Current recommendations on the various methods and tools should not prevent or restrict further research on new, rapid molecular drug-susceptibility tests, especially for assays that can be used as close as possible to where patients with a presumptive diagnosis of TB are identified and where treatment can be initiated. Priorities for further operational research on diagnostics are listed below, grouped for each technology.
Molecular assays intended as initial tests
- Evaluation of the impact of Xpert Ultra testing on patient-important outcomes (cure, mortality, time to diagnosis and time to start treatment).
- Evaluation of the diagnostic accuracy of Xpert Ultra in gastric or stool specimens for pulmonary TB and extrapulmonary TB in children.
- Evaluation of the combinatorial benefit of multiple specimen types. There were limited data suggesting that the combination of non-invasive specimens performs comparably with traditional gastric specimens or induced sputum specimens.
- Additional operational and qualitative research to determine the best approach to less-invasive specimen collection.
- Implementation studies on a method of suction for nasopharyngeal aspiration that is appropriate for low-skill or low-resource environments.
- Extensive operational research into the use of stool as a diagnostic specimen in terms of integration into normal diagnostic clinical pathways, definition of laboratory protocols that successfully balance ease of implementation and diagnostic performance, and the impact of stool testing on patientimportant outcomes. There is a dearth of qualitative research identifying child and family preferences for and acceptability of comparative diagnostic approaches.
- Identification of an improved reference standard that accurately defines TB disease in children and in paucibacillary specimens because sensitivity of all available diagnostics is suboptimal.
- Development of new tools that correctly diagnose a higher proportion of child TB cases. Ideally, the new tools will be rapid, affordable, feasible, and acceptable to children and their parents.
- Comparison of different tests, including Xpert MTB/RIF and Xpert Ultra, to determine which tests (or strategies) yield superior diagnostic accuracy. The preferred study design is one in which all participants receive all available diagnostic tests or are randomly assigned to receive a particular test. Studies should include children and HIV-positive people. Future research should acknowledge the concern associated with culture as a reference standard, and should consider ways to address this limitation.
- Development of rapid point-of-care diagnostic tests for extrapulmonary TB. Research groups should focus on developing diagnostic tests and strategies that use readily available clinical specimens such as urine, rather than specimens that require invasive procedures for collection.
- Operational research to ensure that tests are used optimally in settings of intended use.
- Evaluation of the diagnostic accuracy of Truenat (MTB, MTB Plus and MTB-RIF) in specific patient populations such as People with HIV, former TB patients for pulmonary TB and extrapulmonary TB in adults and children.
TB-LAMP
- Evaluation of diagnostic algorithms in different epidemiological and geographical settings and patient populations.
- Conducting of more rigorous studies with higher quality reference standards (including multiple specimen types and extrapulmonary specimens) to improve confidence in specificity estimates.
- Determination of training needs, and assessments of competency and quality.
- Gathering of more evidence on the impact on TB treatment initiation, morbidity and mortality.
- Performance of country-specific cost–effectiveness and cost–benefit analyses of targeted TB-LAMP use in different programmatic settings.
- Meeting the Standards for Reporting Diagnostic Accuracy Studies (STARD) for future studies.¹⁹
First-line LPA
- Development of improved understanding of the correlation between the detection of resistanceconferring mutations using culture-based DST and patient outcomes.
- Review of evidence to confirm or revise different critical concentrations used in culture-based DST methods.
- Determination of the limit of detection for LPA in detecting heteroresistance.
- Determination of needs for training, assessing competency and ensuring quality assurance.
- Gathering of more evidence on the impact on mortality of initiating appropriate treatment for MDR-TB.
- Meeting the STARD for future diagnostic studies.
- Performance of country-specific cost–effectiveness and cost–benefit analyses of LPA use in different programmatic settings.
Second-line LPA
- Development of improved understanding of the correlation between the detection of resistanceconferring mutations with phenotypic DST results and with patient outcomes.
- Development of improved knowledge of the presence of specific mutations detected with SL-LPA correlated with minimum inhibitory concentrations for individual drugs within the classes of fluoroquinolones and SLIDs.
- Determination of the limit of detection of SL-LPA for the detection of heteroresistance.
- Gathering of more evidence on the impact of MTBDRsl on appropriate MDR-TB treatment initiation and mortality.
- Strongly encourage that future studies follow the recommendations in the STARD (28) statement to improve the quality of reporting.
- Performance of country-specific cost–effectiveness and cost–benefit analyses of the use of SL-LPA in different programmatic settings.
LF-LAM
- Development of simple, more accurate tests based on LAM detection, with the potential to be used for HIV-negative populations.
- Evaluation of the use of LF-LAM in People with HIV without signs and symptoms of TB.
- Evaluation of the use of LF-LAM in children and adolescents with HIV.
- Evaluation of the combination of parallel use of LF-LAM and rapid qualitative CD4 cell count systems.
- Undertaking of implementation research into the acceptance, scale-up and impact of LF-LAM in routine clinical settings.
- Undertaking of qualitative research on user perspectives of LF-LAM for feasibility, accessibility and equity issues.
- Undertaking of implementation research on LF-LAM integrated into HIV care packages.
- Evaluation of the performance of LF-LAM as the HIV epidemic evolves and more people on treatment with viral load suppression are hospitalized.
- Evaluation of the cost–effectiveness of LF-LAM.
- Evaluation of other rapid LAM-based tests such as FujiLAM.
¹⁹ See http://www.equator-network.org/reporting-guidelines/stard/.