David J. Horne

Background Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)‐recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF. Objectives To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x‐ray suggestive of tuberculosis. Search methods We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov and the WHO ICTRP) to 16 October 2023 without language restrictions. A WHO Public Call for ongoing and unpublished studies was made between 30 November 2023 and 15 February 2024. Selection criteria We included cross‐sectional studies, cohort studies, and randomised controlled trials that provided data on the diagnostic accuracy of Xpert Ultra using respiratory specimens in adolescents (aged 10 to 14 years) and adults (aged 15 years and older) with presumptive pulmonary tuberculosis. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture‐based phenotypic drug susceptibility testing with or without whole genome sequencing. Data collection and analysis Two review authors independently extracted data using a standardised form. We assessed risk of bias using QUADAS‐2. We performed meta‐analyses using a bivariate model to produce summary sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarised Xpert Ultra trace‐positive results. Main results Pulmonary tuberculosis detection For detection of pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity against culture were 90.7% (95% confidence interval (CI) 88.2 to 92.7) and 94.8% (95% CI 92.8 to 96.3) (32 studies, 12,529 participants; high‐certainty evidence). Most studies had low risk of bias in all QUADAS‐2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss nine cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 47. In people living with HIV, Xpert Ultra summary sensitivity and specificity were 87.7% (82.0 to 91.7) and 95.3% (92.2 to 97.2) (11 studies, 1164 participants). Amongst people with smear‐negative, culture‐positive pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity were 80.7% (75.4 to 85.0) and 94.0% (91.3 to 95.9) (16 studies, 6460 participants). In people with a history of tuberculosis, Xpert Ultra summary sensitivity and specificity were 84.8% (78.2 to 89.7) and 86.2% (78.9 to 91.3) (9 studies, 809 participants). The proportion of Ultra trace‐positive results that were true positives compared to the microbiological reference standard was 38.8%. Reclassifying trace‐positive results as Xpert Ultra‐negative led to a reduction in sensitivity and modest increase in specificity. Rifampicin resistance detection For detection of rifampicin resistance, Xpert Ultra summary sensitivity and specificity were 95.8% (93.2 to 97.4) and 98.3% (97.0 to 99.0) (10 studies, 1644 participants; high‐certainty evidence). Most studies had low risk of bias in all QUADAS‐2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss four cases. The number of people wrongly diagnosed with rifampicin resistance would be 16 out of the 900 who do not have rifampicin resistance. Xpert Ultra performed similarly, for rifampicin resistance, in people with smear‐positive and smear‐negative tuberculosis. Authors' conclusions Xpert Ultra has high sensitivity and specificity for detection of pulmonary tuberculosis rifampicin resistance. Xpert Ultra for the detection of pulmonary tuberculosis has lower sensitivity in people with smear‐negative/culture‐positive tuberculosis and lower sensitivity and specificity in people with a history of tuberculosis. Xpert Ultra trace‐positive results were common. Strengths of this review include the approach to identifying relevant studies, the number of studies and participants included in this systematic review, and that most studies were at low risk of bias. The small number of studies (six) and participants who were adolescents is a limitation to our accuracy estimates in this age group. Xpert Ultra testing provides accurate results and can allow rapid initiation of treatment for rifampicin‐resistant and multiple‐drug‐resistant tuberculosis. Funding The WHO supported this systematic review. Liverpool School of Tropical Medicine hosted the Cochrane Infectious Diseases Group (CIDG) editorial base, which supported the authors in the development of this review update. The Foreign, Commonwealth and Development Office funded the CIDG. Registration Generic protocol available on Open Science Framework via https://osf.io/26wg7/wiki/home/. Previous protocol and review versions available via DOI 10.1002/14651858.CD009593 and DOI 10.1002/14651858.CD009593.pub5.

National and sub-national population-based surveys, when performed at intervals, may assess important changes in TB prevalence. In 2022 we re-surveyed nine Nairobi County neighbourhoods that were previously surveyed in 2015. We aimed to determine pulmonary TB prevalence, compare prevalence to 2015 estimates, and evaluate changes in risk groups. Participants who reported cough of any duration and/or whose chest x-ray suggested TB submitted sputum for smear microscopy, Xpert Ultra, and liquid culture. We defined prevalent TB as Mycobacterium tuberculosis detection by sputum Xpert or culture, excepting individuals who were only trace positive. Our methods differed from 2015, which used solid media, Xpert MTB/RIF, and cough duration >2 weeks. We calculated TB prevalence using random-effects logistic regression models with missing value imputations and inverse probability weighting. In 2022 among 6369 participants, 1582 submitted ≥1 sputum sample, among whom 42 (2.7%) had TB, a weighted TB prevalence of 806/100,000 (95% confidence interval (CI), 518–1096). An additional 31 (2.0%) participants tested Ultra trace-positive/culture-negative. For comparison to 2015, we excluded 2022 participants (n = 2) whose only criterion for sputum was cough <2 weeks. There was no evidence for a decline in overall TB prevalence from 2015 to 2022. TB prevalence among men was high (1301/100,000) and remained high compared to 2015 (p-value <0.05). The age group with the highest estimated prevalence remained people ages 45–54 years. Among people with prevalent TB who reported cough, 76% had not sought health care. Dissimilar from other serial surveys that showed declines in TB prevalence, we found persistently high TB prevalence over a 7-year period in Nairobi County. Limitations of this study include changes in methodology between the two surveys and complex effects of the COVID-19 pandemic.

National and sub-national population-based surveys, when performed at intervals, may assess important changes in TB prevalence. In 2022 we re-surveyed nine Nairobi County neighbourhoods that were previously surveyed in 2015. We aimed to determine pulmonary TB prevalence, compare prevalence to 2015 estimates, and evaluate changes in risk groups. Participants who reported cough of any duration and/or whose chest x-ray suggested TB submitted sputum for smear microscopy, Xpert Ultra, and liquid culture. We defined prevalent TB as Mycobacterium tuberculosis detection by sputum Xpert or culture, excepting individuals who were only trace positive. Our methods differed from 2015, which used solid media, Xpert MTB/RIF, and cough duration >2 weeks. We calculated TB prevalence using random-effects logistic regression models with missing value imputations and inverse probability weighting. In 2022 among 6369 participants, 1582 submitted >1 sputum sample, among whom 42 (2·7%) had TB, a weighted TB prevalence of 806/100,000 (95% confidence interval (CI), 518-1096). An additional 31 (2·0%) participants tested Ultra trace-positive/culture-negative. For comparison to 2015, we excluded 2022 participants (n=2) whose only criterion for sputum was cough <2 weeks. There was no evidence for a decline in overall TB prevalence from 2015 to 2022. TB prevalence among men was high (1368/100,000) but unchanged compared to 2015 (p-value = 0·50). The age group with the highest estimated prevalence remained people ages 45–54 years. Among people with prevalent TB who reported cough, 76% had not sought health care. Dissimilar from other serial surveys that showed declines in TB prevalence, we found persistently high TB prevalence over a 7-year period in Nairobi County. Limitations of this study include changes in methodology between the two surveys and complex effects of the COVID-19 pandemic.

Interrupting transmission events is critical to tuberculosis control. Cough-generated aerosol cultures predict tuberculosis transmission better than microbiological or clinical markers. We hypothesize that highly infectious individuals with pulmonary tuberculosis (positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals. We performed a prospective, longitudinal study using cough aerosol sampling system. We enrolled 142 participants with treatment-naïve pulmonary tuberculosis in Kenya and assessed the association of clinical, microbiologic, and immunologic characteristics with Mycobacterium tuberculosis aerosolization and transmission in 129 household members. Contacts of the forty-three aerosol culture-positive participants (30%) are more likely to have a positive interferon-gamma release assay (85% vs 53%, P = 0.006) and higher median IFNγ level (P < 0.001, 4.28 IU/ml (1.77-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We find that higher bacillary burden, younger age, larger mean upper arm circumference, and host inflammatory profiles, including elevated serum C-reactive protein and lower plasma TNF levels, associate with positive cough aerosol cultures. Notably, we find pre-treatment whole blood transcriptional profiles associate with aerosol culture status, independent of bacillary load. These findings suggest that tuberculosis infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may identify highly infectious persons.

Background: Latent tuberculosis infection (LTBI) screening and treatment interventions that are tailored to optimize acceptance among the non-U.S.–born population are essential for U.S. tuberculosis elimination. We investigated the impact of medical interpreter use on LTBI treatment acceptance and completion among non-U.S.–born persons in a multisite study. Methods: The Tuberculosis Epidemiologic Studies Consortium was a prospective cohort study that enrolled participants at high risk for LTBI at ten U.S. sites with 18 affiliated clinics from 2012 to 2017. Non-U.S.–born participants with at least one positive tuberculosis infection test result were included in analyses. Characteristics associated with LTBI treatment offer, acceptance, and completion were evaluated using multivariable logistic regression with random intercepts to account for clustering by enrollment site. Our primary outcomes were whether use of an interpreter was associated with LTBI treatment acceptance and completion. We also evaluated whether interpreter usage was associated treatment offer and whether interpreter type was associated with treatment offer, acceptance, or completion. Results: Among 8,761 non-U.S.–born participants, those who used an interpreter during the initial interview had a significantly greater odds of accepting LTBI treatment than those who did not use an interpreter. There was no association between use of an interpreter and a clinician’s decision to offer treatment or treatment completion once accepted. Characteristics associated with lower odds of treatment being offered included experiencing homelessness and identifying as Pacific Islander persons. Lower treatment acceptance was observed in Black and Latino persons and lower treatment completion by participants experiencing homelessness. Successful treatment completion was associated with use of shorter rifamycin-based regimens. Interpreter type was not associated with LTBI treatment offer, acceptance, or completion. Conclusions: We found greater LTBI treatment acceptance was associated with interpreter use among non-U.S.–born individuals.

Interrupting transmission events to prevent new acquisition of infection and disease is a critical part of tuberculosis (TB) control efforts. However, knowledge gaps in understanding the biology and determinants of TB transmission, including poor estimates of individual infectiousness and the lack of accurate and convenient biomarkers, undermine efforts to develop interventions. Cough-generated aerosol cultures have been found to predict TB transmission better than any microbiological or clinical markers in cohorts from Uganda and Brazil. We hypothesized that highly infectious individuals with pulmonary TB (defined as positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals (negative for cough aerosol cultures). We performed a prospective, longitudinal study using a cough aerosol sampling system as in other studies. We enrolled 142 participants with treatment-naïve pulmonary TB in Nairobi, Kenya, and assessed the association of clinical, microbiologic, and immunologic characteristics with Mtb aerosolization and transmission in 143 household members. Contacts of the forty-three aerosol culture-positive participants (30%) were more likely to have a positive IGRA (85% vs 53%, P = 0.005) and a higher median IGRA IFNγ level (P < 0.001, median 4.25 IU/ml (0.90–5.91) vs. 0.71 (0.01–3.56)) compared to aerosol culture-negative individuals. We found that higher bacillary burden, younger age, and larger mean upper arm circumference were associated with positive aerosol cultures. In addition, novel host inflammatory profiles, including elevated serum C-reactive protein and sputum cytokines, were associated with aerosol culture status. Notably, we found pre-treatment whole blood transcriptional profiles associated with aerosol culture status, independent of bacillary load. Together, these findings suggest that TB infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may be used to identify highly infectious persons. These results provide new public health tools and insights into TB pathogenesis.

Recent respiratory disease screening studies suggest promising performance of cough classifiers, but potential biases in model training and dataset quality preclude robust conclusions. To examine tuberculosis (TB) cough diagnostic features, we enrolled subjects with pulmonary TB (N= 149) and controls with other respiratory illnesses (N= 46) in Nairobi. We collected a dataset with 33,000 passive coughs and 1600 forced coughs in a controlled setting with similar demographics. We trained a ResNet18-based cough classifier using images of passive cough scalogram as input and obtained a fivefold cross-validation sensitivity of 0.70 (±0.11 SD). The smartphone-based model had better performance in subjects with higher bacterial load {receiver operating characteristic–area under the curve (ROC-AUC): 0.87 [95% confidence interval (CI): 0.87 to 0.88],P< 0.001} or lung cavities [ROC-AUC: 0.89 (95% CI: 0.88 to 0.89),P< 0.001]. Overall, our data suggest that passive cough features distinguish TB from non-TB subjects and are associated with bacterial burden and disease severity.