• Defining the Needs for Next Generation Assays for Tuberculosis

      Denkinger, C M; Kik, S V; Cirillo, D M; Casenghi, M; Shinnick, T; Weyer, K; Gilpin, C; Boehme, C C; Schito, M; Kimerling, M; et al. (Oxford University Press, 2015-04-01)
      To accelerate the fight against tuberculosis, major diagnostic challenges need to be addressed urgently. Post-2015 targets are unlikely to be met without the use of novel diagnostics that are more accurate and can be used closer to where patients first seek care in affordable diagnostic algorithms. This article describes the efforts by the stakeholder community that led to the identification of the high-priority diagnostic needs in tuberculosis. Subsequently target product profiles for the high-priority diagnostic needs were developed and reviewed in a World Health Organization (WHO)-led consensus meeting. The high-priority diagnostic needs included (1) a sputum-based replacement test for smear-microscopy; (2) a non-sputum-based biomarker test for all forms of tuberculosis, ideally suitable for use at levels below microscopy centers; (3) a simple, low cost triage test for use by first-contact care providers as a rule-out test, ideally suitable for use by community health workers; and (4) a rapid drug susceptibility test for use at the microscopy center level. The developed target product profiles, along with complimentary work presented in this supplement, will help to facilitate the interaction between the tuberculosis community and the diagnostics industry with the goal to lead the way toward the post-2015 global tuberculosis targets.
    • Drug-Resistant Tuberculosis--Current dilemmas, unanswered questions, challenges, and priority needs

      Zumla, A; Abubakar, I; Raviglione, M; Hoelscher, M; Ditiu, L; McHugh, T D; Squire, S B; Cox, H; Ford, N; McNerney, R; et al. (Oxford University Press, 2012-04-03)
      Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed.
    • Effects of Treatment Interruption Patterns on Treatment Success Among Patients With Multidrug-Resistant Tuberculosis in Armenia and Abkhazia

      Bastard, M; Sanchez-Padilla, E; Hewison, C; Hayrapetyan, A; Khurkhumal, S; Varaine, F; Bonnet, M (Oxford University Press, 2014-10-13)
      The success of the current treatment regimen for multidrug-resistant tuberculosis (MDR-TB) is poor partly due to a high defaulter rate. Many studies explored predictors of poor outcomes, but very few assessed the impact of treatment interruptions on MDR-TB treatment outcomes.
    • Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed clinical case definitions for classification of Intrathoracic Tuberculosis Disease. Consensus from an expert panel

      Graham, S M; Ahmed, T; Amanullah, F; Browning, R; Cardenas, V; Casenghi, M; Cuevas, L E; Gale, M; Gie, R P; Grzemska, M; et al. (Oxford University Press, 2012-03-22)
      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.
    • Target Product Profile of a Molecular Drug-Susceptibility Test for Use in Microscopy Centers

      Denkinger, C M; Dolinger, D; Schito, M; Wells, W; Cobelens, F; Pai, M; Zignol, M; Cirillo, D M; Alland, D; Casenghi, M; et al. (Oxford University Press, 2015-04-01)
      Current phenotypic testing for drug resistance in patients with tuberculosis is inadequate primarily with respect to turnaround time. Molecular tests hold the promise of an improved time to diagnosis.
    • Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities.

      McNerney, R; Maeurer, M; Abubakar, I; Marais, B; McHugh, T D; Ford, N; Weyer, K; Lawn, S; Grobusch, M P; Memish, Z; et al. (2012-05-15)
      Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.