Abstract
Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. SHINE is a randomized trial evaluating shorter treatment in 1,204 children with minimal TB disease in Africa and India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with the Xpert MTB/RIF assay (Xpert) and with Lowenstein-Jensen medium (LJ) and liquid mycobacterial growth indicator tube (MGIT) cultures. We selected only uncontaminated stored sample pellets for Ultra testing. We estimated the sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result). Of 398 children, 353 (89%) had culture, Xpert, and Ultra results. The median age was 2.8 years (interquartile range [IQR], 1.3 to 5.3); 8.5% (30/353) were HIV infected, and 54.4% (192/353) were male. Of the 353, 31 (9%) were positive by LJ and/or MGIT culture, 36 (10%) by Ultra, and 16 (5%) by Xpert. Sensitivities (95% confidence intervals [CI]) were 58% (39 to 65% [18/31]) for Ultra and 45% (27 to 64% [14/31]) for Xpert against any culture-positive result, with false positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitivities were 72% (58 to 84% [36/50]) for Ultra and 32% (20 to 47% [16/50]) for Xpert. However, there were 17 samples that were positive only with Ultra (majority trace). Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades.
Highlights
Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test
Two additional multicopy molecular targets for Mycobacterium tuberculosis, IS1081 and IS6110, were introduced, alongside 4 rpoB gene probes, resulting in a decrease in the limit of detection (LOD) in vitro from ϳ113 bacilli per ml of sputum for Xpert to ϳ16 for Ultra, with a trace category added for lowest bacillary load [7]
353 children with Lowenstein-Jensen medium (LJ) or mycobacterial growth indicator tube (MGIT) cultures that were not contaminated and not identified as nontuberculous mycobacteria (NTM) and with valid Xpert results were included in this substudy (Fig. 1)
Summary
Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. A multicenter noninferiority study at ten sites in eight low- and middle-income countries in adults with suspected pulmonary TB found that Ultra was significantly more sensitive than Xpert against a culture-based reference standard in smear-negative TB (63% versus 46%) and HIV-associated pulmonary TB (PTB) (90% versus 77%), but with more modest gains in the general population (88% versus 83%) [7]. In a study on 367 biobanked sputum samples in Cape Town, of those with microbiologically confirmed TB (by composite of MGIT [mycobacterial growth indicator tube] culture, Xpert, or Ultra), the sensitivities of culture, Ultra, and Xpert compared to composite reference were 83%, 74%, and 62%, respectively [10]. In a further study of 215 children, using clinical case definition as the reference standard, the sensitivity was 64% for Ultra compared to 54% for Xpert [11]
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