Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study.

BACKGROUND: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens. METHODS: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS). FINDINGS: The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1). INTERPRETATION: In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum. FUNDING: National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center.

The Global Expansion of LTBI Screening and Treatment Programs: Exploring Gaps in the Supporting Economic Evidence.

The global burden of latent TB infection (LTBI) and the progression of LTBI to active TB disease are important drivers of ongoing TB incidence. Addressing LTBI through screening and TB preventive treatment (TPT) is critical in order to end the TB epidemic by 2035. Given the limited resources available to health ministries around the world in the fight against TB, we must consider economic evidence for LTBI screening and treatment strategies to ensure that limited resources are used to achieve the biggest health impact. In this narrative review, we explore key economic evidence around LTBI screening and TPT strategies in different populations to summarize our current understanding and highlight gaps in existing knowledge. When considering economic evidence supporting LTBI screening or evaluating different testing approaches, a disproportionate number of economic studies have been conducted in high-income countries (HICs), despite the vast majority of TB burden being borne in low- and middle-income countries (LMICs). Recent years have seen a temporal shift, with increasing data from low- and middle-income countries (LMICs), particularly with regard to targeting high-risk groups for TB prevention. While LTBI screening and prevention programs can come with extensive costs, targeting LTBI screening among high-risk populations, such as people living with HIV (PLHIV), children, household contacts (HHC) and immigrants from high-TB-burden countries, has been shown to consistently improve the cost effectiveness of screening programs. Further, the cost effectiveness of different LTBI screening algorithms and diagnostic approaches varies widely across settings, leading to different national TB screening policies. Novel shortened regimens for TPT have also consistently been shown to be cost effective across a range of settings. These economic evaluations highlight key implementation considerations such as the critical nature of ensuring high rates of adherence and completion, despite the costs associated with adherence programs not being routinely assessed and included. Digital and other adherence support approaches are now being assessed for their utility and cost effectiveness in conjunction with novel shortened TPT regimens, but more economic evidence is needed to understand the potential cost savings, particularly in settings where directly observed preventive therapy (DOPT) is routinely conducted. Despite the growth of the economic evidence base for LTBI screening and TPT recently, there are still significant gaps in the economic evidence around the scale-up and implementation of expanded LTBI screening and treatment programs, particularly among traditionally hard-to-reach populations.