At a glance
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Start Taking Action For TB Diagnosis (START4ALL)
In Brief
An observational study evaluating Class 1, Point of Care (POC) Quantitative C-Reactive Protein (CRP)., Class 2, POC Qualitative/Semiquantitative CRP, and 6 other interventions for Diagnosis and Tuberculosis. Completed, enrolled 14,747 participants across 8 sites in 7 countries.
Detailed Summary
Globally, tuberculosis (TB) is one of the main causes of death and the leading cause from a single infectious agent. In 2020, an estimated 9.9 million people developed TB and 1.5 million died. Millions of people remain undiagnosed with TB, hindering efforts to end TB. TB tests have inadequate accuracy or performance characteristics for implementation across all populations and settings. None of the tests meet the WHO-Target-Product Profile for TB screening and most need specialized laboratory staff and infrastructure, making them unsuitable for primary health care (PHC). The overall objectives for this project are to: 1. To evaluate the performance of selected TB tests and test combinations in primary health care settings and KVPs. 2. To identify test combinations that increase the proportion of people diagnosed with microbiologically confirmed TB in comparison to a microbiological reference standard. 3. To demonstrate that test combinations are cost-efficient and feasible for scale-up to facilitate enhanced access to TB diagnosis in locations and for populations where they are not currently available. Methods in brief: Objectives 1 and 2 will use the same methods and will be assessed simultaneously. These objectives will use cross-sectional surveys. Activities will be conducted in Bangladesh, Brazil, Kenya, Cameroon, Malawi, Nigeria, and Viet Nam. Each country will study selected priority populations at risk of TB, including adults attending PHC centers and district hospitals; people living with HIV (PLHIV); marginalized populations (internally displaced, refugees and pastoralists), and children. Activities within countries will use standardized protocols for evaluating diagnostic tests and combinations. Methods for Objective 3 (Phase 1) will be a realist evaluation consisting of a market landscape analysis, evaluation of the costs and cost-efficiency of implementing TB tests and combinations, and a combination of key informant interviews, focus group discussions and/or participatory workshops, depending on appropriateness to stakeholder group and local context, to gather qualitative data on acceptability of TB tests and combinations.
Study Details
Timeline
Interventions
CRP increases after 6 hours in acute inflammatory processes associated with bacterial infections, post operative conditions or tissue damage. Measurement of Values \>10 mg/L are defined as abnormal (In Viet Nam, measurement of values \>5mg/L). In Bangladesh, Brazil, Cameroon and Viet Nam, the quantitative POC device used will be ichroma™ CRP (Boditech Med Inc.'s Technical Services, Gang-won-do, Korea). In Kenya and Malawi, the quantitative POC test kit to be used is the hs-CRP+CRP Fast Test Kit, on the Getein 1160 Immunofluorescence Quantitative Analyzer (Getein Biotech, Inc., Nanjing, China).
CRP qualitative (POC) rapid tests are immunochromatographic based assays for qualitative or semiquantitative determination of CRP circulating in blood, serum or plasma at the Point of Care with a time to result in 5 minutes. Three commercial tests will be considered in the study depending on in-country procurement: Actim® CRP (Medix Biochemica Group, Espoo, Finland), Nadal® CRP test (nal von minden GmbH, Moers, Germany) and PRIMA® home test (Prima Lab SA, Balerna, Switzerland). The principle is the same for the three tests, CRP levels are detected through monoclonal antibodies raised against CRP. Antibodies are labelled with gold particles for visualization.
FujiLAM is a urine-based assay, Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan), which was developed to detect lipoarabinomannan on an instrument-free platform. Results are available in less than 1 hour. The assay combines a pair of high affinity monoclonal antibodies directed towards largely Mycobacterium tuberculosis-specific lipoarabinomannan epitopes and a silver-amplification step that increases the visibility of test and control lines. This enables the detection of urinary lipoarabinomannan concentrations that are approximately 30 times lower than that detected by a previous test called AlereLAM (Alere Determine™ TB LAM) and exhibits improved analytical specificity compared with AlereLAM.
The Xpert® MTB/RIF Ultra Assay (Xpert® Ultra) (Cepheid®, California, USA), is a semi-quantitative, nested real-time polymerase chain reaction (PCR) diagnostic test for the detection of Mycobacterium tuberculosis (MTB) complex DNA in unprocessed sputum samples or concentrated sediments prepared from induced or expectorated sputum. GeneXpert® IV platform will be used to do the pooling in ACF and at the POC in PHC. For ACF and health services with limited infrastructure, the platform will be powered with portable batteries. The platform will be used with 2 modules with the option to add two more modules in Phase 2 of the study to allow the testing of more specimens.
Examples: FujiFilm Xair™ FujiFilm Xair™ (Fujifilm, Tokyo, Japan) is a mobile X-ray machine that facilitates successful diagnoses in various medical settings, serving patients with limited mobility or people living in inaccessible geographies. The image is produced in the X-ray cassette and automatically transmitted to the laptop for visualization and interpretation by the physician. MinXRay MinXray's Impact is an FDA certified, complete battery operated, portable radiography system that can perform a complete range of radiographic procedures with excellent visualization of all body parts. The Impact system was designed and developed for operation in austere environments where the absence of climate controls and difficult terrain may limit access to the region. The rugged design of the system itself and the custom packaging provide exceptional durability during operation and transportation. Operates completely wirelessly.
Qure.ai (Qure.ai, New York, USA) is a computer-aided detection (CAD) software for automated screening of TB. Qure.ai is a mobile-based interpretation software that screens chest X-ray to detect TB in less than a minute. Qure.ai can distinguish abnormal scans from normal and detect abnormalities in the lungs, pleura, mediastinum, bones, diaphragm, and heart. Once the X-ray has been interpreted by Qure.ai, the chest X-ray film image is uploaded from the mobile phone through the qTrack application software automatically. The qTrack is an end-to-end disease management platform that enables access and connectivity to all patient information between administrative platforms, managers, healthcare professionals, laboratory technicians and relevant stakeholders. The use of Qure.ai facilitates the interpretation of chest X-rays on time where there are no qualified clinicians available, preventing delays in TB diagnosis.
Sputum samples will be processed on the GeneXpert® Model GX-IV with 2 modules if the pooling is performed at the same place as the sample collection (POC testing, ACF) or on the GeneXpert® platform available at the reference laboratory. For pooled testing, an equal volume of each of the remaining processed samples (samples already processed to be tested individually) will be pooled together. We aim for pools of 4 samples. If the number of sputum samples received in a day \<4 , those processed samples may be kept in the fridge, and pooled testing resumed the following day if more samples are received. If on the following day, not enough samples are received, pools of 2 or 3 samples will be made. Processed samples cannot be tested after 24 hours. If there is no fridge on-site, or on the last day of the week, all samples will be pooled at the end of the day. Pools of four will be prioritized, but if there are less than four samples, those will be pooled (pools of 2 or 3 samples).
The KIIs and FGDs will be semi-structured and the lead Research Assistant will follow a topic guide with open questions plus probes that provides a framework concerning the topics and issues of interest. KIIs will cover topics around TB tests and test combinations. The in-country KIIs and FGDs will be conducted in the local language, audio recorded, transcribed, translated into English. International KII participants will have their KII conducted with a Co-Investigator and Research Assistant from the Start4All team virtually on a suitable platform, which may include MS Teams or Zoom. The workshops will include interactive presentations and small, interdisciplinary working groups to review the realist evaluation (RE) findings and initial RE-derived program theory, and in-country barriers and enablers. Workshop outputs will be synthesized in an open-access report and shared with participants and selected decision makers and policy-making organizations.