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Tuesday, 17 November 2015 10:39

Paper 2015-10/1

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Uncoupling environmental pH and intrabacterial acidification from pyrazinamide susceptibility in Mycobacterium tuberculosis,
Tuesday, 17 November 2015 10:30

Paper 2015-11/1

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Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study   Timothy M Walker, Thomas A Kohl, Shaheed V Omar, Jessica Hedge, Carlos Del Ojo Elias, Phelim Bradley, Zamin Iqbal, Silke Feuerriegel, Katherine E Niehaus, Daniel J Wilson, David A Clifton, Georgia Kapatai, Camilla L C Ip, Rory Bowden, Francis A Drobniewski, Caroline Allix-Béguec, Cyril Gaudin, Julian Parkhill, Roland Diel, Philip Supply, Derrick W Crook, E Grace Smith, A Sarah Walker, Nazir Ismail, Stefan Niemann, Tim E A Peto, and the Modernizing Medical Microbiology (MMM) Informatics Group   Summary   Background Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drugsusceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistancedetermining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all fi rst-line and second-line drugs for tuberculosis.   Methods Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identifi ed from the drug-resistance scientifi c literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance.   Findings We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specifi city (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identifi ed among mutations under selection pressure in non-candidate genes.   Interpretation A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workfl ows, phasing out phenotypic drugsusceptibility testing while reporting drug resistance early.   Read more here
Saturday, 16 May 2015 16:46

Paper 2015-5/2

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Risk Assessment of Tuberculosis in Contacts by IFN-γ Release Assays. A Tuberculosis Network European Trials Group Study.   Am J Respir Crit Care Med.2015 May 15;191(10):1176-1184.   Zellweger JP, Sotgiu G, Block M, Dore S, Altet N, Blunschi R, Bogyi M, Bothamley G, Bothe C, Codecasa L, Costa P, Dominguez J, Duarte R, Fløe A, Fresard I, García-García JM, Goletti D, Halm P, Hellwig D, Henninger E, Heykes-Uden H, Horn L, Kruczak K, Latorre I, Pache G, Rath H, Ringshausen FC, Ruiz AS, Solovic I, Souza-Galvão ML, Widmer U, Witte P, Lange C; TBNET.   Abstract RATIONALE: Latent infection with Mycobacterium tuberculosis is defined by a positive IFN-γ release assay (IGRA) result in the absence of active tuberculosis. Only few, mostly monocentric studies have evaluated the role of IGRAs to predict the development of tuberculosis in recent contacts in low-incidence countries of tuberculosis.   OBJECTIVES: To analyze IGRA results and the effect of preventive chemotherapy on tuberculosis progression rates among recent contacts.   METHODS: Results from contact investigations at 26 centers in 10 European countries including testing for latent infection with M. tuberculosis by the QuantiFERON-TB Gold In-Tube (QFT) test or the T-SPOT.TB (TSPOT) were prospectively collected and analyzed.   MEASUREMENTS AND MAIN RESULTS: Among 5,020 contacts of 1,023 index cases, 25 prevalent secondary cases were identified at screening. Twenty-four incident cases occurred among 4,513 contacts during 12,326 years of cumulative follow-up. In those with a positive IGRA result, tuberculosis incidence was 0.2 (QFT) and 0 (TSPOT) per 100 patient-years when contacts received preventive chemotherapy versus 1.2 (QFT) and 0.8 (TSPOT) per 100 patient-years in those not treated (38 and 37 patients needed to be treated to prevent one case, respectively). Positive and negative predictive values were 1.9% (95% confidence interval [CI], 1.1-3.0) and 99.9% (95% CI, 99.7-100) for the QFT and 0.7% (95% CI, 0.1-2.6) and 99.7% (95% CI, 99.1-99.9) for the TSPOT.   CONCLUSIONS: Tuberculosis rarely developed among contacts, and preventive chemotherapy effectively reduced the tuberculosis risk among IGRA-positive contacts. Although the negative predictive value of IGRAs is high, the risk for the development of tuberculosis is poorly predicted by these assays.     PMID: 25763458 [PubMed - as supplied by publisher]    
Saturday, 16 May 2015 16:33

Paper 2015-5/1

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Counting pyrazinamide in regimens for multidrug-resistant tuberculosis.   Ann Am Thorac Soc. 2015 May;12(5):674-9. doi: 10.1513/AnnalsATS.201411-538OC. Franke MF, Becerra MC, Tierney DB, Rich ML, Bonilla C, Bayona J, McLaughlin MM, Mitnick CD. Abstract RATIONALE: For treatment of multidrug-resistant tuberculosis, World Health Organization (WHO) guidelines recommend four likely effective drugs plus pyrazinamide (PZA), irrespective of the likely effectiveness of PZA in an individual patient. Whether this regimen should be supplemented in the absence of likely PZA effectiveness is an open question. OBJECTIVES: The objectives of this study were to examine (1) whether individuals receiving four likely effective drugs (based on documented susceptibility or no prior exposure) experienced higher mortality during the intensive phase of treatment than those receiving five likely effective drugs and (2) whether the WHO-recommended regimen (four likely effective drugs plus PZA) may be compromised in individuals in whom PZA is not likely effective. METHODS: Among 668 patients, we compared the hazard of death across regimen groups characterized by the number of likely effective drugs and whether pyrazinamide was one of the likely effective drugs. MEASUREMENTS AND MAIN RESULTS: Relative to five likely effective drugs, regimens of four likely effective drugs and the WHO-recommended regimen used in individuals in whom PZA was not likely effective were associated with higher mortality rates (respectively, adjusted hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.35-6.09 and adjusted HR, 2.76; 95% CI, 0.92-8.27). The mortality rate for a regimen of five likely effective drugs with likely effective PZA was similar to that for the regimen of five likely effective drugs without PZA (HR, 1.00; 95% CI, 0.12-8.00). CONCLUSIONS: Mortality may be reduced by the inclusion of five likely effective drugs, including an injectable, during the intensive phase of treatment. If PZA is unlikely to be effective in an individual patient, these results suggest adding a different, likely effective drug.
Wednesday, 01 April 2015 11:03

Paper 2015-4/2

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Eur Respir J.2014 Nov 13. pii: erj01246-2014. [Epub ahead of print]   Availability, price and affordability of anti-tuberculosis drugs in Europe: A TBNET survey.   Günther G, Gomez GB, Lange C, Rupert S, van Leth F; on behalf of the TBNET.   Abstract Data on availability and cost of anti-tuberculosis (TB) drugs in relation to affordability at national level are scarce. We performed a cross-sectional study on availability and cost of anti-TB drugs at major TB-reference centres in 37 European countries. Costs of standardised treatment regimens used for pan-sensitive TB, multi-drug resistant (MDR), pre-extensively drug-resistant (XDR), and XDR-TB were compared using a purchasing power analysis. Affordability was evaluated in relation to monthly national gross domestic products per capita (GDP). At least one second-line injectable and either moxifloxacin or levofloxacin were available in all countries. Linezolid and clofazimine were available in 79% and 46% of the countries, respectively. Drug cost for XDR-TB was three-times more expensive than those for MDR-TB. The average price of treatment for pan-sensitive TB represented a maximum of 8.5% of the monthly GDP across countries, while for standard MDR-TB treatment this was <30% in only six countries and more than 100% in four countries. Treatment of XDR-TB represented more than 100% of a month's GDP in all countries where the regimen was available. High cost and limited availability of drugs for treatment of drug-resistant TB, particularly beyond resistance to first-line drugs, are a major impediment to successful TB control in Europe.   Full text here
Wednesday, 01 April 2015 07:00

Paper 2015-4/1

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International Journal of  Infectious Diseases Open Access   The economic burden of Tuberculosis in Denmark 1998-2010. Cost analysis in patients and their spouses Andreas Fløe, Ole Hilberg, Christian Wejse, Anders Løkke, Rikke Ibsen, Jakob Kjellberg, Poul Jennum   Abstract Objective To evaluate the economic burden of tuberculosis (TB) in Denmark   Methods 8,433 Danish TB-patients (1998-2010) were matched with 33,707 controls by age, gender, civil status and geography. Health-related costs (health system contacts and –procedures, medications) and socio-economic parameters (foregone earnings and social transfer expenses) were calculated on data from national databases. The same information was obtained for 3,485 spouses of TB-patients, and 17,403 controls.   Results Health-related costs were higher for cases throughout the period. Before diagnosis, cases posed € 1,180 more health costs per year than controls. Excess health costs in the 2 years around diagnosing and treating TB were € 10,509. Cases received an average excess public transfer income of € 3,345 before vs. € 3,121 after diagnosis. Average employment income deficiency was € 11,635 before vs. € 13,885 after diagnosis, but the increasing difference showed a linear shape throughout the period. Spouses also had lower income, more social transfer, and posed higher health-related costs than matched controls.   Conclusion We estimate the direct costs per TB patient to be €10,509. TB patients and their households are characterized by increasingly lower employment income, lower employment rate, and higher dependency on public transfer, but the socio/economic deterioration is rather a risk factor for TB than a direct consequence of the disease.
Monday, 23 March 2015 12:30

Paper 2015-3

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Risk Assessment of Tuberculosis in Contacts by Interferon-γ Release Assays (IGRAs). A TBNET Study. Zellweger JP, Sotgiu G, Block M, Dore S, Altet N, Blunschi R, Bogyi M, Bothamley G, Bothe C, Codecasa L, Costa P, Dominguez J, Duarte R, Fløe A, Fresard I, García-García JM, Goletti D, Halm P, Hellwig D, Henninger E, Heykes-Uden H, Horn L, Kruczak K, Latorre I, Pache G, Rath H, Ringshausen FC, Seminario Ruiz A, Solovic I, de Souza-Galvão ML, Widmer U, Witte P, Lange C; TBNET.   Am J Respir Crit Care Med. 2015 Mar 12. [Epub ahead of print]   RATIONAL:  Latent infection with Mycobacterium tuberculosis is defined by a positive interferon-γ release assay (IGRA) result in the absence of active tuberculosis. OBJECTIVES:  Only few, mostly monocentric studies have evaluated the role of IGRAs to predict the development of tuberculosis in recent contacts in low incidence countries of tuberculosis. We analyzed IGRA results and the effect of preventive chemotherapy on tuberculosis progression rates among recent contacts. METHODS:  Results from contact investigations at 26 centers in 10 European countries including testing for latent infection with Mycobacterium tuberculosis by the QuantiFERON-Gold in-Tube (QFT) test or the T-SPOT.TB (TSPOT) were prospectively collected and analyzed. MAIN RESULTS:  Among 5020 contacts of 1023 index cases, 25 prevalent secondary cases were identified at screening. Twenty-four incident cases occurred among 4513 contacts during 12326 years of cumulative follow-up. In those with a positive IGRA result, tuberculosis incidence was 0.2 (QFT) and 0 (TSPOT) per 100 patient years when contacts received preventive chemotherapy versus 1.2 (QFT) and 0.8 (TSPOT) per 100 patient years in those not treated (38 and 37 patients needed to be treated to prevent one case, respectively). Positive and negative predictive values were 1.9% (95%CI 1.1-3.0) and 99.9% (95%CI 99.7-100) for the QFT and 0.7% (95%CI 0.1-2.6) and 99.7% (95%CI 99.1-99.9) for the TSPOT. CONCLUSIONS:  Tuberculosis rarely developed among contacts and preventive chemotherapy effectively reduced the tuberculosis risk among IGRA-positive contacts. Although the negative predictive value of IGRAs is high, the risk for the development of tuberculosis is poorly predicted by these assays.
Thursday, 05 February 2015 16:57

Paper 2015-02

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Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis.   Tyagi S, Ammerman NC, Li SY, Adamson J, Converse PJ, Swanson RV, Almeida DV, Grosset JH Pubmed: Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):869-74. doi: 10.1073/pnas.1416951112. Epub 2015 Jan 5.   Abstract A key drug for the treatment of leprosy, clofazimine has recently been associated with highly effective and significantly shortened regimens for the treatment of multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that clofazimine may also shorten the duration of treatment for drug-susceptible TB. We conducted a controlled trial in the mouse model of TB chemotherapy comparing the activity of the 6-mo standard regimen for TB treatment, i.e., 2 mo of daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 mo of rifampin and isoniazid, with a 4-mo clofazimine-containing regimen: 2 mo of daily rifampin, isoniazid, pyrazinamide, and clofazimine followed by 2 mo of rifampin, isoniazid, and clofazimine. Treatment efficacy was assessed on the basis of Mycobacterium tuberculosis colony counts in the lungs and spleens during treatment and on the proportion of mice with culture-positive relapse 6 mo after treatment cessation. No additive effect of clofazimine was observed after the first week of treatment, but, by the second week of treatment, the colony counts were significantly lower in the clofazimine-treated mice than in the mice receiving the standard regimen. Lung culture conversion was obtained after 3 and 5 mo in mice treated with the clofazimine-containing and standard regimens, respectively, and relapse-free cure was obtained after 3 and 6 mo of treatment with the clofazimine-containing and standard regimens, respectively. Thus, clofazimine is a promising anti-TB drug with the potential to shorten the duration of TB chemotherapy by at least half (3 mo vs. 6 mo) in the mouse model of TB.
Thursday, 05 February 2015 16:51

Paper 2015-01

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The Sculpting of the Mycobacterium tuberculosis Genome by Host Cell–Derived Pressures Authors: David G. Russell, Wonsik Lee, Shumin Tan, Neelima Sukumar, Maria Podinovskaia, Ruth J. Fahey, Brian C. Vanderven Editors: Graham F. Hatfull, William R. Jacobs Jr.   Abstract Mycobacterium tuberculosis is an incredibly successful pathogen with an extraordinary penetrance of its target host population. The ability to infect many yet cause disease in few is undoubtedly central to this success. This ability relies on sensing and responding to the changing environments encountered during the course of disease in the human host. This article discusses these environmental cues and stresses and explores how the genome of M. tuberculosis has evolved under the purifying selections that they exert. In analyzing the response of M. tuberculosis to a broad range of intracellular pressures, it is clear that, despite genome downsizing, M. tuberculosis has retained an extraordinary flexibility in central carbon metabolism. We believe that it is this metabolic plasticity, more than any of the virulence factors, that is the foundation for M. tuberculosis’s qualities of endurance. Full article.  
Thursday, 02 October 2014 12:59

Paper 2014-10

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Paper of the Month 2014-10   Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis   Stephen H. Gillespie, M.D., D.Sc., Angela M. Crook, Ph.D., Timothy D. McHugh, Ph.D., Carl M. Mendel, M.D., Sarah K. Meredith, M.B., B.S., Stephen R. Murray, M.D., Ph.D., Frances Pappas, M.A., Patrick P.J. Phillips, Ph.D., and Andrew J. Nunn, M.Sc., for the REMoxTB Consortium*   Background Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.     Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.     Results Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-totreat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.     Conclusions The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB number, NCT00864383.)   Read full article here.
Friday, 04 July 2014 10:45

Paper of the month, 2014-7

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Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial Dr Molebogeng X Rangaka PhD, Prof Robert J Wilkinson PhD, Andrew Boulle PhD, Prof Judith R Glynn PhD,Katherine Fielding PhD, Gilles van Cutsem MD, Katalin A Wilkinson PhD, Rene Goliath RN, Shaheed Mathee MBChB, Eric Goemaere MD, Prof Gary Maartens MMed   Summary Background Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. Methods For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with, number NCT00463086. Findings 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6—3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8—4·7; hazard ratio [HR] 0·63, 95% CI 0·41—0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90—4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21—0·86] and 0·43 [0·20—0·96]; for positive tests 0·86 [0·37—2·00] and 0·55 [0·26—1·24], respectively). Interpretation Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. Funding Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).   Full text
Tuesday, 03 June 2014 11:08

Paper of the month, 2014-6

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Paper of the month 2014-6   Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa   Suzanne T. Anderson, Ph.D., M.R.C.P.C.H., Myrsini Kaforou, M.Phil., Andrew J. Brent, Ph.D., M.R.C.P., Victoria J. Wright, Ph.D., Claire M. Banwell, Ph.D., George Chagaluka, M.B., B.S., Amelia C. Crampin, F.F.P.H.M., Hazel M. Dockrell, Ph.D., Neil French, F.R.C.P., Ph.D., Melissa S. Hamilton, Ph.D., Martin L. Hibberd, Ph.D., Florian Kern, M.D., Paul R. Langford, Ph.D., F.S.B., Ling Ling, M.B., B.S., Rachel Mlotha, F.C.P. (Paeds) (SA), Tom H.M. Ottenhoff, M.D., Ph.D., Sandy Pienaar, M.Sc., Vashini Pillay, M.B., Ch.B., J. Anthony G. Scott, F.R.C.P., Hemed Twahir, M.Med., Robert J. Wilkinson, F.R.C.P., Ph.D., Lachlan J. Coin, Ph.D., Robert S. Heyderman, F.R.C.P., Ph.D., Michael Levin, Ph.D., and Brian Eley, F.C.P. (Paeds) (SA), for the ILULU Consortium and KIDS TB Study Group*     Background Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).   Methods The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.   Results We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.   Conclusions RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).   Read full article here.
Tuesday, 06 May 2014 14:47

Paper of the month, 2014-5

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Paper of the month 2014-5   In the quest for a vaccine, this an original paper which shows that removing the main target (immunodominant epitope) of the esat-6 protein allows for other portions of the protein (cryptic epitopes) to be recognized.  This changes the nature of the immune response to one which allowed for more polyfunctional T cells and which may be more protective within the lung tissue.  The lesser inflammatory response may prevent the tissue destruction which is the cause of cavitation in post-primary tuberculosis.      Protective CD4 T cells targeting cryptic epitopes of Mycobacterium tuberculosis resist infection-driven terminal differentiation. Woodworth JS1, Aagaard CS, Hansen PR, Cassidy JP, Agger EM, Andersen P. Abstract CD4 T cells are crucial to the control of Mycobacterium tuberculosis infection and are a key component of current vaccine strategies. Conversely, immune-mediated pathology drives disease, and recent evidence suggests that adaptive and innate responses are evolutionarily beneficial to M. tuberculosis. We compare the functionality of CD4 T cell responses mounted against dominant and cryptic epitopes of the M. tuberculosis 6-kDa early secreted Ag (ESAT-6) before and postinfection. Protective T cells against cryptic epitopes not targeted during natural infection were induced by vaccinating mice with a truncated ESAT-6 protein, lacking the dominant epitope. The ability to generate T cells that recognize multiple cryptic epitopes was MHC-haplotype dependent, including increased potential via heterologous MHC class II dimers. Before infection, cryptic epitope-specific T cells displayed enhanced proliferative capacity and delayed cytokine kinetics. After aerosol M. tuberculosis challenge, vaccine-elicited CD4 T cells expanded and recruited to the lung. In chronic infection, dominant epitope-specific T cells developed a terminal differentiated KLRG1(+)/PD-1(lo) surface phenotype that was significantly reduced in the cryptic epitope-specific T cell populations. Dominant epitope-specific T cells in vaccinated animals developed into IFN-γ- and IFN-γ,TNF-α-coproducing effector cells, characteristic of the endogenous response. In contrast, cryptic epitope-specific CD4 T cells maintained significantly greater IFN-γ(+)TNF-α(+)IL-2(+) and TNF-α(+)IL-2(+) memory-associated polyfunctionality and enhanced proliferative capacity. Vaccine-associated IL-17A production by cryptic CD4 T cells was also enhanced, but without increased neutrophilia/pathology. Direct comparison of dominant/cryptic epitope-specific CD4 T cells within covaccinated mice confirmed the superior ability of protective cryptic epitope-specific T cells to resist M. tuberculosis infection-driven T cell differentiation.   Full article here.
Tuesday, 08 April 2014 09:01

Paper of the month, 2014-4

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Paper of the month 2014-4   Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracing Dr Laura F Anderson PhD Corresponding Author, Surinder Tamne RN, Timothy Brown PhD, John P Watson FRCP, Catherine Mullarkey RN, Dominik Zenner MD, Prof Ibrahim Abubakar FRCP Summary Background Between 2000 and 2012 the number of multidrug-resistant (MDR) tuberculosis cases in the UK increased from 28 per year to 81 per year. We investigated the proportion of MDR tuberculosis cases arising from transmission in the UK and associated risk factors. Method We identified patients with MDR tuberculosis notified in England, Wales, and Northern Ireland between Jan 1, 2004, and Dec 31, 2007, by linking national laboratory and surveillance data. Data for laboratory isolates, including drug sensitivities and 24-mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) typing were obtained routinely from the National Tuberculosis Reference laboratories as part of national tuberculosis surveillance. We investigated clusters of cases with indistinguishable MIRU-VNTR profiles to identify epidemiological links. We calculated transmission using the n—1 method and established associated risk factors by logistic regression. We also assessed the likelihood of transmission to additional secondary active tuberculosis cases, identified through conventional contact tracing. Findings 204 patients were diagnosed with MDR tuberculosis in the study period; 189 (92·6%) had an MIRU-VNTR profile. We identified 12 clusters containing 40 individuals and 149 unique strains. The proportion of cases attributable to recent transmission, on the basis of molecular data, was 15% (40 cases clustered—12 clusters/189 with a strain type). The proportion of cases attributable to recent transmission (ie, transmission within the UK) after adjustment for epidemiological links was 8·5% (22 cases with epidemiological links—six clusters/189 cases with a strain type). Being UK born (odds ratio 4·81; 95% CI 2·03—11·36, p=0·0005) and illicit drug use (4·75; 1·19—18·96, p=0·026) were significantly associated with clustering. The most common transmission setting was the household but 21 of 22 of epidemiological links were missed by conventional contact tracing. 13 secondary active tuberculosis cases identified by conventional contact tracing were mostly contacts of patients with MDR tuberculosis from countries of high tuberculosis burden. 11 (85%) of 13 shared the same country of birth as the index case, of whom ten did not share a strain type or drug resistance pattern. Interpretation Transmission of MDR tuberculosis in the UK is low and associated with being UK born or illicit drug use. MIRU-VNTR typing with cluster investigation was more successful at identifying transmission events than conventional contact tracing. Individuals with tuberculosis who have had contact with a known MDR tuberculosis source case from a country of high tuberculosis burden should have drug-sensitivity testing on isolates to ensure appropriate treatment is given. Funding Public Health England.   Read full article here
Wednesday, 05 March 2014 17:09

Paper of the month, 2014-3

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Paper of the Month 2014-3   Identification of Serum microRNA Biomarkers for Tuberculosis Using RNA-seq. Zhang H1, Sun Z2, Wei W3, Liu Z4, Fleming J3, Zhang S3, Lin N5, Wang M3, Chen M6, Xu Y2, Zhou J7, Li C8, Bi L3, Zhou G9. Abstract Tuberculosis (TB) remains a significant human health issue. More effective biomarkers for use in tuberculosis prevention, diagnosis, and treatment, including markers that can discriminate between healthy individuals and those with latent infection, are urgently needed. To identify a set of such markers, we used Solexa sequencing to examine microRNA expression in the serum of patients with active disease, healthy individuals with latent TB, and those with or without prior BCG inoculation. We identified 24 microRNAs that are up-regulated (2.85-1285.93 fold) and 6 microRNAs that are down-regulated (0.003-0.11 fold) (P<0.05) in patients with active TB relative to the three groups of healthy controls. In addition, 75 microRNAs were up-regulated (2.05-2454.58 fold) and 11 were down-regulated (0.001-0.42 fold) (P<0.05) in latent-TB infected individuals relative to BCG- inoculated individuals. Of interest, 134 microRNAs were differentially-expressed in BCG-inoculated relative to un-inoculated individuals (18 up-regulated 2.9-499.29 fold, 116 down-regulated 0.0002-0.5 fold), providing insights into the effects of BCG inoculation at the microRNA level. Target prediction of differentially-expressed microRNAs by microRNA-Gene Network analysis and analysis of pathways affected suggest that regulation of the host immune system by microRNAs is likely to be one of the main factors in the pathogenesis of tuberculosis. qRT-PCR validation indicated that hsa-miR-196b and hsa-miR-376c have potential as markers for active TB disease. The microRNA differential-expression profiles generated in this study provide a good foundation for the development of markers for TB diagnosis, and for investigations on the role of microRNAs in BCG-inoculated and latent-infected individuals.   Read more here.
Friday, 14 February 2014 11:36

Paper of the Month, 2014-2

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Paper of the Month 2014-2   A Trial of Mass Isoniazid Preventive Therapy for Tuberculosis Control Gavin J. Churchyard, M.B., B.Ch., Ph.D., Katherine L. Fielding, Ph.D., James J. Lewis, Ph.D., Leonie Coetzee, D.Soc.Sc., Elizabeth L. Corbett, M.B., B.Chir., Ph.D., Peter Godfrey-Faussett, F.R.C.P., Richard J. Hayes, D.Sc., Richard E. Chaisson, M.D., and Alison D. Grant, M.B., B.S., Ph.D., for the Thibela TB Study Team   Background Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection. Methods In a cluster-randomized study, we designated 15 clusters with 78,744 miners as either intervention clusters (40,981 miners in 8 clusters) or control clusters (37,763 miners in 7 clusters). In the intervention clusters, all miners were offered tuberculosis screening. If active tuberculosis was diagnosed, they were referred for treatment; if not, they were offered 9 months of isoniazid preventive therapy. The primary outcome was the cluster-level incidence of tuberculosis during the 12 months after the intervention ended. Secondary outcomes included tuberculosis prevalence at study completion. Read more
Monday, 03 February 2014 14:50

Paper of the Month, 2014-1

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Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids C. J. Cambier, Kevin K. Takaki, Ryan P. Larson, Rafael E. Hernandez, David M. Tobin, Kevin B. Urdahl, Christine L. Cosma & Lalita Ramakrishnan   The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues1. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids2 to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs)2 promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence3, and PGL, which (along with CCR2) is known to be associated with human tuberculosis4, 5. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signalling. Published: Nature (2013) doi:10.1038/nature12799 Received 21 May 2013 Accepted 18 October 2013 Published online 15 December 2013 Read more
Tuesday, 26 November 2013 12:02

Explain TB

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Ready to use!! Smartphone based educational videos for tuberculosis patients We are happy to announce that ExplainTB is now ready to use. You can download all educational material from All information is available in 26 languages and covers 23 aspects of tuberculosis that are relevant for patients and their relatives.    
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