and TB were 26.4 (interquartile range [IQR]: 13.0-61.8) and 23.0 (IQR: 11.7-36.1), respectively. The median estimated fraction (PAF%) of tuberculosis in the general population attributable to the exposure in prisons for TB was 8.5% (IQR: 1.9%-17.9%) and 6.3% (IQR: 2.7%-17.2%) in high- and middle/low-income countries, respectively. The very high IRR and the substantial population attributable fraction show that much better TB control in prisons could potentially protect prisoners and staff from within-prison spread of TB and would significantly reduce the national burden of TB. Future studies should measure the impact of the conditions in prisons on TB transmission and assess the population attributable risk of prison-to-community spread. Please see later in the article for the Editors' Summary.

Uncovering the hidden: complexity and strategies for diagnosing latent tuberculosis.

PubMed

Flores-Valdez, Mario Alberto

2017-10-24

Tuberculosis produces two clinical manifestations: active and latent (non-apparent) disease. The latter is estimated to affect one-third of the world population and constitutes a source of continued transmission should the disease emerge from its hidden state (reactivation). Methods to diagnose latent TB have been evolving and aim to detect the disease in people who are truly infected with M. tuberculosis , versus those where other mycobacteria, or even other pathologies not related to TB, are present. The current use of proteomic and transcriptomic approaches may lead to improved detection methods in the coming years.

Occurrence and Nature of Double Alleles in Variable-Number Tandem-Repeat Patterns of More than 8,000 Mycobacterium tuberculosis Complex Isolates in The Netherlands

PubMed Central

Kamst, Miranda; van Hunen, Rianne; de Zwaan, Carolina Catherina; Mulder, Arnout; Supply, Philip; Anthony, Richard; van der Hoek, Wim; van Soolingen, Dick

2017-01-01

ABSTRACT Since 2004, variable-number tandem-repeat (VNTR) typing of Mycobacterium tuberculosis complex isolates has been applied on a structural basis in The Netherlands to study the epidemiology of tuberculosis (TB). Although this technique is faster and technically less demanding than the previously used restriction fragment length polymorphism (RFLP) typing, reproducibility remains a concern. In the period from 2004 to 2015, 8,532 isolates were subjected to VNTR typing in The Netherlands, with 186 (2.2%) of these exhibiting double alleles at one locus. Double alleles were most common in loci 4052 and 2163b. The variables significantly associated with double alleles were urban living (odds ratio [OR], 1.503; 95% confidence interval [CI], 1.084 to 2.084; P = 0.014) and pulmonary TB (OR, 1.703; 95% CI, 1.216 to 2.386; P = 0.002). Single-colony cultures of double-allele strains were produced and revealed single-allele profiles; a maximum of five single nucleotide polymorphisms (SNPs) was observed between the single- and double-allele isolates from the same patient when whole-genome sequencing (WGS) was applied. This indicates the presence of two bacterial populations with slightly different VNTR profiles in the parental population, related to genetic drift. This observation is confirmed by the fact that secondary cases from TB source cases with double-allele isolates sometimes display only one of the two alleles present in the source case. Double alleles occur at a frequency of 2.2% in VNTR patterns in The Netherlands. They are caused by biological variation rather than by technical aberrations and can be transmitted either as single- or double-allele variants. PMID:29142049

BURDEN OF TUBERCULOSIS AMONG STUDENTS IN TWO ETHIOPIAN UNIVERSITIES

PubMed Central

Mekonnen, Abiyu; Petros, Beyene

2017-01-01

Introduction Tuberculosis outbreaks emerge occasionally in long-term care facilities and various educational establishments. This study was designed to determine the five year overall prevalence and trend of tuberculosis and associated factors among students at Adama Science and Technology University and Addis Ababa University Sidist Kilo campus. Methods A five-year retrospective study was conducted on students medical records of tuberculosis Directly Observed Treatment Short Course clinics from September 2009 – July 2014. The overall prevalence and the trend of smear positive, smear negative and extra pulmonary tuberculosis cases was determined. Odds ratio with 95 percent confidence interval was calculated for categorical variables using a multivariate logistic regression model to assess the strength of association. Results A total of 112 and 263 tuberculos cases were recorded in Addis Ababa University Sidist Kilo campus and Adama Science and Technology University, respectively. The mean proportion of tuberculosis cases of all types among the total number of students enrolled at Adama Science and Technology University and Addis Ababa University Sidist Kilo campus was 1098.1 and 511.7 cases per 100,000 population, respectively. There was a statistically significant difference in prevalence of tuberculosis among students in Adama Science and Technology University compared to that in Addis Ababa University Sidist Kilo campus [adjusted odds ration: 2.881, 95% CI (1.76–4.71)]. The trend of tuberculosis prevalence showed a steady decline from the first to the last year of the study period. Conclusion The number of tuberculosis cases observed among university students in this study was high. Governmental and nongovernmental agencies involved in tuberculosis control must consider higher education institutions as focal points for prevention and elimination of tuberculosis in Ethiopia. PMID:29115116

Depression comorbid with tuberculosis and its impact on health status: cross-sectional analysis of community-based data from 48 low- and middle-income countries.

PubMed

Koyanagi, Ai; Vancampfort, Davy; Carvalho, André F; DeVylder, Jordan E; Haro, Josep Maria; Pizzol, Damiano; Veronese, Nicola; Stubbs, Brendon

2017-11-28

Depression in tuberculosis increases the risk for adverse health outcomes. However, little is known about comorbid depression and tuberculosis in the general population. Thus, we assessed the association between depression and tuberculosis, and the decrements in health status associated with this comorbidity in 48 low- and middle-income countries. Cross-sectional, community-based data from the World Health Survey on 242,952 individuals aged ≥ 18 years were analyzed. Based on the World Mental Health Survey version of the Composite International Diagnostic Interview, past 12-month depression was categorized into depressive episode, brief depressive episode, subsyndromal depression, and no depression. Health status across six domains (cognition, interpersonal activities, sleep/energy, self-care, mobility, pain/discomfort) was assessed. Multivariable logistic and linear regression analyses were performed to assess the associations. The prevalence of depressive episode among those with and without tuberculosis was 23.7% and 6.8%, respectively (P < 0.001). Tuberculosis was associated with a 1.98 (95% CI 1.47-2.67), 1.75 (95% CI 1.26-2.42), and 3.68 (95% CI 3.01-4.50) times higher odds for subsyndromal depression, brief depressive episode, and depressive episode, respectively. Depressive episode co-occurring with tuberculosis was associated with significantly worse health status across all six domains compared to tuberculosis alone. Interaction analysis showed that depression significantly amplifies the association between TB and difficulties in self-care but not in other health domains. Depression is highly prevalent in adults with tuberculosis, and is associated with worse health status compared to tuberculosis without depression. Public health efforts directed to the recognition and management of depression in people with tuberculosis may lead to better outcomes.

BURDEN OF TUBERCULOSIS AMONG STUDENTS IN TWO ETHIOPIAN UNIVERSITIES.

PubMed

Mekonnen, Abiyu; Petros, Beyene

2016-10-01

Tuberculosis outbreaks emerge occasionally in long-term care facilities and various educational establishments. This study was designed to determine the five year overall prevalence and trend of tuberculosis and associated factors among students at Adama Science and Technology University and Addis Ababa University Sidist Kilo campus. A five-year retrospective study was conducted on students’ medical records of tuberculosis Directly Observed Treatment Short Course clinics from September 2009– July 2014. The overall prevalence and the trend of smear positive, smear negative and extra pulmonary tuberculosis cases was determined. Odds ratio with 95 percent confidence interval was calculated for categorical variables using a multivariate logistic regression model to assess the strength of association. A total of 112 and 263 tuberculos cases were recorded in Addis Ababa University Sidist Kilo campus and Adama Science and Technology University, respectively. The mean proportion of tuberculosis cases of all types among the total number of students enrolled at Adama Science and Technology University and Addis Ababa University Sidist Kilo campus was 1098.1 and 511.7 cases per 100,000 population, respectively. There was a statistically significant difference in prevalence of tuberculosis among students in Adama Science and Technology University compared to that in Addis Ababa University Sidist Kilo campus [adjusted odds ration: 2.881, 95% CI (1.76-4.71)]. The trend of tuberculosis prevalence showed a steady decline from the first to the last year of the study period. The number of tuberculosis cases observed among university students in this study was high. Governmental and nongovernmental agencies involved in tuberculosis control must consider higher education institutions as focal points for prevention and elimination of tuberculosis in Ethiopia.

Alternation of Gut Microbiota in Patients with Pulmonary Tuberculosis.

PubMed

Luo, Mei; Liu, Yong; Wu, Pengfei; Luo, Dong-Xia; Sun, Qun; Zheng, Han; Hu, Richard; Pandol, Stephen J; Li, Qing-Feng; Han, Yuan-Ping; Zeng, Yilan

2017-01-01

One-third of the world's population has been infected with Mycobacterium tuberculosis ( M. tuberculosis ), a primary pathogen of the mammalian respiratory system, while about 10% of latent infections progress to active tuberculosis (TB), indicating that host and environmental factors may determine the outcomes such as infection clearance/persistence and treatment prognosis. The gut microbiota is essential for development of host immunity, defense, nutrition and metabolic homeostasis. Thus, the pattern of gut microbiota may contribute to M. tuberculosis infection and prognosis. In current study we characterized the differences in gut bacterial communities in new tuberculosis patients (NTB), recurrent tuberculosis patients (RTB), and healthy control. The abundance-based coverage estimator (ACE) showed the diversity index of the gut microbiota in the patients with recurrent tuberculosis was increased significantly compared with healthy controls ( p < 0.05). At the phyla level, Actinobacteria and Proteobacteria, which contain many pathogenic species, were significantly enriched in the feces RTB patients. Conversely, phylum Bacteroidetes, containing a variety of beneficial commensal organisms, was reduced in the patients with the recurrent tuberculosis compared to healthy controls. The Gram-negative genus Prevotella of oral origin from phylum of Bacteroidetes and genus Lachnospira from phylum of Firmicutes were significantly decreased in both the new and recurrent TB patient groups, compared with the healthy control group ( p < 0.05). We also found that there was a positive correlation between the gut microbiota and peripheral CD4+ T cell counts in the patients. This study, for the first time, showed associations between gut microbiota with tuberculosis and its clinical outcomes. Maintaining eubiosis, namely homeostasis of gut microbiota, may be beneficial for host recovery and prevention of recurrence of M. tuberculosis infection.

Study of Mycobacterium tuberculosis drug resistance in the region of Galicia, Spain.

PubMed

Pérez del Molino Bernal, M L; Túñez, V; Cruz-Ferro, E; Fernández-Villar, A; Vázquez-Gallardo, R; Díaz-Cabanela, D; Anibarro, L

2005-11-01

Galicia, a region in north-east Spain with its own government and health system and a population of 2 695 880. To study the epidemiology of resistant tuberculosis (TB). A prospective, descriptive, and observational study of all Mycobacterium tuberculosis isolates processed by each of the laboratories in Galicia that perform mycobacterial cultures. The study followed the methodology recommended by the World Health Organization and the International Union Against Tuberculosis and Lung Disease, and included isolates processed between 1 November 2001 and 1 June 2002. Of 400 strains analysed, 360 corresponded to previously untreated cases and 40 to previously treated cases. Of the previously untreated cases, 88.3% contained strains susceptible to isoniazid, rifampicin, streptomycin and ethambutol, while 4.4% were resistant to isoniazid. The rate of susceptibility to the four drugs was 77.5% in the previously treated cases. Multidrug-resistant TB was detected in 1.4% of the previously untreated cases and in 7.5% of the previously treated cases. Although Galicia has a high incidence of TB (49.4 cases per 100 000 population in 2001), the resistance levels detected by the study do not currently pose a serious problem for the region.

Ethical Responsibility for the Social Production of Tuberculosis.

PubMed

Yamada, Seiji; Riklon, Sheldon; Maskarinec, Gregory G

2016-03-01

Approximately one in two hundred persons in the Marshall Islands have active tuberculosis (TB). We examine the historical antecedents of this situation in order to assign ethical responsibility for the present situation. Examining the antecedents in terms of Galtung's dialectic of personal versus structural violence, we can identify instances in the history of the Marshall Islands when individual subjects made decisions (personal violence) with large-scale ecologic, social, and health consequences. The roles of medical experimenters, military commanders, captains of the weapons industry in particular, and industrial capitalism in general (as the cause of global warming) are examined. In that, together with Lewontin, we also identify industrial capitalism as the cause of tuberculosis, we note that the distinction between personal versus structural violence is difficult to maintain. By identifying the cause of the tuberculosis in the Marshall Islands, we also identify what needs be done to treat and prevent it.

Tuberculosis and HIV at the national level in Kenya: results from the Second Kenya AIDS Indicator Survey.

PubMed

Mbithi, Agneta; Gichangi, Anthony; Kim, Andrea A; Katana, Abraham; Weyenga, Herman; Williamson, John; Robinson, Katherine; Oluoch, Tom; Maina, William K; Kellogg, Timothy A; De Cock, Kevin M

2014-05-01

Co-morbidity with tuberculosis and HIV is a common cause of mortality in sub-Saharan Africa. In the second Kenya AIDS Indicator Survey, we collected data on knowledge and experience of HIV and tuberculosis, as well as on access to and coverage of relevant treatment services and antiretroviral therapy (ART) in Kenya. A national, population-based household survey was conducted from October 2012 to February 2013. Information was collected through household questionnaires, and blood samples were taken for HIV, CD4 cell counts, and HIV viral load testing at a central laboratory. Overall, 13,720 persons aged 15-64 years participated; 96.7% [95% confidence interval (CI): 96.3 to 97.1] had heard of tuberculosis, of whom 2.0% (95% CI: 1.7 to 2.2) reported having prior tuberculosis. Among those with laboratory-confirmed HIV infection, 11.6% (95% CI: 8.9 to 14.3) reported prior tuberculosis. The prevalence of laboratory-confirmed HIV infection in persons reporting prior tuberculosis was 33.2% (95% CI: 26.2 to 40.2) compared to 5.1% (95% CI: 4.5 to 5.8) in persons without prior tuberculosis. Among those in care, coverage of ART for treatment-eligible persons was 100% for those with prior tuberculosis and 88.6% (95% CI: 81.6 to 95.7) for those without. Among all HIV-infected persons, ART coverage among treatment-eligible persons was 86.9% (95% CI: 74.2 to 99.5) for persons with prior tuberculosis and 58.3% (95% CI: 47.6 to 69.0) for those without. Morbidity from tuberculosis and HIV remain major health challenges in Kenya. Tuberculosis is an important entry point for HIV diagnosis and treatment. Lack of knowledge of HIV serostatus is an obstacle to access to HIV services and timely ART for prevention of HIV transmission and HIV-associated disease, including tuberculosis.

Lupus vulgaris and tuberculosis verrucosa cutis (TBVC)--a clinical, pathological and epidemiological study of 71 cases.

PubMed

Padmavathy, L; Lakshmana Rao, L; Pari, T; Ethirajan, N; Krishnaswamy, B

2008-10-01

The epidemiological aspects and diagnostic problems encountered in a rural set up are largely unknown. The present study on cutaneous tuberculosis encompassing clinical, pathological and epidemiological aspects was undertaken at Rajah Muthiah Medical college and Hospital (RMMC&H), a teaching hospital mainly catering to the health needs of a predominantly rural population from villages and hamlets around Chidambaram, a taluq headquarters, located in Cuddalore district ofTamil Nadu. During the period of study, 5744 cases (82%) of pulmonary tuberculosis and 1261 (18%) of extra-pulmonary tuberculosis were encountered. Cutaneous tuberculosis accounted for 117 (1.67%) of tuberculosis cases. Of the seventy-one patients with cutaneous tuberculosis, 39 had lupus vulgaris and 32 with TBVC. Lupus vulgaris was more prevalent with male pre-ponderance. The maximum incidence was seen in the second decade of life. Both LV and TBVC showed a male pre-ponderance, M:F ratio being 3:2 and 2:1 in LV and TBVC respectively. A majority of patients with LV (27 cases; 69.2%) and TBVC (31 cases; 96.8%) manifested with a single site of involvement. Lower extremities were more commonly involved among patients hailing from poor economic strata who were not habituated to the use of footwear while working out doors. Over crowding was also a contributing factor. The relationships between BCG vaccination and Mantoux test with cutaneous tuberculosis, association with pulmonary tuberculosis in addition to the underlying predisposing socio-economic factors are discussed.

Assessing vaccination as a control strategy in an ongoing epidemic: Bovine tuberculosis in African buffalo

USGS Publications Warehouse

Cross, P.C.; Getz, W.M.

2006-01-01

Bovine tuberculosis (BTB) is an exotic disease invading the buffalo population (Syncerus caffer) of the Kruger National Park (KNP), South Africa. We used a sex and age-structured epidemiological model to assess the effectiveness of a vaccination program and define important research directions. The model allows for dispersal between a focal herd and background population and was parameterized with a combination of published data and analyses of over 130 radio-collared buffalo in the central region of the KNP. Radio-tracking data indicated that all sex and age categories move between mixed herds, and males over 8 years old had higher mortality and dispersal rates than any other sex or age category. In part due to the high dispersal rates of buffalo, sensitivity analyses indicate that disease prevalence in the background population accounts for the most variability in the BTB prevalence and quasi-eradication within the focal herd. Vaccination rate and the transmission coefficient were the second and third most important parameters of the sensitivity analyses. Further analyses of the model without dispersal suggest that the amount of vaccination necessary for quasi-eradication (i.e. prevalence 70% of the calf population would have to be vaccinated every year to reduce the prevalence to less than 1%. If the half-life of the vaccine is less than 5 years, even vaccinating every calf for 50 years may not eradicate BTB. Thus, although vaccination provides a means of controlling BTB prevalence it should be combined with other control measures if eradication is the objective.

Coloring the white plague: a syndemic approach to immigrant tuberculosis in Canada.

PubMed

Reitmanova, Sylvia; Gustafson, Diana L

2012-01-01

In this article, we adopt a syndemic approach to immigrant tuberculosis (TB) in Canada as a way of challenging contemporary epidemiological models of infectious diseases that tend to racialize and medicalize the risk of infections in socio-economically disadvantage populations and obscure the role of social conditions in sustaining the unequal distribution of diseases in these populations. A syndemic approach unravels social and biological connections which shape the distribution of infections over space and time and is useful in de-racializing and de-medicalizing these epidemiologic models. The socio-historic framework allows us to examine social factors which, refracted through medical science, were central to the development of TB control in Canada at the beginning of twentieth century. We expose the ideological assumptions about race, immigration, and social status which underpin current policies designed to control TB within the immigrant population. We argue that TB control policies which divert the attention from structural health determinants perpetuate health and social inequities of racialized populations in Canada. Medical screening and surveillance is an ineffective control policy because the proportion of TB cases attributed to immigrants increased from 18 to 66% between 1970 and 2007. More effective TB control policies require shifting the focus from the individual disease carriers toward social inequities which underlie the problem of immigrant TB in Canada. In addition, de-racialization and de-medicalization of the contemporary epidemiological models of infectious diseases entail an in-depth exploration of how the categories of ethnicity, culture, and immigration status are played out in everyday health-related experiences of racialized groups.

FadA5 a thiolase from Mycobacterium tuberculosis - a unique steroid-binding pocket reveals the potential for drug development against tuberculosis

PubMed Central

Schaefer, Christin M.; Lu, Rui; Nesbitt, Natasha M.; Schiebel, Johannes; Sampson, Nicole S.; Kisker, Caroline

2014-01-01

Summary With the exception of HIV, tuberculosis (TB) is the leading cause of mortality among infectious diseases. The urgent need to develop new anti-tubercular drugs is apparent due to the increasing number of drug resistant Mycobacterium tuberculosis (Mtb) strains. Proteins involved in cholesterol import and metabolism have recently been discovered as potent targets against TB. FadA5, a thiolase from Mtb, is catalyzing the last step of the β-oxidation reaction of the cholesterol side-chain degradation under release of critical metabolites and was shown to be of importance during the chronic stage of TB infections. To gain structural and mechanistic insight on FadA5 we characterized the enzyme in different stages of the cleavage reaction and with a steroid bound to the binding pocket. Structural comparisons to human thiolases revealed that it should be possible to target FadA5 specifically and the steroid-bound structure provides a solid basis for the development of inhibitors against FadA5. PMID:25482540

Assessing vaccination as a control strategy in an ongoing epidemic: Bovine tuberculosis in African buffalo

USGS Publications Warehouse

Cross, Paul C.; Getz, W.M.

2006-01-01

Bovine tuberculosis (BTB) is an exotic disease invading the buffalo population (Syncerus caffer) of the Kruger National Park (KNP), South Africa. We used a sex and age-structured epidemiological model to assess the effectiveness of a vaccination program and define important research directions. The model allows for dispersal between a focal herd and background population and was parameterized with a combination of published data and analyses of over 130 radio-collared buffalo in the central region of the KNP. Radio-tracking data indicated that all sex and age categories move between mixed herds, and males over 8 years old had higher mortality and dispersal rates than any other sex or age category. In part due to the high dispersal rates of buffalo, sensitivity analyses indicate that disease prevalence in the background population accounts for the most variability in the BTB prevalence and quasi-eradication within the focal herd. Vaccination rate and the transmission coefficient were the second and third most important parameters of the sensitivity analyses. Further analyses of the model without dispersal suggest that the amount of vaccination necessary for quasi-eradication (i.e. prevalence < 5%) depends upon the duration that a vaccine grants protection. Vaccination programs are more efficient (i.e. fewer wasted doses) when they focus on younger individuals. However, even with a lifelong vaccine and a closed population, the model suggests that >70% of the calf population would have to be vaccinated every year to reduce the prevalence to less than 1%. If the half-life of the vaccine is less than 5 years, even vaccinating every calf for 50 years may not eradicate BTB. Thus, although vaccination provides a means of controlling BTB prevalence it should be combined with other control measures if eradication is the objective.

HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response

PubMed Central

Abdool Karim, Salim S.; Churchyard, Gavin J.; Abdool Karim, Quarraisha; Lawn, Stephen D.

2009-01-01

One of the greatest challenges facing post-apartheid South Africa is the control of the concomitant HIV and tuberculosis epidemics. HIV continues to spread relentlessly, and tuberculosis has been declared a national emergency. In 2007, South Africa, with 0·7% of the world’s population, had 17% of the global burden of HIV infection, and one of the world’s worst tuberculosis epidemics, compounded by rising drug resistance and HIV co-infection. Until recently, the South African Government’s response to these diseases has been marked by denial, lack of political will, and poor implementation of policies and programmes. Nonetheless, there have been notable achievements in disease management, including substantial improvements in access to condoms, expansion of tuberculosis control efforts, and scale-up of free antiretroviral therapy (ART). Care for acutely ill AIDS patients and long-term provision of ART are two issues that dominate medical practice and the health-care system. Decisive action is needed to implement evidence-based priorities for the control of the HIV and tuberculosis epidemics. By use of the framework of the Strategic Plans for South Africa for tuberculosis and HIV/AIDS, we provide prioritised four-step approaches for tuberculosis control, HIV prevention, and HIV treatment. Strong leadership, political will, social mobilisation, adequate human and financial resources, and sustainable development of health-care services are needed for successful implementation of these approaches. PMID:19709731

Private sector tuberculosis prevention in the US: Characteristics associated with interferon-gamma release assay or tuberculin skin testing.

PubMed

Stockbridge, Erica L; Miller, Thaddeus L; Carlson, Erin K; Ho, Christine

2018-01-01

To determine whether latent tuberculosis infection risk factors are associated with an increased likelihood of latent tuberculosis infection testing in the US private healthcare sector. A national sample of medical and pharmacy claims representing services rendered January 2011 through December 2013 for 3,997,986 commercially insured individuals in the US who were 0 to 64 years of age. We used multivariable logistic regression models to determine whether TB/LTBI risk factors were associated with an increased likelihood of Interferon-Gamma Release Assay (IGRA) or Tuberculin Skin Test (TST) testing in the private sector. 4.31% (4.27-4.34%) received at least one TST/IGRA test between 2011 and 2013 while 1.69% (1.67-1.72%) received a TST/IGRA test in 2013. Clinical risk factors associated with a significantly increased likelihood of testing included HIV, immunosuppressive therapy, exposure to tuberculosis, a history of tuberculosis, diabetes, tobacco use, end stage renal disease, and alcohol use disorder. Other significant variables included gender, age, asthma, the state tuberculosis rate, population density, and percent of foreign-born persons in a county. Private sector TST/IGRA testing is not uncommon and testing varies with clinical risk indicators. Thus, the private sector can be a powerful resource in the fight against tuberculosis. Analyses of administrative data can inform how best to leverage private sector healthcare toward tuberculosis prevention activities.

[Risk factors for developing tuberculosis].

PubMed

Skodrić-Trifunović, Vesna

2004-01-01

Application of modern achievements in the field of medicine such as organ transplantation, long-term immunosuppressive therapy in treatment of numerous diseases, dialysis, successful treatment of malignant diseases prolonged duration of life and consequential continuation of long-term immunodeficiency. HIV infection currently represents a major risk factor for reactivation of tuberculosis with its associated relative risk being 30-170 times higher in comparison to the control group, in regard to the number of CD4 T-lymphocytes. Malignant diseases (hematological, lung and breast carcinomas) are important immunocompromising conditions affecting reactivation of tuberculosis, whereas the relative risk is 16. Development of tuberculosis among diabetics is considerably more frequent in comparison to general population (relative risk 2-4). Prominent glycoregulation disorders point to greater liability to development of tuberculosis. Alcoholism is characterized by general reduction of resistance, resulting from alcohol intoxication, malnutrition, irregular life style, etc. In malabsorption, immunosuppression is induced by deficiency of nutritive components and thus, relative risk for reactivation of tuberculosis is 5-12 in gastrectomy and 27-63 in jejunoileal bypass. In patients with chronic renal failur the relative risk ranges from 10 (nephropathies) to 37 (transplantation). Numerous patients use long-term immunosuppressive therapy that contributes to increased risk for developing tuberculosis (relative risk 12) as early as one month after application of a dose above 15 mg/day. There are numerous of risk factors that have frequently combined effects responsible for immunologic imbalance and development of tuberculosis.

Application of a Hybrid Model for Predicting the Incidence of Tuberculosis in Hubei, China

PubMed Central

Zhang, Guoliang; Huang, Shuqiong; Duan, Qionghong; Shu, Wen; Hou, Yongchun; Zhu, Shiyu; Miao, Xiaoping; Nie, Shaofa; Wei, Sheng; Guo, Nan; Shan, Hua; Xu, Yihua

2013-01-01

Background A prediction model for tuberculosis incidence is needed in China which may be used as a decision-supportive tool for planning health interventions and allocating health resources. Methods The autoregressive integrated moving average (ARIMA) model was first constructed with the data of tuberculosis report rate in Hubei Province from Jan 2004 to Dec 2011.The data from Jan 2012 to Jun 2012 were used to validate the model. Then the generalized regression neural network (GRNN)-ARIMA combination model was established based on the constructed ARIMA model. Finally, the fitting and prediction accuracy of the two models was evaluated. Results A total of 465,960 cases were reported between Jan 2004 and Dec 2011 in Hubei Province. The report rate of tuberculosis was highest in 2005 (119.932 per 100,000 population) and lowest in 2010 (84.724 per 100,000 population). The time series of tuberculosis report rate show a gradual secular decline and a striking seasonal variation. The ARIMA (2, 1, 0) × (0, 1, 1)12 model was selected from several plausible ARIMA models. The residual mean square error of the GRNN-ARIMA model and ARIMA model were 0.4467 and 0.6521 in training part, and 0.0958 and 0.1133 in validation part, respectively. The mean absolute error and mean absolute percentage error of the hybrid model were also less than the ARIMA model. Discussion and Conclusions The gradual decline in tuberculosis report rate may be attributed to the effect of intensive measures on tuberculosis. The striking seasonal variation may have resulted from several factors. We suppose that a delay in the surveillance system may also have contributed to the variation. According to the fitting and prediction accuracy, the hybrid model outperforms the traditional ARIMA model, which may facilitate the allocation of health resources in China. PMID:24223232

Socio-demographic determinants and prevalence of Tuberculosis knowledge in three slum populations of Uganda.

PubMed

Obuku, Ekwaro A; Meynell, Clea; Kiboss-Kyeyune, Jemimah; Blankley, Simon; Atuhairwe, Christine; Nabankema, Evelyn; Lab, Morris; Jeffrey, Nikki; Ndungutse, David

2012-07-23

Knowledge of tuberculosis has been shown to influence health seeking behaviour; and urban slum dwellers are at a higher risk of acquiring tuberculosis than the general population. The study aim was to assess knowledge of tuberculosis and identify the associated socio-demographic determinants, in order to inform tailored interventions for advocacy, communication and social mobilisation in three urban-slum communities of Uganda. A cross-sectional survey of 1361 adults between April and October 2011. Data was analyzed by descriptive statistics. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) of potential determinants of tuberculosis (TB) knowledge were estimated by multivariable ordinal logistic regression using Stata 11.2 software. We found low knowledge of TB cause (26.7%); symptoms (46.8%), transmission (54.3%), prevention (34%) and free treatment (35%). Knowledge about TB treatment (69.4) and cure (85.1) was relatively high. Independent determinants of poor knowledge of TB in the multivariable analysis included (aOR, 95% CI) lack of formal education (0.56; 0.38 - 0.83, P = 0.004), unemployment (0.67; 0.49 - 0.90, P = 0.010) and never testing for HIV (0.69; 0.51 - 0.92, P < 0.012). Whilst, older age (1.73; 1.30 - 2.29, P < 0.001) and residing in Lira (2.02; 1.50 - 2.72, P < 0.001) were independent determinants of higher knowledge of TB. This study revealed deficiencies in the public health knowledge about TB symptoms, diagnosis and treatment among urban-slum dwellers in Uganda. Tuberculosis control programmes in similar settings should consider innovative strategies for TB education, advocacy, communication and social mobilisation to reach the youth, unemployed and less-educated; as well as those who have never tested for HIV.

Transmission of tuberculosis among people living in the border areas of Poland, the Czech Republic, and Slovakia.

PubMed

Kozińska, Monika; Zientek, Jerzy; Augustynowicz-Kopeć, Ewa; Zwolska, Zofia; Kozielski, Jerzy

2016-01-01

In 2007, Poland, the Czech Republic, and Slovakia joined the Schengen Agreement, abolishing restrictions on people crossing the borders. Currently, these areas are places of population movements for economic, family, and touristic reasons. This favors the transmission of infectious diseases, including tuberculosis, and requires enhanced control over the spread of the source of infection in the population of patients living in the border areas. The aim of this study was to investigate the genetic relatedness among Mycobacterium tuberculosis complex strains isolated from patients living in 3 border areas: Poland, the Czech Republic, and Slovakia. PATIENTS AND METHODS The study group consisted of 209 patients with tuberculosis diagnosed and treated between 2007 and 2011 in health care facilities in the Silesia Province in Poland (121 patients [58%]), Žilina in Slovakia (57 [27%]), and the Moravian-Silesian Region in the Czech Republic (31 [15%]). Genotyping of strains was performed using spoligotyping and IS6110-Mtb1-Mtb2 polymerase chain reaction. Among 209 strains, 23 molecular families (clusters) were identified. Seventeen clusters were identified as national. Six international clusters consisted of 30 strains isolated from patients of various nationalities. We identified 6 potential outbreaks of tuberculosis transmission between patients of different nationalities. The circumstances favorable to potential contacts of patients included mainly travelling to the neighboring countries, hospital stays, and addictions. However, there was no evidence of an epidemiological link between these patients, so it may be assumed that if they had come in contact with one another, it was accidental. We observed that the greater incidence of tuberculosis on the Polish territory did not affect the incidence in the Czech Republic or Slovakia over the analysis period.

Characterization of the genetic diversity of Mycobacterium tuberculosis in São Paulo city, Brazil.

PubMed

Mendes, Natália H; Melo, Fernando Af; Santos, Adolfo Cb; Pandolfi, José Rc; Almeida, Elisabete A; Cardoso, Rosilene F; Berghs, Henri; David, Suzana; Johansen, Faber K; Espanha, Lívia G; Leite, Sergio Ra; Leite, Clarice Qf

2011-07-29

Tuberculosis is a major health problem in São Paulo, Brazil, which is the most populous and one of the most cosmopolitan cities in South America. To characterize the genetic diversity of Mycobacterium tuberculosis in the population of this city, the genotyping techniques of spoligotyping and MIRU were applied to 93 isolates collected in two consecutive years from 93 different tuberculosis patients residing in São Paulo city and attending the Clemente Ferreira Institute (the reference clinic for the treatment of tuberculosis). Spoligotyping generated 53 different spoligotype patterns. Fifty-one isolates (54.8%) were grouped into 13 spoligotyping clusters. Seventy- two strains (77.4%) showed spoligotypes described in the international databases (SpolDB4, SITVIT), and 21 (22.6%) showed unidentified patterns. The most frequent spoligotype families were Latin American Mediterranean (LAM) (26 isolates), followed by the T family (24 isolates) and Haarlem (H) (11 isolates), which together accounted for 65.4% of all the isolates. These three families represent the major genotypes found in Africa, Central America, South America and Europe. Six Spoligo-International-types (designated SITs by the database) comprised 51.8% (37/72) of all the identified spoligotypes (SIT53, SIT50, SIT42, SIT60, SIT17 and SIT1). Other SITs found in this study indicated the great genetic diversity of M. tuberculosis, reflecting the remarkable ethnic diversity of São Paulo city inhabitants. The MIRU technique was more discriminatory and did not identify any genetic clusters with 100% similarity among the 93 isolates. The allelic analysis showed that MIRU loci 26, 40, 23 and 10 were the most discriminatory. When MIRU and spoligotyping techniques were combined, all isolates grouped in the 13 spoligotyping clusters were separated. Our data indicated the genomic stability of over 50% of spoligotypes identified in São Paulo and the great genetic diversity of M. tuberculosis isolates in the remaining SITs, reflecting the large ethnic mix of the São Paulo city inhabitants. The results also indicated that in this city, M. tuberculosis isolates acquired drug resistance independently of genotype and that resistance was more dependent on the selective pressure of treatment failure and the environmental circumstances of patients.

Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (PNU-100480) and its major metabolite against intracellular Mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis.

PubMed

Zhu, Tong; Friedrich, Sven O; Diacon, Andreas; Wallis, Robert S

2014-06-01

Sutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (-0.269 log10 per day; 90% CI, -0.237 to -0.293 log10 per day) than single daily dosing (-0.186 log10 per day; 90% CI, -0.160 to -0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Evidence to inform resource allocation for tuberculosis control in Myanmar: a systematic review based on the SYSRA framework.

PubMed

Khan, Mishal S; Schwanke Khilji, Sara U; Saw, Saw; Coker, Richard J

2017-02-01

Myanmar represents an extreme example of the difficulties in optimally allocating resources for maximum public health benefit, on the basis of limited information. At the recent Myanmar Health Forum 'Investing in Health' much of the discussion revolved around what to invest in, how health systems could be strengthened, and what research and capacity building areas the international donor community should prioritise for support. Funding for infectious disease control, particularly HIV and tuberculosis, is being channelled to the country at an unprecedented rate, but very little research has been conducted in recent years, and existing information has not yet been synthesised. This paper presents findings of the first systematic literature review on tuberculosis control and the health system in Myanmar, with the aim of informing the development of optimal research priorities and strategies. Medline and grey literature were searched for relevant papers. Inclusion criteria and analyses were structured to capture data on the Myanmar health system, healthcare delivery, financing, tuberculosis control indicators and information systems. A total of 77 papers were included in the analysis. The results indicate that there has been a large increase in the number of peer-reviewed articles published on tuberculosis in Myanmar over the past decade, although the absolute number of studies remains small. We identified several areas in which evidence to inform policy and resource allocation decisions is lacking, including research focused on rural and/or vulnerable populations, analyses of risk factors for TB and drug resistance that can inform prevention strategies and economic analyses for optimising resource allocation. The gaps in research to inform policy identified through this study may be relevant to other low resource settings with extremely limited research capacity. © The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Drug Resistance in Newly Presenting and Previously Treated Tuberculosis Patients in Guangxi Province, People's Republic of China.

PubMed

Luo, Dan; Zhao, Jinming; Lin, Mei; Liu, Feiying; Huang, Shuhai; Zhang, Yingkun; Huang, Minying; Li, Juan; Zhou, Yang; Lan, Rushu; Zhao, Yanlin

2017-05-01

Drug-resistant Mycobacterium tuberculosis strains are a major threat to the control of tuberculosis (TB), but the prevalence of drug-resistant TB is still unknown in the southern ethnic region of China. A cluster-randomized sampling method was used to include the study population. Isolates were tested for resistance to 6 antituberculosis drugs, and genotyped to identify Beijing strains. Overall, 11.3% (139/1229) of new cases and 33.0% (126/382) of retreated cases had drug-resistant tuberculosis. Multiple previous TB treatment episodes and multiple treatment interruptions were risk factors for both drug-resistant and multidrug-resistant TB among retreated cases. A total of 53.2% of the patients were infected with a Beijing strain of M tuberculosis. Infection with a Beijing strain was significantly associated with drug resistance among new cases (odds ratio, 1.44; 95% CI, 1.01-2.07). Novel strategies to rapid diagnosis and effective treatment are urgently needed to prevent the development of drug resistance.

[MOLECULAR CHARACTERISTICS OF THE MULTIDRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS STRAINS IN THE NORTHWEST RUSSIA].

PubMed

Vyazovaya, A A; Mokrousov, I V; Zhuravlev, V Yu; Solovieva, N S; Otten, T F; Manicheva, O A; Vishnevsky, B I; Narvskaya, O V

2016-01-01

The goal of this work was to study the genotypic characteristics of the multidrug-resistant (MDR, i.e., resistant to at least rifampicine and isoniazid) Mycobacterium tuberculosis strains isolated in 2011-2012 from tuberculosis (TB) patients in the Northwest Russia. Spoligotyping of 195 M. tuberculosis isolates identified 14 different spoligotypes and assigned isolates to the genetic families Beijing (n = 162, 83%), LAM (n = 15), H3/URAL (n = 14), as well as T, Haarlem and X. Spoligotypes SIT1 (Beijing), SIT42 (LAM) and SIT262 (H3/URAL) were the most prevalent. Irrespective to the genotype, all the isolates were resistant to streptomycin. The multidrug resistance was accompanied by the resistance to ethionamide (56%), amikacin (31%), kanamycin (40%), and capreomycin (33%). The ethambutol resistance was found in 71% (n = 115) and 42% (n = 14) of the Beijing and non-Beijing strains, respectively (p < 0.05). In conclusion, the multidrug resistant M. tuberculosis population circulating in the Northwest Russia continues to be dominated by the Beijing family strains.

Phenotypic assays for Mycobacterium tuberculosis infection.

PubMed

Song, Ok-Ryul; Deboosere, Nathalie; Delorme, Vincent; Queval, Christophe J; Deloison, Gaspard; Werkmeister, Elisabeth; Lafont, Frank; Baulard, Alain; Iantomasi, Raffaella; Brodin, Priscille

2017-10-01

Tuberculosis (TB) is still a major global threat, killing more than one million persons each year. With the constant increase of Mycobacterium tuberculosis strains resistant to first- and second-line drugs, there is an urgent need for the development of new drugs to control the propagation of TB. Although screenings of small molecules on axenic M. tuberculosis cultures were successful for the identification of novel putative anti-TB drugs, new drugs in the development pipeline remains scarce. Host-directed therapy may represent an alternative for drug development against TB. Indeed, M. tuberculosis has multiple specific interactions within host phagocytes, which may be targeted by small molecules. In order to enable drug discovery strategies against microbes residing within host macrophages, we developed multiple fluorescence-based HT/CS phenotypic assays monitoring the intracellular replication of M. tuberculosis as well as its intracellular trafficking. What we propose here is a population-based, multi-parametric analysis pipeline that can be used to monitor the intracellular fate of M. tuberculosis and the dynamics of cellular events such as phagosomal maturation (acidification and permeabilization), zinc poisoning system or lipid body accumulation. Such analysis allows the quantification of biological events considering the host-pathogen interplay and may thus be derived to other intracellular pathogens. © 2017 International Society for Advancement of Cytometry. © 2017 International Society for Advancement of Cytometry.

Knowledge, attitude and perceived stigma towards tuberculosis among pastoralists; Do they differ from sedentary communities? A comparative cross-sectional study.

PubMed

Sima, Bezawit Temesgen; Belachew, Tefera; Abebe, Fekadu

2017-01-01

Ethiopia is ninth among the world high tuberculosis (TB) burden countries, pastoralists being the most affected population. However, there is no published report whether the behavior related to TB are different between pastoralist and the sedentary communities. Therefore, the main aim of this study is to assess the pastoralist community knowledge, attitude and perceived stigma towards tuberculosis and their health care seeking behavior in comparison to the neighboring sedentary communities and this may help to plan TB control interventions specifically for the pastoralist communities. A community-based cross-sectional survey was carried out from September 2014 to January 2015, among 337 individuals from pastoralist and 247 from the sedentary community of Kereyu district. Data were collected using structured questionnaires. Three focus group discussions were used to collect qualitative data, one with men and the other with women in the pastoralist and one with men in the sedentary groups. Data were analyzed using Statistical Software for Social Science, SPSS V 22 and STATA. A Lower proportion of pastoralists mentioned bacilli (bacteria) as the cause of PTB compared to the sedentary group (63.9% vs. 81.0%, p<0.01), respectively. However, witchcraft was reported as the causes of TB by a higher proportion of pastoralists than the sedentary group (53.6% vs.23.5%, p<0.01), respectively. Similarly, a lower proportion of pastoralists indicated PTB is preventable compared to the sedentary group (95.8% vs. 99.6%, p<0.01), respectively. Moreover, majority of the pastoralists mentioned that most people would reject a TB patient in their community compared to the sedentary group (39.9% vs. 8.9%, p<0.001), respectively, and the pastoralists expressed that they would be ashamed/embarrassed if they had TB 68% vs.36.4%, p<0.001), respectively. The finding indicates that there is a lower awareness about TB, a negative attitude towards TB patients and a higher perceived stigma among pastoralists compared to their neighbor sedentary population. Strategic health communications pertinent to the pastoralists way of life should be planned and implemented to improve the awareness gap about tuberculosis.

Snapshot of Quantiferon TB gold testing in Northern Mexico.

PubMed

González-Salazar, F; Vargas-Villarreal, J; Garcialuna-Martínez, F J; Rivera, G; Moreno-Treviño, M G; Montfort-Gardeazabal, J M; Garcialuna-Martínez, E

2011-12-01

Most people infected with Mycobacterium tuberculosis have an asymptomatic condition named latent tuberculosis. These people do not have bacilli in the corporal secretions and are hard to diagnose by conventional laboratory tests. Diagnosis of latent tuberculosis infection (LTBI) in México is based on the tuberculin skin test (TST). This test has disadvantages, principally because the vaccine containing the Bacille Calmette-Guérin (BCG) is applied to 99% of this population and causes false positive TST outcomes. Recently, interferon-gamma release assays (IGRA) have been demonstrated to be a good test to detect latent tuberculosis with equal or better sensitivity to TST and without interference from BCG. However, in México the IGRA are an uncommon test due to the higher cost compared to TST. The main objective of this work was demonstrate the potential utility of the Quantiferon TB(®) gold in tube (QTB(®)-GIT) test to detect latent TB in a population from northern México. Samples from 106 subjects with close contact, or without contact, with actively infected TB patients were tested to detect LTBI. Our results show a significant difference between individuals in close contact with active TB patients (39.7%) compared to those without contact (3.2%), p < 0.01. The concordance between TST and QTB(®)-GIT was poor (κ = 0.31). Our preliminary results show that the QTB(®)-GIT has better capacity than TST to detect latent tuberculosis infection. Copyright © 2011 Elsevier Ltd. All rights reserved.

Evaluation of Xpert MTB/RIF assay performance in the diagnosis of abdominal tuberculosis.

PubMed

Kumar, Suraj; Bopanna, Sawan; Kedia, Saurabh; Mouli, Pratap; Dhingra, Rajan; Padhan, Rajesh; Kohli, Mikashmi; Chaubey, Jigyasa; Sharma, Rohini; Das, Prasenjit; Dattagupta, S; Makharia, Govind; Sharma, S K; Ahuja, Vineet

2017-04-01

The use of genetic probes for the diagnosis of pulmonary tuberculosis (TB) has been well described. However, the role of these assays in the diagnosis of intestinal tuberculosis is unclear. We therefore assessed the diagnostic utility of the Xpert Mycobacterium tuberculosis /rifampicin (MTB/RIF) assay, and estimated the prevalence of multidrug-resistant (MDR) TB in the Indian population. Of 99 patients recruited, 37 had intestinal TB; two control groups comprised 43 with Crohn's disease (CD) and 19 with irritable bowel syndrome. Colonoscopy was performed before starting any therapy; mucosal biopsies were subjected to histopathology, acid-fast bacilli staining, Lowenstein-Jensen culture, and nucleic acid amplification testing using the Xpert MTB/RIF assay. Patients were followed up for 6 months to confirm the diagnosis and response to therapy. A composite reference standard was used for diagnosis of TB and assessment of the diagnostic utility of the Xpert MTB/RIF assay. Of 37 intestinal TB patients, the Xpert MTB/RIF assay was positive in three of 37 (8.1%), but none had MDR-TB. The sensitivity, specificity, positive predictive value, and negative predictive value of the Xpert MTB/RIF assay was 8.1%, 100%, 100%, and, 64.2%, respectively. The Xpert MTB/RIF assay has low sensitivity but high specificity for intestinal TB, and may be helpful in endemic tuberculosis areas, when clinicians are faced with difficulty differentiating TB and CD. Based on the Xpert MTB/RIF assay, the prevalence of intestinal MDR-TB is low in the Indian population.

Mycobacterium bovis in a European bison (Bison bonasus) raises concerns about tuberculosis in Brazilian captive wildlife populations: a case report.

PubMed

Zimpel, Cristina Kraemer; Brum, Juliana Sperotto; de Souza Filho, Antônio Francisco; Biondo, Alexander Welker; Perotta, João Henrique; Dib, Cristina Corsi; Bonat, Marcelo; Neto, José Soares Ferreira; Brandão, Paulo Eduardo; Heinemann, Marcos Bryan; Guimaraes, Ana Marcia Sa

2017-02-10

Tuberculosis caused by Mycobacterium bovis is an important worldwide zoonosis and has been reported to cause clinical disease in several animal species, including captive wildlife. This report describes a case of M. bovis infection in a European bison from a Brazilian zoo and compiles a number of literature reports that raise concern regarding tuberculosis among captive wildlife in Brazil. A 13 year-old captive-born male bison (Bison bonasus) from a Brazilian zoo began presenting weight loss, diarrhea and respiratory symptoms, which inevitably led to his death. At the animal's necropsy, inspection of the thoracic and abdominal cavities revealed multiple enlarged lymph nodes, ranging from 4 to 10 cm, and pulmonary nodules containing caseous masses with firm white materials consistent with mineralization. Histopathology findings showed a significant amount of acid-alcohol resistant bacilli compatible with Mycobacterium spp. Specimens from lymph nodes and lungs were cultured on Petragnani and Stonebrink media, and specific PCR assays of the bacterial isolate identified it as M. bovis. The European bison reported herein died from a severe form of disseminated tuberculosis caused by M. bovis. A review of the available literature indicates possible widespread occurrence of clinical disease caused by M. bovis or M. tuberculosis affecting multiple animal species in Brazilian wildlife-related institutions. These likely underestimated numbers raise concern regarding the control of the disease in captive animal populations from Brazil.

Mycobacterium tuberculosis Complex and HIV Co-Infection among Extrapulmonary Tuberculosis Suspected Cases at the University of Gondar Hospital, Northwestern Ethiopia

PubMed Central

Fanosie, Alemu; Gelaw, Baye; Tessema, Belay; Tesfay, Wogahta; Admasu, Aschalew; Yitayew, Gashaw

2016-01-01

Background Extrapulmonary Tuberculosis (EPTB) and Human Immunodeficiency Virus (HIV) infection are interrelated as a result of immune depression. The aim of this study was to determine the prevalence of Mycobacterium tuberculosis complex isolates and the burden of HIV co-infection among EPTB suspected patients. Method An institution based cross-sectional study was conducted among EPTB suspected patients at the University of Gondar Hospital. Socio-demographic characteristics and other clinical data were collected using a pretested questionnaire. GeneXpert MTB/RIF assay was performed to diagnosis Mycobacterium tuberculosis complex and Rifampicin resistance. All samples were also investigated by cytology and culture. The HIV statuses of all patients were screened initially by KHB, and all positive cases were further re-tested by STAT-pack. Data was analyzed using SPSS version 20 computer software and a P-value of < 0.05 was taken as statistically significant. Results A total of 141 extrapulmonary suspected patients were enrolled in this study. The overall prevalence of culture confirmed extrapulmonary tuberculosis infection was 29.8%, but the GeneXpert result showed a 26.2% prevalence of Mycobacterium tuberculosis complex infection. The 78.4% prevalence of extrapulmonary tuberculosis infection was found to be higher among the adult population. The prevalence of HIV infection among EPTB suspected patients was 14.1%, while it was 32.4% among GeneXpert-confirmed extrapulmonary TB cases (12/37). Tuberculosis lymphadenitis was the predominant (78.4%) type of EPTB infection followed by tuberculosis cold abscess (10.7%). Adult hood, previous history of contact with known pulmonary tuberculosis patients, and HIV co-infection showed a statistically significant association with extrapulmonary tuberculosis infection (P<0.013). Conclusion The prevalence of culture confirmed-EPTB infection was high, and a higher EPTB-HIV co-infection was also observed. PMID:26950547

[Epidemic of tuberculosis in Meiji and Taisho eras in Japan and excess deaths from tuberculosis in females].

PubMed

Aoki, K

1995-08-01

Acute increase in tuberculosis mortality between 1885 and 1910 could be explained by rapidly increased birth rate, consequently large expansion of noninfected population, and gradual increase in opportunity of contact with infectious patients by changing working environments and living conditions. Prevalence of tuberculosis patients was not so few in the beginning of Meiji era. Vicious spiral of increased young susceptibles, many infectious sources and increased opportunity of infection had been continued for long. Lower nutrition from infant to adult, hard work and poor living conditions had worsen prognosis of the patients. Nation-wide tuberculosis control campaign, mainly avoiding contact with patients and contaminated materials had started around 1910 and then issued Factory act which had been improved working conditions in the factories, although the speed was very slow. Tuberculosis mortality began to decrease in 1910s, but sharp temporary rise of tuberculosis mortality was marked in 1918-19 by epidemic of influenza, then the mortality had been declined again. Excess mortality by influenza caused temporary reduction of infectious sources, which had affected mortality rate of tuberculosis in the younger ages after 1920. Large raise-up of wages for factory workers around 1920 and increase trend in income for other workers by economic growth since 1900 had been improved not only working and living conditions, but also dietary life with increased higher intake of animal foods. Female excess deaths from tuberculosis comparing those of males had continued until 1930, then male mortality exceeded females. Mobilization of young women to spinning and textile industries in Meiji and Taisho eras forced to increase in tuberculosis mortality among them.(ABSTRACT TRUNCATED AT 250 WORDS)

Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes

PubMed Central

Janssen, Saskia; Schutz, Charlotte; Ward, Amy; Nemes, Elisa; Wilkinson, Katalin A; Scriven, James; Huson, Mischa A; Aben, Nanne; Maartens, Gary; Burton, Rosie; Wilkinson, Robert J; Grobusch, Martin P; Van der Poll, Tom; Meintjes, Graeme

2017-01-01

Abstract Background Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population. Methods This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia. Results Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22–132); 16 (27%) died after a median of 12 (IQR, 0–24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Conclusions Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis. PMID:28369200

Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes.

PubMed

Janssen, Saskia; Schutz, Charlotte; Ward, Amy; Nemes, Elisa; Wilkinson, Katalin A; Scriven, James; Huson, Mischa A; Aben, Nanne; Maartens, Gary; Burton, Rosie; Wilkinson, Robert J; Grobusch, Martin P; Van der Poll, Tom; Meintjes, Graeme

2017-07-01

Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population. This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia. Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Strategies for the fight against tuberculosis.

PubMed

Enarson, D A

1994-02-01

Tuberculosis killed 1 of every 150 persons in the general population in cities such as London, Stockholm, New York, Hamburg, Taipei, and Tokyo in the late 18th, early 19th, and late 19th century. Presently, the level is more than 100 times lower. The rate of decline has recently slowed or stopped. As tuberculosis declines in the community, it becomes a disease of subgroups who either have been previously infected (immigrants), whose immunity is reduced (AIDS, silicosis, or diabetes patients) or among whom transmission continues at a high rate (in urban slums). In Canada, 80% of all cases arise among high-risk groups in whom the notification rate is over 10 times higher than in the general community. The most important of these groups are immigrants. From 1970 to 1990, the proportion of cases among immigrants to Canada rose from 20% to 50% of all cases. The explanation for the rise in the proportion was the change in source of immigrants to Canada from mostly Europeans in 1965 to mostly Asians in 1975. The record of tuberculosis in developing countries has not been as positive as in industrialized countries due to the inability to achieve satisfactory treatment in patients with active tuberculosis. Recently, within cost-effective tuberculosis programs developed by the International Union Against Tuberculosis and Lung Disease in collaboration with Tanzania, Malawi, Mozambique, Benin and Nicaragua, and with Norway, Switzerland, and the Netherlands as donor partners, more than 70,000 cases of tuberculosis are diagnosed and treated per year, and more than 75% are cured. The strategy of fighting tuberculosis includes the proper education of health care workers in developing countries; in industrialized countries focusing attention on the high risk groups and the care and prevention of tuberculosis; and preventive chemotherapy.

[Quality control in the follow-up of pulmonary tuberculosis contacts in Camagüey, Cuba (2008-2011)].

PubMed

Dair, Roberto; Torres, Etelivar; Rodríguez, Odalys; Cruz, Ramona; Hernández, Lizzie

2014-02-19

Tuberculosis is currently a health problem in the municipality of Camagüey. To assess compliance of guidelines issued by the National Program for the Control of Tuberculosis for the follow-up of contacts of positive cases of pulmonary tuberculosis in the municipality of Camagüey, Cuba. Descriptive cross-sectional design. 1,242 contacts resulting from 39 reported cases of tuberculosis during the study period were included in the municipality of Camagüey between 2008 and 2011. Epidemiological surveys and records of reported cases were reviewed. The results were processed and analyzed in SPSS 17.0 statistical software and subsequently presented in tables and graphs. The results were summarized by percentages. The “follow-up form for contacts of pulmonary tuberculosis” was used as main guideline, which was created by experts of the Investigation and Monitoring of Tuberculosis, Acute Respiratory Infections, and Leprosy Workshop of Tropical Medicine Institute Pedro Kourí. Contacts that had an initial examination and four checkups had 96.2% of acceptability. Contacts that had fewer than four checkups showed less than 10% acceptability (3.3%). All contacts were assessed from the outset and were treated, in accordance with program guidelines. We found adequate compliance of National Program for the Control of the Tuberculosis guidelines for follow-up of contacts of positive cases of pulmonary tuberculosis. Compliance is greater in younger age groups and in the actively employed (25 to 54 years). This evaluation contributed to identify existing weaknesses in follow-up, such as low interest of this population to undergo appropriate testing in the National Program of Control of Tuberculosis.

[Managment of tuberculosis in an University of Campania].

PubMed

Uccello, R; Monaco, M G L; Feola, D; Garzillo, E M; Muoio, M; Sannolo, N; Lamberti, M

2012-01-01

Tuberculosis (TBC) is an infectious disease with the highest mortality and morbidity by single pathogen, affecting about one third of worldwide population. Although Mantoux test is the most used, IGRA (Interferon-gamma Release Assays) tests seem to give good results for presumptive diagnosis of active or latent tuberculosis. From June 2011 to June 2012 we made about 1,000 visits for TBC prevention among the exposed to biological risks of our University. The management of suspected latent or active tuberculosis infection was carried out in collaboration with the pulmonologist, assessing the risk of contagion among exposed or affected operators. Health surveillance protocol and judgements of suitability for specific task were made not only in consideration of worker health, but also considerating the possible risk for patients, since this disease is a major problem for public health.

[Ethical aspects of tuberculosis control under fascism].

PubMed

Hahn, S

1983-05-01

At the instance of the development of the tuberculosis control in the period from 1933 to 1945 is tried to elaborate the ethical principles which are the basis of the medical care of the German population in fascist Germany. The utilitaristic and biologistic opinions of the value dominating at this time proved as altogether characterized by the social aims of fascism and at the same time serve for their realization in the field of health politics. Also in the tuberculosis control--like in other social fields--transitory progress in organisation and prophylaxis and finally to be paid with deranging setbacks which reveal the inhumanity of fascism also in this field.

Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freundlich, Joel S.; Wang, Feng; Vilchèze, Catherine

Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivativesmore » was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC{sub 50} value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 {mu}g mL{sup -1} (13 {mu}M), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.« less

Chemistry of Peptidoglycan in Mycobacterium tuberculosis Life Cycle: An off-the-wall Balance of Synthesis and Degradation.

PubMed

Squeglia, Flavia; Ruggiero, Alessia; Berisio, Rita

2018-02-21

The cell wall envelope of mycobacteria is structurally distinct from that of both Gram-positive and Gram-negative bacteria. In Mycobacterium tuberculosis, this cell wall has unique structural features and plays a crucial role in drug resistance and macrophage survival under stress conditions. Peptidoglycan is the major constituent of this cell wall, with an important structural role, giving structural strength, and counteracting the osmotic pressure of the cytoplasm. Synthesis of this complex polymer takes place in three stages that occur at three different locations in the cell, from the cytoplasm to the external side of the cell membrane, where polymerization occurs. A fine balance of peptidoglycan synthesis and degradation is responsible for a plethora of molecular mechanisms which are key to the pathogenicity of M. tuberculosis. Enlargement of mycobacterial cells can occur through the synthesis of new peptidoglycan, autolysis of old peptidoglycan, or a combination of both processes. Here, we discuss the chemical aspects of peptidoglycan synthesis and degradation, in relation to metabolic stages of M. tuberculosis. Going from inside the mycobacterial cytoplasm to outside its membrane, we describe the assembly line of peptidoglycan synthesis and polymerization, and continue with its depolymerization events and their consequences on mycobacterial life and resuscitation from dormancy. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Submitting to disease, controlling disease, industrialization and medical technology: the case of tuberculosis].

PubMed

Thebaud, A; Lert, F

1985-01-01

This article presents an overview of the research work undertaken in France and Algeria on tuberculosis and the application of tuberculosis treatments. Tuberculosis is one of the best medical pointers to social inequality. The disease is seen here as typical of the links between industrialization and health, with regard to the evolution of the epidemiological model and the influence of innovational+ treatments, based on chemotherapy, on the organization of care for tubercular patients, together with the socio-economic and cultural changes that have affected both French and Algerian society during the twentieth century. The first part of the article shows how the epidemiology of tuberculosis tends to vary in accordance with the dynamic evolution of social relationships as industrialization occurs in each country, and how world-wide epidemiological trends are one of the best medical pointers to the North-South divide. The second part of the article is given over to a study of the way in which the application of tuberculosis treatments in both France and Algeria is a function of the organization of the health system in each country, of the status and power of the medical profession within society, and of the impact of technical innovations on the changing forms of care for tubercular patients in both countries. In France, it can be seen that the structure of the system set up to combat tuberculosis in the inter-war years has tended to remain unchanged, despite the opportunities for re-organization of tuberculosis treatment and for making therapy less onerous which have arisen as the incidence of the disease has dropped and antibiotics have been introduced. This resistance to change seems due primarily to the difficulty of achieving redeployment of medical staff, and the inertia caused by the rigid structure of tuberculosis care within the French socio-medical system.(ABSTRACT TRUNCATED AT 250 WORDS)

Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.

PubMed

Horne, David J; Graustein, Andrew D; Shah, Javeed A; Peterson, Glenna; Savlov, Meg; Steele, Sergio; Narita, Masahiro; Hawn, Thomas R

2016-10-15

Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI. We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication. In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy. These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis.

PubMed

Lam, Karen K Y; Zheng, Xingji; Forestieri, Roberto; Balgi, Aruna D; Nodwell, Matt; Vollett, Sarah; Anderson, Hilary J; Andersen, Raymond J; Av-Gay, Yossef; Roberge, Michel

2012-01-01

Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment.

Structural measurements and cell line studies of the copper-PEG-Rifampicin complex against Mycobacterium tuberculosis.

PubMed

Manning, Thomas; Mikula, Rachel; Wylie, Greg; Phillips, Dennis; Jarvis, Jackie; Zhang, Fengli

2015-02-01

The bacterium responsible for tuberculosis is increasing its resistance to antibiotics resulting in new multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). In this study, several analytical techniques including NMR, FT-ICR, MALDI-MS, LC-MS and UV/Vis are used to study the copper-Rifampicin-Polyethylene glycol (PEG-3350) complex. The copper (II) cation is a carrier for the antibiotic Rifampicin as well as nutrients for the bacterium. The NIH-NIAID cell line containing several Tb strains (including antibiotic resistant strains) is tested against seven copper-PEG-RIF complex variations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tuberculosis at Raffic Hariri University Hospital (RHUH) during 10 years period 2005-2015, cross sectional, observational study.

PubMed

Zadeh, Catherina; Tayara, Loubna

2018-07-01

Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis. It represents, according to WHO, one of the most leading causes of death worldwide. 1 BACKGROUND: Based on our regional conditions, such as Syrian immigration, poor nutritional status, are contributors for the development of the disease. This was a retrospective analytical cross sectional study done to review all cases of tuberculosis newly diagnosed at RHUH during 10 years period (2005-2015). 128 TB labeled patients were retrieved. A standardized checklist was used to collect data. Patients were then classified as TB diseased and TB infected. The total number of TB suspected patients was 128 over 10 years which represents 1.77% of all patients admitted to the medical floor. Among these, the total number of PPD positive patients was 40.6% from our study population (2005-2015), 48% were TB infected and 52% had positive CXR. Among those with positive CXR, 41% were confirmed TB disease and 59% not confirmed TB disease. There was significant variation in evolution through years (2005-2015). By comparing the socio-demographic findings between TB disease, TB infection and non-TB group no statistical significance was found. Same analysis were repeated between TB infection and TB disease groups showed one significant association between age and TB disease vs. TB infection (p=0.034), where the younger population belongs to TB infected group (42%), while 50% of TB diseased group were older. As for scoring severity index, ANOVA in the three groups showed a significant association with a p value of 0.046. The TB diseased patients have the highest severity score index. TB disease is still present in Lebanon with fluctuating level with the highest peak found in 2013 explained by the influx of Syrian refugee population. Followed by a gradual drop in the following years. The younger population belongs to TB infected group, while TB disease patients had the most severe clinical course compared to TB infected and non TB patients. Copyright © 2017 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

Method for efficient storage and transportation of sputum specimens for molecular testing of tuberculosis.

PubMed

Guio, H; Okayama, H; Ashino, Y; Saitoh, H; Xiao, P; Miki, M; Yoshihara, N; Nakanowatari, S; Hattori, T

2006-08-01

The polymerase chain reaction (PCR) is a highly sensitive method for the detection of Mycobacterium tuberculosis and is available in most countries, though to a lesser extent in rural areas. To amplify M. tuberculosis DNA sequences of sputum spotted on FTA cards and compare them with the results of microscopic examination among culture-positive samples. A total of 102 sputum specimens of TB patients in treatment were spotted on FTA cards and stored at room temperature until DNA analysis. We assessed the IS6110 region of M. tuberculosis. The efficacy of the PCR assay for the direct detection of M. tuberculosis was evaluated and compared with the results of cultures (Middlebrook 7H9 broth) and smears of fresh sputum specimens. We were able to detect 10 fg/microl of mycobacterial DNA even after 6 months in storage. The PCR sensitivity and specificity using the FTA card system were 82% and 96%, while microscopic examination showed 41% and 95%, respectively. The FTA card system for the storage of bacterial DNA from sputum samples should be considered for the molecular diagnosis of tuberculosis. Samples can easily be obtained from geographically isolated populations and shipped by mail for accurate molecular diagnosis.

[Factors linked to delayed diagnosis of tuberculosis in Conakry (Guinea)].

PubMed

Camara, A; Diallo, A; Camara, L M; Fielding, K; Sow, O Y; Chaperon, J

2006-03-01

Untreated smear-positive pulmonary tuberculosis constitutes a reservoir of infection which is highly contagious. The present study was conducted in Conakry, Guinea, to determine the different options which are available when seeking treatment or care, and to ascertain the average delay in diagnosis of pulmonary tuberculosis and the main factors linked to the delay in diagnosis after the initial onset of symptoms. Through a cross-sectional study, 113 consecutive patients with smear-positive pulmonary tuberculosis were interviewed through the use of a questionnaire. The median total delay from the onset of symptoms of pulmonary tuberculosis until the diagnosis was 11 weeks. This delay period exceeded 4 weeks for 90 of the patients (80%). The average delay linked to the conventional health care system was double that of the one at the fault of the patient (6 weeks versus 3 weeks, respectively). 54% of the patients had initially resorted to non-conventional care. To shorten this mean delay period, it is necessary to both strengthen the professional abilities and skills which train for one to better to detect tuberculosis and to sensitize the population to the subject matter and information on the illness and its symptoms.

Implementing a successful tuberculosis programme within primary care services in a conflict area using the stop TB strategy: Afghanistan case study

PubMed Central

2014-01-01

Introduction Afghanistan has faced health consequences of war including those due to displacement of populations, breakdown of health and social services, and increased risks of disease transmission for over three decades. Yet it was able to restructure its National Tuberculosis Control Programme (NTP), integrate tuberculosis treatment into primary health care and achieve most of its targets by the year 2011. What were the processes that enabled the programme to achieve its targets? More importantly, what were the underpinning factors that made this success possible? We addressed these important questions through a case study. Case description We adopted a processes and outcomes framework for this study, which began with examining the change in key programme indicators, followed by backwards tracing of the processes and underlying factors, responsible for this change. Methods included review of the published and grey literature along with in-depth interviews of 15 key informants involved with the care of tuberculosis patients in Afghanistan. Discussion and evaluation TB incidence and mortality per 100,000 decreased from 325 and 92 to 189 and 39 respectively, while case notification and treatment success improved during the decade under study. Efficient programme structures were enabled through high political commitment from the Government, strong leadership from the programme, effective partnership and coordination among stakeholders, and adequate technical and financial support from the development partners. Conclusions The NTP Afghanistan is an example that public health programmes can be effectively implemented in fragile states. High political commitment and strong local leadership are essential factors for such programmes. To ensure long-term effectiveness of the NTP, the international support should be withdrawn in a phased manner, coupled with a sequential increase in resources allocated to the NTP by the Government of Afghanistan. PMID:24507446

Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Isolates Collected in Australia

PubMed Central

Lavender, Caroline; Globan, Maria; Sievers, Aina; Billman-Jacobe, Helen; Fyfe, Janet

2005-01-01

Elucidation of the molecular basis of isoniazid (INH) resistance in Mycobacterium tuberculosis has led to the development of different genotypic approaches for the rapid detection of INH resistance in clinical isolates. Mutations in katG, in particular the S315T substitution, are responsible for INH resistance in a large proportion of tuberculosis cases. However, the frequency of the katG S315T substitution varies with population samples. In this study, 52 epidemiologically unrelated clinical INH-resistant M. tuberculosis isolates collected in Australia were screened for mutations at katG codon 315 and the fabG1-inhA regulatory region. Importantly, 52 INH-sensitive isolates, selected to reflect the geographic and genotypic diversity of the isolates, were also included for comparison. The katG S315T substitution and fabG1-inhA −15 C-to-T mutation were identified in 34 and 13 of the 52 INH-resistant isolates, respectively, and none of the INH-sensitive isolates. Three novel katG mutations, D117A, M257I, and G491C, were identified in three INH-resistant strains with a wild-type katG codon 315, fabG1-inhA regulatory region, and inhA structural gene. When analyzed for possible associations between resistance mechanisms, resistance phenotype, and genotypic groups, it was found that neither the katG S315T nor fabG1-inhA −15 C-to-T mutation clustered with any one genotypic group, but that the −15 C-to-T substitution was associated with isolates with intermediate INH resistance and isolates coresistant to ethionamide. In total, 90.4% of unrelated INH-resistant isolates could be identified by analysis of just two loci: katG315 and the fabG1-inhA regulatory region. PMID:16189082

Factors associated with tuberculosis treatment outcomes among tuberculosis patients attending tuberculosis treatment centres in 2016-2017 in Mogadishu, Somalia.

PubMed

Ali, Marian Khalif; Karanja, Simon; Karama, Mohammed

2017-01-01

World Health Organization (WHO) reported that tuberculosis (TB) was a major health problem and the second leading cause of mortality globally. An estimated 1.8 million TB deaths were reported in 2015. In Somalia, the average TB incidence was 274 cases per 100,000 people in 2014; prevalence was 513 per 100,000 population; and mortality rate excluding human immune deficiency virus (HIV)/TB co-infection was 64/100,000. In addition, the prevalence rates of multi-drug resistant (MDR)-TB are still high, 5.2% among new cases and 40.7% for retreatment cases. The objective of this study was to determine individual and institutional level factors associated with TB treatment outcomes (TB-TOs) among patients attending TBTCs in Mogadishu. The study design was cross-sectional, using quantitative and qualitative methods. Data was collected using interviewer administered semi-structured questionnaires and key in-depth interviews in 2016/2017. Qualitative data was coded using NVIVO8 and quantitative data analyzed using descriptive and inferential statistics at 95% confidence interval using SPSS20 software. The study used a sample of 385 TB patients. There were 315(81.8%) successful TB-TOs. Individual level factors-marital status, education level, HIV status, treatment category and knowledge on TB influenced TB-TOs (p-value < 0.05). Being married, educated, HIV-negative, new treatment case and knowledgeable on TB increased odds of successful TB-TOs (OR > 0, p value < 0.05) compared to other patients. TBTCs factors did not influence TB-TOs (p-value > 0.05). TB-TOs were mainly affected by patient individual factors. There was need for patient education on TB management and treatment; and improved patient-health provider relationship.

Factors associated with tuberculosis treatment outcomes among tuberculosis patients attending tuberculosis treatment centres in 2016-2017 in Mogadishu, Somalia

PubMed Central

Ali, Marian Khalif; Karanja, Simon; Karama, Mohammed

2017-01-01

Introduction World Health Organization (WHO) reported that tuberculosis (TB) was a major health problem and the second leading cause of mortality globally. An estimated 1.8 million TB deaths were reported in 2015. In Somalia, the average TB incidence was 274 cases per 100,000 people in 2014; prevalence was 513 per 100,000 population; and mortality rate excluding human immune deficiency virus (HIV)/TB co-infection was 64/100,000. In addition, the prevalence rates of multi-drug resistant (MDR)-TB are still high, 5.2% among new cases and 40.7% for retreatment cases. The objective of this study was to determine individual and institutional level factors associated with TB treatment outcomes (TB-TOs) among patients attending TBTCs in Mogadishu. Methods The study design was cross-sectional, using quantitative and qualitative methods. Data was collected using interviewer administered semi-structured questionnaires and key in-depth interviews in 2016/2017. Qualitative data was coded using NVIVO8 and quantitative data analyzed using descriptive and inferential statistics at 95% confidence interval using SPSS20 software. Results The study used a sample of 385 TB patients. There were 315(81.8%) successful TB-TOs. Individual level factors-marital status, education level, HIV status, treatment category and knowledge on TB influenced TB-TOs (p-value < 0.05). Being married, educated, HIV-negative, new treatment case and knowledgeable on TB increased odds of successful TB-TOs (OR > 0, p value < 0.05) compared to other patients. TBTCs factors did not influence TB-TOs (p-value > 0.05). Conclusion TB-TOs were mainly affected by patient individual factors. There was need for patient education on TB management and treatment; and improved patient-health provider relationship. PMID:29610635

Development and Psychometric Properties of a Tuberculosis-Specific Multidimensional Health-Related Quality-of-Life Measure for Patients with Pulmonary Tuberculosis.

PubMed

Abdulelah, Juman; Sulaiman, Syed Azhar Syed; Hassali, Mohamed A; Blebil, Ali Q; Awaisu, Ahmed; Bredle, Jason M

2015-05-01

Various generic instruments exist to assess health-related quality of life (HRQOL) in patients with tuberculosis (TB), but a psychometrically sound disease-specific instrument is lacking. The present study aimed to develop and psychometrically validate a multidimensional TB-specific HRQOL instrument relevant to the value of patients with pulmonary TB in Iraq with an eye toward cross-cultural application. The core general HRQOL questionnaire is composed of the Functional Assessment of Cancer Therapy-General items. A modular approach was followed for the development of the Functional Assessment of Chronic Illness Therapy-Tuberculosis (FACIT-TB) questionnaire in which a set of items assessing quality-of-life (QOL) issues not sufficiently covered by the core Functional Assessment of Cancer Therapy-General items, but considered to be relevant to the target population, was added. Moreover, principal-component analysis was used to determine the new subscale structure of the questionnaire. In addition to the 27 items of the core questionnaire, a set of 20 items referring to disease symptoms related to the site of infection, adverse effects, and additional QOL dimensions such as fatigue, social stigma, and economic burden of the illness was included. Factor analysis demonstrated that the FACIT-TB construct comprised five domains. A rigorous method was applied in the development of the FACIT-TB measure to fully understand the impact of TB on patients' QOL. The instrument is psychometrically sound and portrays multiple important dimensions of HRQOL. FACIT-TB is relatively brief, is easy to administer and score, and is appropriate for use in clinical trials and practice. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Differences in immune cell function between tuberculosis positive and negative Asian elephants.

PubMed

Landolfi, Jennifer A; Miller, Michele; Maddox, Carol; Zuckermann, Federico; Langan, Jennifer N; Terio, Karen A

2014-07-01

Tuberculosis is an important health concern for Asian elephant (Elephas maximus) populations worldwide, however, mechanisms underlying susceptibility to Mycobacterium tuberculosis are unknown. Proliferative responses assessed via brominated uridine incorporation and cytokine expression measured by real-time RT-PCR were evaluated in peripheral blood mononuclear cell (PBMC) cultures from 8 tuberculosis negative and 8 positive Asian elephants. Cultures were stimulated with Mycobacterium bovis purified protein derivative (PPD-B), M. tuberculosis culture filtrate protein (CFP)-10, and Mycobacterium avium PPD (PPD-A). Following stimulation with PPD-B, proliferation was higher (α = 0.005) in positive samples; no significant differences were detected following CFP-10 or PPD-A stimulation. Tumor necrosis factor (TNF)-α, interleukin (IL)-12, and interferon (IFN)-γ expression was greater in samples from positive elephants following stimulation with PPD-B (α = 0.025) and CFP-10 (α = 0.025 TNF-α and IL-12; α = 0.005 IFN-γ). Stimulation with PPD-A also produced enhanced IL-12 expression in positive samples (α = 0.025). Findings suggested that differences in immune cell function exist between tuberculosis positive and negative elephants. Proliferative responses and expression of TNF-α, IL-12, and IFN-γ in response to stimulation with PPD-B and CFP-10 differ between tuberculosis positive and negative elephants, suggesting these parameters may be important to tuberculosis immunopathogenesis in this species. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prevalence of Tuberculosis among Veterans, Military Personnel and their Families in East Azerbaijan Province Violators of the last 15 Years.

PubMed

Azad Aminjan, Maboud; Moaddab, Seyyed Reza; Hosseini Ravandi, Mohammad; Kazemi Haki, Behzad

2015-10-01

Nowadays in the world, tuberculosis is the second largest killer of adults after HIV. Due to the location of presidios that is mostly located in hazardous zones soldiers and army personnel are considered high risk, therefore we decided to determine the prevalence of tuberculosis status in this group of people. This was a cross-sectional descriptive research that studied the prevalence of pulmonary tuberculosis in soldiers and military personnel in the last 15 years in tuberculosis and lung disease research center at Tabriz University of Medical Sciences. The statistical population consisted of all the soldiers and military personnel. The detection method in this study was based on microscopic examination following Ziehl-Neelsen Stain and in Leuven Stein Johnson culturing. Descriptive statistics was used for statistical analysis and statistical values less than 0.05 were considered significant. By review information in this center since the 1988-2013 with 72 military personnel suffering from tuberculosis, it was revealed that among them 30 women, 42 men, 14 soldiers, 29 family members, and 29 military personnel are pointed. A significant correlation was found between TB rates among military personnel and their families. Although in recent years, the national statistics indicate a decline of tuberculosis, but the results of our study showed that TB is still a serious disease that must comply with the first symptoms of tuberculosis in military personnel and their families that should be diagnosed as soon as possible.

High Resolution Chest Computerized Tomography in the Diagnosis of Ocular Sarcoidosis in a High TB Endemic Population.

PubMed

Babu, Kalpana; Shukla, Sai Bhakti; Philips, Mariamma

2017-04-01

To review the role of high resolution chest computed tomography (HRCT) in ocular sarcoidosis in a high TB endemic population. This was a retrospective study. Out of 140 cases, 54 had ocular sarcoidosis, while 86 cases had ocular tuberculosis. Abnormal HRCT findings was noted in 52 cases (96.3%) of ocular sarcoidosis compared with 55 cases (64.7%) of ocular tuberculosis (p = 0.001). Mediastinal lymphadenopathy was the most common finding in both groups (p = 0.544). Hilar lymphadenopathy and fissural nodules were significantly seen in ocular sarcoidosis (p = 0.001). Necrosis was seen in three cases of ocular sarcoidosis. In nearly half of the cases, it was not possible to differentiate between sarcoidosis and tuberculosis on HRCT. HRCT is a useful diagnostic tool in ocular sarcoidosis. Bilateral hilar lymphadenopathy and fissural nodules are significant findings in ocular sarcoidosis. A confident diagnosis of ocular sarcoidosis is made by the amalgamation of results of clinical, radiologic, and other laboratory investigations.

Experience of tuberculosis in immigrants from South East Asia--implications for the imminent lease back of Hong Kong.

PubMed

Nisar, M; Williams, C S; Davies, P D

1991-05-01

We have undertaken a retrospective survey of patients of South East Asian ethnic origin (SEA), presenting with tuberculosis (between 1980 and 1989) while resident in the Liverpool district. Of 708 notifications in the 10-year period, 42 (6%) were SEA patients mainly from Hong Kong or mainland China. A total of 22 (52%) of the SEA patients presented with an extrapulmonary site of disease. Drug resistance was present in 11% of those for whom sensitivity results were available. Rates of disease in Hong Kong are similar to those seen in the Indian Subcontinent (ISC) population in the U.K. With the expected immigration of Hong Kong Chinese and possibly other SEA individuals to the U.K. as a result of the lease back of Hong Kong in 1997, all clinicians must be alerted to the possibility of tuberculosis whenever these individuals present with disease. The high incidence of extra pulmonary disease in SEA immigrants is striking and similar to that seen in the ISC population.

The D543N polymorphism of the SLC11A1/NRAMP1 gene is associated with treatment failure in male patients with pulmonary tuberculosis.

PubMed

Salinas-Delgado, Yvain; Galaviz-Hernández, Carlos; Toral, René García; Ávila Rejón, Carmen A; Reyes-Lopez, Miguel A; Martínez, Antonio Rojas; Martínez-Aguilar, Gerardo; Sosa-Macías, Martha

2015-09-01

Polymorphisms in SLC11A1/NRAMP1 have shown an important association with susceptibility to tuberculosis and progression to active disease. However, whether there is an association of these polymorphisms with treatment failure is unknown. The aim of this study was to determine the association of SLC11A1 polymorphisms with treatment failure in Mexican subjects with pulmonary tuberculosis. Thirty-three subjects with treatment failure were paired by age and body mass index with 33 patients who successfully completed treatment and were considered cured. We assessed the polymorphisms of SLC11A1 in the regions of D543N and INT4 via polymerase chain reaction real-time TaqMan® single nucleotide polymorphism (SNP) genotyping. We found that D543N (G/A genotype) was associated with treatment failure in patients with pulmonary tuberculosis [odds ratio (OR) 11.61, 95% confidence interval (CI) 3.66-36.78]. When adjusted by gender, this association remained significant in males (OR 11.09, 95% CI 3.46-35.51). In our male population, the presence of the D543N polymorphism of SLC11A1 is a risk factor for treatment failure. This finding should be confirmed in other populations.

Socio-economic factors and tuberculosis: a district-based ecological analysis in Hong Kong.

PubMed

Leung, C C; Yew, W W; Tam, C M; Chan, C K; Chang, K C; Law, W S; Wong, M Y; Au, K F

2004-08-01

Relatively little is known about the impact of socio-economic factors on tuberculosis in a metropolitan city with high disease incidence. District-specific tuberculosis notification rates for 1995--1997 and 2000--2002 were indirectly sex- and age-adjusted and compared with the socio-economic characteristics in the 1996 by-census and 2001 census. The differences between the 18 districts persisted after 3-year averaging and indirect standardisation. Only the percentage of population born locally, the percentage of the population widowed or divorced and the percentage of households residing in rooms or bedsits were consistently associated with the standardised notification ratios (SNR) for both periods, the first being negatively so (all P < 0.05). In a combined analysis with a general linear model for both periods, birth in China, residence <7 years, speaking other Asian languages, being married and in a single household were also significantly associated with the SNR (all P < 0.05). Using a backward conditional approach, only local birth, being married, and residing in rooms or bedsits were independent predictors of SNR (all P < 0.05). There was no significant association between SNR and socio-economic indices on education, occupation, unemployment and income. Socio-economic factors other than simple poverty are affecting the district-specific tuberculosis rates in Hong Kong.

Feasibility, Yield, and Cost of Active Tuberculosis Case Finding Linked to a Mobile HIV Service in Cape Town, South Africa: A Cross-sectional Study

PubMed Central

Kranzer, Katharina; Lawn, Stephen D.; Meyer-Rath, Gesine; Vassall, Anna; Raditlhalo, Eudoxia; Govindasamy, Darshini; van Schaik, Nienke; Wood, Robin; Bekker, Linda-Gail

2012-01-01

Background The World Health Organization is currently developing guidelines on screening for tuberculosis disease to inform national screening strategies. This process is complicated by significant gaps in knowledge regarding mass screening. This study aimed to assess feasibility, uptake, yield, treatment outcomes, and costs of adding an active tuberculosis case-finding program to an existing mobile HIV testing service. Methods and Findings The study was conducted at a mobile HIV testing service operating in deprived communities in Cape Town, South Africa. All HIV-negative individuals with symptoms suggestive of tuberculosis, and all HIV-positive individuals regardless of symptoms were eligible for participation and referred for sputum induction. Samples were examined by microscopy and culture. Active tuberculosis case finding was conducted on 181 days at 58 different sites. Of the 6,309 adults who accessed the mobile clinic, 1,385 were eligible and 1,130 (81.6%) were enrolled. The prevalence of smear-positive tuberculosis was 2.2% (95% CI 1.1–4.0), 3.3% (95% CI 1.4–6.4), and 0.4% (95% CI 1.4 015–6.4) in HIV-negative individuals, individuals newly diagnosed with HIV, and known HIV, respectively. The corresponding prevalence of culture-positive tuberculosis was 5.3% (95% CI 3.5–7.7), 7.4% (95% CI 4.5–11.5), 4.3% (95% CI 2.3–7.4), respectively. Of the 56 new tuberculosis cases detected, 42 started tuberculosis treatment and 34 (81.0%) completed treatment. The cost of the intervention was US$1,117 per tuberculosis case detected and US$2,458 per tuberculosis case cured. The generalisability of the study is limited to similar settings with comparable levels of deprivation and TB and HIV prevalence. Conclusions Mobile active tuberculosis case finding in deprived populations with a high burden of HIV and tuberculosis is feasible, has a high uptake, yield, and treatment success. Further work is now required to examine cost-effectiveness and affordability and whether and how the same results may be achieved at scale. PMID:22879816

How to optimize tuberculosis case finding: explorations for Indonesia with a health system model

PubMed Central

2009-01-01

Background A mathematical model was designed to explore the impact of three strategies for better tuberculosis case finding. Strategies included: (1) reducing the number of tuberculosis patients who do not seek care; (2) reducing diagnostic delay; and (3) engaging non-DOTS providers in the referral of tuberculosis suspects to DOTS services in the Indonesian health system context. The impact of these strategies on tuberculosis mortality and treatment outcome was estimated using a mathematical model of the Indonesian health system. Methods The model consists of multiple compartments representing logical movement of a respiratory symptomatic (tuberculosis suspect) through the health system, including patient- and health system delays. Main outputs of the model are tuberculosis death rate and treatment outcome (i.e. full or partial cure). We quantified the model parameters for the Jogjakarta province context, using a two round Delphi survey with five Indonesian tuberculosis experts. Results The model validation shows that four critical model outputs (average duration of symptom onset to treatment, detection rate, cure rate, and death rate) were reasonably close to existing available data, erring towards more optimistic outcomes than are actually reported. The model predicted that an intervention to reduce the proportion of tuberculosis patients who never seek care would have the biggest impact on tuberculosis death prevention, while an intervention resulting in more referrals of tuberculosis suspects to DOTS facilities would yield higher cure rates. This finding is similar for situations where the alternative sector is a more important health resource, such as in most other parts of Indonesia. Conclusion We used mathematical modeling to explore the impact of Indonesian health system interventions on tuberculosis treatment outcome and deaths. Because detailed data were not available regarding the current Indonesian population, we relied on expert opinion to quantify the parameters. The fact that the model output showed similar results to epidemiological data suggests that the experts had an accurate understanding of this subject, thereby reassuring the quality of our predictions. The model highlighted the potential effectiveness of active case finding of tuberculosis patients with limited access to DOTS facilities in the developing country setting. PMID:19505296

The growing impact of HIV infection on the epidemiology of tuberculosis in England and Wales: 1999–2003

PubMed Central

Ahmed, Aliko B; Abubakar, Ibrahim; Delpech, Valerie; Lipman, Marc; Boccia, Delia; Forde, Josh; Antoine, Delphine; Watson, John M

2007-01-01

Background Previous studies have estimated the prevalence of tuberculosis and HIV infection in population subgroups in the UK. This study was undertaken to describe recent trends in the proportion of individuals with HIV infection among reported cases of tuberculosis in England and Wales, and to review the implications for clinical and public health care. Methods A population‐based matching study using national surveillance databases was used to investigate all persons aged 15 years and over reported with a diagnosis of tuberculosis to the Health Protection Agency in England and Wales in 1999–2003. Record linkage was used to match the national tuberculosis and HIV/AIDS surveillance databases to identify all cases of tuberculosis and determine the proportion of patients with tuberculosis co‐infected with HIV. The distribution and characteristics of the cases were determined and the trend examined by year. Results Of 30 670 cases of tuberculosis reported in England and Wales between 1999 and 2003, an estimated 1743 (5.7%) were co‐infected with HIV. There was a year on year increase in the proportion from 3.1% (169/5388) in 1999 to 8.3% (548/6584) in 2003 (p for trend <0.0001). Co‐infected patients contributed to almost a third of the increase in the number of cases of tuberculosis during the 5 year period. Patients co‐infected with HIV were predominantly those born abroad. 18.5% (n = 323) of co‐infected patients had not been reported as active cases of tuberculosis on the national tuberculosis database. Conclusion The proportion of patients with tuberculosis co‐infected with HIV in England and Wales is increasing, with the greatest impact on those born abroad regardless of their ethnic origin. With HIV infection contributing substantially to the increase in the number of cases of tuberculosis, close cooperation in the clinical management and accurate notification of patients is vital if appropriate care and public health action is to be achieved. PMID:17311840

Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons.

PubMed

Quiroga, Maria Florencia; Angerami, Matias Tomas; Santucci, Natalia; Ameri, Diego; Francos, Jose Luis; Wallach, Jorge; Sued, Omar; Cahn, Pedro; Salomón, Horacio; Bottasso, Oscar

2012-01-01

Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons

PubMed Central

Quiroga, Maria Florencia; Angerami, Matias Tomas; Santucci, Natalia; Ameri, Diego; Francos, Jose Luis; Wallach, Jorge; Sued, Omar; Cahn, Pedro; Salomón, Horacio; Bottasso, Oscar

2012-01-01

Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS. PMID:22431997

Structure of the MazF-mt9 toxin, a tRNA-specific endonuclease from Mycobacterium tuberculosis.

PubMed

Chen, Ran; Tu, Jie; Liu, Zhihui; Meng, Fanrong; Ma, Pinyun; Ding, Zhishan; Yang, Chengwen; Chen, Lei; Deng, Xiangyu; Xie, Wei

2017-05-06

Tuberculosis (TB) is a severe disease caused by Mycobacterium tuberculosis (M. tb) and the well-characterized M. tb MazE/F proteins play important roles in stress adaptation. Recently, the MazF-mt9 toxin has been found to display endonuclease activities towards tRNAs but the mechanism is unknown. We hereby present the crystal structure of apo-MazF-mt9. The enzyme recognizes tRNA Lys with a central UUU motif within the anticodon loop, but is insensitive to the sequence context outside of the loop. Based on our crystallographic and biochemical studies, we identified key residues for catalysis and proposed the potential tRNA-binding site. Copyright © 2017 Elsevier Inc. All rights reserved.

The impact of social protection and poverty elimination on global tuberculosis incidence: a statistical modelling analysis of Sustainable Development Goal 1.

PubMed

Carter, Daniel J; Glaziou, Philippe; Lönnroth, Knut; Siroka, Andrew; Floyd, Katherine; Weil, Diana; Raviglione, Mario; Houben, Rein M G J; Boccia, Delia

2018-05-01

The End TB Strategy and the Sustainable Development Goals (SDGs) are intimately linked by their common targets and approaches. SDG 1 aims to end extreme poverty and expand social protection coverage by 2030. Achievement of SDG 1 is likely to affect the tuberculosis epidemic through a range of pathways. We estimate the reduction in global tuberculosis incidence that could be obtained by reaching SDG 1. We developed a conceptual framework linking key indicators of SDG 1 progress to tuberculosis incidence via well described risk factor pathways and populated it with data from the SDG data repository and the WHO tuberculosis database for 192 countries. Correlations and mediation analyses informed the strength of the association between the SDG 1 subtargets and tuberculosis incidence, resulting in a simplified framework for modelling. The simplified framework linked key indicators for SDG 1 directly to tuberculosis incidence. We applied an exponential decay model based on linear associations between SDG 1 indicators and tuberculosis incidence to estimate tuberculosis incidence in 2035. Ending extreme poverty resulted in a reduction in global incidence of tuberculosis of 33·4% (95% credible interval 15·5-44·5) by 2035 and expanding social protection coverage resulted in a reduction in incidence of 76·1% (45·2-89·9) by 2035; both pathways together resulted in a reduction in incidence of 84·3% (54·7-94·9). Full achievement of SDG 1 could have a substantial effect on the global burden of tuberculosis. Cross-sectoral approaches that promote poverty reduction and social protection expansion will be crucial complements to health interventions, accelerating progress towards the End TB targets. World Health Organization. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Tuberculosis in vulnerable populations in Eastern Mediterranean Region-Implications for control.

PubMed

Shakoor, Sadia; Hasan, Rumina

2016-12-01

Socially and economically disadvantaged or "vulnerable" people are at high risk of tuberculosis (TB) and also contribute to active chains of TB transmission. Included in such vulnerable populations are children, women, prisoners, people living with human immunodeficiency virus, the homeless, and displaced people. The ongoing active transmission of TB among such populations is made more difficult to assess and control by difficult access, health inequities, poverty, and other chronic and debilitating health conditions at individual, domestic, and community levels. The 22 Eastern Mediterranean Region member states encompass diverse sociopolitical and socioeconomic situations with far-reaching effects on vulnerable populations in each country, thereby threatening the control of TB. Here, we examined the impact of these populations on the incidence and transmission of TB in light of these risks. Approximately 60% of the regional population comprises children and adolescents ⩽19years of age, increasing the population at risk. Additionally, up to 11% of the population suffers from mental- or substance-abuse disorders, while >50% of the world refugee populations live in the Eastern Mediterranean Region. TB control requires a strategic approach at the country level to access these vulnerable populations. Copyright © 2016.

Total synthesis of cyclomarins A, C and D, marine cyclic peptides with interesting anti-tuberculosis and anti-malaria activities.

PubMed

Barbie, Philipp; Kazmaier, Uli

2016-07-07

Cyclomarins are cyclic heptapeptides containing four unusual amino acids. New synthetic protocols toward their synthesis have been developed, leading to the synthesis and biological evaluation of three natural occurring cyclomarins. Interestingly, cyclomarins address two completely different targets: Clp C1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Ase of Plasmodium falciparum. Therefore, cyclomarins are interesting lead structures for the development of drugs against tuberculosis and malaria.

Multi-drug-resistant tuberculosis in HIV positive patients in Eastern Europe.

PubMed

Post, Frank A; Grint, Daniel; Werlinrud, Anne Marie; Panteleev, Alexander; Riekstina, Vieja; Malashenkov, Evgeniy A; Skrahina, Alena; Duiculescu, Dan; Podlekareva, Daria; Karpov, Igor; Bondarenko, Vasiliy; Chentsova, Nelly; Lundgren, Jens; Mocroft, Amanda; Kirk, Ole; Miro, Jose M

2014-03-01

Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature. We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB in Eastern Europe between 2004 and 2006 to 89 patients whose Mycobacterium tuberculosis isolates were susceptible to isoniazid and rifampicin. Patients with HIV and MDR TB were young and predominantly male with high rates of intravenous drug use, imprisonment and hepatitis C co-infection. Eighty-four per cent of patients with MDR TB had no history of previous TB drug exposure suggesting that the majority of MDR TB resulted from transmission of drug-resistant M. tuberculosis. The use of non-standardized tuberculosis treatment was common, and the use of antiretroviral therapy infrequent. Compared to those with susceptible tuberculosis, patients with MDR TB were less likely to achieve cure or complete tuberculosis treatment (21.8% vs. 62.9%, p < 0.0001), and they were more likely to die (65.5% vs. 27.0%, p < 0.0001). Our study documents suboptimal management and poor outcomes in HIV positive patients with MDR TB. Implementation of WHO guidelines, rapid TB diagnostics and TB drug susceptibility testing for all patients remain a priority in this region. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Tuberculosis control in postcolonial South India and Southeast Asia: Fractured sovereignties in international health, 1948-1960

PubMed Central

Neelakantan, Vivek

2018-01-01

Between 1948 and 1960, South India (Madras State) and Southeast Asia—with an emphasis on Indonesia, the Philippines, and Burma— emerged as global centres for tuberculosis control. This article attempts to situate tuberculosis control of these two regions within the broader context of transnational health. It investigates the unique ways in which tuberculosis control in South India and Southeast Asia reflected the inner tensions between the notional magic bullet approach, which focuses on specific cures to root out the cause of the disease, and a more holistic approach that relates disease prevention to overall well-being of the population. The implementation of tuberculosis control programs across South India and Southeast Asia shed light on the nature of the postcolonial state sovereignty in public health. Across India, as in Southeast Asia, the state sovereignty appertaining to the implementation of health policy was fractured, as evident in the opposition to the Bacillus Calmette–Guérin (BCG) vaccination. Based on a wide range of archival materials, this article situates tuberculosis control within the context of nationalist discourse and preventive medicine. In doing so, it adds not only to the historiography of tuberculosis in non-Western contexts, which has hitherto focused on India, Sri Lanka, or Africa but also to the relatively new field of Southeast Asian medical history. PMID:29770359

Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy.

PubMed

Mieras, Liesbeth; Anthony, Richard; van Brakel, Wim; Bratschi, Martin W; van den Broek, Jacques; Cambau, Emmanuelle; Cavaliero, Arielle; Kasang, Christa; Perera, Geethal; Reichman, Lee; Richardus, Jan Hendrik; Saunderson, Paul; Steinmann, Peter; Yew, Wing Wai

2016-06-08

Post-exposure prophylaxis (PEP) for leprosy is administered as one single dose of rifampicin (SDR) to the contacts of newly diagnosed leprosy patients. SDR reduces the risk of developing leprosy among contacts by around 60 % in the first 2-3 years after receiving SDR. In countries where SDR is currently being implemented under routine programme conditions in defined areas, questions were raised by health authorities and professional bodies about the possible risk of inducing rifampicin resistance among the M. tuberculosis strains circulating in these areas. This issue has not been addressed in scientific literature to date. To produce an authoritative consensus statement about the risk that SDR would induce rifampicin-resistant tuberculosis, a meeting was convened with tuberculosis (TB) and leprosy experts. The experts carefully reviewed and discussed the available evidence regarding the mechanisms and risk factors for the development of (multi) drug-resistance in M. tuberculosis with a view to the special situation of the use of SDR as PEP for leprosy. They concluded that SDR given to contacts of leprosy patients, in the absence of symptoms of active TB, poses a negligible risk of generating resistance in M. tuberculosis in individuals and at the population level. Thus, the benefits of SDR prophylaxis in reducing the risk of developing leprosy in contacts of new leprosy patients far outweigh the risks of generating drug resistance in M. tuberculosis.

Social organization and control of tuberculosis: the experience of a Brazilian town.

PubMed

Bulgarelli, Alexandre Favero; Villa, Tereza Cristina Scatena; Pinto, Ione Carvalho

2013-01-01

This study was aimed at analyzing the participation of a committee formed by representatives of the community in tuberculosis control based on a participatory management model. This is a Case Study involving a tuberculosis committee with data collected through semi-structured interviews conducted with nine individuals. The data, organized through the Association of Ideas Map technique, were analyzed based on the Social Constructionism perspective. The participation of the Tuberculosis Committee studied was shown to be effective and associated with aspects articulated according to the measures taken by the social parties involved in the committee, culminating with assistances inserted into certain parts of the town's co-management. It was concluded that the reality of this case study shows that relationships among civil society can guide the management model in the search for effective processes of tuberculosis control.

Accuracy of the QuantiFERON-TB Gold in Tube for diagnosing tuberculosis in a young pediatric population previously vaccinated with Bacille Calmette-Guérin

PubMed Central

Vallada, Marcelo Genofre; Okay, Thelma Suely; Del Negro, Gilda Maria B.; Antonio, Claudio Amaral; Yamamoto, Lidia; Ramos, Sonia Regina T. S.

2014-01-01

Objective: To evaluate the accuracy of an interferongamma release assay (QuantiFERON-TB Gold in Tube) for diagnosing Mycobacterium tuberculosis infection in a young pediatric population. Methods: 195 children previously vaccinated with BCG were evaluated, being 184 healthy individuals with no clinical or epidemiological evidence of mycobacterial infection, and 11 with Mycobacterium tuberculosis infection, according to clinical, radiological, and laboratory parameters. A blood sample was obtained from each child and processed according to the manufacturer's instructions. The assay performance was evaluated by a Receiver Operating Characteristic (ROC) curve. Results: In the group of 184 non-infected children, 130 (70.6%) were under the age of four years (mean age of 35 months). In this group, 177 children (96.2%) had negative test results, six (3.2%) had indeterminate results, and one (0.5%) had a positive result. In the group of 11 infected children, the mean age was 58.5 months, and two of them (18%) had negative results. The ROC curve had an area under the curve of 0.88 (95%CI 0.82-0.92; p<0.001), disclosing a predictive positive value of 81.8% for the test (95%CI 46.3-97.4). The assay sensitivity was 81.8% (95%CI 48.2-97.2) and the specificity was 98.8% (95%CI 96-99.8). Conclusions: In the present study, the QuantiFERON-TB Gold in Tube performance for diagnosing M. tuberculosis infection was appropriate in a young pediatric population. PMID:24676183

Long-Term Assessment of Wild Boar Harvesting and Cattle Removal for Bovine Tuberculosis Control in Free Ranging Populations

PubMed Central

Mentaberre, Gregorio; Romero, Beatriz; de Juan, Lucía; Navarro-González, Nora; Velarde, Roser; Mateos, Ana; Marco, Ignasi; Olivé-Boix, Xavier; Domínguez, Lucas; Lavín, Santiago; Serrano, Emmanuel

2014-01-01

Wild boar is a recognized reservoir of bovine tuberculosis (TB) in the Mediterranean ecosystems, but information is scarce outside of hotspots in southern Spain. We describe the first high-prevalence focus of TB in a non-managed wild boar population in northern Spain and the result of eight years of TB management. Measures implemented for disease control included the control of the local wild boar population through culling and stamping out of a sympatric infected cattle herd. Post-mortem inspection for detection of tuberculosis-like lesions as well as cultures from selected head and cervical lymph nodes was done in 745 wild boar, 355 Iberian ibexes and five cattle between 2004 and 2012. The seasonal prevalence of TB reached 70% amongst adult wild boar and ten different spoligotypes and 13 MIRU-VNTR profiles were detected, although more than half of the isolates were included in the same clonal complex. Only 11% of infected boars had generalized lesions. None of the ibexes were affected, supporting their irrelevance in the epidemiology of TB. An infected cattle herd grazed the zone where 168 of the 197 infected boars were harvested. Cattle removal and wild boar culling together contributed to a decrease in TB prevalence. The need for holistic, sustained over time, intensive and adapted TB control strategies taking into account the multi-host nature of the disease is highlighted. The potential risk for tuberculosis emergence in wildlife scenarios where the risk is assumed to be low should be addressed. PMID:24558435

The impact of migration on tuberculosis epidemiology and control in high-income countries: a review.

PubMed

Pareek, Manish; Greenaway, Christina; Noori, Teymur; Munoz, Jose; Zenner, Dominik

2016-03-23

Tuberculosis (TB) causes significant morbidity and mortality in high-income countries with foreign-born individuals bearing a disproportionate burden of the overall TB case burden in these countries. In this review of tuberculosis and migration we discuss the impact of migration on the epidemiology of TB in low burden countries, describe the various screening strategies to address this issue, review the yield and cost-effectiveness of these programs and describe the gaps in knowledge as well as possible future solutions.The reasons for the TB burden in the migrant population are likely to be the reactivation of remotely-acquired latent tuberculosis infection (LTBI) following migration from low/intermediate-income high TB burden settings to high-income, low TB burden countries.TB control in high-income countries has historically focused on the early identification and treatment of active TB with accompanying contact-tracing. In the face of the TB case-load in migrant populations, however, there is ongoing discussion about how best to identify TB in migrant populations. In general, countries have generally focused on two methods: identification of active TB (either at/post-arrival or increasingly pre-arrival in countries of origin) and secondly, conditionally supported by WHO guidance, through identifying LTBI in migrants from high TB burden countries. Although health-economic analyses have shown that TB control in high income settings would benefit from providing targeted LTBI screening and treatment to certain migrants from high TB burden countries, implementation issues and barriers such as sub-optimal treatment completion will need to be addressed to ensure program efficacy.

Xpert® MTB/RIF: Usefulness for the diagnosis of tuberculosis and resistance to rifampicin.

PubMed

Vergara Gómez, Andrea; González-Martín, Julià; García-Basteiro, Alberto L

2017-11-09

The advent of the Xpert® MTB/RIF technique was a revolution in the diagnosis of tuberculosis, especially in areas with high incidence and low resources. It allows the detection of Mycobacterium tuberculosis complex and simultaneously the most common resistance mutations to rifampicin in less than 2h. For respiratory samples the sensitivity is very high, but it decreases for extrapulmonary samples and children. Although it is faster and simpler than conventional methods, it presents some limitations and new and better techniques are needed to reduce the number of cases and deaths caused by tuberculosis. This review aims to assess the scientific evidence around the diagnostic performance of Xpert® MTB/RIF in different types of samples and populations, as well as analyse its strengths and limitations for TB diagnosis. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Shared characteristics between Mycobacterium tuberculosis and fungi contribute to virulence.

PubMed

Willcocks, Sam; Wren, Brendan W

2014-01-01

Mycobacterium tuberculosis, an etiologic agent of tuberculosis, exacts a heavy toll in terms of human morbidity and mortality. Although an ancient disease, new strains are emerging as human population density increases. The emergent virulent strains appear adept at steering the host immune response from a protective Th1 type response towards a Th2 bias, a feature shared with some pathogenic fungi. Other common characteristics include infection site, metabolic features, the composition and display of cell surface molecules, the range of innate immune receptors engaged during infection, and the ability to form granulomas. Literature from these two distinct fields of research are reviewed to propose that the emergent virulent strains of M. tuberculosis are in the process of convergent evolution with pathogenic fungi, and are increasing the prominence of conserved traits from environmental phylogenetic ancestors that facilitate their evasion of host defenses and dissemination.

Structural and functional analyses of Mycobacterium tuberculosis Rv3315c-encoded metal-dependent homotetrameric cytidine deaminase.

PubMed

Sánchez-Quitian, Zilpa A; Schneider, Cristopher Z; Ducati, Rodrigo G; de Azevedo, Walter F; Bloch, Carlos; Basso, Luiz A; Santos, Diógenes S

2010-03-01

The emergence of drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, has exacerbated the treatment and control of this disease. Cytidine deaminase (CDA) is a pyrimidine salvage pathway enzyme that recycles cytidine and 2'-deoxycytidine for uridine and 2'-deoxyuridine synthesis, respectively. A probable M. tuberculosis CDA-coding sequence (cdd, Rv3315c) was cloned, sequenced, expressed in Escherichia coli BL21(DE3), and purified to homogeneity. Mass spectrometry, N-terminal amino acid sequencing, gel filtration chromatography, and metal analysis of M. tuberculosis CDA (MtCDA) were carried out. These results and multiple sequence alignment demonstrate that MtCDA is a homotetrameric Zn(2+)-dependent metalloenzyme. Steady-state kinetic measurements yielded the following parameters: K(m)=1004 microM and k(cat)=4.8s(-1) for cytidine, and K(m)=1059 microM and k(cat)=3.5s(-1) for 2'-deoxycytidine. The pH dependence of k(cat) and k(cat)/K(M) for cytidine indicate that protonation of a single ionizable group with apparent pK(a) value of 4.3 abolishes activity, and protonation of a group with pK(a) value of 4.7 reduces binding. MtCDA was crystallized and crystal diffracted at 2.0 A resolution. Analysis of the crystallographic structure indicated the presence of a Zn(2+) coordinated by three conserved cysteines and the structure exhibits the canonical cytidine deaminase fold. (c) 2009 Elsevier Inc. All rights reserved.

Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naffin-Olivos, Jacqueline L.; Daab, Andrew; White, Andre

The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 Å and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two-domain protein, one of which contains the catalytic residues that are the signature of a serinemore » protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity« less

Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c).

PubMed

Naffin-Olivos, Jacqueline L; Daab, Andrew; White, Andre; Goldfarb, Nathan E; Milne, Amy C; Liu, Dali; Baikovitz, Jacqueline; Dunn, Ben M; Rengarajan, Jyothi; Petsko, Gregory A; Ringe, Dagmar

2017-05-02

The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 Å and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two-domain protein, one of which contains the catalytic residues that are the signature of a serine protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity.

Time series analysis of demographic and temporal trends of tuberculosis in Singapore.

PubMed

Wah, Win; Das, Sourav; Earnest, Arul; Lim, Leo Kang Yang; Chee, Cynthia Bin Eng; Cook, Alex Richard; Wang, Yee Tang; Win, Khin Mar Kyi; Ong, Marcus Eng Hock; Hsu, Li Yang

2014-10-31

Singapore is an intermediate tuberculosis (TB) incidence country, with a recent rise in TB incidence from 2008, after a fall in incidence since 1998. This study identified population characteristics that were associated with the recent increase in TB cases, and built a predictive model of TB risk in Singapore. Retrospective time series analysis was used to study TB notification data collected from 1995 to 2011 from the Singapore Tuberculosis Elimination Program (STEP) registry. A predictive model was developed based on the data collected from 1995 to 2010 and validated using the data collected in 2011. There was a significant difference in demographic characteristics between resident and non-resident TB cases. TB risk was higher in non-residents than in residents throughout the period. We found no significant association between demographic and macro-economic factors and annual incidence of TB with or without adjusting for the population-at-risk. Despite growing non-resident population, there was a significant decrease in the non-resident TB risk (p < 0.0001). However, there was no evidence of trend in the resident TB risk over this time period, though differences between different demographic groups were apparent with ethnic minorities experiencing higher incidence rates. The study found that despite an increasing size of non-resident population, TB risk among non-residents was decreasing at a rate of about 3% per year. There was an apparent seasonality in the TB reporting.

Knowledge about tuberculosis transmission and prevention and perceptions of health service utilization among index cases and contacts in Brazil: Understanding losses in the latent tuberculosis cascade of care.

PubMed

Salame, Flavia Matos; Ferreira, Márcia Danielle; Belo, Marcia Teresa; Teixeira, Eleny Guimarães; Cordeiro-Santos, Marcelo; Ximenes, Ricardo Arraes; de Albuquerque, Maria de Fátima Militão; Hill, Philip C; Menzies, Dick; Trajman, Anete

2017-01-01

Tuberculosis contacts are candidates for active and latent tuberculosis infection screening and eventual treatment. However, many losses occur in the different steps of the contacts' cascade of care. Reasons for this are poorly understood. To describe the different steps where losses in the contact cascade occur and to explore knowledge and attitudes regarding tuberculosis transmission/prevention and perceptions about tuberculosis services in order to understand the reasons for losses from the tuberculosis service users' perspective. We collected routine data from the index case and contact registry books and from patients' records to build the cascade of care of contacts in 12 health facilities in three Brazilian cities with high tuberculosis incidence rates. During a knowledge, attitudes and practices (KAP) survey, trained interviewers administered a semi-structured questionnaire to 138 index cases and 98 contacts. Most of the losses in the cascade occurred in the first two steps (contact identification, 43% and tuberculin skin testing placement, 91% of the identified contacts). Among KAP-interviewed contacts, 67% knew how tuberculosis is transmitted, 87% knew its key symptoms and 81% declared they would take preventive therapy if prescribed. Among KAP-interviewed index cases, 67% knew they could spread tuberculosis, 70% feared for the health of their families and 88% would like their family to be evaluated in the same services. Only a small proportion of contacts are evaluated for active and latent tuberculosis, despite their-and their index cases'-reasonable knowledge, positive attitudes towards prevention and satisfaction with tuberculosis services. In these services, education of service users would not be a sufficient solution. Healthcare workers' and managers' perspective, not explored in this study, may bring more light to this subject.

Childhood tuberculosis in the State of Qatar: the effect of a limited expatriate screening programme on the incidence of tuberculosis.

PubMed

Al-Marri, M R

2001-09-01

To determine incidence rates and the effectiveness of the expatriate screening programme on paediatric tuberculosis (TB) in the State of Qatar. A state-wide, population-based, retrospective analysis of all cases of tuberculosis among children 0-14 years of age reported to the TB Unit of the Division of Public Health during 1983-1996. One hundred and forty-four children with tuberculous disease were identified, with a steadily declining incidence rate (rate of notification) from 11/100000 children (0-14 years) population in 1983 to 7/100000 in 1996. This decrease in the childhood TB case notification rate correlated with foreign-born children, older children and the implementation of expatriate screening in 1986. Diagnosis in 56% of children was made abroad or within 3 months of arrival from vacation and 30% within one year of arrival. Comparison of the three age groups (<5, 5-9 and 10-14 years) showed no significant difference with regard to nationality, sex, type of TB, radiological findings and screening. However older children were more likely to be symptomatic (P < 0.0001) and to have positive tuberculin skin test (TST) reactivity (P = 0.012), culture (P < 0.0001), and gastric aspirates (P = 0.018). Although there was a 36% decrease in paediatric TB incidence after the implementation of expatriate screening in 1986, Qatar has a high rate of paediatric tuberculosis. The policy of BCG vaccination at birth should be continued, and screening children at school entry and on return from vacation would be useful for further case identification.

Conventional and molecular epidemiology of tuberculosis in Manitoba.

PubMed

Blackwood, Kym S; Al-Azem, Assaad; Elliott, Lawrence J; Hershfield, Earl S; Kabani, Amin M

2003-08-13

To describe the demographic and geographic distribution of tuberculosis (TB) in Manitoba, thus determining risk factors associated with clustering and higher incidence rates in distinct subpopulations. Data from the Manitoba TB Registry was compiled to generate a database on 855 patients with tuberculosis and their contacts from 1992-1999. Recovered isolates of M. tuberculosis were typed by IS6110 restriction fragment length polymorphisms. Bivariate and multivariate logistic regression models were used to identify risk factors involved in clustering. A trend to clustering was observed among the Canadian-born treaty Aboriginal subgroup in contrast to the foreign-born. The dominant type, designated fingerprint type 1, accounts for 25.8% of total cases and 75.3% of treaty Aboriginal cases. Among type 1 patients residing in urban areas, 98.9% lived in Winnipeg. In rural areas, 92.8% lived on Aboriginal reserves. Statistical models revealed that significant risk factors for acquiring clustered tuberculosis are gender, age, ethnic origin and residence. Those at increased risk are: males (p < 0.05); those under age 65 (p < 0.01 for each age subgroup); treaty Aboriginals (p < 0.001), and those living on reserve land (p < 0.001). Molecular typing of isolates in conjunction with contact tracing data supports the notion of the largest ongoing transmission of a single strain of TB within the treaty-status population of Canada recorded to date. This data demonstrates the necessity of continued surveillance of countries with low prevalence of the disease in order to determine and target high-risk populations for concentrated prevention and control measures.

Conventional and molecular epidemiology of Tuberculosis in Manitoba

PubMed Central

Blackwood, Kym S; Al-Azem, Assaad; Elliott, Lawrence J; Hershfield, Earl S; Kabani, Amin M

2003-01-01

Background To describe the demographic and geographic distribution of tuberculosis (TB) in Manitoba, thus determining risk factors associated with clustering and higher incidence rates in distinct subpopulations. Methods Data from the Manitoba TB Registry was compiled to generate a database on 855 patients with tuberculosis and their contacts from 1992–1999. Recovered isolates of M. tuberculosis were typed by IS6110 restriction fragment length polymorphisms. Bivariate and multivariate logistic regression models were used to identify risk factors involved in clustering. Results A trend to clustering was observed among the Canadian-born treaty Aboriginal subgroup in contrast to the foreign-born. The dominant type, designated fingerprint type 1, accounts for 25.8% of total cases and 75.3% of treaty Aboriginal cases. Among type 1 patients residing in urban areas, 98.9% lived in Winnipeg. In rural areas, 92.8% lived on Aboriginal reserves. Statistical models revealed that significant risk factors for acquiring clustered tuberculosis are gender, age, ethnic origin and residence. Those at increased risk are: males (p < 0.05); those under age 65 (p < 0.01 for each age subgroup); treaty Aboriginals (p < 0.001), and those living on reserve land (p < 0.001). Conclusion Molecular typing of isolates in conjunction with contact tracing data supports the notion of the largest ongoing transmission of a single strain of TB within the treaty-status population of Canada recorded to date. This data demonstrates the necessity of continued surveillance of countries with low prevalence of the disease in order to determine and target high-risk populations for concentrated prevention and control measures. PMID:12917019

Development of an automated MODS plate reader to detect early growth of Mycobacterium tuberculosis.

PubMed

Comina, G; Mendoza, D; Velazco, A; Coronel, J; Sheen, P; Gilman, R H; Moore, D A J; Zimic, M

2011-06-01

In this work, an automated microscopic observation drug susceptibility (MODS) plate reader has been developed. The reader automatically handles MODS plates and after autofocussing digital images are acquired of the characteristic microscopic cording structures of Mycobacterium tuberculosis, which are the identification method utilized in the MODS technique to detect tuberculosis and multidrug resistant tuberculosis. In conventional MODS, trained technicians manually move the MODS plate on the stage of an inverted microscope while trying to locate and focus upon the characteristic microscopic cording colonies. In centres with high tuberculosis diagnostic demand, sufficient time may not be available to adequately examine all cultures. An automated reader would reduce labour time and the handling of M. tuberculosis cultures by laboratory personnel. Two hundred MODS culture images (100 from tuberculosis positive and 100 from tuberculosis negative sputum samples confirmed by a standard MODS reading using a commercial microscope) were acquired randomly using the automated MODS plate reader. A specialist analysed these digital images with the help of a personal computer and designated them as M. tuberculosis present or absent. The specialist considered four images insufficiently clear to permit a definitive reading. The readings from the 196 valid images resulted in a 100% agreement with the conventional nonautomated standard reading. The automated MODS plate reader combined with open-source MODS pattern recognition software provides a novel platform for high throughput automated tuberculosis diagnosis. © 2011 The Authors Journal of Microscopy © 2011 Royal Microscopical Society.

Evidence for tuberculosis in 18th/19th century slaves in Anse Sainte-Marguerite (Guadeloupe - French Western Indies).

PubMed

Lösch, Sandra; Kim, Mi-Ra; Dutour, Olivier; Courtaud, Patrice; Maixner, Frank; Romon, Thomas; Sola, Christophe; Zink, Albert

2015-06-01

During the American colonization in the 18th and 19th century, Africans were captured and shipped to America. Harsh living and working conditions often led to chronic diseases and high mortality rates. Slaves in the Caribbean were forced to work mainly on sugar plantations. They were buried in cemeteries like Anse Sainte-Marguerite on the isle of Grande-Terre (Guadeloupe) which was examined by archaeologists and physical anthropologists. Morphological studies on osseous remains of 148 individuals revealed 15 cases with signs for bone tuberculosis and a high frequency of periosteal reactions which indicates early stages of the disease. 11 bone samples from these cemeteries were analysed for ancient DNA. The samples were extracted with established procedures and examined for the cytoplasmic multicopy β-actin gene and Mycobacterium tuberculosis complex DNA (IS 6110) by PCR. An amplification product for M. tuberculosis with the size of 123 bp was obtained. Sequencing confirmed the result. This study shows evidence of M. tuberculosis complex DNA in a Caribbean slave population. Copyright © 2015 Elsevier Ltd. All rights reserved.

Association of tuberculosis with multimorbidity and social networks.

PubMed

Valenzuela-Jiménez, Hiram; Manrique-Hernández, Edgar Fabian; Idrovo, Alvaro Javier

2017-01-01

The combination of tuberculosis with other diseases can affect tuberculosis treatment within populations. In the present study, social network analysis of data retrieved from the Mexican National Epidemiological Surveillance System was used in order to explore associations between the number of contacts and multimorbidity. The node degree was calculated for each individual with tuberculosis and included information from 242 contacts without tuberculosis. Multimorbidity was identified in 49.89% of individuals. The node degrees were highest for individuals with tuberculosis + HIV infection (p < 0.04) and lowest for those with tuberculosis + pulmonary edema (p < 0.07). Social network analysis should be used as a standard method for monitoring tuberculosis and tuberculosis-related syndemics. RESUMO A combinação de tuberculose e outras doenças pode afetar o tratamento da tuberculose nas populações. No presente estudo, a análise de redes sociais de dados extraídos do Sistema Nacional de Vigilância Epidemiológica do México foi usada para explorar as relações entre o número de contatos e a multimorbidade. O grau do nó foi calculado para cada indivíduo com tuberculose e incluiu informações a respeito de 242 contatos sem tuberculose. A multimorbidade foi identificada em 49,89% dos indivíduos. Os maiores graus dos nós foram os referentes a indivíduos com tuberculose + infecção pelo HIV (p < 0,04), e os menores foram os referentes a indivíduos com tuberculose + edema pulmonar (p < 0,07). A análise de redes sociais deve ser usada como método-padrão para monitorar a tuberculose e a sindemia relacionada com a tuberculose.

The Burden and Clinical Presentation of Pulmonary Tuberculosis in Adults With Severe Respiratory Illness in a High Human Immunodeficiency Virus Prevalence Setting, 2012-2014.

PubMed

Walaza, Sibongile; Tempia, Stefano; Dreyer, Andries; Dawood, Halima; Variava, Ebrahim; Martinson, Neil A; Moyes, Jocelyn; Cohen, Adam L; Wolter, Nicole; von Mollendorf, Claire; von Gottberg, Anne; Haffejee, Sumayya; Treurnicht, Florette; Hellferscee, Orienka; Ismail, Nazir; Cohen, Cheryl

2017-01-01

Understanding the burden and clinical presentation of tuberculosis in patients with severe respiratory illness (SRI) has important implications for anticipating treatment requirements. Hospitalized patients aged ≥15 years with SRI at 2 public teaching hospitals in periurban areas in 2 provinces (Edendale Hospital in Pietermaritzburg, KwaZulu-Natal Province and Tshepong Hospital in Klerksdorp, North West Province) were enrolled prospectively from 2012 to 2014. Tuberculosis testing included smear microscopy, culture, or Xpert MTB/Rif. We enrolled 2486 individuals with SRI. Of these, 2097 (84%) were tested for tuberculosis, 593 (28%) were positive. Tuberculosis detection rate was 18% (133 of 729) in individuals with acute (≤14 days) presentation and 34% (460 of 1368) in those with chronic (>14 days) presentation. Among laboratory-confirmed tuberculosis cases, those with acute presentation were less likely to present with cough (88% [117 of 133] vs 97% [447 of 460]; ajusted odds ratio [aOR] = 0.2, 95% confidence interval [CI] = 0.1-0.5), night sweats (57% [75 of 132] vs 73% [337 of 459]; aOR = 0.4, 95% CI = 0.3-0.7), or be started on tuberculosis treatment on admission (63% [78 of 124] vs 81% [344 of 423]; aOR = 0.4, 95% CI = 0.3-0.7), but they were more likely to be coinfected with pneumococcus (13% [16 of 124] vs 6% [26 of 411]; aOR 2.3, 95% CI 1.3-5.3) than patients with chronic presentation. Annual incidence of acute and chronic tuberculosis-associated SRI per 100000 population was 28 (95% CI = 22-39) and 116 (95% CI = 104-128), respectively. In this setting, tuberculosis, including acute presentation, is common in patients hospitalized with SRI.

Genotyping and drug resistance patterns of M. tuberculosis strains in Pakistan.

PubMed

Tanveer, Mahnaz; Hasan, Zahra; Siddiqui, Amna R; Ali, Asho; Kanji, Akbar; Ghebremicheal, Solomon; Hasan, Rumina

2008-12-24

The incidence of tuberculosis in Pakistan is 181/100,000 population. However, information about transmission and geographical prevalence of Mycobacterium tuberculosis strains and their evolutionary genetics as well as drug resistance remains limited. Our objective was to determine the clonal composition, evolutionary genetics and drug resistance of M. tuberculosis isolates from different regions of the country. M. tuberculosis strains isolated (2003-2005) from specimens submitted to the laboratory through collection units nationwide were included. Drug susceptibility was performed and strains were spoligotyped. Of 926 M. tuberculosis strains studied, 721(78%) were grouped into 59 "shared types", while 205 (22%) were identified as "Orphan" spoligotypes. Amongst the predominant genotypes 61% were Central Asian strains (CAS ; including CAS1, CAS sub-families and Orphan Pak clusters), 4% East African-Indian (EAI), 3% Beijing, 2% poorly defined TB strains (T), 2% Haarlem and LAM (0.2). Also TbD1 analysis (M. tuberculosis specific deletion 1) confirmed that CAS1 was of "modern" origin while EAI isolates belonged to "ancestral" strain types.Prevalence of CAS1 clade was significantly higher in Punjab (P < 0.01, Pearsons Chi-square test) as compared with Sindh, North West Frontier Province and Balochistan provinces. Forty six percent of isolates were sensitive to five first line antibiotics tested, 45% were Rifampicin resistant, 50% isoniazid resistant. MDR was significantly associated with Beijing strains (P = 0.01, Pearsons Chi-square test) and EAI (P = 0.001, Pearsons Chi-square test), but not with CAS family. Our results show variation of prevalent M. tuberculosis strain with greater association of CAS1 with the Punjab province. The fact that the prevalent CAS genotype was not associated with drug resistance is encouraging. It further suggests a more effective treatment and control programme should be successful in reducing the tuberculosis burden in Pakistan.

Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis.

PubMed

Chisholm, Rebecca H; Trauer, James M; Curnoe, Darren; Tanaka, Mark M

2016-08-09

Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a wildly successful group of organisms and the leading cause of death resulting from a single bacterial pathogen worldwide. It is generally accepted that MTBC established itself in human populations in Africa and that animal-infecting strains diverged from human strains. However, the precise causal factors of TB emergence remain unknown. Here, we propose that the advent of controlled fire use in early humans created the ideal conditions for the emergence of TB as a transmissible disease. This hypothesis is supported by mathematical modeling together with a synthesis of evidence from epidemiology, evolutionary genetics, and paleoanthropology.

Addressing the double-burden of diabetes and tuberculosis: lessons from Kyrgyzstan.

PubMed

Skordis-Worrall, Jolene; Round, Jeff; Arnold, Matthias; Abdraimova, Aida; Akkazieva, Baktygul; Beran, David

2017-03-15

The incidence of diabetes and tuberculosis co-morbidity is rising, yet little work has been done to understand potential implications for health systems, healthcare providers and individuals. Kyrgyzstan is a priority country for tuberculosis control and has a 5% prevalence of diabetes in adults, with many health system challenges for both conditions. Patient exit interviews collected data on demographic and socio-economic characteristics, health spending and care seeking for people with diabetes, tuberculosis and both diabetes and tuberculosis. Qualitative data were collected through semi-structured interviews with healthcare workers involved in diabetes and tuberculosis care, to understand delivery of care and how providers view effectiveness of care. The experience of co-affected individuals within the health system is different than those just with tuberculosis or diabetes. Co-affected patients do not receive more care and also have different care for their tuberculosis than people with only tuberculosis. Very high levels of catastrophic spending are found among all groups despite these two conditions being included in the Kyrgyz state benefit package especially for medicines. This study highlights that different patterns of service provision by disease group are found. Although Kyrgyzstan has often been cited as an example in terms of health reforms and developing Primary Health Care, this study highlights the challenge of managing conditions that are viewed as "too complicated" for non-specialists and the impact this has on costs and management of individuals.

[Education and training for tuberculosis in medical schools and in hospitals].

PubMed

1998-01-01

The recent decrease of the number of tuberculosis patients in Japan, by the economical development and the establishment of standard regimen with INH, RFP, SM/EB and PZA, have brought decrease of concern to tuberculosis not only in the masses but also in the medical personnel, and the worsening of the medical economy by the advancing of the ages in the nations is forcing to close the tuberculosis wards. On the other hand, the recent situation of tuberculosis in Japan, such as the increase of HIV infection, the additional inflow of the foreign tuberculosis patients, the increase of tuberculosis patients in the younger population by the increase of mass-infection, and recent progress of the maldistributions of the tuberculosis patients realized the efforts of the education and training for tuberculosis to the medical students and medical personnel, even in the increase of items that they must learn. The Japanese Society for Tuberculosis set a Symposium "How Tuberculosis be Taught in Medical Education" in 1986. It will be worth to have Round Table Discussion concerning to the education and training for the tuberculosis, after 11 years. Doctor Sato from Nagoya City University reported as follows. To survey the actual condition of tuberculosis education before graduation, a nationwide medical school questionnaire survey was carried out. Answers were received from 80 institutions (100%). It was found that 58 institutions (72%) lacked tuberculosis ward. When the results from this survey, in the area of medical school lecture, were compared to the previous survey of 11 years ago, it showed a decrease in the time and frequency that tuberculosis covered during lecture. This tendency was clearly seen, with the exception of internal medicine, in surgery, in plastic surgery, in urology and in public health. Furthermore, medical schools lacking tuberculosis ward were found to have a lesser percentage of clinical lectures and bed-side teaching when compared to ones with tuberculosis ward. He concluded that in the medical school without tuberculosis ward, the tuberculosis education is virtually impossible, and it is necessary to carry out with hospitals that have tuberculosis ward. Doctor Honda from Sapporo Medical University reported that in the University Hospital, the Third Department of Internal Medicine holds 6 isolation sick-beds for tuberculosis (3 for men and 3 for women) which containing an exclusive day room and bath room, in 52 beds alloted to their department. They always give 2 or 3 lectures about tuberculosis to medical students and also give bed-side teaching using these beds. He concluded education on tuberculosis is necessary for the protection of doctor's delay, and the tuberculosis ward in the university is very useful in the education of tuberculosis to medical students, even the economical efficiency of these beds are low. Doctor Nakabayashi from Sapporo National Hospital reported that his hospital is a general hospital with 513 beds but has no tuberculosis-bed, and that this hospital is combined with Hokkaido Cancer Center and 91.7% of in-patients of pulmonary division are lung cancer and one or two residents are trained in pulmonary division by 6 months rotation. He also reported that in his hospital, 18 mycobacteria positive cases were treated through 1996, however the training for tuberculosis to residents are mainly by the differential diagnosis of tuberculosis with lung cancer through case conferences with staff doctors. Doctor Yosikawa from Daido Hospital reported as follows. In his hospital, tuberculosis-beds and other respiratory-beds are in the same nursing unit managed with the same standard for nursing, although tuberculosis-beds are separated from other respiratory-beds by door and have exclusive toilets and bath-room. The doctors could study general respiratory diseases and tuberculosis at the same time. Thirteen doctors have finished this training, and all of them could deepen their knowledge to tuberculosi

Activity loss by H46A mutation in Mycobacterium tuberculosis isocitrate lyase is due to decrease in structural plasticity and collective motions of the active site.

PubMed

Shukla, Rohit; Shukla, Harish; Tripathi, Timir

2018-01-01

Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a crucial enzyme of the glyoxylate cycle and is a validated anti-tuberculosis drug target. Structurally distant, non-active site mutation (H46A) in MtbICL has been found to cause loss of enzyme activity. The aim of the present work was to explore the structural alterations induced by H46A mutation that caused the loss of enzyme activity. The structural and dynamic consequences of H46A mutation were studied using multiple computational methods such as docking, molecular dynamics simulation and residue interaction network analysis (RIN). Principal component analysis and cross correlation analysis revealed the difference in conformational flexibility and collective modes of motions between the wild-type and mutant enzyme, particularly in the active site region. RIN analysis revealed that the active site geometry was disturbed in the mutant enzyme. Thus, the dynamic perturbation of the active site led to enzyme transition from its active form to inactive form upon mutation. The computational analyses elucidated the mutant-specific conformational alterations, differential dominant motions, and anomalous residue level interactions that contributed to the abrogated function of mutant MtbICL. An understanding of interactions of mutant enzymes may help in modifying the existing drugs and designing improved drugs for successful control of tuberculosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization of the genetic diversity of Mycobacterium tuberculosis in São Paulo city, Brazil

PubMed Central

2011-01-01

Background Tuberculosis is a major health problem in São Paulo, Brazil, which is the most populous and one of the most cosmopolitan cities in South America. To characterize the genetic diversity of Mycobacterium tuberculosis in the population of this city, the genotyping techniques of spoligotyping and MIRU were applied to 93 isolates collected in two consecutive years from 93 different tuberculosis patients residing in São Paulo city and attending the Clemente Ferreira Institute (the reference clinic for the treatment of tuberculosis). Findings Spoligotyping generated 53 different spoligotype patterns. Fifty-one isolates (54.8%) were grouped into 13 spoligotyping clusters. Seventy- two strains (77.4%) showed spoligotypes described in the international databases (SpolDB4, SITVIT), and 21 (22.6%) showed unidentified patterns. The most frequent spoligotype families were Latin American Mediterranean (LAM) (26 isolates), followed by the T family (24 isolates) and Haarlem (H) (11 isolates), which together accounted for 65.4% of all the isolates. These three families represent the major genotypes found in Africa, Central America, South America and Europe. Six Spoligo-International-types (designated SITs by the database) comprised 51.8% (37/72) of all the identified spoligotypes (SIT53, SIT50, SIT42, SIT60, SIT17 and SIT1). Other SITs found in this study indicated the great genetic diversity of M. tuberculosis, reflecting the remarkable ethnic diversity of São Paulo city inhabitants. The MIRU technique was more discriminatory and did not identify any genetic clusters with 100% similarity among the 93 isolates. The allelic analysis showed that MIRU loci 26, 40, 23 and 10 were the most discriminatory. When MIRU and spoligotyping techniques were combined, all isolates grouped in the 13 spoligotyping clusters were separated. Conclusions Our data indicated the genomic stability of over 50% of spoligotypes identified in São Paulo and the great genetic diversity of M. tuberculosis isolates in the remaining SITs, reflecting the large ethnic mix of the São Paulo city inhabitants. The results also indicated that in this city, M. tuberculosis isolates acquired drug resistance independently of genotype and that resistance was more dependent on the selective pressure of treatment failure and the environmental circumstances of patients. PMID:21801364

Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.

PubMed

Zignol, Matteo; Cabibbe, Andrea Maurizio; Dean, Anna S; Glaziou, Philippe; Alikhanova, Natavan; Ama, Cecilia; Andres, Sönke; Barbova, Anna; Borbe-Reyes, Angeli; Chin, Daniel P; Cirillo, Daniela Maria; Colvin, Charlotte; Dadu, Andrei; Dreyer, Andries; Driesen, Michèle; Gilpin, Christopher; Hasan, Rumina; Hasan, Zahra; Hoffner, Sven; Hussain, Alamdar; Ismail, Nazir; Kamal, S M Mostofa; Khanzada, Faisal Masood; Kimerling, Michael; Kohl, Thomas Andreas; Mansjö, Mikael; Miotto, Paolo; Mukadi, Ya Diul; Mvusi, Lindiwe; Niemann, Stefan; Omar, Shaheed V; Rigouts, Leen; Schito, Marco; Sela, Ivita; Seyfaddinova, Mehriban; Skenders, Girts; Skrahina, Alena; Tahseen, Sabira; Wells, William A; Zhurilo, Alexander; Weyer, Karin; Floyd, Katherine; Raviglione, Mario C

2018-06-01

In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development. © 2018 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

The Role of Private Health Sector for Tuberculosis Control in Debre Markos Town, Northwest Ethiopia.

PubMed

Reta, Alemayehu; Simachew, Addis

2018-01-01

Tuberculosis has been declared to be a global epidemic. Despite all the effort, only less than half the annual estimated cases are reported by health authorities to the WHO. This could be due to poor reporting from the private sector. In Ethiopia, tuberculosis has also been a major public health problem. The aim of this study was to assess the role of the private health sector in tuberculosis control in Debre Markos. An institution based cross-sectional descriptive study was carried out in private health facilities. A total of 260 tuberculosis suspects attending the private clinics were interviewed. Focus group discussion, checklist, and structured questionnaire were used. Majority of the private clinics were less equipped, poorly regulated, and owned by health workers who were self-employed on a part-time basis. Provider delay of 4 and more months was significantly associated higher likelihood of turning to a private provider (OR = 2.70, 95% CI = (1.20, 6.08)). There is significant delay among tuberculosis patients. Moreover, there is poor regulation of the private health sector by public health authorities. The involvement of the private sector in tuberculosis control should be limited to identification and refer to tuberculosis cases and suspects.

Expanding the epidemiologic profile: risk factors for active tuberculosis in people immigrating to Ontario

PubMed Central

Wobeser, Wendy L.; Yuan, Lilian; Naus, Monika; Corey, Paul; Edelson, Jeff; Heywood, Neil; Holness, D. Linn

2000-01-01

Background Many people immigrating to Canada come from countries with a high burden of tuberculosis. The aim of this study was to develop a detailed epidemiologic profile of foreign-born people with tuberculosis living in Ontario. Methods In this population-based case-control study, cases of tuberculosis diagnosed in 1994-1995 were identified from the database of the Ontario Reportable Disease Information Service and were considered eligible for analysis if a record of landing (receipt of permission to establish residence in Canada) from the period 1986-1995 was found in the Citizenship and Immigration Canada (CIC) database, if the person was at least 11 years of age at the time their visa was issued, and if the person had not been diagnosed with tuberculosis before becoming legally landed in Canada. Control subjects, who met the same criteria as the case subjects but who did not have tuberculosis in 1994-1995, were identified from a CIC database for landed immigrants. Results A total of 1341 cases of tuberculosis in foreign-born people were reported in Ontario in 1994-1995. A record of landing was found in CIC databases for 1099 of these people, 224 of whom were not legally landed at the time of diagnosis. In total, 602 cases met the inclusion criteria. The 2 strongest determinants of risk among those who had become landed within the preceding 10 years were referral for medical surveillance by immigration officials (odds ratio [OR] 3.8, 95% confidence interval [CI] 2.6-6.0) and world region of origin (Somalia [OR 67.7, 95% CI 31.3-154.9], Vietnam [OR 25.0, 95% CI 12.5-50.0], the Philippines [OR 11.9, 95% CI 6.0-23.3], other sub-Saharan African countries [OR 11.6, 95% CI 5.7-23.2], India [OR 9.7, 95% CI 4.9-18.9], China [OR 6.1, 95% CI 3.1-12.1], other Asian countries [OR 4.7, 95% CI 2.4-9.1], the Middle East [OR 4.1, 95% CI 2.0-8.3], Latin America [OR 1.9, 95% CI 0.9-3.8), and the former socialist countries of Europe [OR 1.8, 95% CI 0.8-3.8]; the reference category was countries with established market economies). Low socioeconomic status was an independent risk factor. Interpretation The risk of tuberculosis in groups of people migrating to Ontario is highly variable and is influenced by several factors. Successful population-based tuberculosis prevention strategies will need to accommodate this variability. PMID:11033709

Sliding Clamp of DNA Polymerase III as a Drug Target for TB Therapy: Comprehensive Conformational and Binding Analysis from Molecular Dynamic Simulations.

PubMed

Machaba, Kgothatso E; Cele, Favorite N; Mhlongo, Ndumiso N; Soliman, Mahmoud E S

2016-12-01

Tuberculosis, caused by Mycobacterium tuberculosis, is one of the most common causes of death in the world. Mycobacterium tuberculosis -sliding clamp is a protein essential for many important DNA transactions including replication and DNA repair proteins, thus, a potential drug target for tuberculosis. Further investigation is needed in understanding DNA polymerase sliding clamp structure, especially from a computational perspective. In this study, we employ a wide-range of comparative molecular dynamic analyses on two systems: Mycobacterium tuberculosis - sliding clamp enzyme in its apo and bound form. The results reported in this study shows apo conformation to be less stable, as compared to bound conformation with an average radius of gyration of 25.812 and 25.459 Å, respectively. This was further supported by root mean square fluctuation, where an apo enzyme showed a higher degree of flexibility. However, the presence of the ligand lowers radius of gyration and root mean square fluctuation and also leads to an existence of negative correlated motions. Principal component analysis further justifies the same findings, whereby the apo enzyme exhibits a higher fluctuation compared to the bound complex. In addition, a stable 3 10 helix located at the binding site appears to be unstable in the presence of the ligand. Hence, it is possible that the binding of the ligand may have caused a rearrangement of the structure, leading to a change in the unwinding of 3 10 helix. Findings reported in this study further enhance the understanding of Mycobacterium tuberculosis -DnaN and also give a lead to the development of potent tuberculosis drugs.

Globalization of pediatric transplantation: The risk of tuberculosis or not tuberculosis.

PubMed

McCulloch, Mignon; Lin, Philana Ling

2017-05-01

The risk of TB among pediatric SOT recipients increases as the globalization of medical care continues to broaden. Unlike adults, children and especially infants are more susceptible to TB as a complication after transplantation. Little data exist regarding the true incidence of TB and the optimal risk-based management of this very vulnerable population. Here, we highlight the theoretical and practical issues that complicate the management of these patients and pose some questions that should be addressed when managing these patients. More data are needed to provide optimal guidance of the best diagnostic and management practices to this unique population. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology.

PubMed

Chandra, Pallavi; Rajmani, R S; Verma, Garima; Bhavesh, Neel Sarovar; Kumar, Dhiraj

2016-01-01

In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a host factor exploited by virulent M. tuberculosis for intracellular survival. We show that Src inhibition can effectively control tuberculosis in infected guinea pigs. Moreover, Src inhibition ameliorated TB-associated pathology in guinea pigs. Thus, Src inhibitors have strong potential to be developed as possible anti-TB drugs.

Dietary Cholesterol Increases the Risk whereas PUFAs Reduce the Risk of Active Tuberculosis in Singapore Chinese12

PubMed Central

Soh, Avril Z; Chee, Cynthia BE; Wang, Yee-Tang; Yuan, Jian-Min; Koh, Woon-Puay

2016-01-01

Background: Experimental studies suggest that cholesterol enhances the intracellular survival of Mycobacterium tuberculosis, whereas marine ω-3 (n–3) and ω-6 (n–6) fatty acids (FAs) may modulate responses to M. tuberculosis in macrophage and animal models. However, there are no epidemiologic data from prospective studies of the relation between dietary cholesterol and FAs and the risk of developing active tuberculosis. Objective: We aimed to investigate the relation between dietary intake of cholesterol and FAs and the risk of active tuberculosis in a prospective cohort in Singapore. Methods: We analyzed data from the Singapore Chinese Health Study, a cohort of 63,257 Chinese men and women aged 45–74 y recruited between 1993 and 1998. Dietary intake of cholesterol and FAs was determined with the use of a validated food-frequency questionnaire. Incident cases of active tuberculosis were identified via linkage with the nationwide tuberculosis registry. Analysis was performed with the use of Cox proportional hazards models. Results: As of 31 December 2013, 1136 incident cases of active tuberculosis were identified. Dietary cholesterol was positively associated with an increased risk of active tuberculosis in a dose-dependent manner. Compared with the lowest intake quartile, the HR was 1.22 (95% CI: 1.00, 1.47) for the highest quartile (P-trend = 0.04). Conversely, dietary marine n–3 and n–6 FAs were associated with a reduced risk of active tuberculosis in a dose-dependent manner. Compared with the lowest quartile, the HR for the highest intake quartile was 0.77 (95% CI: 0.62, 0.95) for marine n–3 FAs (P-trend = 0.01) and 0.82 (95% CI: 0.68, 0.98) for n–6 FAs (P-trend = 0.03). There was no association with saturated, monounsaturated, or plant-based n–3 FA intake. Conclusion: Dietary intake of cholesterol may increase the risk of active tuberculosis, whereas marine n–3 and n–6 FAs may reduce the risk of active tuberculosis in the Chinese population. PMID:27075903

Incidence of tuberculosis among school-going adolescents in South India.

PubMed

Uppada, Dharma Rao; Selvam, Sumithra; Jesuraj, Nelson; Lau, Esther L; Doherty, T Mark; Grewal, Harleen M S; Vaz, Mario; Lindtjørn, Bernt

2016-07-26

Tuberculosis (TB) incidence data in vaccine target populations, particularly adolescents, are important for designing and powering vaccine clinical trials. Little is known about the incidence of tuberculosis among adolescents in India. The objective of current study is to estimate the incidence of pulmonary tuberculosis (PTB) disease among adolescents attending school in South India using two different surveillance methods (active and passive) and to compare the incidence between the two groups. The study was a prospective cohort study with a 2-year follow-up period. The study was conducted in Palamaner, Chittoor District of Andhra Pradesh, South India from February 2007 to July 2010. A random sampling procedure was used to select a subset of schools to enable approximately 8000 subjects to be available for randomization in the study. A stratified randomization procedure was used to assign the selected schools to either active or passive surveillance. Participants who met the criteria for being exposed to TB were referred to the diagnostic ward for pulmonary tuberculosis confirmation. A total number of 3441 males and 3202 females between the ages 11 and less than 18 years were enrolled into the study. Of the 3102 participants in the active surveillance group, four subjects were diagnosed with definite tuberculosis, four subjects with probable tuberculosis, and 71 subjects had non-tuberculous Mycobacteria (NTM) isolated from their sputum. Of the 3541 participants in the passive surveillance group, four subjects were diagnosed with definite tuberculosis, two subjects with probable tuberculosis, and 48 subjects had non-tuberculosis Mycobacteria isolated from their sputum. The incidence of definite + probable TB was 147.60 / 100,000 person years in the active surveillance group and 87 / 100,000 person years in the passive surveillance group. The incidence of pulmonary tuberculosis among adolescents in our study is lower than similar studies conducted in South Africa and Eastern Uganda - countries with a higher incidence of tuberculosis and human immunodeficiency virus (HIV) than India. The study data will inform sample design for vaccine efficacy trials among adolescents in India.

[Multidrug-resistant tuberculosis (MDR-TB) in a black African carceral area: Experience of Mali].

PubMed

Toloba, Y; Ouattara, K; Soumaré, D; Kanouté, T; Berthé, G; Baya, B; Konaté, B; Keita, M; Diarra, B; Cissé, A; Camara, F S; Diallo, S

2018-02-01

Prison constitutes a risk factor for the emergence of multi-drug resistance of tuberculosis (MDR-TB). The aim of this work was to study MDR-TB in a black African carceral center. Prospective study from January to December 2016 at the central house of arrest for men, Bamako. The study population was composed of tuberculous detainee. The suspicion of MDR-TB was done in any tuberculosis case remained positive in the second month of first-line treatment or in contact with an MDR-TB case. Among 1622 detainee, 21 cases of pulmonary tuberculosis were notified (1.29%), with an annual incidence of 13 cases/1000 detainee, they were 16 cases of SP-PTB (microscopy smear positive tuberculosis) and five cases of microscopy smear negative tuberculosis. The mean age was 28±7 years, extremes of 18 and 46 years. A negative association was found between the notion of smoking and occupation in the occurrence of tuberculosis (OR=0.036, [95% CI: 0.03-0.04], P=0.03. Among the 21 tuberculosis cases notified, one confirmed case of MDR-TB was detected (4.7%). In the first semester of 2016 cohort, we notified a cure rate of 87.5% (7/8 SP-PTB cases), and the confirmed MDR-TB case on treatment (21-month regimen), evolution enameled of pulmonary and hearing sequelae at seven months treatment. It was the first case of MDR-TB detected in a prison in Mali. Late diagnosis, evolution is enameled of sequelae and side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Increasing Access to Tuberculosis Services in Ethiopia: Findings From a Patient-Pathway Analysis.

PubMed

Fekadu, Lelisa; Hanson, Christy; Osberg, Mike; Makayova, Julia; Mingkwan, Pia; Chin, Daniel

2017-11-06

In Ethiopia, extensive scale-up of the availability of health extension workers (HEWs) at the community level has been credited with increased identification and referral of patients with presumptive tuberculosis, which has contributed to increased tuberculosis case notification and better treatment outcomes. However, nearly 30% of Ethiopia's estimated 191000 patients with tuberculosis remained unnotified in 2015. A better understanding of patient care-seeking practices may inform future government action to reach all patients with tuberculosis. A patient-pathway analysis was completed to assess the alignment between patient care initiation and the availability of diagnostic and treatment services at the national level. More than one third of patients initiated care with HEWs, who refer patients to health centers for diagnosis. An additional one third of patients initiated care at health centers. Of those health centers, >80% had microscopy services, but few had access to Xpert. Despite an extensive microscopy and radiography network at middle levels of the health system, a quarter of all notified patients with tuberculosis had no bacteriological confirmation of disease. While 30% of patients reported receiving some form of care from the private sector, private-sector facilities, especially pharmacies, were not widely accessed for tuberculosis diagnosis. The availability of HEWs can increase access to tuberculosis diagnostic and treatment support services, particularly for rural populations. Continued strengthening of referral systems from HEWs and health posts are needed to enable consistent and timely access to Xpert as an initial diagnostic test and to drug resistance screening. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Conspicuous multidrug-resistant Mycobacterium tuberculosis cluster strains do not trespass country borders in Latin America and Spain.

PubMed

Ritacco, Viviana; Iglesias, María-José; Ferrazoli, Lucilaine; Monteserin, Johana; Dalla Costa, Elis R; Cebollada, Alberto; Morcillo, Nora; Robledo, Jaime; de Waard, Jacobus H; Araya, Pamela; Aristimuño, Liselotte; Díaz, Raúl; Gavin, Patricia; Imperiale, Belen; Simonsen, Vera; Zapata, Elsa M; Jiménez, María S; Rossetti, Maria L; Martin, Carlos; Barrera, Lucía; Samper, Sofia

2012-06-01

Multidrug-resistant Mycobacterium tuberculosis strain diversity in Ibero-America was examined by comparing extant genotype collections in national or state tuberculosis networks. To this end, genotypes from over 1000 patients with multidrug-resistant tuberculosis diagnosed from 2004 through 2008 in Argentina, Brazil, Chile, Colombia, Venezuela and Spain were compared in a database constructed ad hoc. Most of the 116 clusters identified by IS6110 restriction fragment length polymorphism were small and restricted to individual countries. The three largest clusters, of 116, 49 and 25 patients, were found in Argentina and corresponded to previously documented locally-epidemic strains. Only 13 small clusters involved more than one country, altogether accounting for 41 patients, of whom 13 were, in turn, immigrants from Latin American countries different from those participating in the study (Peru, Ecuador and Bolivia). Most of these international clusters belonged either to the emerging RD(Rio) LAM lineage or to the Haarlem family of M. tuberculosis and four were further split by country when analyzed with spoligotyping and rifampin resistance-conferring mutations, suggesting that they did not represent ongoing transnational transmission events. The Beijing genotype accounted for 1.3% and 10.2% of patients with multidrug-resistant tuberculosis in Latin America and Spain, respectively, including one international cluster of two cases. In brief, Euro-American genotypes were widely predominant among multidrug-resistant M. tuberculosis strains in Ibero-America, reflecting closely their predominance in the general M. tuberculosis population in the region, and no evidence was found of acknowledged outbreak strains trespassing country borders. Copyright © 2011 Elsevier B.V. All rights reserved.

Update on the Spoligotypes of Mycobacterium tuberculosis complex isolates from the Fernando Fonseca Hospital (Amadora-Sintra, Portugal).

PubMed

David, Suzana; Barros, Vanessa; Portugal, Clara; Antunes, Abílio; Cardoso, Angela; Calado, Ana; Sancho, Luísa; de Sousa, José Germano

2005-01-01

The present population study, from 1999 to 2003, has been based on the use of Spoligotyping in the genotyping of 452 isolates of the Mycobacterium tuberculosis complex from tuberculosis patients of the Fernando Fonseca Hospital. Spoligotypes were identified as "shared types" (STs) with the aid of an international database. Eleven rarely found STs, not identified in the database, grouped 8.4% of the isolates. Moreover, particular to Portugal, may be the predominance of STs identified in the database but not previously classified as genotypic families, such as ST244, ST150 and ST389, representing 13.3 % of the total. The identification of clinical isolates of M. africanum genotype Afri1 and of M. tuberculosis genotype CAS1 may confirm import of isolates of African and Asian origin. M. tuberculosis of the Beijing family was first reported by us as of 1999. Since then, the number of isolates at the Hospital has passed from one to five annually, representing 2.2% of the total and the tenth most predominant family in the present study. M. tuberculosis Beijing may correspond to an emerging problem in Portugal due to recent immigration from Eastern Europe and Asia. Other genotypes, ST150 and ST389, have shown increase, the significance of which is not clear. However, the relative frequencies of the predominant families LAM, T1 and Haarlem remained relatively stable. The present study confirms the genetic variability in Portugal of M. tuberculosis complex isolates. These studies may contribute to the definition of priorities in the national tuberculosis control programs.

Outcomes of standard and tailored anti-tuberculosis regimens in patients with tuberculous pleural effusion.

PubMed

Kim, C H; Lim, J K; Lee, D H; Yoo, S S; Lee, S Y; Cha, S I; Park, J Y; Lee, J

2016-11-01

In an era of increasing concerns about drug resistance, there are limited data on treatment outcomes and recurrence rates after standard short-course anti-tuberculosis treatment in patients with culture-negative tuberculous pleural effusion (TPE). To compare treatment outcomes and recurrence rates between a standard anti-tuberculosis regimen with negative culture and unavailable drug susceptibility testing (DST) data, and a tailored anti-tuberculosis regimen based on individual DST data. We analysed the data of all patients with TPE from the TB registry database at Kyungpook National University Hospital, South Korea, during 2008-2012. The study population was divided into two groups according to regimen. Standard and tailored anti-tuberculosis regimens were administered to respectively 124 and 146 patients with TPE. Drug resistance was detected in 10% of patients with TPE, about a quarter of whom were multidrug-resistant. The treatment completion rate was not significantly different between the two groups (91% vs. 93%). During a median 20-month follow-up, the recurrence rate was also similar in both groups (1% vs.1%). Despite limited statistical power, these preliminary results support the hypothesis that immunocompetent patients with culture-negative TPE can be appropriately managed with a standard short-course anti-tuberculosis regimen, even in this era of increasing concerns about drug resistance.

Epidemiological characteristics of cases of death from tuberculosis and vulnerable territories1

PubMed Central

Yamamura, Mellina; Santos-Neto, Marcelino; dos Santos, Rebeca Augusto Neman; Garcia, Maria Concebida da Cunha; Nogueira, Jordana de Almeida; Arcêncio, Ricardo Alexandre

2015-01-01

Objective: to characterize the differences in the clinical and epidemiological profile of cases of death that had tuberculosis as an immediate or associated cause, and to analyze the spatial distribution of the cases of death from tuberculosis within the territories of Ribeirão Preto, Brazil. Method: an ecological study, in which the population consisted of 114 cases of death from tuberculosis. Bivariate analysis was carried out, as well as point density analysis, defined with the Kernel estimate. Results: of the cases of death from tuberculosis, 50 were the immediate cause and 64 an associated cause. Age (p=.008) and sector responsible for the death certificate (p=.003) were the variables that presented statistically significant associations with the cause of death. The spatial distribution, in both events, did not occur randomly, forming clusters in areas of the municipality. Conclusion: the difference in the profiles of the cases of death from tuberculosis, as a basic cause and as an associated cause, was governed by the age and the sector responsible for the completion of the death certificate. The non-randomness of the spatial distribution of the cases suggests areas that are vulnerable to these events. Knowing these areas can contribute to the choice of disease control strategies. PMID:26487142

Rifampin vs. rifapentine: what is the preferred rifamycin for tuberculosis?

PubMed

Alfarisi, Omamah; Alghamdi, Wael A; Al-Shaer, Mohammad H; Dooley, Kelly E; Peloquin, Charles A

2017-10-01

One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited.

Directly observed treatment, short-course strategy and multidrug-resistant tuberculosis: are any modifications required?

PubMed Central

Bastian, I.; Rigouts, L.; Van Deun, A.; Portaels, F.

2000-01-01

Multidrug-resistant tuberculosis (MDRTB) should be defined as tuberculosis with resistance to at least isoniazid and rifampicin because these drugs are the cornerstone of short-course chemotherapy, and combined isoniazid and rifampicin resistance requires prolonged treatment with second-line agents. Short-course chemotherapy is a key ingredient in the tuberculosis control strategy known as directly observed treatment, short-course (DOTS). For populations in which multidrug-resistant tuberculosis is endemic, the outcome of the standard short-course chemotherapy regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced. As a consequence there have been calls for well-functioning DOTS programmes to provide additional services in areas with high rates of multidrug-resistant tuberculosis. These "DOTS-plus for MDRTB programmes" may need to modify all five elements of the DOTS strategy: the treatment may need to be individualized rather than standardized; laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing; reliable supplies of a wide range of expensive second-line agents would have to be supplied; operational studies would be required to determine the indications for and format of the expanded programmes; financial and technical support from international organizations and Western governments would be needed in addition to that obtained from local governments. PMID:10743297

Migrants and tuberculosis: analysing epidemiological data with ethnography.

PubMed

Littleton, Judith; Park, Julie; Thornley, Craig; Anderson, Anneka; Lawrence, Jody

2008-04-01

Media portrayals of tuberculosis (TB) in New Zealand are of immigrants who enter the country with active disease and pose a threat to inhabitants, which fosters a popular perception that border control is the best and only response to disease control. This paper reviews both New Zealand and international data on TB rates, causes and transmission among migrant populations to elucidate the precise nature of the link between immigration and TB rates. Recent information from scholarly journals on immigration and TB was reviewed. Surveillance data from New Zealand and comparable information from other low-incidence countries were reviewed. The importation of active TB is only a minor part of the total TB burden. While effective border control is essential, equally, if not more important, are the circumstances that promote the reactivation of latent TB infection in migrant communities, including migrants' experiences in transit and after arrival, structural conditions, and personal characteristics. For sound prevention strategies, attention needs to be paid to the existence of transnational communities and the conditions for migrants, rather than placing a singular focus on place of birth.

Knowledge, attitudes and practices regarding tuberculosis among immigrants of Somalian ethnic origin in London: a cross-sectional study.

PubMed

Shetty, N; Shemko, M; Abbas, A

2004-03-01

The objectives were to study knowledge, attitudes, and practices (KAP) regarding tuberculosis (TB) among Somalian subjects in inner London. We administered structured, fixed response KAP questionnaires to 23 patients (culture proved TB), and two groups of controls: 25 contacts (family members) and 27 lay controls (general Somali immigrant population). Responses were summed on a five-point scale. Most were aware of the infectious nature of TB but uncertain of other risk factors. Many were uncertain about coping with the disease and its effect on lifestyle. Belief in biomedicine for TB was unequivocal with men having a significantly higher belief score than women (p = 0.02); the need to comply with TB medication was unambiguously understood. Somalians interviewed were educated, multilingual, and aware of important health issues. Uncertainties in core TB knowledge need to be addressed with direct educational input, especially in women and recent entrants into the country. Volunteers from the established Somalian community could play a valuable part as links in the community to fight TB.

Structural Forces and the Production of TB-related Stigma among Haitians in Two Contexts

PubMed Central

Coreil, Jeannine; Mayard, Gladys; Simpson, Kelly M; Lauzardo, Michael; Zhu, Yiliang; Weiss, Mitchell

2012-01-01

In recent years renewed interest in health-related stigma has underscored the importance of better understanding the structural underpinnings of stigma processes. This study investigated the influence of sociocultural context on perceived components of tuberculosis-related stigma in non-affected persons by comparing Haitians living in South Florida, USA, with Haitians residing in Léogane Commune, Haiti. Using the methods of cultural epidemiology, a two-phase study based on fieldwork between 2004–07 collected ethnographic data on the cultural context and components of tuberculosis (TB) stigma, and administered a stigma scale developed specifically for these populations. Thematic analysis of stigma components expressed in interviews, focus groups and observation revealed commonalities as well as distinctive emphases of TB stigma in the two comparison groups. Factor analyses of stigma scale scores confirmed the thematic differences revealed in ethnographic findings and highlight the influence of political and economic factors in shaping the meaning and experience of illness. Perceived components of TB stigma among Haitians in South Florida incorporated aspects of Haitian identity as a negatively stereotyped minority community within the larger society, while in Haiti, stigma was associated primarily with poverty, malnutrition, and HIV co-infection. Discussion of findings focuses on the social production of perceived and anticipated stigma as it is influenced by structural forces including the influences of politics, economics, institutional policies, and health service delivery structures. The findings also demonstrate the value of a transnational framework encompassing both sending and receiving countries for understanding TB related stigma in immigrant communities. PMID:20724052

Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors

NASA Astrophysics Data System (ADS)

Bhowmick, Tuhin; Ghosh, Soumitra; Dixit, Karuna; Ganesan, Varsha; Ramagopal, Udupi A.; Dey, Debayan; Sarma, Siddhartha P.; Ramakumar, Suryanarayanarao; Nagaraja, Valakunja

2014-06-01

The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.

Tuberculosis among elderly Chinese in residential homes: tuberculin reactivity and estimated prevalence.

PubMed

Woo, J; Chan, H S; Hazlett, C B; Ho, S C; Chan, R; Sham, A; Davies, P D

1996-01-01

Objectives of this study were to determine the prevalence of positive tuberculin reactivity and associated factors among elderly nursing home residents in a population with a relatively high tuberculosis notification rate, to estimate the prevalence of active tuberculosis, and to assess tuberculin reactivity as a screening tool. A stratified, disproportional, randomized cluster sample of residents was selected and the Mantoux test (using 0.1 ml of 5 tuberculin units of purified protein derivative of tuberculin) carried out. All subjects with a positive test had a chest X-ray followed by sputum smear and culture if the X-ray was abnormal. Sputum examination was also carried out in a random sample of controls, matched for age and gender, drawn from subjects with a negative Mantoux test. Information regarding medical history, tobacco smoking habits, symptoms related to tuberculosis, and communal eating habits were gathered. Also anthropometric data were collected. Sixteen nursing homes in the catchment area of a major district hospital in Hong Kong comprising 587 residents (136 men, 451 women, mean age 80 +/- 8 years) participated in this study. The weighted prevalence of tuberculin reactivity was 43.8%. It was higher in men, among those who took their meals in a common area, in the younger age group, and in those with no previous history of hospitalization. No association was found between prevalence and duration of residence, smoking, skinfold thickness, past medical history, or any relevant symptoms. Following radiological and sputum examination, the estimated prevalence of active tuberculosis ranged from 1.2 to 2.6%. The sensitivity of the tuberculin test was 86, the specificity 30%. The prevalence of active tuberculosis in nursing homes in Hong Kong is high, but it is unclear whether cross-infection or poor health of the residents is the major contributing factor. Tuberculin skin testing does not appear to be a useful screening method in this population.

Process of assay selection and optimization for the study of case and control samples from a phase IIb efficacy trial of a candidate tuberculosis vaccine, MVA85A.

PubMed

Harris, Stephanie A; Satti, Iman; Matsumiya, Magali; Stockdale, Lisa; Chomka, Agnieszka; Tanner, Rachel; O'Shea, Matthew K; Manjaly Thomas, Zita-Rose; Tameris, Michele; Mahomed, Hassan; Scriba, Thomas J; Hanekom, Willem A; Fletcher, Helen A; McShane, Helen

2014-07-01

The first phase IIb safety and efficacy trial of a new tuberculosis vaccine since that for BCG was completed in October 2012. BCG-vaccinated South African infants were randomized to receive modified vaccinia virus Ankara, expressing the Mycobacterium tuberculosis antigen 85A (MVA85A), or placebo. MVA85A did not significantly boost the protective effect of BCG. Cryopreserved samples provide a unique opportunity for investigating the correlates of the risk of tuberculosis disease in this population. Due to the limited amount of sample available from each infant, preliminary work was necessary to determine which assays and conditions give the most useful information. Peripheral blood mononuclear cells (PBMC) were stimulated with antigen 85A (Ag85A) and purified protein derivative from M. tuberculosis in an ex vivo gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) and a Ki67 proliferation assay. The effects of a 2-h or overnight rest of thawed PBMC on ELISpot responses and cell populations were determined. Both the ELISpot and Ki67 assays detected differences between the MVA85A and placebo groups, and the results correlated well. The cell numbers and ELISpot responses decreased significantly after an overnight rest, and surface flow cytometry showed a significant loss of CD4(+) and CD8(+) T cells. Of the infants tested, 50% had a positive ELISpot response to a single pool of flu, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (FEC) peptides. This pilot work has been essential in determining the assays and conditions to be used in the correlate study. Moving forward, PBMC will be rested for 2 h before assay setup. The ELISpot assay, performed in duplicate, will be selected over the Ki67 assay, and further work is needed to evaluate the effect of high FEC responses on vaccine-induced immunity and susceptibility to tuberculosis disease. Copyright © 2014 Harris et al.

Socio-demographic determinants and prevalence of Tuberculosis knowledge in three slum populations of Uganda

PubMed Central

2012-01-01

Background Knowledge of tuberculosis has been shown to influence health seeking behaviour; and urban slum dwellers are at a higher risk of acquiring tuberculosis than the general population. The study aim was to assess knowledge of tuberculosis and identify the associated socio-demographic determinants, in order to inform tailored interventions for advocacy, communication and social mobilisation in three urban-slum communities of Uganda. Methods A cross-sectional survey of 1361 adults between April and October 2011. Data was analyzed by descriptive statistics. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) of potential determinants of tuberculosis (TB) knowledge were estimated by multivariable ordinal logistic regression using Stata 11.2 software. Results We found low knowledge of TB cause (26.7%); symptoms (46.8%), transmission (54.3%), prevention (34%) and free treatment (35%). Knowledge about TB treatment (69.4) and cure (85.1) was relatively high. Independent determinants of poor knowledge of TB in the multivariable analysis included (aOR, 95% CI) lack of formal education (0.56; 0.38 – 0.83, P = 0.004), unemployment (0.67; 0.49 – 0.90, P = 0.010) and never testing for HIV (0.69; 0.51 – 0.92, P < 0.012). Whilst, older age (1.73; 1.30 – 2.29, P < 0.001) and residing in Lira (2.02; 1.50 – 2.72, P < 0.001) were independent determinants of higher knowledge of TB. Conclusion This study revealed deficiencies in the public health knowledge about TB symptoms, diagnosis and treatment among urban-slum dwellers in Uganda. Tuberculosis control programmes in similar settings should consider innovative strategies for TB education, advocacy, communication and social mobilisation to reach the youth, unemployed and less-educated; as well as those who have never tested for HIV. PMID:22824498

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

PubMed Central

Denti, Paolo; Martinson, Neil; Cohn, Silvia; Mashabela, Fildah; Hoffmann, Jennifer; Msandiwa, Reginah; Castel, Sandra; Wiesner, Lubbe; Chaisson, Richard E.; McIlleron, Helen

2015-01-01

Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0–24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear. PMID:26643345

Structural Characterization and Ligand/Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1*

PubMed Central

Chenge, Jude T.; Duyet, Le Van; Swami, Shalini; McLean, Kirsty J.; Kavanagh, Madeline E.; Coyne, Anthony G.; Rigby, Stephen E. J.; Cheesman, Myles R.; Girvan, Hazel M.; Levy, Colin W.; Rupp, Bernd; von Kries, Jens P.; Abell, Chris; Leys, David; Munro, Andrew W.

2017-01-01

The Mycobacterium tuberculosis H37Rv genome encodes 20 cytochromes P450, including P450s crucial to infection and bacterial viability. Many M. tuberculosis P450s remain uncharacterized, suggesting that their further analysis may provide new insights into M. tuberculosis metabolic processes and new targets for drug discovery. CYP126A1 is representative of a P450 family widely distributed in mycobacteria and other bacteria. Here we explore the biochemical and structural properties of CYP126A1, including its interactions with new chemical ligands. A survey of azole antifungal drugs showed that CYP126A1 is inhibited strongly by azoles containing an imidazole ring but not by those tested containing a triazole ring. To further explore the molecular preferences of CYP126A1 and search for probes of enzyme function, we conducted a high throughput screen. Compounds containing three or more ring structures dominated the screening hits, including nitroaromatic compounds that induce substrate-like shifts in the heme spectrum of CYP126A1. Spectroelectrochemical measurements revealed a 155-mV increase in heme iron potential when bound to one of the newly identified nitroaromatic drugs. CYP126A1 dimers were observed in crystal structures of ligand-free CYP126A1 and for CYP126A1 bound to compounds discovered in the screen. However, ketoconazole binds in an orientation that disrupts the BC-loop regions at the P450 dimer interface and results in a CYP126A1 monomeric crystal form. Structural data also reveal that nitroaromatic ligands “moonlight” as substrates by displacing the CYP126A1 distal water but inhibit enzyme activity. The relatively polar active site of CYP126A1 distinguishes it from its most closely related sterol-binding P450s in M. tuberculosis, suggesting that further investigations will reveal its diverse substrate selectivity. PMID:27932461

Assessment of the patient, health system, and population effects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach.

PubMed

Langley, Ivor; Lin, Hsien-Ho; Egwaga, Saidi; Doulla, Basra; Ku, Chu-Chang; Murray, Megan; Cohen, Ted; Squire, S Bertel

2014-10-01

Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm. We used an integrated model to assess the effects of different algorithms of Xpert MTB/RIF and light-emitting diode (LED) fluorescence microscopy in Tanzania. To understand the effects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the effects and cost-effectiveness of different diagnostic options. Among the diagnostic options considered, we identified three strategies as cost effective in Tanzania. Full scale-up of Xpert would have the greatest population-level effect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-effectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104-265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fluorescence microscopy is the next most effective strategy with an ICER of $45 (95% CrI 25-74), followed by LED fluorescence microscopy with an ICER of $29 (6-59). Compared with same-day LED fluorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a follow-on test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania. For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-effective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation. Copyright © 2014 Langley et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by .. All rights reserved.

[Mycobacterium tuberculosis strain transmission caused by migratory processes in the Russian Federation (in case of populational migration from the Caucasian Region to Moscow and the Moscow Region)].

PubMed

Andreevskaia, S N; Chernousova, L N; Smirnova, T G; Larionova, E E; Kuz'min, A V

2006-01-01

The investigation was carried out on 134 M. tuberculosis isolated from 134 patients treated at the Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences. The patients were divided into 2 groups: 1) those who were natives of Moscow and the Moscow Region (MR patients); 2) those who were migrants to the Moscow Region from Azerbaijan, Daghestan, Chechnya, Ingushetia, Karachai-Cherkessia, North Ossetia (the Caucasian Region) (CR patients) who had fallen in the place of birth. Genotyping by the polymorphism of lengths of the restriction fragments containing the insertion sequence IS6110 revealed a genetic diversity of M. tuberculosis strains. The examined M. tuberculosis strains belonged to 13 genotypic families. The W and AI families were prevalent. The family W M. tuberculosis strains isolated from the Caucasians were highly clustered, as confirmed by the overwhelming predominance of the strain variant W148 (19.7%). The spectrum of the strain variants of the W family, and those of the AI family in particular, greatly differed in MR and CR patients. Only one strain variant AI12 occurring both in MR and CR patients was detected. A study of the transmission activity coefficient (TAC) of the families W and AI indicated that the transmission activity of W strains was significantly higher than that of M. tuberculosis strains of the AI family. A comparative analysis of the TAC of M. tuberculosis strains of the AI family demonstrated that the transmission activity of the strains of this family was identical no matter where a patient had fallen ill (1.59 and 1.41% in the Moscow and Caucasian Regions, respectively). Unlike M. tuberculosis strains of the AI family, the TAC of W strains isolated from the patients infected in the Moscow Region (28.17 and 19.05%, respectively), which suggests the more intensive transmission of the pathogen M. tuberculosis of the W family in the Caucasian Region.

Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice

PubMed Central

Parra, Marcela; Derrick, Steven C.; Yang, Amy; Tian, JinHua; Kolibab, Kristopher; Oakley, Miranda; Perera, Liyanage P.; Jacobs, William R.; Kumar, Sanjai; Morris, Sheldon L.

2011-01-01

Background Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. Principal Findings Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naïve mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-γ, TNF-α, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. Conclusions Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas. PMID:22205939

Why wait? The social determinants underlying tuberculosis diagnostic delay

PubMed Central

Saunders, Matthew James; Zegarra, Roberto; Evans, Carlton; Alegria-Flores, Kei; Guio, Heinner

2017-01-01

Background Early detection and diagnosis of tuberculosis remain major global priorities for tuberculosis control. Few studies have used a qualitative approach to investigate the social determinants contributing to diagnostic delay and none have compared data collected from individual, community, and health-system levels. We aimed to characterize the social determinants that contribute to diagnostic delay among persons diagnosed with tuberculosis living in resource-constrained settings. Methods/Principle findings Data were collected in public health facilities with high tuberculosis incidence in 19 districts of Lima, Peru. Semi-structured interviews with persons diagnosed with tuberculosis (n = 105) and their family members (n = 63) explored health-seeking behaviours, community perceptions of tuberculosis and socio-demographic circumstances. Focus groups (n = 6) were conducted with health personnel (n = 35) working in the National Tuberculosis Program. All interview data were transcribed and analysed using a grounded theory approach. The median delay between symptom onset and the public health facility visit that led to the first positive diagnostic sample was 57 days (interquartile range 28–126). The great majority of persons diagnosed with tuberculosis distrusted the public health system and sought care at public health facilities only after exhausting other options. It was universally agreed that persons diagnosed with tuberculosis faced discrimination by public and health personnel. Self-medication with medicines bought at local pharmacies was reported as the most common initial health-seeking behaviour due to the speed and low-cost of treatment in pharmacies. Most persons diagnosed with tuberculosis initially perceived their illness as a simple virus. Conclusions Diagnostic delay was common and prolonged. When individuals reached a threshold of symptom severity, they addressed their health with the least time-consuming, most economically feasible, and well-known healthcare option available to them. In high-burden settings, more human and material resources are required to promote tuberculosis case-finding initiatives, reduce tuberculosis associated stigma and address the social determinants underlying diagnostic delay. PMID:28945782

Why wait? The social determinants underlying tuberculosis diagnostic delay.

PubMed

Bonadonna, Lily Victoria; Saunders, Matthew James; Zegarra, Roberto; Evans, Carlton; Alegria-Flores, Kei; Guio, Heinner

2017-01-01

Early detection and diagnosis of tuberculosis remain major global priorities for tuberculosis control. Few studies have used a qualitative approach to investigate the social determinants contributing to diagnostic delay and none have compared data collected from individual, community, and health-system levels. We aimed to characterize the social determinants that contribute to diagnostic delay among persons diagnosed with tuberculosis living in resource-constrained settings. Data were collected in public health facilities with high tuberculosis incidence in 19 districts of Lima, Peru. Semi-structured interviews with persons diagnosed with tuberculosis (n = 105) and their family members (n = 63) explored health-seeking behaviours, community perceptions of tuberculosis and socio-demographic circumstances. Focus groups (n = 6) were conducted with health personnel (n = 35) working in the National Tuberculosis Program. All interview data were transcribed and analysed using a grounded theory approach. The median delay between symptom onset and the public health facility visit that led to the first positive diagnostic sample was 57 days (interquartile range 28-126). The great majority of persons diagnosed with tuberculosis distrusted the public health system and sought care at public health facilities only after exhausting other options. It was universally agreed that persons diagnosed with tuberculosis faced discrimination by public and health personnel. Self-medication with medicines bought at local pharmacies was reported as the most common initial health-seeking behaviour due to the speed and low-cost of treatment in pharmacies. Most persons diagnosed with tuberculosis initially perceived their illness as a simple virus. Diagnostic delay was common and prolonged. When individuals reached a threshold of symptom severity, they addressed their health with the least time-consuming, most economically feasible, and well-known healthcare option available to them. In high-burden settings, more human and material resources are required to promote tuberculosis case-finding initiatives, reduce tuberculosis associated stigma and address the social determinants underlying diagnostic delay.

HIV infection among tuberculosis patients in Vietnam: prevalence and impact on tuberculosis notification rates.

PubMed

Thanh, D H; Sy, D N; Linh, N D; Hoan, T M; Dien, H T; Thuy, T B; Hoa, N P; Tung, L B; Cobelens, F

2010-08-01

Vietnam has an emerging human immunodeficiency virus (HIV) epidemic (estimated population prevalence 0.5%), but valid data on HIV prevalence among tuberculosis (TB) patients are limited. Recent increases in TB notification rates among young adults may be related to HIV. To assess the prevalence of HIV infection among smear-positive TB patients in six provinces with relatively high HIV population prevalence in Vietnam. All patients who registered for treatment of smear-positive TB during the fourth quarter of 2005 were offered HIV testing. Of the 1217 TB patients included in the study, 100 (8.2%) tested HIV-positive. HIV prevalence varied between 2% and 17% in the provinces, and was strongly associated with age < 35 years, injecting drug use, commercial sex work and a history of sexually transmitted disease. Among men aged 15-34 years, the rate of notification of new smear-positive TB that was attributable to HIV infection varied from 3-4 per 100,000 population in mainly rural provinces to 20-42/100,000 in provinces with rapid industrial and commercial development. Among TB patients in Vietnam, HIV infection is concentrated in drug users, as well as in specific geographic areas where it has considerable impact on TB notification rates among men aged 15-34 years.

Public-private mix in tuberculosis control: an assessment of level of implementation in Jos, Plateau State.

PubMed

Daboer, J C; Lar, L A; Afolaranmi, T O; Bupwatda, P W; Dani, N

2013-12-01

After the initial gains in Tuberculosis case detection and cure rates, progress became stunted by persisting constraints and challenges in the implementation of the Directly Observed Treatment Short course strategy. This prompted the Stop Tuberculosis partners in 2006 to adopt innovative approaches including the Public-Private Mix, to improve access to and quality of care. This paper assesses the level of Public-Private Mix in Tuberculosis control in Jos, Plateau State. This was a facility-based, cross sectional study where data from all consenting private health care facilities owned by medically trained personnel and private medical practitioners in Jos North and Jos South Local Government Areas was collected using structured questionnaires. Eight (47.1%) of all 17 facilities assessed gave anti Tuberculosis drugs on clinical suspicion of Tuberculosis, 5(29.4%) required Acid Fast Bacillus result and 3(17.6%) referred elsewhere for the Tuberculosis management. Only 6 facilities (35.3%) were microscopy, treatment centres, or both. Ten (58.8%) of the facilities had the Directly Observed Treatment Short course guidelines, but these could be sighted in only 5 (29.4%), while six (35.3%) had Tuberculosis record and referral forms. In 13 (76.5%) of the facilities, no local government Tuberculosis and Leprosy supervisors had ever visited them. Only 30 (57.7%) medical practitioners had access to the Directly Observed Treatment Short course. Thirty two (61.5%) respondents treated Tuberculosis according to the Directly Observed Treatment Short course strategy, but 19 (36.5%) still used the conventional method. Only 22(42.3%) practitioners had ever received any training on the Directly Observed Treatment Short course strategy. The level of Public-Private Mix in Tuberculosis control in Jos is low.

Emerging Infections: Microbial Threats to Health in the United States

DTIC Science & Technology

1992-01-01

change in the U.S. public health system since the release of that report. The recent rapid increases in the incidence of measles and tuberculosis are...estimnated $3 to _S4 in savings: these savings increase dramatically when the cost of’ reatiniz multidrug-resistant tuberculosis is factored inl. We also...McNeill. 1976). Plague infection is now en/ootic in much of the rodent population in the western United States, Mexico . and Canada. Thanks to modern

Material incentives and enablers in the management of tuberculosis.

PubMed

Lutge, Elizabeth E; Wiysonge, Charles Shey; Knight, Stephen E; Volmink, Jimmy

2012-01-18

Patient adherence to medications, particularly for conditions requiring prolonged treatment such as tuberculosis, is frequently less than ideal, and can result in poor treatment outcomes. Material incentives (given as cash, vouchers and tokens), have been used to improve adherence. To assess the effects of material incentives in people undergoing diagnostic testing, or receiving prophylactic or curative therapy, for tuberculosis. We undertook a comprehensive search of the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; Science Citation Index; and reference lists of relevant publications; to 22 June 2011. Randomized controlled trials of material incentives in patients being investigated for tuberculosis, or on treatment for latent or active disease. At least two authors independently screened and selected studies, extracted data, and assessed the risk of bias. The effects of interventions are compared using risk ratios (RR), and presented with 95% confidence intervals (CI). The quality of the evidence was assessed using GRADE. We identified 11 eligible studies. Ten were conducted in the USA: in adolescents (one trial), in injection drug or cocaine users (four trials), in homeless adults (three trials), and in prisoners (two trials). One additional trial recruited malnourished men receiving active treatment for tuberculosis in Timor-Leste.Material incentives may increase the return rate for reading of tuberculin skin test results compared to normal care (two trials, 1371 participants: RR 2.16, 95% CI 1.41 to 3.29, low quality evidence).Similarly, incentives probably improve clinic re-attendance for initiation or continuation of antituberculosis prophylaxis (three trials, 595 participants: RR 1.58, 95% CI 1.27 to 1.96, moderate quality evidence), and may improve subsequent completion of prophylaxis in some settings (three trials, 869 participants: RR 1.79, 95% CI 0.70 to 4.58, low quality evidence).We currently don't know if incentives can improve long-term adherence and completion of antituberculosis treatment for active disease. Only one trial has assessed this and the incentive, given as a daily hot meal, was not well received by the population due to the inconvenience of attending the clinic at midday (one trial, 265 participants, RR 0.98, 95%CI 0.86 to 1.12, very low quality evidence).Several trials have compared different forms or levels of incentive. These comparisons remain limited to single trials and robust conclusions cannot be made. In summary, cash incentives may be more effective than non-cash incentives (return for test results: one trial, 651 participants: RR 1.13, 95%CI 1.07 to 1.19, low quality evidence, adherence to tuberculosis prophylaxis: one trial, 141 participants: RR 1.26, 95%CI 1.02 to 1.56, low quality evidence) and higher amounts of cash may be more effective than lower amounts (return for test results: one trial, 404 participants: RR 1.08, 95%CI 1.01 to 1.16, low quality evidence).Material incentives may also be more effective than motivational education at improving return for tuberculin skin test results (low quality evidence), but may be no more effective than peer counselling, or structured education at improving continuation or completion of prophylaxis (low quality evidence). There is limited evidence to support the use of material incentives to improve return rates for tuberculosis diagnostic test results and adherence to antituberculosis preventive therapy. The data are currently limited to trials among predominantly male drug users, homeless, and prisoner subpopulations in the USA, and therefore the results are not easily generalised to the wider adult population, or to low- and middle-income countries, where the tuberculosis burden is highest.Further high-quality studies are needed to assess both the costs and effectiveness of incentives to improve adherence to long-term treatment of tuberculosis.

Epidemiologic Consequences of Microvariation in Mycobacterium tuberculosis

PubMed Central

Mathema, Barun; Kurepina, Natalia; Yang, Guibin; Shashkina, Elena; Manca, Claudia; Mehaffy, Carolina; Bielefeldt-Ohmann, Helle; Ahuja, Shama; Fallows, Dorothy A.; Izzo, Angelo; Bifani, Pablo; Dobos, Karen; Kaplan, Gilla

2012-01-01

Background. Evidence from genotype-phenotype studies suggests that genetic diversity in pathogens have clinically relevant manifestations that can impact outcome of infection and epidemiologic success. We studied 5 closely related Mycobacterium tuberculosis strains that collectively caused extensive disease (n = 862), particularly among US-born tuberculosis patients. Methods. Representative isolates were selected using population-based genotyping data from New York City and New Jersey. Growth and cytokine/chemokine response were measured in infected human monocytes. Survival was determined in aerosol-infected guinea pigs. Results. Multiple genotyping methods and phylogenetically informative synonymous single nucleotide polymorphisms showed that all strains were related by descent. In axenic culture, all strains grew similarly. However, infection of monocytes revealed 2 growth phenotypes, slower (doubling ∼55 hours) and faster (∼25 hours). The faster growing strains elicited more tumor necrosis factor α and interleukin 1β than the slower growing strains, even after heat killing, and caused accelerated death of infected guinea pigs (∼9 weeks vs 24 weeks) associated with increased lung inflammation/pathology. Epidemiologically, the faster growing strains were associated with human immunodeficiency virus and more limited in spread, possibly related to their inherent ability to induce a strong protective innate immune response in immune competent hosts. Conclusions. Natural variation, with detectable phenotypic changes, among closely related clinical isolates of M. tuberculosis may alter epidemiologic patterns in human populations. PMID:22315279

The Evolutionary History, Demography, and Spread of the Mycobacterium tuberculosis Complex.

PubMed

Barbier, Maxime; Wirth, Thierry

2016-08-01

With the advent of next-generation sequencing technology, the genotyping of clinical Mycobacterium tuberculosis strains went through a major breakup that dramatically improved the field of molecular epidemiology but also revolutionized our deep understanding of the M. tuberculosis complex evolutionary history. The intricate paths of the pathogen and its human host are reflected by a common geographical origin in Africa and strong biogeographical associations that largely reflect the past migration waves out of Africa. This long coevolutionary history is cardinal for our understanding of the host-pathogen dynamic, including past and ongoing demographic components, strains' genetic background, as well as the immune system genetic architecture of the host. Coalescent- and Bayesian-based analyses allowed us to reconstruct population size changes of M. tuberculosis through time, to date the most recent common ancestor and the several phylogenetic lineages. This information will ultimately help us to understand the spread of the Beijing lineage, the rise of multidrug-resistant sublineages, or the fall of others in the light of socioeconomic events, antibiotic programs, or host population densities. If we leave the present and go through the looking glass, thanks to our ability to handle small degraded molecules combined with targeted capture, paleomicrobiology covering the Pleistocene era will possibly unravel lineage replacements, dig out extinct ones, and eventually ask for major revisions of the current model.

[Cost-benefit analysis of the active screening of pulmonary tuberculosis in a recluse population entering prison].

PubMed

Martín, V; Domínguez, A; Alcaide, J

1997-01-01

In spanish prisons, tuberculosis is a serious problem of public health and health authorities don't take it seriously. To prove the efficiency of pulmonary tuberculosis case-finding on arrival at prison in order to get location resources in this activity. Cost-benefit analysis of a case-finding program compared with to wait for diagnostic to illness. The sensitivity of test was fixed in 80% and the specificity in 99.99%. The cost was based on market prices. Sensitivity analysis was done in every variables as well as tridimensional analysis in those one of more influence. The case-finding was efficient on prevalences of tuberculosis over 5 per mil. Its efficiency was hardly affected by discount social rates or the sensitivity of diagnostic tests. The prevalence of illness, the cost of diagnostic activities as well as the success of treatment and the specificity of diagnostic tests used had as influence on the efficiency model. The tridimensional analysis proved that the case-finding of pulmonary tuberculosis has efficiency on low prevalences (1 per thousand), provided the number of people cured is a 5% higher than the alternative one and the costs of case-finding less than 1,000 pesetas per subject. The case-finding pulmonary tuberculosis on arrival at prisons is of high efficiency. In a cost-opportunity situation (location of available resources, penitentiary and extrapenitentiary) the program is very efficacious taking into account the fact of higher prevalence of pulmonary tuberculosis in this people.

Prevalence of nutritional deficiency in patients with pulmonary tuberculosis*

PubMed Central

Piva, Silvana Gomes Nunes; Costa, Maria da Conceição Nascimento; Barreto, Florisneide Rodrigues; Pereira, Susan Martins

2013-01-01

OBJECTIVE: To determine the prevalence of nutritional deficiency among patients with pulmonary tuberculosis. METHODS: This was a cross-sectional study using data obtained from the Brazilian Case Registry Database and from the medical records of patients diagnosed with pulmonary tuberculosis (15-59 years of age) residing in one of the municipalities that make up the 16th Regional Health District of the state of Bahia. We calculated the incidence, lethality, and mortality rates, as well as the prevalence of nutritional deficiency, as evaluated by body mass index. Demographic, social, clinical, and epidemiological data were collected. RESULTS: Of the 72 confirmed cases of tuberculosis, 59 (81.9%) were in males, and 21 (29.2%) of the patients were in the 40-49 year age bracket. The majority (85.3%) described themselves as Mulatto or Black; 55.2% reported using alcohol; and approximately 90% were treated as outpatients. In the district and age bracket studied, the incidence of pulmonary tuberculosis was 30.6/100,000 population. Among the 72 patients, data regarding nutritional status was available for 34. Of those, 50% and 25%, respectively, presented nutritional deficiency at the beginning and at the end of treatment. No statistically significant differences were found between normal-weight and malnourished patients regarding the characteristics studied. CONCLUSIONS: The prevalence of nutritional deficiency was high among our sample of patients with pulmonary tuberculosis. This underscores the importance of nutritional follow-up for the assessment of tuberculosis treatment in the decision-making process regarding therapeutic interventions. PMID:24068270

The Influence of HIV on the Evolution of Mycobacterium tuberculosis

PubMed Central

Brites, Daniela; Stucki, David; Evans, Joanna C.; Seldon, Ronnett; Heekes, Alexa; Mulder, Nicola; Nicol, Mark; Oni, Tolu; Mizrahi, Valerie; Warner, Digby F.; Parkhill, Julian; Gagneux, Sebastien; Martin, Darren P.; Wilkinson, Robert J.

2017-01-01

Abstract HIV significantly affects the immunological environment during tuberculosis coinfection, and therefore may influence the selective landscape upon which M. tuberculosis evolves. To test this hypothesis whole genome sequences were determined for 169 South African M. tuberculosis strains from HIV-1 coinfected and uninfected individuals and analyzed using two Bayesian codon-model based selection analysis approaches: FUBAR which was used to detect persistent positive and negative selection (selection respectively favoring and disfavoring nonsynonymous substitutions); and MEDS which was used to detect episodic directional selection specifically favoring nonsynonymous substitutions within HIV-1 infected individuals. Among the 25,251 polymorphic codon sites analyzed, FUBAR revealed that 189-fold more were detectably evolving under persistent negative selection than were evolving under persistent positive selection. Three specific codon sites within the genes celA2b, katG, and cyp138 were identified by MEDS as displaying significant evidence of evolving under directional selection influenced by HIV-1 coinfection. All three genes encode proteins that may indirectly interact with human proteins that, in turn, interact functionally with HIV proteins. Unexpectedly, epitope encoding regions were enriched for sites displaying weak evidence of directional selection influenced by HIV-1. Although the low degree of genetic diversity observed in our M. tuberculosis data set means that these results should be interpreted carefully, the effects of HIV-1 on epitope evolution in M. tuberculosis may have implications for the design of M. tuberculosis vaccines that are intended for use in populations with high HIV-1 infection rates. PMID:28369607

The Prevalence of Tuberculosis in Zambia: Results from the First National TB Prevalence Survey, 2013-2014.

PubMed

Kapata, Nathan; Chanda-Kapata, Pascalina; Ngosa, William; Metitiri, Mine; Klinkenberg, Eveline; Kalisvaart, Nico; Sunkutu, Veronica; Shibemba, Aaron; Chabala, Chishala; Chongwe, Gershom; Tembo, Mathias; Mulenga, Lutinala; Mbulo, Grace; Katemangwe, Patrick; Sakala, Sandra; Chizema-Kawesha, Elizabeth; Masiye, Felix; Sinyangwe, George; Onozaki, Ikushi; Mwaba, Peter; Chikamata, Davy; Zumla, Alimuddin; Grobusch, Martin P

2016-01-01

Tuberculosis in Zambia is a major public health problem, however the country does not have reliable baseline data on the TB prevalence for impact measurement; therefore it was among the priority countries identified by the World Health Organization to conduct a national TB prevalence survey. To estimate the prevalence of tuberculosis among the adult Zambian population aged 15 years and above, in 2013-2014. A cross-sectional population-based survey was conducted in 66 clusters across all the 10 provinces of Zambia. Eligible participants aged 15 years and above were screened for TB symptoms, had a chest x-ray (CXR) performed and were offered an HIV test. Participants with TB symptoms and/or CXR abnormality underwent an in-depth interview and submitted one spot- and one morning sputum sample for smear microscopy and liquid culture. Digital data collection methods were used throughout the process. Of the 98,458 individuals who were enumerated, 54,830 (55.7%) were eligible to participate, and 46,099 (84.1%) participated. Of those who participated, 45,633/46,099 (99%) were screened by both symptom assessment and chest x-ray, while 466/46,099 (1.01%) were screened by interview only. 6,708 (14.6%) were eligible to submit sputum and 6,154/6,708 (91.7%) of them submitted at least one specimen for examination. MTB cases identified were 265/6,123 (4.3%). The estimated national adult prevalence of smear, culture and bacteriologically confirmed TB was 319/100,000 (232-406/100,000); 568/100,000 (440-697/100,000); and 638/100,000 (502-774/100,000) population, respectively. The risk of having TB was five times higher in the HIV positive than HIV negative individuals. The TB prevalence for all forms was estimated to be 455 /100,000 population for all age groups. The prevalence of tuberculosis in Zambia was higher than previously estimated. Innovative approaches are required to accelerate the control of TB.

Vitamin D receptor gene polymorphisms and susceptibility M. tuberculosis in native Paraguayans.

PubMed

Wilbur, Alicia K; Kubatko, Laura Salter; Hurtado, Ana M; Hill, Kim R; Stone, Anne C

2007-07-01

Tuberculosis (TB) is a significant health problem for most of the world's populations, and prevalence among indigenous groups is typically higher than among their nonindigenous neighbors. Native South Americans experience high rates of TB, but while research in several other world populations indicates that susceptibility is multifactorial, polygenic, and population-specific, little work has been undertaken to investigate factors involved in Native American susceptibility. We conducted a family-based association study to examine immunologically relevant polymorphisms of a candidate gene, the vitamin D receptor, in conjunction with three measures of TB status in two Native Paraguayan populations, the Aché and the Avá. This is the first large-scale genetic analysis of Native South Americans to examine susceptibility to both infection and disease following exposure to M. tuberculosis. These two types of susceptibility reflect differences in innate and acquired immunity that have proven difficult to elucidate in other populations. Our results indicate that among the Aché, the FokI F allele protects individuals from infection, while the TaqI t allele protects against active disease but not infection. In particular, FF homozygotes are 17 times more likely to test positive for exposure to TB, but no more likely to have ever been diagnosed with active TB. TT individuals are 42 times less likely to mount a delayed-type hypersensitivity response, and the T allele was significantly more likely to have been transmitted to offspring who have been diagnosed with active TB. This ongoing research is of vital importance to indigenous groups of the Americas, because if there is a population-specific component to TB susceptibility, it will likely prove most effective to incorporate this into future treatment and prevention strategies.

Predicting global variation in infectious disease severity: A bottom-up approach.

PubMed

Jensen, Per M; De Fine Licht, Henrik H

2016-02-15

Understanding the underlying causes for the variation in case-fatality-ratios (CFR) is important for assessing the mechanism governing global disparity in the burden of infectious diseases. Variation in CFR is likely to be driven by factors such as population genetics, demography, transmission patterns and general health status. We present data here that support the hypothsis that changes in CFRs for specific diseases may be the result of serial passage through different hosts. For example passage through adults may lead to lower CFR, whereas passage through children may have the opposite effect. Accordingly changes in CFR may occur in parallel with demographic transitions. We explored the predictability of CFR using data obtained from the World Health Organization (WHO) disease databases for four human diseases: mumps, malaria, tuberculosis and leptospirosis and assessed these for association with a range of population characteristics, such as crude birth and death rates, median age of the population, mean body mass index, proportion living in urban areas and tuberculosis vaccine coverage. We then tested this predictive model on Danish historical demographic and population data. Birth rates were the best predictor for mumps and malaria CFR. For tuberculosis CFR death rates were the best predictor and for leptospirosis population density was a significant predictor. CFR predictors differed among diseases according to their biology. We suggest that the overall result reflects an interaction between the forces driving demographic change and the virulence of human-to-human transmitted diseases. © The Author(s) 2016. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey.

PubMed

Ismail, Nazir Ahmed; Mvusi, Lindiwe; Nanoo, Ananta; Dreyer, Andries; Omar, Shaheed V; Babatunde, Sanni; Molebatsi, Thabo; van der Walt, Martie; Adelekan, Adeboye; Deyde, Varough; Ihekweazu, Chikwe; Madhi, Shabir A

2018-04-20

Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001-02 estimates. A cross-sectional survey was done between June 15, 2012-June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model. 101 422 participants were tested in 2012-14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5-2·7) among new tuberculosis cases and 4·6% (3·2-6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9-2·9) and 5·1% (3·7-7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5-5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0-3·6; p=0·01). Comparing the current survey with the previous (2001-02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9-63·6) and 59·1% (49·0-69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0-8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively. The overall prevalence of MDR tuberculosis in South Africa in 2012-14 was similar to that in 2001-02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management. President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tuberculosis: finding a new potential antimycobacterium derivative in a aldehyde-arylhydrazone-oxoquinoline series.

PubMed

da C Santos, Fernanda; Castro, Helena C; Lourenço, Maria Cristina S; Abreu, Paula A; Batalha, Pedro N; Cunha, Anna C; Carvalho, Guilherme S L; Rodrigues, Carlos R; Medeiros, Cid A; Souza, Simone D; Ferreira, Vitor F; de Souza, Maria C B V

2012-10-01

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC = 6.25 μg/mL) better than other acylhydrazones described in the literature (MIC = 12.5 μg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.

Structure of the Response Regulator PhoP from Mycobacterium tuberculosis Reveals a Dimer Through the Receiver Domain

DOE Office of Scientific and Technical Information (OSTI.GOV)

S Menon; S Wang

The PhoP protein from Mycobacterium tuberculosis is a response regulator of the OmpR/PhoB subfamily, whose structure consists of an N-terminal receiver domain and a C-terminal DNA-binding domain. How the DNA-binding activities are regulated by phosphorylation of the receiver domain remains unclear due to a lack of structural information on the full-length proteins. Here we report the crystal structure of the full-length PhoP of M. tuberculosis. Unlike other known structures of full-length proteins of the same subfamily, PhoP forms a dimer through its receiver domain with the dimer interface involving {alpha}4-{beta}5-{alpha}5, a common interface for activated receiver domain dimers. However, themore » switch residues, Thr99 and Tyr118, are in a conformation resembling those of nonactivated receiver domains. The Tyr118 side chain is involved in the dimer interface interactions. The receiver domain is tethered to the DNA-binding domain through a flexible linker and does not impose structural constraints on the DNA-binding domain. This structure suggests that phosphorylation likely facilitates/stabilizes receiver domain dimerization, bringing the DNA-binding domains to close proximity, thereby increasing their binding affinity for direct repeat DNA sequences.« less

Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis

PubMed Central

Lack, Nathan; Lowe, Edward D.; Liu, Jie; Eltis, Lindsay D.; Noble, Martin E. M.; Sim, Edith; Westwood, Isaac M.

2008-01-01

Tuberculosis is a major cause of death worldwide. Understanding of the pathogenicity of Mycobacterium tuberculosis has been advanced by gene analysis and has led to the identification of genes that are important for intracellular survival in macrophages. One of these genes encodes HsaD, a meta-cleavage product (MCP) hydrolase that catalyzes the hydrolytic cleavage of a carbon–carbon bond in cholesterol metabolism. This paper describes the production of HsaD as a recombinant protein and, following crystallization, the determination of its three-dimensional structure to 2.35 Å resolution by X-ray crystallography at the Diamond Light Source in Oxfordshire, England. To the authors’ knowledge, this study constitutes the first report of a structure determined at the new synchrotron facility. The volume of the active-site cleft of the HsaD enzyme is more than double the corresponding active-site volumes of related MCP hydrolases involved in the catabolism of aromatic compounds, consistent with the specificity of HsaD for steroids such as cholesterol. Knowledge of the structure of the enzyme facilitates the design of inhibitors. PMID:18097091

Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis.

PubMed

Lack, Nathan; Lowe, Edward D; Liu, Jie; Eltis, Lindsay D; Noble, Martin E M; Sim, Edith; Westwood, Isaac M

2008-01-01

Tuberculosis is a major cause of death worldwide. Understanding of the pathogenicity of Mycobacterium tuberculosis has been advanced by gene analysis and has led to the identification of genes that are important for intracellular survival in macrophages. One of these genes encodes HsaD, a meta-cleavage product (MCP) hydrolase that catalyzes the hydrolytic cleavage of a carbon-carbon bond in cholesterol metabolism. This paper describes the production of HsaD as a recombinant protein and, following crystallization, the determination of its three-dimensional structure to 2.35 A resolution by X-ray crystallography at the Diamond Light Source in Oxfordshire, England. To the authors' knowledge, this study constitutes the first report of a structure determined at the new synchrotron facility. The volume of the active-site cleft of the HsaD enzyme is more than double the corresponding active-site volumes of related MCP hydrolases involved in the catabolism of aromatic compounds, consistent with the specificity of HsaD for steroids such as cholesterol. Knowledge of the structure of the enzyme facilitates the design of inhibitors.

Genotypic characterisation of Mycobacterium tuberculosis isolates from tuberculous meningitis patients at a tertiary neurocare centre in Southern India.

PubMed

Chandramuki, Akepati; Khanna, Neelam; Shashkina, Elena; Kurepina, Natalia; Mathema, Barun; Kreiswirth, Barry N; Venkataswamy, Manjunatha M

2017-01-01

Specific genotypes of Mycobacterium tuberculosis (MTB) have been reported to cause outbreaks of pulmonary tuberculosis (TB) in geographical areas that are endemic to TB. However, since there is little epidemiological evidence on the association of particular genotypes that cause tuberculous meningitis (TBM), we sought to investigate the association of specific MTB strains with infection of the central nervous system (CNS). We carried out a genetic characterisation of 89 MTB isolates from TBM patients at a Southern Indian tertiary neurocare centre and compared the genotypes with strains of pulmonary TB isolated from Indian immigrants in New York City. We applied the standard methods of genotyping of MTB, namely, IS6110-based restriction fragment length polymorphism and spoligotyping for strain identification, along with principal genetic grouping and single-nucleotide polymorphism cluster analysis. The analysis revealed a high-level of diversity amongst the strain population. The genotypes of the isolates from TBM patients paralleled the pulmonary TB strain population recovered from the Indian immigrants in NYC. We conclude that there is no apparent association between genotypes of MTB and propensity to infect CNS tissue.

The converging burdens of infectious and non-communicable diseases in rural-to-urban migrant Sub-Saharan African populations: a focus on HIV/AIDS, tuberculosis and cardio-metabolic diseases.

PubMed

Peer, Nasheeta

2015-01-01

Africa has the unenviable challenge of dealing with a double burden of disease: infectious diseases (IDs) such as HIV/AIDS and tuberculosis are high while non-communicable diseases (NCDs) are rapidly rising in the region. Populations with increased susceptibility to both include migrants. This review highlights the susceptibility of rural-to-urban migrants in Sub-Saharan Africa to the IDs of HIV/AIDS and tuberculosis, and to NCDs, particularly cardiovascular diseases. The disruption that occurs with migration is often accompanied by unhealthy exposures and environments. These include partaking in risky sexual practices and a subsequent greater risk for HIV infection in migrants than the general populations which contributes to the spread of the disease. Migrants frequently work and live in conditions that are poorly ventilated and overcrowded with suboptimal sanitation which increases their risk for tuberculosis. Considering that migrants have an increased risk of acquiring both HIV/AIDS and tuberculosis, and in view of the interaction between these diseases, they are likely to be at high risk for co-infection. They are also likely to facilitate the geographical spread of these infections and serve as conduits of disease dissemination to rural areas. Changes in lifestyle behaviours that accompany migration and urbanisation are exemplified primarily by shifts in physical activity and dietary patterns which promote the development of obesity, diabetes, hypertension and cardiovascular diseases. Urban living and employment is generally less physically exerting than rural routines; when migrants relocate from their rural residence they adapt to their new environment by significantly reducing their physical activity levels. Also, nutritional patterns among migrants in urban centres change rapidly with a shift to diets higher in fat, sugar and salt. Consequently, increases in weight, blood pressure and glucose levels have been reported within a year of migration. Interactions between IDs and NCDs are common; considering that migrants have an increased susceptibility to IDs and demonstrate a rapid rise in their risk for NCDs, the concurrent prevalence of both is likely in this population. There is a need for a combined strategy to combat IDs and NCDs with screening and treatment programmes geared towards this high risk group.

Tuberculosis and infection control.

PubMed

Karim, Kelvin

Against a background of rising tuberculosis (TB) rates, increasing incidence of TB and human immunodeficiency virus (HIV) co-infection, coupled with the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), the need for effective TB infection control has never been more vital (World Health Organization (WHO), 2009). TB infection control has been defined as 'a combination of measures aimed at minimizing the risk of TB transmission within populations' (WHO, 2009: p.ix). Health professionals are frequently confused about appropriate infection control measures when caring for patients affected by infectious respiratory tuberculosis (Mohandas and Cunniffe, 2009). This article aims to address the key infection control measures required to optimize patient care and reduce the risk of TB transmission within hospital and community settings.

Animal-adapted members of the Mycobacterium tuberculosis complex endemic to the southern African subregion.

PubMed

Clarke, Charlene; Van Helden, Paul; Miller, Michele; Parsons, Sven

2016-04-26

Members of the Mycobacterium tuberculosis complex (MTC) cause tuberculosis (TB) in both animals and humans. In this article, three animal-adapted MTC strains that are endemic to the southern African subregion - that is, Mycobacterium suricattae, Mycobacterium mungi, and the dassie bacillus - are reviewed with a focus on clinical and pathological presentations, geographic distribution, genotyping methods, diagnostic tools and evolution. Moreover, factors influencing the transmission and establishment of TB pathogens in novel host populations, including ecological, immunological and genetic factors of both the host and pathogen, are discussed. The risks associated with these infections are currently unknown and further studies will be required for greater understanding of this disease in the context of the southern African ecosystem.

Animal-adapted members of the Mycobacterium tuberculosis complex endemic to the southern African subregion.

PubMed

Clarke, Charlene; Van Helden, Paul; Miller, Michele; Parsons, Sven

2016-04-26

Members of the Mycobacterium tuberculosis complex (MTC) cause tuberculosis (TB) in both animals and humans. In this article, three animal-adapted MTC strains that are endemic to the southern African subregion - that is, Mycobacterium suricattae, Mycobacterium mungi, and the dassie bacillus - are reviewed with a focus on clinical and pathological presentations, geographic distribution, genotyping methods, diagnostic tools and evolution. Moreover, factors influencing the transmission and establishment of TB pathogens in novel host populations, including ecological, immunological and genetic factors of both the host and pathogen, are discussed. The risks associated with these infections are currently unknown and further studies will be required for greater understanding of this disease in the context of the southern African ecosystem.

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response.

PubMed

Queiroz, Adriano; Riley, Lee W

2017-01-01

The lipid-rich cell wall of Mycobacterium tuberculosis is a dynamic structure that is involved in the regulation of the transport of nutrients, toxic host-cell effector molecules, and anti-tuberculosis drugs. It is therefore postulated to contribute to the long-term bacterial survival in an infected human host. Accumulating evidence suggests that M. tuberculosis remodels the lipid composition of the cell wall as an adaptive mechanism against host-imposed stress. Some of these lipid species (trehalose dimycolate, diacylated sulphoglycolipid, and mannan-based lipoglycans) trigger an immunopathologic response, whereas others (phthiocerol dimycocerosate, mycolic acids, sulpholipid-1, and di-and polyacyltrehalose) appear to dampen the immune responses. These lipids appear to be coordinately expressed in the cell wall of M. tuberculosis during different phases of infection, ultimately determining the clinical fate of the infection. This review summarizes the current state of knowledge on the metabolism, transport, and homeostatic or immunostatic regulation of the cell wall lipids, and their orchestrated interaction with host immune responses that results in bacterial clearance, persistence, or tuberculosis.

Tuberculosis Screening by Tuberculosis Skin Test or QuantiFERON®-TB Gold In-Tube Assay among an Immigrant Population with a High Prevalence of Tuberculosis and BCG Vaccination

PubMed Central

Painter, John A.; Graviss, Edward A.; Hai, Hoang Hoa; Nhung, Duong Thi Cam; Nga, Tran Thi Thanh; Ha, Ngan P.; Wall, Kirsten; Loan, Le Thien Huong; Parker, Matt; Manangan, Lilia; O’Brien, Rick; Maloney, Susan A.; Hoekstra, R. M.; Reves, Randall

2013-01-01

Rationale Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth. Objectives 1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR. Methods We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR. Results The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants. Conclusions During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population.  PMID:24367546

Diabetes mellitus: an important risk factor for reactivation of tuberculosis.

PubMed

Solá, Ernesto; Rivera, Carmen; Mangual, Michelle; Martinez, José; Rivera, Kelvin; Fernandez, Ricardo

2016-01-01

Diabetes mellitus was identified as a risk factor for developing tuberculosis (TB) infection, and relapse after therapy. The risk of acquiring TB is described as comparable to that of HIV population. The fact that diabetics are 3× times more prone to develop pulmonary TB than nondiabetics cannot be overlooked. With DM recognized as global epidemic, and TB affecting one-third of the world population, physicians must remain vigilant. We present a 45-year-old woman born in Dominican Republic (DR), with 10-year history of T2DM treated with metformin, arrived to our Urgency Room complaining of dry cough for the past 3months. Interview unveiled unintentional 15lbs weight loss, night sweats, occasional unquantified fever, and general malaise but denied bloody sputum. She traveled to DR 2years before, with no known ill exposure. Physical examination showed a thin body habitus, otherwise well appearing woman with stable vital signs, presenting solely right middle lung field ronchi. LDH, ESR, hsCRP and Hg A1C were elevated. Imaging revealed a right middle lobe cavitation. Sputum for AFB disclosed active pulmonary TB. Our case portrays that the consideration of TB as differential diagnosis in diabetics should be exercised with the same strength, as it is undertaken during the evaluation of HIV patients with lung cavitation. Inability to recognize TB will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace. Diabetes mellitus should be considered an important risk factor for the reactivation of pulmonary tuberculosis.High clinical suspicious should be taken into consideration as radiological findings for pulmonary tuberculosis in patients with diabetes mellitus may be atypical, involving middle and lower lobes.Inability to recognize pulmonary tuberculosis will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace.

Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology

PubMed Central

Brudey, Karine; Driscoll, Jeffrey R; Rigouts, Leen; Prodinger, Wolfgang M; Gori, Andrea; Al-Hajoj, Sahal A; Allix, Caroline; Aristimuño, Liselotte; Arora, Jyoti; Baumanis, Viesturs; Binder, Lothar; Cafrune, Patricia; Cataldi, Angel; Cheong, Soonfatt; Diel, Roland; Ellermeier, Christopher; Evans, Jason T; Fauville-Dufaux, Maryse; Ferdinand, Séverine; de Viedma, Dario Garcia; Garzelli, Carlo; Gazzola, Lidia; Gomes, Harrison M; Guttierez, M Cristina; Hawkey, Peter M; van Helden, Paul D; Kadival, Gurujaj V; Kreiswirth, Barry N; Kremer, Kristin; Kubin, Milan; Kulkarni, Savita P; Liens, Benjamin; Lillebaek, Troels; Ly, Ho Minh; Martin, Carlos; Martin, Christian; Mokrousov, Igor; Narvskaïa, Olga; Ngeow, Yun Fong; Naumann, Ludmilla; Niemann, Stefan; Parwati, Ida; Rahim, Zeaur; Rasolofo-Razanamparany, Voahangy; Rasolonavalona, Tiana; Rossetti, M Lucia; Rüsch-Gerdes, Sabine; Sajduda, Anna; Samper, Sofia; Shemyakin, Igor G; Singh, Urvashi B; Somoskovi, Akos; Skuce, Robin A; van Soolingen, Dick; Streicher, Elisabeth M; Suffys, Philip N; Tortoli, Enrico; Tracevska, Tatjana; Vincent, Véronique; Victor, Tommie C; Warren, Robin M; Yap, Sook Fan; Zaman, Khadiza; Portaels, Françoise; Rastogi, Nalin; Sola, Christophe

2006-01-01

Background The Direct Repeat locus of the Mycobacterium tuberculosis complex (MTC) is a member of the CRISPR (Clustered regularly interspaced short palindromic repeats) sequences family. Spoligotyping is the widely used PCR-based reverse-hybridization blotting technique that assays the genetic diversity of this locus and is useful both for clinical laboratory, molecular epidemiology, evolutionary and population genetics. It is easy, robust, cheap, and produces highly diverse portable numerical results, as the result of the combination of (1) Unique Events Polymorphism (UEP) (2) Insertion-Sequence-mediated genetic recombination. Genetic convergence, although rare, was also previously demonstrated. Three previous international spoligotype databases had partly revealed the global and local geographical structures of MTC bacilli populations, however, there was a need for the release of a new, more representative and extended, international spoligotyping database. Results The fourth international spoligotyping database, SpolDB4, describes 1939 shared-types (STs) representative of a total of 39,295 strains from 122 countries, which are tentatively classified into 62 clades/lineages using a mixed expert-based and bioinformatical approach. The SpolDB4 update adds 26 new potentially phylogeographically-specific MTC genotype families. It provides a clearer picture of the current MTC genomes diversity as well as on the relationships between the genetic attributes investigated (spoligotypes) and the infra-species classification and evolutionary history of the species. Indeed, an independent Naïve-Bayes mixture-model analysis has validated main of the previous supervised SpolDB3 classification results, confirming the usefulness of both supervised and unsupervised models as an approach to understand MTC population structure. Updated results on the epidemiological status of spoligotypes, as well as genetic prevalence maps on six main lineages are also shown. Our results suggests the existence of fine geographical genetic clines within MTC populations, that could mirror the passed and present Homo sapiens sapiens demographical and mycobacterial co-evolutionary history whose structure could be further reconstructed and modelled, thereby providing a large-scale conceptual framework of the global TB Epidemiologic Network. Conclusion Our results broaden the knowledge of the global phylogeography of the MTC complex. SpolDB4 should be a very useful tool to better define the identity of a given MTC clinical isolate, and to better analyze the links between its current spreading and previous evolutionary history. The building and mining of extended MTC polymorphic genetic databases is in progress. PMID:16519816

Characterization of Antibacterial and Hemolytic Activity of Synthetic Pandinin 2 Variants and Their Inhibition against Mycobacterium tuberculosis

PubMed Central

Rodríguez, Alexis; Villegas, Elba; Montoya-Rosales, Alejandra; Rivas-Santiago, Bruno; Corzo, Gerardo

2014-01-01

The contention and treatment of Mycobacterium tuberculosis and other bacteria that cause infectious diseases require the use of new type of antibiotics. Pandinin 2 (Pin2) is a scorpion venom antimicrobial peptide highly hemolytic that has a central proline residue. This residue forms a structural “kink” linked to its pore-forming activity towards human erythrocytes. In this work, the residue Pro14 of Pin2 was both substituted and flanked using glycine residues (P14G and P14GPG) based on the low hemolytic activities of antimicrobial peptides with structural motifs Gly and GlyProGly such as magainin 2 and ponericin G1, respectively. The two Pin2 variants showed antimicrobial activity against E. coli, S. aureus, and M. tuberculosis. However, Pin2 [GPG] was less hemolytic (30%) than that of Pin2 [G] variant. In addition, based on the primary structure of Pin2 [G] and Pin2 [GPG], two short peptide variants were designed and chemically synthesized keeping attention to their physicochemical properties such as hydrophobicity and propensity to adopt alpha-helical conformations. The aim to design these two short antimicrobial peptides was to avoid the drawback cost associated to the synthesis of peptides with large sequences. The short Pin2 variants named Pin2 [14] and Pin2 [17] showed antibiotic activity against E. coli and M. tuberculosis. Besides, Pin2 [14] presented only 25% of hemolysis toward human erythrocytes at concentrations as high as 100 µM, while the peptide Pin2 [17] did not show any hemolytic effect at the same concentration. Furthermore, these short antimicrobial peptides had better activity at molar concentrations against multidrug resistance M. tuberculosis than that of the conventional antibiotics ethambutol, isoniazid and rifampicin. Therefore, Pin2 [14] and Pin2 [17] have the potential to be used as an alternative antibiotics and anti-tuberculosis agents with reduced hemolytic effects. PMID:25019413

Interferon Gamma-Based Detection of Latent Tuberculosis Infection in the Border States of Nuevo Leon and Tamaulipas, Mexico

PubMed Central

Oren, Eyal; Alatorre-Izaguirre, Gabriela; Vargas-Villarreal, Javier; Moreno-Treviño, Maria Guadalupe; Garcialuna-Martinez, Javier; Gonzalez-Salazar, Francisco

2015-01-01

Nearly one-third of the world’s population is infected with latent tuberculosis (LTBI). Tuberculosis (TB) rates in the border states are higher than national rates in both the US and Mexico, with the border accounting for 30% of total registered TB cases in both countries. However, LTBI rates in the general population in Mexican border states are unknown. In this region, LTBI is diagnosed using the tuberculin skin test (TST). New methods of detection more specific than TST have been developed, although there is currently no gold standard for LTBI detection. Our objective is to demonstrate utility of the Quantiferon TB gold In-Tube (QFT-GIT) test compared with the TST to detect LTBI among border populations. This is an observational, cross-sectional study carried out in border areas of the states of Nuevo Leon and Tamaulipas, Mexico. Participants (n = 210) provided a TST and blood sample for the QFT-GIT. Kappa coefficients assessed the agreement between TST and QFT-GIT. Participant characteristics were compared using Fisher exact tests. Thirty-eight percent of participants were diagnosed with LTBI by QFT-GIT. The proportion of LTBI detected using QFT-GIT was almost double [38% (79/210)] that found by TST [19% (39/210)] (P < 0.001). Concordance between TST and QFT-GIT was low (kappa = 0.37). We recommend further studies utilizing the QFT-GIT test to detect LTBI among border populations. PMID:26484340

Interferon Gamma-Based Detection of Latent Tuberculosis Infection in the Border States of Nuevo Leon and Tamaulipas, Mexico.

PubMed

Oren, Eyal; Alatorre-Izaguirre, Gabriela; Vargas-Villarreal, Javier; Moreno-Treviño, Maria Guadalupe; Garcialuna-Martinez, Javier; Gonzalez-Salazar, Francisco

2015-01-01

Nearly one-third of the world's population is infected with latent tuberculosis (LTBI). Tuberculosis (TB) rates in the border states are higher than national rates in both the US and Mexico, with the border accounting for 30% of total registered TB cases in both countries. However, LTBI rates in the general population in Mexican border states are unknown. In this region, LTBI is diagnosed using the tuberculin skin test (TST). New methods of detection more specific than TST have been developed, although there is currently no gold standard for LTBI detection. Our objective is to demonstrate utility of the Quantiferon TB gold In-Tube (QFT-GIT) test compared with the TST to detect LTBI among border populations. This is an observational, cross-sectional study carried out in border areas of the states of Nuevo Leon and Tamaulipas, Mexico. Participants (n = 210) provided a TST and blood sample for the QFT-GIT. Kappa coefficients assessed the agreement between TST and QFT-GIT. Participant characteristics were compared using Fisher exact tests. Thirty-eight percent of participants were diagnosed with LTBI by QFT-GIT. The proportion of LTBI detected using QFT-GIT was almost double [38% (79/210)] that found by TST [19% (39/210)] (P < 0.001). Concordance between TST and QFT-GIT was low (kappa = 0.37). We recommend further studies utilizing the QFT-GIT test to detect LTBI among border populations.

The rural-to-urban migrant population in China: gloomy prospects for tuberculosis control.

PubMed

Tobe, Ruoyan Gai; Xu, Lingzhong; Song, Peipei; Huang, Yong

2011-12-01

The migrant population is a population with a high risk of tuberculosis (TB) infection and transmission. Globally, migration is likely to have a significant impact on TB epidemiology, particularly in countries that receive substantial numbers of migrants from countries with a high infection burden. China, a country with the world's second highest TB burden, faces a considerable increase in the number of rural-to-urban migrants. This population has a significant impact on urban TB epidemics and is specifically targeted by national guidelines for TB control. TB control among the migrant population has had relatively poor outcomes. Barriers to detection and treatment have both financial and non-financial aspects, such as the "migratory" nature of the migrant population, their marginalized working and living environment, poor financial status, little awareness of TB, inadequate referral to TB dispensaries, and potential social stigma in the workplace. Currently, the free TB treatment policy has limited ability to relieve the financial burden on most migrant TB patients as would allow optimal outcomes of TB detection and treatment. Universal health insurance coverage and fostering of personnel in community-based primary health care for the rural-to- urban migrant population represent two pillars of successful TB control.

Structure of the Mycobacterium tuberculosis D-Alanine:D-Alanine Ligase, a Target of the Antituberculosis Drug D-Cycloserine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia

D-Alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoinedmore » by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.« less

Analysis of Mycobacterium tuberculosis Genotypic Lineage Distribution in Chile and Neighboring Countries

PubMed Central

Lagos, Jaime; Couvin, David; Arata, Loredana; Tognarelli, Javier; Aguayo, Carolina; Leiva, Tamara; Arias, Fabiola; Hormazabal, Juan Carlos; Rastogi, Nalin; Fernández, Jorge

2016-01-01

Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (MTB), remains a disease of high importance to global public health. Studies into the population structure of MTB have become vital to monitoring possible outbreaks and also to develop strategies regarding disease control. Although Chile has a low incidence of MTB, the current rates of migration have the potential to change this scenario. We collected and analyzed a total of 458 M. tuberculosis isolates (1 isolate per patient) originating from all 15 regions of Chile. The isolates were genotyped using the spoligotyping method and the data obtained were analyzed and compared with the SITVIT2 database. A total of 169 different patterns were identified, of which, 119 patterns (408 strains) corresponded to Spoligotype International Types (SITs) and 50 patterns corresponded to orphan strains. The most abundantly represented SITs/lineages were: SIT53/T1 (11.57%), SIT33/LAM3 (9.6%), SIT42/LAM9 (9.39%), SIT50/H3 (5.9%), SIT37/T3 (5%); analysis of the spoligotyping minimum spanning tree as well as spoligoforest were suggestive of a recent expansion of SIT42, SIT50 and SIT37; all of which potentially evolved from SIT53. The most abundantly represented lineages were LAM (40.6%), T (34.1%) and Haarlem (13.5%). LAM was more prevalent in the Santiago (43.6%) and Concepción (44.1%) isolates, rather than the Iquique (29.4%) strains. The proportion of X lineage was appreciably higher in Iquique and Concepción (11.7% in both) as compared to Santiago (1.6%). Global analysis of MTB lineage distribution in Chile versus neighboring countries showed that evolutionary recent lineages (LAM, T and Haarlem) accounted together for 88.2% of isolates in Chile, a pattern which mirrored MTB lineage distribution in neighboring countries (n = 7378 isolates recorded in SITVIT2 database for Peru, Brazil, Paraguay, and Argentina; and published studies), highlighting epidemiological advantage of Euro-American lineages in this region. Finally, we also observed exclusive emergence of patterns SIT4014/X1 and SIT4015 (unknown lineage signature) that have hitherto been found exclusively in Chile, indicating that conditions specific to Chile, along with the unique genetic makeup of the Chilean population, might have allowed for a possible co-evolution leading to the success of these emerging genotypes. PMID:27518286

Tolerability and Healthcare Utilization in Maintenance Hemodialysis Patients Undergoing Treatment for Tuberculosis-Related Conditions

PubMed Central

Hamadah, Abdurrahman M.; Beaulieu, Lynn M.; Wilson, John W.; Aksamit, Timothy R.; Gregoire, James R.; Williams, Amy W.; Dillon, John J.; Albright, Robert C.; Onuigbo, Macaulay; Iyer, Venkateshwaran K.; Hickson, LaTonya J.

2016-01-01

Background The incidence of tuberculosis in end-stage renal disease is significantly higher than the general population. Among those with kidney dysfunction, anti-tuberculosis treatment is associated with increased side effects, but the effect on healthcare utilization is unknown. Methods/Aim To assess patient-reported symptoms, adverse effects and describe changes in healthcare utilization patterns during treatment for tuberculosis, we conducted a case series (n=12) of patients receiving maintenance hemodialysis from Mayo Clinic Dialysis Services and concurrent drug therapy for tuberculosis from January 2002 through May 2014. Healthcare utilization (hospitalizations and emergency department visits independent of hospital admission) was compared before and during treatment. Results Patients were treated for latent (n=7) or active (n=5) tuberculosis. The majority of patients with latent disease were treated with isoniazid (n=5, 71%), while active-disease patients received a 4-drug regimen. Adverse effects were reported in 83% of patients. Compared to measurements prior to drug initiation, serum albumin and dialysis weights were similar at 3 months. Commonly reported anti-tuberculosis drug toxicities were described. More than half (58%) of patients were hospitalized at least once. No emergency department or hospital admissions occurred in the period prior to drug therapy, but healthcare utilization increased during treatment in the latent disease group (hospitalization rate per person-month: pre, 0 vs. post, 1). Conclusions Among hemodialysis patients, anti-tuberculosis therapy is associated with frequent patient-reported symptoms and increased healthcare utilization. Patients receiving treatment for latent disease may have the greatest increase in healthcare use. Careful monitoring and early complication detection may help optimize medication adherence and minimize hospitalizations. PMID:26859893

The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

PubMed Central

Lin, Philana Ling; Dietrich, Jes; Tan, Esterlina; Abalos, Rodolfo M.; Burgos, Jasmin; Bigbee, Carolyn; Bigbee, Matthew; Milk, Leslie; Gideon, Hannah P.; Rodgers, Mark; Cochran, Catherine; Guinn, Kristi M.; Sherman, David R.; Klein, Edwin; Janssen, Christopher; Flynn, JoAnne L.; Andersen, Peter

2011-01-01

It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56. PMID:22133873

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sigal, G. B.; Segal, M. R.; Mathew, A.

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers withmore » baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8 weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study. Keywords: host immune response; tuberculosis; biomarkers; clinical trials« less

Tuberculosis Screening and Control in the US Military in War and Peace.

PubMed

Mancuso, James D

2017-01-01

Tuberculosis (TB) has a well-established association with military populations, but the association of increased TB risk during armed conflict is less certain. This historical review focuses on the evolution of screening practices, the changing epidemiology of TB, and the risk of TB among US military service members during armed conflict from 1885 to the present. Overall, deployed soldiers were not at increased risk for TB compared with nondeployed soldiers in any of these conflicts, and the risk of TB in the US military largely reflected that of the underlying US population. Nevertheless, there are focal risk groups with higher rates of TB in the military, including prisoners of war. Although the principles of TB control in the military conform to those used in the civilian population, unique military exposures during both times of peace and of armed conflict require additional screening, surveillance, and control measures.

Targeting phenotypically tolerant Mycobacterium tuberculosis

PubMed Central

Gold, Ben; Nathan, Carl

2016-01-01

While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan. PMID:28233509

The 1.25 Å resolution structure of phosphoribosyl-ATP pyrophosphohydrolase from Mycobacterium tuberculosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Javid-Majd, Farah; Yang, Dong; Ioerger, Thomas R.

2008-06-23

Phosphoribosyl-ATP pyrophosphohydrolase is the second enzyme in the histidine-biosynthetic pathway, irreversibly hydrolyzing phosphoribosyl-ATP to phosphoribosyl-AMP and pyrophosphate. It is encoded by the hisE gene, which is present as a separate gene in many bacteria and archaea but is fused to hisI in other bacteria, fungi and plants. Because of its essentiality for growth in vitro, HisE is a potential drug target for tuberculosis. The crystal structures of two native (uncomplexed) forms of HisE from Mycobacterium tuberculosis have been determined to resolutions of 1.25 and 1.79 {angstrom}. The structure of the apoenzyme reveals that the protein is composed of five -helicesmore » with connecting loops and is a member of the {alpha}-helical nucleoside-triphosphate pyrophosphatase superfamily. The biological unit of the protein is a homodimer, with an active site on each subunit composed of residues exclusively from that subunit. A comparison with the Campylobacter jejuni dUTPase active site allowed the identification of putative metal- and substrate-binding sites in HisE, including four conserved glutamate and glutamine residues in the sequence that are consistent with a motif for pyrophosphohydrolase activity. However, significant differences between family members are observed in the loop region between {alpha}-helices H1 and H3. The crystal structure of M. tuberculosis HisE provides insights into possible mechanisms of substrate binding and the diversity of the nucleoside-triphosphate pyrophosphatase superfamily.« less

Crystallization and preliminary X-ray diffraction study of phosphopantetheine adenylyltransferase from M. tuberculosis crystallizing in space group P3{sub 2}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timofeev, V. I., E-mail: tostars@mail.ru; Chupova, L. A.; Esipov, R. S.

Crystals of M. tuberculosis phosphopantetheine adenylyltransferase were grown in microgravity by the capillary counter-diffusion method through a gel layer. The X-ray diffraction data set suitable for the determination of the three-dimensional structure at atomic resolution was collected from one crystal at the Spring-8 synchrotron facility to 2.00-Å resolution. The crystals belong to sp. gr. P3{sub 2} and have the following unit-cell parameters: a = b = 106.47 Å, c = 71.32 Å, α = γ = 90°, β = 120°. The structure was solved by the molecular-replacement method. There are six subunits of the enzyme comprising a hexamer per asymmetricmore » unit. The hexamer is a biologically active form of phosphopantetheine adenylyltransferase from M. tuberculosis.« less

Nicotinamidase/pyrazinamidase of Mycobacterium tuberculosis forms homo-dimers stabilized by disulfide bonds

PubMed Central

Rueda, Daniel; Sheen, Patricia; Gilman, Robert H.; Bueno, Carlos; Santos, Marco; Pando-Robles, Victoria; Batista, Cesar V.; Zimic, Mirko

2014-01-01

Recombinant wild-pyrazinamidase from H37Rv M. tuberculosis was analyzed by gel electrophoresis under differential reducing conditions to evaluate its quaternary structure. PZAse was fractionated by size exclusion chromatography under non-reducing conditions. PZAse activity was measured and mass spectrometry analysis was performed to determine the identity of proteins by de novo sequencing and to determine the presence of disulfide bonds. This study confirmed that M. tuberculosis wild type PZAse was able to form homo-dimers in vitro. Homo-dimers showed a slightly lower specific PZAse activity compared to monomeric PZAse. PZAse dimers were dissociated into monomers in response to reducing conditions. Mass spectrometry analysis confirmed the existence of disulfide bonds (C72-C138 and C138-C138) stabilizing the quaternary structure of the PZAse homo-dimer. PMID:25199451