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Wallis R.S.,Pfizer | Pai M.,McGill University | Pai M.,Montreal Chest Institute | Menzies D.,McGill University | And 5 more authors.
The Lancet | Year: 2010

Human infection with Mycobacterium tuberculosis can progress to active disease, be contained as latent infection, or be eradicated by the host response. Tuberculosis diagnostics classify a patient into one of these categories. These are not fixed distinct states, but rather are continua along which patients can move, and are affected by HIV infection, immunosuppressive therapies, antituberculosis treatments, and other poorly understood factors. Tuberculosis biomarkers-host or pathogen-specific-provide prognostic information, either for individual patients or study cohorts, about these outcomes. Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis. Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible-with political commitment, increased funding, and engagement of all stakeholders. © 2010 Elsevier Ltd. All rights reserved.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.3.2-10 | Award Amount: 14.12M | Year: 2009

This proposal will establish an integrated and synergistic network to address the challenge of multiple drug resistant tuberculosis (MDR-TB) facing the EU. The objective will be attained through the establishment of a European consortium of expert partners with extensive experience in the conduct of basic and clinical research relating to MDR-TB, TB control and epidemiology. This Consortium will achieve this by: Conducting an extensive and focused programme of basic/clinical research to improve the diagnosis and management of MDR-TB Develop a broad training curriculum leading to the creation of a new generation of scientists and clinicians expert in the management of drug resistant TB Create field sites across the EU with the capacity for evaluating new diagnostic systems and novel drug therapies on behalf of European industry and government Establish a unified and robust quality assurance mechanism for the accurate and rapid diagnosis of drug resistance and develop appropriate safety standard for European health care workers Improving our understanding of the transmission of MDR-TB at the molecular level and host-related risk factors for its development, The Consortium will disseminate its findings and analyses widely to the benefit of specialists, general health care staff, EU governments, NGOs and health policy makers. This will provide researchers and clinicians with appropriate knowledge and improved tools to fight MDR-TB, and assist European industry in the development of new diagnostics and treatments. Consortium outputs will assist governments in the development and implementation of appropriate health and social policies to limit and control the spread of MDR-TB within the member states of the EU. Internationally, these objectives will assist countries bordering the EU and international agencies such as the WHO and ECDC in reducing the impact of drug resistance.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.3.2-3 | Award Amount: 4.07M | Year: 2008

Recent developments in molecular tools combined with updated epidemiological data provide novel challenges to the development of modern molecular diagnostics. The increasing threat of infections due to Mycobacterium tuberculosis, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections poses important questions that call for development of integrated tools for rapid diagnosis. In the specific case of tuberculosis (TB), an integrated rapid diagnostic approach should be able to allow at the same time species identification, drug susceptibility testing and molecular typing. We propose to develop and validate a silicon-based platform for molecular biology testing consisting in a single disposable device (biochip) and on associated specific instruments (reader). This technology is able to simultaneously serve as a platform for high specificity amplification and hybridisation of selected targets, and to provide the diagnostic report within few hours. Main advancement over existing technology (i.e. Real-Time PCR) consists in the possibility to perform the test at competitive costs, using an higher number of genetic probes by integrating multiple, separate PCR chambers and medium density array (50-200 probes), with faster and more stable amplification and hybridisation reactions through optimised and controlled thermal ramps and profile. In addition to the technology development, special focus will be put on the feasibility and cost-effectiveness of such a novel tool with high technological content for application in countries with high TB, MDR- and XDR-TB incidence. In parallel to the development and validation of the chip-based diagnostic platform for TB, a feasibility study on its applicability to other poverty related diseases such as malaria, will be carried out. In summary, the present proposal aims at developing an affordable, high-tech platform for rapid molecular diagnosis applicable to TB and other infectious and poverty-related diseases

Denkinger C.M.,Beth Israel Deaconess Medical Center | Denkinger C.M.,McGill University | Schumacher S.G.,McGill University | Boehme C.C.,Foundation for Innovative New Diagnostics | And 4 more authors.
European Respiratory Journal | Year: 2014

Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the detection of extrapulmonary TB. We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta-regression for predefined covariates. We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently >98.7% against CRS across different sample types. Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis. Copyright ©ERS 2014.

Parsons L.M.,Centers for Disease Control and Prevention | Somoskovi A.,Foundation for Innovative New Diagnostics | Gutierrez C.,Foundation for Innovative New Diagnostics | Lee E.,Foundation for Innovative New Diagnostics | And 5 more authors.
Clinical Microbiology Reviews | Year: 2011

With an estimated 9.4 million new cases globally, tuberculosis (TB) continues to be a major public health concern. Eighty percent of all cases worldwide occur in 22 high-burden, mainly resource-poor settings. This devastating impact of tuberculosis on vulnerable populations is also driven by its deadly synergy with HIV. Therefore, building capacity and enhancing universal access to rapid and accurate laboratory diagnostics are necessary to control TB and HIV-TB coinfections in resource-limited countries. The present review describes several new and established methods as well as the issues and challenges associated with implementing quality tuberculosis laboratory services in such countries. Recently, the WHO has endorsed some of these novel methods, and they have been made available at discounted prices for procurement by the public health sector of high-burden countries. In addition, international and national laboratory partners and donors are currently evaluating other new diagnostics that will allow further and more rapid testing in point-of-care settings. While some techniques are simple, others have complex requirements, and therefore, it is important to carefully determine how to link these new tests and incorporate them within a country's national diagnostic algorithm. Finally, the successful implementation of these methods is dependent on key partnerships in the international laboratory community and ensuring that adequate quality assurance programs are inherent in each country's laboratory network. © American Society for Microbiology. All Rights Reserved.

Boehme C.C.,Foundation for Innovative New Diagnostics | Nabeta P.,Foundation for Innovative New Diagnostics | Hillemann D.,Forschungszentrum Borstel | Nicol M.P.,University of Cape Town | And 15 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection. Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect. METHODS: We assessed the performance of Xpert MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF), with fully integrated sample processing in 1730 patients with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis. Eligible patients in Peru, Azerbaijan, South Africa, and India provided three sputum specimens each. Two specimens were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and one specimen was used for direct testing with microscopy and the MTB/RIF test. RESULTS: Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive tuberculosis (98.2%) and 124 of 171 with smear-negative tuberculosis (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). Among patients with smear-negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2%. As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria. Sequencing resolved all but two cases in favor of the MTB/RIF assay. CONCLUSIONS: The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time. (Funded by the Foundation for Innovative New Diagnostics.). Copyright © 2010 Massachusetts Medical Society.

Okeke I.N.,Haverford College | Peeling R.W.,London School of Hygiene and Tropical Medicine | Goossens H.,University of Antwerp | Auckenthaler R.,Unilabs SA | And 5 more authors.
Drug Resistance Updates | Year: 2011

Antibacterial drugs are overused and often inappropriately selected. This exacerbates drug resistance and exacts a high burden from acute respiratory tract, bloodstream, sexually-transmitted, diarrheal and other infections. Appropriate use of existing diagnostic tests, and developing better ones, could avert these costs and would avoid selective pressure from unnecessary antibacterial use. Product profiles of resistance-averting tests would specify WHO 'ASSURED' (Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment-free and Deliverable) criteria and request susceptibility as well as etiological information. Advances in genomics, nanoscience, microfluidics and bioengineering, as well as innovative funding paradigms can help to overcome research and development barriers for such diagnostics if they are deliberately and forcefully applied. Rapid uptake of new tests requires timely translation of research on cost-benefit analyses into policy, value-based subsidies and reimbursements, as well as behavioral change of health care providers and users. © 2011 Elsevier Ltd. All Rights Reserved.

Vadwai V.,P D Hinduja National Hospital | Boehme C.,Foundation for Innovative New Diagnostics | Nabeta P.,Foundation for Innovative New Diagnostics | Shetty A.,P D Hinduja National Hospital | And 2 more authors.
Journal of Clinical Microbiology | Year: 2011

Approximately 10 to 15% of tuberculosis (TB) cases in India are estimated to have extrapulmonary disease, and due to a lack of diagnostic means, they often remain untreated. The early detection of Mycobacterium tuberculosis and multidrug resistance is a priority in TB diagnosis to improve the successful treatment rate of TB and reduce transmission. The Xpert MTB/RIF (Xpert) test, recently endorsed by the World Health Organization for the detection of pulmonary TB, was evaluated to test its utility in 547 patients with suspected extrapulmonary tuberculosis. Five hundred forty-seven extrapulmonary specimens were split and processed simultaneously for both culture (solid and liquid) and Xpert testing. For culture, the sensitivity was low, 53% (150/283 specimens). Xpert sensitivity and specificity results were assessed in comparison to a composite reference standard made up of smear and culture results and clinical, radiological, and histological findings. The sensitivity of the Xpert assay was 81% (228/283 specimens) (64% [89/138] for smear-negative cases and 96% [139/145] for smear-positive cases), with a specificity of 99.6%. The sensitivity was found to be high for the majority of specimen types (63 to 100%) except for cerebrospinal fluid, the sensitivity of which was 29% (2/7 specimens). The Xpert test correctly identified 98% of phenotypic rifampin (RIF)-resistant cases and 94% of phenotypic RIF-susceptible cases. Sequencing of the 6 discrepant samples resolved 3 of them, resulting in an increased specificity of 98%. In conclusion, the results of this study suggest that the Xpert test also shows good potential for the diagnosis of extrapulmonary TB and that its ease of use makes it applicable for countries where TB is endemic. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Agency: Cordis | Branch: FP7 | Program: CP-SICA | Phase: HEALTH-2007-2.3.4-1 | Award Amount: 3.41M | Year: 2009

African trypanosomiasis is in need of new diagnostic detection tools and new treatment methods. To date the widely used card agglutination test for trypanosomiasis is not very specific as the test is based on the screening for cross-reactive host antibodies. The availability of treatment for Trypanosmiasis on the other hand is limited due to the fact that only very few drugs are registered for use, and all can cause serious side effects in treated patients or animals. Hence, this project will focus on the development of new and innovative diagnosis and treatment tools, using the nanobody technology that has been developed by the coordinating partner of this network. Nanobodies are small single domain antibody fragments that have unique properties that include their capacity to recognize particular epitopes (not recognized by conventional antibodies) and their improved stability. In addition, they can be used as molecular target- or transport devices of other biological active components. As such they are excellent tools to support this project. Despite the fact that the coordinating laboratory has been a pioneer in differential molecular characterization of African trypanosomes and were involved in the initial release of diagnostic PCR methods that have now been adopted by many other research groups, this project will deliberately adopt a different approach. Indeed, in comparison to nanobody technology, PCR based diagnostics are much more costly and require an infrastructure that is hard to sustain over prolonged periods of time in African field situations. The simplicity of the nanobody technology on the other hand makes it an excellent topic for knowledge transfer. Despite its high-technology approach, the technique it will be relatively easy to be adopted by laboratories of participating African partner groups.

Gordon J.,Foundation for Innovative New Diagnostics | Michel G.,Foundation for Innovative New Diagnostics
Clinical Chemistry | Year: 2012

BACKGROUND: In the search for more powerful tools for diagnoses of endemic diseases in resource-limited settings, we have been analyzing technologies with potential applicability. Increasingly, the process focuses on readily accessible bodily fluids combined with increasingly powerful multiplex capabilities to unambiguously diagnose a condition without resorting to reliance on a sophisticated reference laboratory. Although these technological advances may well have important implications for the sensitive and specific detection of disease, to date their clinical utility has not been demonstrated, especially in resource-limited settings. Furthermore, many emerging technological developments are in fields of physics or engineering, which are not readily available to or intelligible to clinicians or clinical laboratory scientists. CONTENT: This review provides a look at technology trends that could have applicability to high-sensitivity multiplexed immunoassays in resource-limited settings. Various technologies are explained and assessed according to potential for reaching relevant limits of cost, sensitivity, and multiplex capability. Frequently, such work is reported in technical journals not normally read by clinical scientists, and the authorsmakeenthusiastic claims for the potential of their technology while ignoring potential pitfalls. Thus it is important to draw attention to technical hurdles that authors may not be publicizing. SUMMARY: Immunochromatographic assays, optical methods including those involving waveguides, electrochemical methods, magnetorestrictive methods, and field-effect transistor methods based on nanotubes, nanowires, and nanoribbons reveal possibilities as next-generation technologies. © 2012 American Association for Clinical Chemistry.

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