Effectiveness and cost-effectiveness of community-based TB screening algorithms using Computer-Aided Detection (CAD) technology alone compared to CAD combined with point-of-care C-reactive protein testing: protocol for a paired screen-positive trial

IntroductionTuberculosis (TB) remains a significant public health challenge in many African communities, where underreporting and underdiagnosis are prevalent due to barriers in accessing care and inadequate diagnostic tools. This is particularly concerning in hard-to-reach areas with a high burden of TB/HIV co-infection, where missed or delayed diagnoses exacerbate disease transmission, increase mortality, and lead to severe economic and health consequences. To address these challenges, it is crucial to evaluate innovative, cost-effective, community-based screening strategies that can improve early detection and linkage to care. Methods and AnalysisWe conduct a prospective, community-based, diagnostic, pragmatic trial in communities of the Butha Buthe District in Lesotho and the Greater Edendale area of Msunduzi Municipality, KwaZulu-Natal in South Africa to compare two strategies for population-based TB screening: Computer-Aided Detection (CAD) technology alone (CAD4TBv7 approach) vs. CAD combined with point-of-care C-reactive protein (CRP) testing (CAD4TBv7-CRP approach). Following a chest X-ray, CAD produces an abnormality score, which indicates the likelihood of TB. Score thresholds informing the screening logic for both approaches were determined based on the World Health Organizations (WHO) target product profile for a TB screening test. CAD scores above a threshold pre-specified for the CAD4TBv7 approach indicate confirmatory testing for TB (Xpert MTB/RIF Ultra). For the CAD4TBv7-CRP approach, a CAD score within a pre-defined window requires the conduct of the second screening test, CRP, while a score above the respective upper threshold is followed by Xpert MTB/RIF Ultra. A CRP result above the selected cut-off also requires a confirmatory TB test. Participants with CAD scores below the (lower) threshold and those with CRP levels below the cut-off are considered screen-negative. The trial aims to compare the yield of detected TB cases and cost-effectiveness between two screening approaches by applying a paired screen-positive design. 20,000 adult participants will be enrolled and will receive a posterior anterior digital chest X-ray which is analysed by CAD software. Ethics and disseminationThe protocol was approved by National Health Research Ethics Committee in Lesotho (NH-REC, ID52-2022), the Human Sciences Research Council Research Ethics Committee (HSRC REC, REC 2/23/09/20) and the Provincial Health Research Committee of the Department of Health of KwaZulu-Natal (KZ_202209_022) in South Africa and from the Swiss Ethics Committee Northwest and Central Switzerland (EKNZ, AO_2022-00044). This manuscript is based on protocol version 4.0, 19 January 2024. Trial findings will be disseminated through peer-reviewed publications, conference presentations and through communication offices of the consortium partners and the projects website (https://tbtriage.com/). Trial registrationClinicalTrials.gov (NCT05526885), South African National Clinical Trials Register (SANCTR; DOH-27-092022-8096). Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis pragmatic trial will constitute the first comparative evaluation of two screening approaches for pulmonary TB using CAD4TB alone or in combination with point-of-care CRP. C_LIO_LIResults from this study will help in identifying the most (cost-)effective strategy for community-based TB screening. C_LIO_LIPragmatic inclusion criteria and trial delivery will allow an approximation to the real world. C_LI