Xpert-Ultra to Detect and Quantify HIV-Associated Mycobacterium tuberculosis Blood Stream Infection: A Cohort Study

Background: Mycobacterium tuberculosis bloodstream infection (MTBBSI) is a leading cause of death in people living with HIV. Tools to rapidly identify and quantify MTBBSI could facilitate both diagnosis and research for this critical condition. Methods: We developed a method to detect M. tuberculosis in blood using lysis-wash steps and the Xpert MTB/RIF Ultra platform, testing it on biobanked blood from participants hospitalized with HIV-associated TB. We assessed diagnostic yield (proportion of cases detected, with unavailable test results coded as negative) against a microbiological reference, both as a function of markers of critical-illness and compared with other rapid-diagnostics. Quantitative blood Xpert-Ultra results were evaluated as a disease biomarker by assessing association with disease phenotype defined by principal component analysis of 32 host-response markers, and prognostic value compared to other tuberculosis biomarkers models to predict 12-week mortality. Findings: Of 582 participants, 447 (77%) had tuberculosis; 165 out of 447 were blood Xpert-Ultra positive giving diagnostic yield 0·37 (95%CI 0·32 to 0·42). Diagnostic yield increased with lower CD4 cell count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert-Ultra results predicted mortality better than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan or urine-Xpert. Both blood Xpert-Ultra positivity and cycle threshold were strongly associated with a principal component of clinical phenotype capturing markers of inflammation, tissue damage and organ dysfunction. Interpretation: Xpert-Ultra testing of pre-processed blood could be used as a rapid diagnostic test in critically ill patients with suspected HIV-associated tuberculosis, while also giving additional prognostic information compared with other available markers. A dose-response relationship between quantitative blood Xpert-Ultra results, host-response phenotype, and mortality risk adds to evidence that suggests MTBBSI bacillary load is causally related to outcomes.  Funding Information: Wellcome Trust, Fogarty International Center, South African MRC, NIHR(UK), National Research Foundation of South Africa. Declaration of Interests: All authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the University of Cape Town Human Research Ethics Committee (HREC 057/2013).