Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.

Correction: Early mortality in tuberculosis patients initially lost to follow up following diagnosis in provincial hospitals and primary health care facilities in Western Cape, South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0252084.].

Association between tuberculosis and pregnancy outcomes: a retrospective cohort study of women in Cape Town, South Africa.

BACKGROUND: Tuberculosis (TB) remains a leading cause of mortality among women of childbearing age and a significant contributor to maternal mortality. Pregnant women with TB are at high risk of adverse pregnancy outcomes. This study aimed to determine risk factors for an adverse pregnancy outcome among pregnant women diagnosed with TB. METHODS: Using TB programmatic data, this retrospective cohort analysis included all women who were routinely diagnosed with TB in the public sector between October 2018 and March 2020 in two health subdistricts of Cape Town, and who were documented to be pregnant during their TB episode. Adverse pregnancy outcome was defined as either a live birth of an infant weighing <2500 g and/or with a gestation period <37 weeks or as stillbirth, miscarriage, termination of pregnancy, maternal or early neonatal death. Demographics, TB and pregnancy characteristics were described by HIV status. Logistic regression was used to determine risk factors for adverse pregnancy outcome. RESULTS: Of 248 pregnant women, half (52%) were living with HIV; all were on antiretroviral therapy at the time of their TB diagnosis. Pregnancy outcomes were documented in 215 (87%) women, of whom 74 (34%) had an adverse pregnancy outcome. Being older (35-44 years vs 25-34 years (adjusted OR (aOR): 3.99; 95% CI: 1.37 to 11.57), living with HIV (aOR: 2.72; 95% CI: 0.99 to 4.63), having an unfavourable TB outcome (aOR: 2.29; 95% CI: 1.03 to 5.08) and having presented to antenatal services ≤1 month prior to delivery (aOR: 10.57; 95% CI: 4.01 to 27.89) were associated with higher odds of an adverse pregnancy outcome. CONCLUSIONS: Pregnancy outcomes among women with TB were poor, irrespective of HIV status. Pregnant women with TB are a complex population who need additional support prior to, during and after TB treatment to improve TB treatment and pregnancy outcomes. Pregnancy status should be considered for inclusion in TB registries.

Reducing Initial Loss to Follow-up Among People With Bacteriologically Confirmed Tuberculosis: LINKEDin, a Quasi-experimental Study in South Africa.

Every person diagnosed with tuberculosis (TB) needs to initiate treatment. The World Health Organization estimated that 61% of people who developed TB in 2021 were included in a TB treatment registration system. Initial loss to follow-up (ILTFU) is the loss of persons to care between diagnosis and treatment initiation/registration. LINKEDin, a quasi-experimental study, evaluated the effect of 2 interventions (hospital recording and an alert-and-response patient management intervention) in 6 subdistricts across 3 high-TB burden provinces of South Africa. Using integrated electronic reports, we identified all persons diagnosed with TB (Xpert MTB/RIF positive) in the hospital and at primary health care facilities. We prospectively determined linkage to care at 30 days after TB diagnosis. We calculated the risk of ILTFU during the baseline and intervention periods and the relative risk reduction in ILTFU between these periods. We found a relative reduction in ILTFU of 42.4% (95% CI, 28.5%-53.7%) in KwaZulu Natal (KZN) and 22.3% (95% CI, 13.3%-30.4%) in the Western Cape (WC), with no significant change in Gauteng. In KZN and the WC, the relative reduction in ILTFU appeared greater in subdistricts where the alert-and-response patient management intervention was implemented (KZN: 49.3%; 95% CI, 32.4%-62%; vs 32.2%; 95% CI, 5.4%-51.4%; and WC: 34.2%; 95% CI, 20.9%-45.3%; vs 13.4%; 95% CI, 0.7%-24.4%). We reported a notable reduction in ILTFU in 2 provinces using existing routine health service data and applying a simple intervention to trace and recall those not linked to care. TB programs need to consider ILTFU a priority and develop interventions specific to their context to ensure improved linkage to care.

Cost-effectiveness of Low-complexity Screening Tests in Community-based Case-finding for Tuberculosis.

INTRODUCTION: In high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood. METHODS: We developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs. RESULTS: Universal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted. CONCLUSIONS: Screening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Breathing Back Better! A State of the Art on the Benefits of Functional Evaluation and Rehabilitation of Post-Tuberculosis and Post-COVID Lungs.

Currently, tuberculosis (TB) and COVID-19 account for substantial morbidity and mortality worldwide, not only during their acute phase, but also because of their sequelae. This scoping review aims to describe the specific aspects of post-TB and post-COVID (long-COVID-19) sequelae, and the implications for post-disease follow-up and rehabilitation. In particular, evidence on how to identify patients affected by sequelae is presented and discussed. A section of the review is dedicated to identifying patients eligible for pulmonary rehabilitation (PR), as not all patients with sequelae are eligible for PR. Components of PR are presented and discussed, as well as their effectiveness. Other essential components to implement comprehensive rehabilitation programmes such as counselling and health education of enrolled patients, evaluation of cost-effectiveness of PR and its impact on health systems as well as research priorities for the future are included in this scoping review.

Spatially targeted digital chest radiography to reduce tuberculosis in high-burden settings: A study of adaptive decision making.

BACKGROUND: Spatially-targeted approaches to screen for tuberculosis (TB) could accelerate TB control in high-burden populations. We aimed to estimate gains in case-finding yield under an adaptive decision-making approach for spatially-targeted, mobile digital chest radiography (dCXR)-based screening in communities with varying levels of TB prevalence. METHODS: We used a Monte-Carlo simulation model to simulate a spatially-targeted screening intervention in 24 communities with TB prevalence estimates derived from a large community-randomized trial. We implemented a Thompson sampling algorithm to allocate screening units based on Bayesian probabilities of local TB prevalence that are continuously updated during weekly screening rounds. Four mobile units for dCXR-based screening and subsequent Xpert Ultra-based testing were allocated among the communities during a 52-week period. We estimated the yield of bacteriologically-confirmed TB per 1000 screenings comparing scenarios of spatially-targeted and untargeted resource allocation. RESULTS: We estimated that under the untargeted scenario, an expected 666 (95% uncertainty interval 522-825) TB cases would be detected over one year, equivalent to 8.9 (7.5-10.3) per 1000 individuals screened. Allocating the screening units to the communities with the highest (prior-year) cases notification rates resulted in an expected 760 (617-926) TB cases detected, 10.1 (8.6-11.8) per 1000 screened. Adaptive, spatially-targeted screening resulted in an expected 1241 (995-1502) TB cases detected, 16.5 (14.5-18.7) per 1000 screened. Numbers of dCXR-based screenings needed to detect one additional TB case declined during the first 12-14 weeks as a result of Bayesian learning. CONCLUSION: We introduce a spatially-targeted screening strategy that could reduce the number of screenings necessary to detect additional TB in high-burden settings and thus improve the efficiency of screening interventions. Empirical trials are needed to determine whether this approach could be successfully implemented.

Targeting screening and treatment for latent tuberculosis infection towards asylum seekers from high-incidence countries - a model-based cost-effectiveness analysis.

BACKGROUND: Enhancing tuberculosis (TB) prevention and care in a post-COVID-19-pandemic phase will be essential to ensure progress towards global TB elimination. In low-burden countries, asylum seekers constitute an important high-risk group. TB frequently arises post-immigration due to the reactivation of latent TB infection (LTBI). Upon-entry screening for LTBI and TB preventive treatment (TPT) are considered worthwhile if targeted to asylum seekers from high-incidence countries who usually present with higher rates of LTBI. However, there is insufficient knowledge about optimal incidence thresholds above which introduction could be cost-effective. We aimed to estimate, among asylum seekers in Germany, the health impact and costs of upon-entry LTBI screening/TPT introduced at different thresholds of country-of-origin TB incidence. METHODS: We sampled hypothetical cohorts of 30-45 thousand asylum seekers aged 15 to 34 years expected to arrive in Germany in 2022 from cohorts of first-time applicants observed in 2017-2019. We modelled LTBI prevalence as a function of country-of-origin TB incidence fitted to data from observational studies. We then used a probabilistic decision-analytic model to estimate health-system costs and quality-adjusted life years (QALYs) under interferon gamma release assay (IGRA)-based screening for LTBI and rifampicin-based TPT (daily, 4 months). Incremental cost-effectiveness ratios (ICERs) were calculated for scenarios of introducing LTBI screening/TPT at different incidence thresholds. RESULTS: We estimated that among 15- to 34-year-old asylum seekers arriving in Germany in 2022, 17.5% (95% uncertainty interval: 14.2-21.6%) will be latently infected. Introducing LTBI screening/TPT above 250 per 100,000 country-of-origin TB incidence would gain 7.3 (2.7-14.8) QALYs at a cost of €51,000 (€18,000-€114,100) per QALY. Lowering the threshold to ≥200 would cost an incremental €53,300 (€19,100-€122,500) per additional QALY gained relative to the ≥250 threshold scenario; ICERs for the ≥150 and ≥ 100 thresholds were €55,900 (€20,200-€128,200) and €62,000 (€23,200-€142,000), respectively, using the next higher threshold as a reference, and considerably higher at thresholds below 100. CONCLUSIONS: LTBI screening and TPT among 15- to 34-year-old asylum seekers arriving in Germany could produce health benefits at reasonable additional cost (with respect to international benchmarks) if introduced at incidence thresholds ≥100. Empirical trials are needed to investigate the feasibility and effectiveness of this approach.

Lifetime burden of disease due to incident tuberculosis: a global reappraisal including post-tuberculosis sequelae.

BACKGROUND: Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality. METHODS: We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease. FINDINGS: Globally, we estimated 122 (95% uncertainty interval [UI] 98-151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38-83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37-57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0-14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6-7·0) were from the disease episode and 5·8 DALYs (3·8-8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23-34) accruing 15 or more years after incident tuberculosis. INTERPRETATION: Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. FUNDING: National Institutes of Health.

Early mortality in tuberculosis patients initially lost to follow up following diagnosis in provincial hospitals and primary health care facilities in Western Cape, South Africa.

In South Africa, low tuberculosis (TB) treatment coverage and high TB case fatality remain important challenges. Following TB diagnosis, patients must link with a primary health care (PHC) facility for initiation or continuation of antituberculosis treatment and TB registration. We aimed to evaluate mortality among TB patients who did not link to a TB treatment facility for TB treatment within 30 days of their TB diagnosis, i.e. who were "initial loss to follow-up (ILTFU)" in Cape Town, South Africa. We prospectively included all patients with a routine laboratory or clinical diagnosis of TB made at PHC or hospital level in Khayelitsha and Tygerberg sub-districts in Cape Town, using routine TB data from an integrated provincial health data centre between October 2018 and March 2020. Overall, 74% (10,208/13,736) of TB patients were diagnosed at PHC facilities and ILTFU was 20.0% (2,742/13,736). Of ILTFU patients, 17.1% (468/2,742) died, with 69.7% (326/468) of deaths occurring within 30 days of diagnosis. Most ILTFU deaths (85.5%; 400/468) occurred in patients diagnosed in hospital. Multivariable logistic regression identified increasing age, HIV positive status, and hospital-based TB diagnosis (higher in the absence of TB treatment initiation and being ILTFU) as predictors of mortality. Although hospitals account for a modest proportion of diagnosed TB patients they have high TB-associated mortality. A hospital-based TB diagnosis is a critical opportunity to identify those at high risk of early and overall mortality. Interventions to diagnose TB before hospital admission, improve linkage to TB treatment following diagnosis, and reduce mortality in hospital-diagnosed TB patients should be prioritised.

Inference of Naturally Acquired Immunity Using a Self-matched Negative-Control Design.

Host adaptive immune responses may protect against infection or disease when a pathogen is repeatedly encountered. The hazard ratio of infection or disease, given previous infection, is typically sought to estimate the strength of protective immunity. However, variation in individual exposure or susceptibility to infection may introduce frailty bias, whereby a tendency for infections to recur among individuals with greater risk confounds the causal association between previous infection and susceptibility. We introduce a self-matched "case-only" inference method to control for unmeasured individual heterogeneity, making use of negative-control endpoints not attributable to the pathogen of interest. To control for confounding, this method compares event times for endpoints due to the pathogen of interest and negative-control endpoints during counterfactual risk periods, defined according to individuals' infection history. We derive a standard Mantel-Haenszel (matched) odds ratio conveying the effect of prior infection on time to recurrence. We compare performance of this approach to several proportional hazards modeling frameworks and estimate statistical power of the proposed strategy under various conditions. In an example application, we use the proposed method to reestimate naturally acquired protection against rotavirus gastroenteritis using data from previously published cohort studies. This self-matched negative-control design may present a flexible alternative to existing approaches for analyzing naturally acquired immunity, as well as other exposures affecting the distribution of recurrent event times.

Cost-effectiveness of post-treatment follow-up examinations and secondary prevention of tuberculosis in a high-incidence setting: a model-based analysis.

BACKGROUND: In settings of high tuberculosis incidence, previously treated individuals remain at high risk of recurrent tuberculosis and contribute substantially to overall disease burden. Whether tuberculosis case finding and preventive interventions among previously treated people are cost-effective has not been established. We aimed to estimate costs and health benefits of annual post-treatment follow-up examinations and secondary preventive therapy for tuberculosis in a tuberculosis-endemic setting. METHODS: We developed a transmission-dynamic mathematical model and calibrated it to data from two high-incidence communities of approximately 40 000 people in suburban Cape Town, South Africa. We used the model to estimate overall cost and disability-adjusted life-years (DALYs) associated with annual follow-up examinations and secondary isoniazid preventive therapy (IPT), alone and in combination, among individuals completing tuberculosis treatment. We investigated scenarios under which these interventions were restricted to the first year after treatment completion, or extended indefinitely. For each intervention scenario, we projected health system costs and DALYs averted with respect to the current status quo of tuberculosis control. All estimates represent mean values derived from 1000 epidemic trajectories simulated over a 10-year period (2019-28), with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values. FINDINGS: We estimated that a single follow-up examination at the end of the first year after treatment completion combined with 12 months of secondary IPT would avert 2472 DALYs (95% UI -888 to 7801) over a 10-year period and is expected to be cost-saving compared with current control efforts. Sustained annual follow-up and continuous secondary IPT beyond the first year after treatment would avert an additional 1179 DALYs (-1769 to 4377) over 10 years at an expected additional cost of US$18·2 per DALY averted. Strategies of follow-up without secondary IPT were dominated (ie, expected to result in lower health impact at higher costs) by strategies that included secondary IPT. INTERPRETATION: In this high-incidence setting, post-treatment follow-up and secondary preventive therapy can accelerate declines in tuberculosis incidence and potentially save resources for tuberculosis control. Empirical trials to assess the feasibility of these interventions in settings most severely affected by tuberculosis are needed. FUNDING: National Institutes of Health, Günther Labes Foundation, Oskar Helene Heim Foundation.

Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study.

BACKGROUND: Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal. METHODS: In this two-cohort diagnostic accuracy study, we used sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results. FINDINGS: Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21). INTERPRETATION: In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings. FUNDING: South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.

Transmission Modeling with Regression Adjustment for Analyzing Household-based Studies of Infectious Disease: Application to Tuberculosis.

BACKGROUND: Household contacts of people infected with a transmissible disease may be at risk due to this proximate exposure, or from other unobserved sources. Understanding variation in infection risk is essential for targeting interventions. METHODS: We develop an analytical approach to estimate household and exogenous forces of infection, while accounting for individual-level characteristics that affect susceptibility to disease and transmissibility. We apply this approach to a cohort study conducted in Lima, Peru, of 18,544 subjects in 4,500 households with at least one active tuberculosis (TB) case and compare the results to those obtained by Poisson and logistic regression. RESULTS: HIV-coinfected (susceptibility hazard ratio [SHR] = 3.80, 1.56-9.29), child (SHR = 1.72, 1.32-2.23), and teenage (SHR = 2.00, 1.49-2.68) household contacts of TB cases experience a higher hazard of TB than do adult contacts. Isoniazid preventive therapy (SHR = 0.30, 0.21-0.42) and Bacillus Calmette-Guérin (BCG) vaccination (SHR = 0.66, 0.51-0.86) reduce the risk of disease among household contacts. TB cases without microbiological confirmation exert a smaller hazard of TB among their close contacts compared with smear- or culture-positive cases (excess hazard ratio = 0.88, 0.82-0.93 for HIV- cases and 0.82, 0.57-0.94 for HIV+ cases). The extra household force of infection results in 0.01 (95% confidence interval [CI] = 0.004, 0.028) TB cases per susceptible household contact per year and the rate of transmission between a microbiologically confirmed TB case and susceptible household contact at 0.08 (95% CI = 0.045, 0.129) TB cases per pair per year. CONCLUSIONS: Accounting for exposure to infected household contacts permits estimation of risk factors for disease susceptibility and transmissibility and comparison of within-household and exogenous forces of infection.