An eXpert AFB smear?

The development, evaluation, and World Health Organization (WHO) endorsement of the Xpert MTB/RIF automated real-time polymerase chain reaction (PCR) assay has generated considerable excitement as a revolutionary diagnostic test for tuberculosis. However, one of its limitations is the inability to determine which patients with pulmonary tuberculosis have sputum positive for acid-fast bacilli (AFB) on microscopy, the current laboratory indicator of infectiousness [1]. The AFB smear is currently used to guide infection control practices and household contact investigations across the globe, and to monitor response to treatment. How the Xpert MTB/RIF assay can fill these roles is unknown. Given this uncertainty, Theron et al [2] evaluated the relationship between quantitative cycle-threshold (CT) data generated by this system and conventional AFB sputum smear data from tuberculosis suspects in Cape Town, South Africa, a setting with a high rate of tuberculosis–human immunodeficiency virus (HIV) coinfection. In this issue of Clinical Infectious Diseases, they report their findings and conclude that the CT is a moderately good test for ruling out smear positivity of sputa specimens but a poor test for confirming or ruling in smear positivity. The Xpert MTB/RIF assay uses realtime PCR technology to detect both the presence of Mycobacterium tuberculosis DNA and rifampin resistance based on presence of the rpoB gene and its mutations. A sputum specimen is mixed with a sample reagent and homogenized before transfer to a cartridge that is then placed into the closed system. The CT refers to the cycle number at which the fluorescent signal from the molecular beacon probes becomes detectable above the background [3]. An excellent review with more detail on the development, evaluation, and implementation of this new diagnostic test has recently been published [4]. The study reported by Theron et al [2] was conducted by a well-respected, experienced research team in Cape Town, South Africa, a setting beset by a devastating epidemic of tuberculosis complicated by high rates of HIV coinfection and multidrug-resistant tuberculosis (MDR-TB). To make matters worse, South Africa is now the epicenter of extensively drug-resistant tuberculosis, with well-documented nosocomial transmission to both patients and healthcare workers [5, 6]. Given the strong recommendation from the WHO that the Xpert MTB/RIF be used as the initial diagnostic test in individuals suspected of MDR-TB or HIV-associated tuberculosis [7], the setting for this study could not be more appropriate. Much of the literature on the Xpert MTB/RIF to date has been from the developers of the assay, so this article from an independent group is welcome, even though they received funding from the Foundation for Innovative New Diagnostics, one of the developers. The rationale for using the CT as a surrogate for bacillary concentration is supported by the log-linear relationship observed between the CT and quantitative culture from the original developers [8] and by the significant correlation between the CT and days to positive in liquid culture reported by this group in the parent study of this report [9]. The study from Theron et al [2] is similar to another recent report from Blakemore et al [10], the original developers of the assay. Both are follow-up studies using cohorts from well-designed parent studies on the performance characteristics of the assay for diagnosing pulmonary tuberculosis. In the Blakemore et al study [10], there were 741 tuberculosis suspects from 5 sites, 2 of which were in South Africa and were the only sites with high rates of HIV coinfection [11]. Blakemore et al [10] included only samples from patients with culture confirmed tuberculosis, whereas Theron et al [2] included all 496 of the original tuberculosis suspects. Both Received 30 September 2011; accepted 6 October 2011; electronically published 1 December 2011. Correspondence: Kevin P. Fennelly, MD, MPH, Associate Professor of Medicine, Division of Mycobacteriology, Department of Medicine, Southeastern National Tuberculosis Center, Emerging Pathogens Institute, Room 257, University of Florida, Gainesville, FL 32611 (kevin.fennelly@medicine. ufl.edu). Clinical Infectious Diseases 2012;54(3):389–91 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/cid/cir825