Diagnosing Tuberculosis: What Do New Technologies Allow Us to (Not) Do?

Abstract

New tuberculosis (TB) diagnostics are at a crossroads: their development, evaluation, and implementation is severely damaged by resource diversion due to COVID-19. Yet several technologies, especially those with potential for non-invasive non-sputum-based testing, hold promise for efficiently triaging and rapidly confirming TB near point-of-care. Such tests are, however, progressing through the pipeline slowly and will take years to reach patients and health workers. Compellingly, such tests will create new opportunities for difficult-to-diagnose populations, including primary care attendees (all-comers in high burden settings irrespective of reason for presentation) and community members (with early stage disease or risk factors like HIV), many of whom cannot easily produce sputum. Critically, all upcoming technologies have limitations that implementers and health workers need to be cognizant of to ensure optimal deployment without undermining confidence in a technology that still offers improvements over the status quo. In this state-of-the-art review, we critically appraise such technologies for active pulmonary TB diagnosis. We highlight strengths, limitations, outstanding research questions, and how current and future tests could be used in the presence of these limitations and uncertainties. Among triage tests, CRP (for which commercial near point-of-care devices exist) and computer-aided detection software with digital chest X-ray hold promise, together with late-stage blood-based assays that detect host and/or microbial biomarkers; however, aside from a handful of prototypes, the latter category has a shortage of promising late-stage alternatives. Furthermore, positive results from new triage tests may have utility in people without TB; however, their utility for informing diagnostic pathways for other diseases is under-researched (most sick people tested for TB do not have TB). For confirmatory tests, few true point-of-care options will be available soon; however, combining novel approaches like tongue swabs with established tests like Ultra have short-term promise but first require optimizations to specimen collection and processing procedures. Concerningly, no technologies yet have compelling evidence of meeting the World Health Organization optimal target product profile performance criteria, especially for important operational criteria crucial for field deployment. This is alarming as the target product profile criteria are themselves almost a decade old and require urgent revision, especially to cater for technologies made prominent by the COVID-19 diagnostic response (e.g., at-home testing and connectivity solutions). Throughout the review, we underscore the importance of how target populations and settings affect test performance and how the criteria by which these tests should be judged vary by use case, including in active case finding. Lastly, we advocate for health workers and researchers to themselves be vocal proponents of the uptake of both new tests and those – already available tests that remain suboptimally utilized.

Mycosome-Coated Gold Nanoparticles for Plasmonic Detection of Tuberculosis-Associated Antibodies

“…In its current state, the method presented here could be applied in field studies to qualitatively establish the relationship between antibodies and the presence of TB. According to the agreements established by the WHO for TB diagnostics, a rapid test with a minimal sensitivity of 65% is urgently needed. , The assays performed herein with human samples fit this requirement; moreover, because the sensitivity of diagnosis could probably be enhanced through the use of multiple antigens, the ease of modifying the lipid composition within the proposed construct seems greatly attractive. Noteworthy, a large set of amphipathic lipids represent a hallmark shared within the different M.…”

Diagnóstico no bacteriológico de la tuberculosis. Indicadores de la respuesta inmune. Parte II

“…46 La implementación a gran escala de nuevas pruebas diagnósticas en aplicaciones clínicas y en salud pública todavía es limitada por una serie de factores: la falta de soluciones estandarizadas, los requisitos técnicos de los laboratorios, altos costos asociados con la implementación y el mantenimiento de estas tecnologías moleculares, la infraestructura de Internet y la computación en la nube. 47 Esperamos que abordar estas barreras mejore los resultados de los pacientes, pero aún se necesita una verdadera prueba POC para superar los desafíos restantes, como la preparación de muestras y las demandas de recursos humanos.…”

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management

“…The Deeplex has 3% sensitivity for the detection of heteroresistance and is also able to identify non-tuberculous mycobacteria, as well as lineages and spoligotypes (Feuerriegel et al, 2021). Despite this progress, an accurate and rapid POC test for drug resistant TB that is usable under field conditions is still unavailable, suggesting that greater research effort is required to convert these often-complex laboratory technologies into robust, accurate and cost-effective POC programs (Abdulgader et al, 2022). The Covid-19 pandemic has expanded the framework for self-testing to enable greater diagnostic pickup of infection, such approaches should be considered and developed for rapid TB diagnosis.…”