Abstract
BackgroundNucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid-fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV.MethodsWe prospectively enrolled 211 consecutive adults with cough ≥2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified® Mycobacterium tuberculosis Direct (MTD) test (Gen-Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment.ResultsOf 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/µL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28–51) and that of secA1 was 24% (95% CI 15–35). Both tests had specificities of 95% (95% CI 90–98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate.ConclusionsThe secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations.
Highlights
In 2009, 43% of the 4.6 million new pulmonary tuberculosis cases reported to the World Health Organization were diagnosed without microbiologic confirmation [1]
We have previously shown in a small study that a novel Nucleic-acid amplification tests (NAATs) targeting a conserved region of the mycobacterial-genus secretory gene A1 target test (secA1) gene and capable of identifying all clinically significant species of mycobacteria including M. tuberculosis, has a sensitivity of 100% and a specificity of 90% in sputum smear-negative tuberculosis. doi (TB) suspects in Uganda, most of whom were HIV-seropositive [7]
Results of Sputum NAATs Using mycobacterial culture results as the gold standard, the sensitivity of Mycobacterium Tuberculosis Direct (MTD) for diagnosing TB was 39% (95% Confidence Interval (CI) 28–51), which was 15% higher than that of secA1, which had a sensitivity of 24%
Summary
In 2009, 43% of the 4.6 million new pulmonary tuberculosis cases reported to the World Health Organization were diagnosed without microbiologic confirmation [1]. The failure to confirm a diagnosis with microbiologic testing can result in inappropriate management due to misdiagnosis and failure to initiate appropriate therapy early in the disease process. These disadvantages are especially relevant in low-income countries where supplementary imaging and laboratory data are usually not available to support an empiric diagnosis, and where late presentation for care is more common. Nucleic-acid amplification tests (NAATs) targeting Mycobacterium tuberculosis (MTB) have enormous potential to improve TB case detection, with commercial NAATs, such as the GenProbe AmplifiedH Mycobacterium Tuberculosis Direct (MTD) Test (Gen-Probe Inc, San Diego, CA), reported to have nearly perfect sensitivity in sputum smear-positive patients and a sensitivity of 61–76% in smear-negative patients [3,4,5,6].
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