Background
Accessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries.

Methods
We prospectively screened adults with ≥2 weeks of cough at primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. Participants received chest-X-ray, Cepheid Xpert TB Host Response (Xpert HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech). Chest-X-ray images were processed using CAD4TB v7, a computer-aided detection algorithm. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to maximize specificity at 90% sensitivity. Two-test screening algorithms were considered, using 1) sequential negative serial screening (positive defined as positive on either test) and 2) sequential positive serial screening (positive defined as positive on both tests).

Results
Between July 2021 and August 2022, 1,392 participants with presumptive TB had valid index tests and reference standard results, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity at 90% sensitivity (70.3% vs. 65.1% for Xpert HR, difference 95% CI 1.6 to 8.9; 49.7% for CRP, difference 95% CI 17.0 to 24.3). Three two-test screening algorithms met WHO target product profile (TPP) minimum accuracy thresholds and had higher accuracy than any test alone. At 90% sensitivity, the specificity was 79.6% for Xpert HR-CAD4TB [sequential negative], 75.9% for CRP-CAD4TB [sequential negative], and 73.7% for Xpert HR-CAD4TB [sequential positive].

Conclusions
CAD4TB achieves TPP targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy.

Registration
NCT04923958