Head-to-head comparison of diagnostic accuracy of TB screening tests: Chest-X-ray, Xpert TB host response, and C-reactive protein

Abstract

Background: Accessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries. We compared the diagnostic accuracy of available TB triage tests.

Methods: We prospectively screened consecutive adults with ≥2 weeks of cough presenting to primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. All participants received the index tests: chest-X-ray (CXR), venous or capillary Cepheid Xpert TB Host Response (HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech iChroma II). CXR images were processed using computer-aided detection (CAD) algorithms. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to achieve sensitivity ≥90% and maximize specificity. Two-test screening algorithms were considered, using two approaches: 1) sequential negative serial screening in which the second screening test is conducted only if the first is negative and positive is defined as positive on either test and 2) sequential positive serial screening, in which the second screening test is conducted only if the first is positive and positive is defined as positive on both tests.

Results: Between July 2021 and August 2022, 1,392 participants with presumptive TB had valid results on index tests and the reference standard, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity when using a cut-point that achieves 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). Among the possible two-test screening algorithms, three 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. Cost and feasibility of two-test screening algorithms should be explored.

Registration: NCT04923958.

Figure 1.. Study population.

Note. Culture is not performed for participants with positive results on sputum Xpert Ultra.

Figure 2.. Receiver operating characteristic curve.

ROC curves against the microbiologic reference standard with AUC and 95% CI displayed for CAD4TB, Xpert HR, and CRP. The upper-left area shaded in gray notes the region where tests meet TPP targets (≥90% sensitivity, ≥70% specificity). N=1,392 participants from the Philippines, Vietnam, Uganda, South Africa, and India with presumptive TB (n=303, 22% with microbiologically confirmed TB).

Figure 3.. Selection of cut points for two-step screening algorithm combining Xpert HR and CAD4TB.

Panel (A) shows the possible cut-points using sequential negative serial screening, in which the second screening test is conducted only if the first is negative and a positive screen is defined as positive on either test. Panel (B) shows the possible cut-points using sequential positive serial screening, in which the second screening test is conducted only if the first is positive and a positive screen is defined as positive on both tests. The x-axis shows all potential cut-points for Xpert HR (test positive defined as less than or equal to the cut point chosen), and the y-axis shows all potential cut points for CAD4TB (test positive defined as greater than or equal to the cut point chosen). Each point on the graph corresponds to a pair of cut points used to define a positive screening algorithm. The colors represent the range of sensitivities and specificities possible. The outlined region contains pairs with sensitivity≥90% and specificity ≥70% (n=417 in panel A, n=31 in panel B).