Diagnostic Accuracy of Tuberculosis Screening Tests in a Prospective Multinational Cohort: Chest Radiography With Computer-Aided Detection, Xpert Tuberculosis Host Response, and C-Reactive Protein
Rebecca Crowder, Balamugesh Thangakunam, Alfred Andama, Devasahayam Jesudas Christopher, Victoria Dalay, Welile V. Dube-Nwamba, Sandra V. Kik, Dong Van Nguyen, Nguyen Viet Nhung, Patrick Phillips, Morten Rühwald, Grant Theron, William Worodria, Charles Yu, Payam Nahid, Adithya Cattamanchi, Ankur Gupta‐Wright, Claudia M. Denkinger, for the R2D2 TB Network, Shanmugasundaram Elango, Jerusha Emmanuel, Vinita Ernest, Priyadarshini Gajendran, Flavita John, Bharath Karthikeyan, Divya Mangal, Swetha Sankar, Rajasekar Sekar, Reena Sekar, Deepa Shankar, Mary Shibiya, Sai Vijayasree, Jared Almonte, Kevin Joshua Alonzo, Mary Faith Angcaya, Joseph Edwin L Bascuña, Ramon P Basilio, Asella Ruvijean Cariaga, Gabriella Castillon, Karlo Dayawon, Raul Destura, Jezreel Esguerra, Eleonor Garcia, Darecil Gelina, Joseph Aldwin Goleña, Maria Marissa Golla, Emmanuelle Gutierrez, Gidalthi Jonathan Ilagan, Dodge R Lim, Jaiem Maranan, Danaida Marcelo, Leonedy Masangcay, Jenkin Mendoza, Angelita Pabruada, Laarean Perlas, Annalyn Reyes, Roeus Vincent Arjay G Reyes, Lorenzo Reyes, Maria Guileane Sanchez-Pogosa, Maricef Tonquin, Shima Abdulgadar, Cammy Botha, Brigitta Derendinger, Jane Fortuin, Siphosethu Gonya, Chumani Hatile, Megan Hendrikse, Charlotte Lawn, Disha Mathoorah, Desiree Lem Mbu, Zintle Ntetha, Anna Okunola, Zaida Palmer, Fikiswa Seti, Charmaine Van Der Walt, Lusanda Yekani, Lucy Asege, Alice Bukirwa, David Katumba, Esther Kisakye, Wilson Mangeni, Job Mukwatamundu, Sandra Mwebe, Annet Nakaweesa, Martha Nakaye, Talemwa Nalugwa, Irene Nassuna, Irene Nekesa, Justine Nyawere, John Baptist Ssonko, Hai Dang, Luong Dinh, Hang Do, Tam Do, Thuong Do, Dung Dao, Ha Doan, Thien Doan, Huy Ha, Oanh Lai
Abstract
BACKGROUND: Accessible, accurate screening tests are necessary to advance tuberculosis 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 underwent chest radiography, Cepheid Xpert TB Host Response (Xpert HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech). Chest radiographs were processed using CAD4TB v7, a computer-aided detection (CAD) algorithm. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cutoff points were chosen to maximize specificity at 90% sensitivity. Two-test screening algorithms were considered, using (1) sequential negative serial screening (with positive defined as positive on either test) and (2) sequential positive serial screening (with positive defined as positive on both tests). RESULTS: Between July 2021 and August 2022, a total of 1392 participants with presumptive tuberculosis had valid index tests and reference standard results, and 303 (22%) had confirmed tuberculosis. In head-to-head comparisons, CAD4TB v7 showed the highest specificity at 90% sensitivity (70.3% vs 65.1% for Xpert HR [95% confidence interval for absolute difference in specificity, 1.6%-8.9%] and vs 49.7% for CRP [17.0%-24.3%]). Three 2-test screening algorithms met World Health Organization target product profile 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 target product profile targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy. Clinical Trials Registration. NCT04923958.