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Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans  [PDF]
Roberto Colangeli, Vic L. Arcus, Ray T. Cursons, Ali Ruthe, Noel Karalus, Kathy Coley, Shannon D. Manning, Soyeon Kim, Emily Marchiano, David Alland
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091024
Abstract: Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10?10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10?11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10?11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
Social Activity Patterns Drive High Rates of Latent Tuberculosis Infection among Adolescents in Urban Tanzania
—Latent TB Infection in Adolescents, Tanzania

Isaac I. Maro, Keiko Nakamura, Kaoruko Seino, Kisali Pallangyo, Patricia Munseri, Mecky Matee, Charles Fordham von Reyn
Journal of Tuberculosis Research (JTR) , 2018, DOI: 10.4236/jtr.2018.61008
Abstract: SETTING: Dar es Salaam, Tanzania. OBJECTIVE: To determine the prevalence of latent tuberculosis (TB) infection (LTBI) among adolescents in a country with a high TB burden, and examine risks of LTBI according to their social activity patterns. METHODS: A cross-sectional study nested within a phase 2b randomised, placebo controlled, double blind study and consisted of 824 adolescents, 13 - 15 years old who had received Bacillus Calmette-Guérin (BCG) vaccine, were attending public secondary schools and had no evidence of active tuberculosis (TB). Anthropometric measurements were obtained, a questionnaire administered, and phlebotomy performed for a T spot interferon-γ?release assay (IGRA) to detect LTBI. RESULTS: Among 824 subjects, 149 (18%) had a positive IGRA. After adjusting for the influence of household socioeconomic status, history of TB contact, living environment and nutritional status, LTBI risk was higher in subjects with than without regular informal encounters with traditional alcoholic beverage drinkers (AOR, 6.37 [1.84 - 22.00]). Other significant factors for LTBI risk included contact with TB patient at school (AOR, 3.34 [1.14 - 9.80]), and living close to a health facility, as was observed among those from houses within a 10 - 30-minute walking distance to the nearest health facility, who were less likely to be IGRA-positive than those who were living within a 10-minute walking distance (AOR, 0.30 [95%CI, 0.13 - 0.69]). CONCLUSION: This IGRA study revealed a high prevalence of LTBI among adolescents in Dar es Salaam, Tanzania with prior BCG immunization. Informal social encounters were identified as independent risk factors for LTBI, along with a history of contact with TB patients, living environment characteristics and household socioeconomic status. Efforts focusing on risk of MTB transmission in adolescents at informal social gatherings will improve interventions to reduce LTBI in this population and consequently the subsequent risk of developing active TB disease.
Saudi guidelines for testing and treatment of latent tuberculosis infection  [cached]
Al Jahdali Hamdan,Baharoon Salim,Abba Abdullah,Memish Ziad
Annals of Saudi Medicine , 2010,
Abstract: Pulmonary tuberculosis is a common disease in Saudi Arabia. As most cases of tuberculosis are due to reactivation of latent infection, identification of individuals with latent tuberculosis infection (LTBI) who are at increased risk of progression to active disease, is a key element of tuberculosis control programs. Whereas general screening of individuals for LTBI is not cost-effective, targeted testing of individuals at high risk of disease progression is the right approach. Treatment of those patients with LTBI can diminish the risk of progression to active tuberculosis disease in the majority of treated patients. This statement is the first Saudi guideline for testing and treatment of LTBI and is a result of the cooperative efforts of four local Saudi scientific societies. This Guideline is intended to provide physicians and allied health workers in Saudi Arabia with the standard of care for testing and treatment of LTBI.
Current management options for latent tuberculosis: a review  [cached]
Norton BL,Holl,DP
Infection and Drug Resistance , 2012,
Abstract: Brianna L Norton, David P HollandDepartment of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USAAbstract: Tuberculosis remains the world’s second leading infectious cause of death, with nearly one-third of the global population latently infected. Treatment of latent tuberculosis infection is a mainstay of tuberculosis-control efforts in low-to medium-incidence countries. Isoniazid monotherapy has been the standard of care for decades, but its utility is impaired by poor completion rates. However, new, shorter-course regimens using rifamycins improve completion rates and are cost-saving compared with standard isoniazid monotherapy. We review the currently available therapies for latent tuberculosis infection and their toxicities and include a brief economic comparison of the different regimens.Keywords: isoniazid, rifampin, rifapentine, tuberculin skin test, interferon-gamma release assay
Current management options for latent tuberculosis: a review
Norton BL, Holland DP
Infection and Drug Resistance , 2012, DOI: http://dx.doi.org/10.2147/IDR.S29180
Abstract: rrent management options for latent tuberculosis: a review Review (1472) Total Article Views Authors: Norton BL, Holland DP Published Date November 2012 Volume 2012:5 Pages 163 - 173 DOI: http://dx.doi.org/10.2147/IDR.S29180 Received: 29 August 2012 Accepted: 01 October 2012 Published: 29 November 2012 Brianna L Norton, David P Holland Department of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA Abstract: Tuberculosis remains the world’s second leading infectious cause of death, with nearly one-third of the global population latently infected. Treatment of latent tuberculosis infection is a mainstay of tuberculosis-control efforts in low-to medium-incidence countries. Isoniazid monotherapy has been the standard of care for decades, but its utility is impaired by poor completion rates. However, new, shorter-course regimens using rifamycins improve completion rates and are cost-saving compared with standard isoniazid monotherapy. We review the currently available therapies for latent tuberculosis infection and their toxicities and include a brief economic comparison of the different regimens.
Prevalence and Risk Factors for Latent Tuberculosis Infection among Health Care Workers in China: A Cross-Sectional Study  [PDF]
Xia Zhang, Hongyan Jia, Fei Liu, Liping Pan, Aiying Xing, Shuxiang Gu, Boping Du, Qi Sun, Rongrong Wei, Zongde Zhang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066412
Abstract: Background Health care workers (HCWs) are at risk of latent tuberculosis infection (LTBI). In China, tuberculosis (TB) is a major public health problem, but the prevalence of LTBI in HCWs especially in the hospital for pulmonary diseases has not been assessed enough. The aim of this study was to determine the prevalence and putative risk factors of LTBI among HCWs in a chest hospital and a TB research institute in China. Methodology/Principal Findings A cross-sectional study was conducted among HCWs in China in 2012. LTBI was assessed by T-SPOT.TB, and information on HCWs was collected using a standardised questionnaire. Risk factors for LTBI were analyzed by univariate and multivariate regression. The overall prevalence of LTBI among HCWs was 33.6%. Analyzed by job category, the highest prevalence was found among laboratory staff (43.4%). In the different workplaces, the proportion of LTBI was significantly higher among the high risk workplaces (37.4%) compared to the low risk workplaces. The duration of employment had a significant impact on the prevalence of LTBI. Positive T-SPOT.TB test results accounted for 17.6%, 16.8%, 23.5%, 41.8% and 41.6% in groups of ≤2, 3–5, 6–10, 11–20, and >20 working years respectively. In multivariate analysis, job categories (Laboratory staff [2.76 (95% CI: 1.36; 5.60)], technician staff [2.02 (95% CI: 1.12; 3.64)]); working duration as a HCW for 11 to 20 years [3.57 (95% CI: 1.46; 8.71)], and 20 years above [3.41 (95% CI: 1.28; 9.11)]; and the history of household TB contact [2.47 (95% CI: 1.15; 5.33)] were associated with increased risk of LTBI. Conclusions/Significance Prevalence of LTBI estimated by T-SPOT.TB is high among Chinese HCWs and working duration, job category and the history of household TB contact were associated with increased risk. These data highlight adequate infection control measures should be undertaken.
Tuberculosis latente Latent tuberculosis
Juan C Rodríguez D
Revista Chilena de Enfermedades Respiratorias , 2012,
Abstract: La tuberculosis continúa siendo un problema enorme en salud pública. Se ha estimado que anualmente en todo el mundo 9 millones de personas contraen esta enfermedad y que 2 millones de muertes se deben a la tuberculosis. La exposición al M. tuberculosis causa la enfermedad en cerca del 10% de la población expuesta. En el 90% restante de los expuestos la respuesta inmune inhibe la multiplicación del M. tuberculosis. En una parte de las personas expuestas (~40%) algunos bacilos no son muertos permaneciendo en una condición que no les permite replicarse, generándose así la infección denominada tuberculosis latente. Los bacilos inactivos pueden recuperar su vitalidad (capacidad de replicación) y causar una tuberculosis activa, si la respuesta inmune está alterada. La detección y el tratamiento de la infección tuberculosa latente han sido reconocidos como objetivos estratégicos efectivos en el control de la tuberculosis. En el pasado reciente, el único test disponible para la detección de infección tuberculosa latente era el test cutáneo con tuberculina (PPD). Recientemente se ha desarrollado un ensayo basado en la liberación "in vitro" de interferón-gama (IGRA)por células T. Este ensayo usa antígenos específicos del M. tuberculosis y no es interferido por la vacunación previa con BCG, lo que lo convierte en un test de tamizaje útil en poblaciones vacunadas con BCG. La FDA ha aprobado dos IGRAs comerciales: a) QuantiFERON-TB Gold (QFT, Cellestis) cuya variación simplificada se denomina Quantiferon T in Tube (QFT-G-IT) y b) el T-SPOT TB test (Oxford, Immunotec). Según el Programa Nacional de Control de la Tuberculosis el tratamiento para la infección tuberculosa latente es la administración diaria de isoniacida por 9 meses; este tratamiento proporciona una protección superior al 90% si es administrado regularmente. Otra opción, usada en EE.UU. y Europa es prescribir rifampicina por 4 meses. La identificación y el tratamiento de los portadores de tuberculosis latente es una acción crucial en los esfuerzos para disminuir la incidencia de tuberculosis en países en desarrollo con tasas de incidencia de tuberculosis intermedias o bajas. Tuberculosis continues being a huge public health problem. It has been estimated that worldwide every year about 9 million people adquire the disease and 2 million of deaths are because of tuberculosis. Exposure to Mycobacterium tuberculosis causes active disease in nearly 10% of the people. In the remaining 90% of the exposed population the immune response inhibits M. tuberculosis multiplication. In part of the exposed people (~40%)
Tuberculosis and latent tuberculosis in prison inmates
Nogueira,Péricles Alves; Abrah?o,Regina Maura Cabral de Melo; Galesi,Vera Maria Neder;
Revista de Saúde Pública , 2012, DOI: 10.1590/S0034-89102011005000080
Abstract: objective: to estimate the prevalences of tuberculosis and latent tuberculosis in inmates. methods: observational study was carried out with inmates of a prison and a jail in the state of s?o paulo, southeastern brazil, between march and december of 2008. questionnaires were used to collect sociodemographic and epidemiological data. tuberculin skin testing was administered (ppd-rt23-2tu/0.1 ml), and the following laboratory tests were also performed: sputum smear examination, sputum culture, identification of strains isolated and drug susceptibility testing. the variables were compared using pearson's chi-square (χ2) association test, fisher's exact test and the proportion test. results: of the 2,435 inmates interviewed, 2,237 (91.9%) agreed to submit to tuberculin skin testing and of these, 73.0% had positive reactions. the prevalence of tuberculosis was 830.6 per 100,000 inmates. the coefficients of prevalence were 1,029.5/100,000 for inmates of the prison and 525.7/100,000 for inmates of the jail. the sociodemographic characteristics of the inmates in the two groups studied were similar; most of the inmates were young and single with little schooling. the epidemiological characteristics differed between the prison units, with the number of cases of previous tuberculosis and of previous contact with the disease greater in the prison and coughing, expectoration and smoking more common in the jail. among the 20 mycobacterium tuberculosis strains identified, 95.0% were sensitive to anti-tuberculosis drugs, and 5.0% were resistant to streptomycin. conclusions: the prevalences of tuberculosis and latent tuberculosis were higher in the incarcerated population than in the general population, and they were also higher in the prison than in the jail.
Latent tuberculosis in nursing professionals of a Brazilian hospital
Karen Severo, Julia Oliveira, Marcelo Carneiro, Andréia Valim, Eliane Krummenauer, Lia Possuelo
Journal of Occupational Medicine and Toxicology , 2011, DOI: 10.1186/1745-6673-6-15
Abstract: Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis, is one of the most ancient and neglected diseases of humanity[1]. According to the World Health Organization (WHO), one third of the world's population, around 1.7 billion people, are infected with TB [2].Health-care workers (HCWs) present a higher risk of infection compared to the general population. A longer period of employment as health professional, patient's delayed diagnosis of the disease, professional category, certain work locations such as inpatient TB facility, laboratory, internal medicine, and emergency facilities, in addition to the lack of proper respiratory protection (N95 masks), are factors that can contribute to the infection [3-5].The adoption of measures to control the transmission of the disease in the work environment can be helpful in decreasing the incidence of the disease in the population. Declaring that a disease is an occupational one is an important warning, so that specific control measures can be taken in order to avoid its dissemination among institution employees [4,6].The risk of infection will depend on many factors such as: amount of bacilli expelled by the patient; duration of patient's infectiousness; bacillus concentration in the air, determined by ventilation; exposure time and individual susceptibility. There are no safe levels of exposure to TB. Currently, the Center for Disease Control (CDC) and the Occupational Safety and Health Administration (OSHA) acknowledge that in centers where appropriate control measures are applied the risk of contracting TB among HCWs is comparable to that in the community where they live. TST testing is still a low-cost strategy for the screening of health-care workers infected by M. tuberculosis.There are few data about the prevalence of M. tuberculosis infection among HCWs in south Brazil, hence, the aim of the present study is to estimate the prevalence of latent TB infection (LTBI) and to evaluate the characteristics related t
Primary health care staff's perceptions of childhood tuberculosis: a qualitative study from Tanzania
Stephanie Bjerrum, Michala V Rose, Ib C Bygbjerg, Sayoki G Mfinanga, Britt P Tersboel, Pernille Ravn
BMC Health Services Research , 2012, DOI: 10.1186/1472-6963-12-6
Abstract: We conducted a qualitative study that included 13 semi-structured interviews and 3 focus group discussions with a total of 29 health staff purposively sampled from primary health care facilities. Analysis was performed in accordance with the principles of a phenomenological analysis.Primary health care staff perceived childhood tuberculosis to be uncommon in the society and tuberculosis was rarely considered as a likely differential diagnosis. Long duration and severe signs of disease together with known exposure to tuberculosis were decisive for the staff to suspect tuberculosis in children and refer them to hospital. None of the staff felt equipped to identify cases of childhood tuberculosis and they experienced lack of knowledge, applicable tools and guidelines as the main challenges. They expressed the need for more training, supervision and referral feedback to improving case identification.Inadequate awareness of the burden of childhood tuberculosis, limited knowledge of the wide spectrum of clinical presentation and lack of clinical decision support strategies is detrimental to the health staff's central responsibility of suspecting and referring children with tuberculosis especially in the early disease stages. Activities to improve case identification should focus on skills required by primary health care staff to fulfil their responsibility and reflect primary health care level capacities and challenges.Tuberculosis (TB) in children is a serious condition, and in endemic regions TB is a likely cause of death among children with symptoms of respiratory infection [1]. The relative proportion of TB cases occurring in children is found to vary significantly between countries [2], and Marais et al. have estimated that children are likely to represent 15-20% of the disease burden in areas where the TB epidemic is poorly controlled [1]. Diagnosing TB in children is complex and challenged by investigations methods being inaccessible in resource-poor areas [1,3-5].
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