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A MULTICENTER DIAGNOSTIC ACCURACY STUDY OF THE XPERT ULTRA FOR TUBERCULOSIS DIAGNOSIS
Samuel G. Schumacher1, Pamela Nabeta1, Catharina C. Boehme1, Jerrold Ellner2, David Alland3, Susan E. Dorman4, Claudia M. Denkinger1
1FIND, Geneva, Switzerland,2Boston Med Cntr, Boston, MA, USA,3Univ of Med and Dentistry of New Jersey, Newark, NJ, USA,4Johns Hopkins Univ, Baltimore, MD, USA
The development of the Xpert MTB/RIF (Xpert) was a major step forward for improving tuberculosis (TB) and rifampin (RIF) diagnosis globally. However, Xpert sensitivity is imperfect in smear-negative and HIV-associated TB and some limitations also remain in the determination of RIF-resistance status. The Xpert Ultra (Ultra) has been developed as the next-generation assay to overcome these limitations.
This was a prospective multicenter diagnostic accuracy study in adults with signs/symptoms of pulmonary TB. Xpert and Ultra were performed from the same specimen and accuracy determined with four cultures as the reference standard for TB detection (two MGIT tubes + two LJ slants, performed on two specimens obtained on separate days) and phenotypic drug-susceptibility testing for RIF resistance detection.
1,520 patients were enrolled in 10 sites across 8 countries. Sensitivity of the Ultra was 5% higher than that of Xpert (95%CI +2.7, +7.8) but specificity was 3.2% lower (95%CI -2.1, -4.7). Sensitivity-increases were higher among smear-negative patients (+17%, 95%CI +10, +25) and among HIV-infected patients (+12%, 95%CI +4.9, +21). Specificity-decreases were higher in patients with a history of TB (-5.4%, 95%CI -9.1, -3.1) than in patients with no history of TB (-2.4%, 95%CI -4.0, -1.3). Reclassifying 'trace calls' (the semi-quantitative category of the Ultra assay that corresponds to the lowest bacillary burden) as 'TB-negative'-either in all cases or in those with a history- mitigates some of the specificity losses (Specificity –1.0%/-1.9% if trace reclassified for all cases/cases with history) while maintaining some of the sensitivity gains over Xpert (Sensitivity +7.6%/+15%). Ultra classified more patients correctly as RIF-resistant (+1.1%, 95%CI -2.0, +4.6) and RIF-sensitive (+2.6%, 95%CI +0.2, +5.2) overall because the Xpert missed TB in patients with very paucibacillary disease entirely.
Ultra has higher sensitivity than Xpert in smear-negative and HIV-infected patients and improved accuracy for RIF detection. However, as a result of the increased sensitivity, Ultra also detects TB DNA in some patients with prior TB disease, possibly due to persistence of non-viable bacilli, leading to reduced specificity. Similar results can be expected for other upcoming next-generation molecular TB assays. A discussion of resulting implementation challenges and the willingness to trade off specificity for increased sensitivity in different settings is urgently needed.