"This is an illness. No one is supposed to be treated badly": community-based stigma assessments in South Africa to inform tuberculosis stigma intervention design.

Background: Though tuberculosis (TB)-related stigma is a recognized barrier to care, interventions are lacking, and gaps remain in understanding the drivers and experiences of TB-related stigma. We undertook community-based mixed methods stigma assessments to inform stigma intervention design. Methods: We adapted the Stop TB Partnership stigma assessment tool and trained three peer research associates (PRAs; two TB survivors, one community health worker) to conduct surveys with people with TB (PWTB, n = 93) and caregivers of children with TB (n = 24) at peri-urban and rural clinic sites in Khayelitsha, Western Cape, and Hammanskraal, Gauteng Province, South Africa. We descriptively analyzed responses for each stigma experience (anticipated, internal, and enacted), calculated stigma scores, and undertook generalized linear regression analysis. We conducted 25 in-depth interviews with PWTB (n = 21) and caregivers of children with TB (n = 4). Using inductive thematic analysis, we performed open coding to identify emergent themes, and selective coding to identify relevant quotes. Themes were organized using the Constraints, Actions, Risks, and Desires (CARD) framework. Results: Surveys revealed almost all PWTB (89/93, 96%) experienced some form of anticipated, internal, and/or enacted stigma, which affected engagement throughout the care cascade. Participants in the rural setting (compared to peri-urban) reported higher anticipated, internal, and enacted stigma (ß-coefficient 0.72, 0.71, 0.74). Interview participants described how stigma experiences, including HIV intersectional stigma, act individually and together as key constraints to impede care, leading to decisions not to disclose a TB diagnosis, isolation, and exclusion. Stigma resilience arose through the understanding that TB can affect anyone and should not diminish self-worth. Risks of stigma, driven by fears related to disease severity and infectiousness, led to care disengagement and impaired psychological well-being. Participants desired counselling, identifying a specific role for TB survivors as peer counselors, and community education. Conclusions: Stigma is highly prevalent and negatively impacts TB care and the well-being of PWTB, warranting its assessment as a primary outcome rather than an intermediary contributor to poor outcomes. Multi-component, multi-level stigma interventions are needed, including counseling for PWTB and education for health workers and communities. Such interventions must incorporate contextual differences based on gender or setting, and use survivor-guided messaging to foster stigma resilience. Supplementary Information: The online version contains supplementary material available at 10.1186/s44263-024-00070-5.

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.

Barriers to engagement in the care cascade for tuberculosis disease in India: A systematic review of quantitative studies.

BACKGROUND: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease in India. METHODS AND FINDINGS: We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. CONCLUSIONS: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps-particularly regarding TB care for children or in the private sector-to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade.

Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru.

Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy. We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors. In the triage cohort (n = 387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n = 191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort. qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs.

"As a patient I do not belong to the clinic, I belong to the community." Co-developing a multi-level, person-centred tuberculosis stigma intervention in Cape Town, South Africa.

Background: Anticipated, internal, and enacted stigma are major barriers to TB care engagement, and directly impact patient well-being. Unfortunately, targeted stigma interventions are lacking. We aimed to co-develop a person-centred stigma intervention with TB-affected community members and health workers in South Africa. Methods: Using a community-based participatory research approach, we conducted ten group discussions with people diagnosed with TB (past or present), caregivers, and health workers (total n=87) in Khayelitsha, Cape Town. Group discussions were facilitated by TB survivors. Discussion guides explored experiences and drivers of stigma and used human-centred design principles to co-develop solutions. Recordings were transcribed, coded, thematically analysed and then further interpreted using the socio-ecological model. Results: Intervention components across socio-ecological levels shared common behaviour change strategies, namely education, empowerment, engagement, and innovation. At the individual level, participants recommended counselling to improve TB knowledge and provide ongoing support. TB survivors can guide messaging to nurture stigma resilience by highlighting that TB can affect anyone and is curable, and provide lived experiences of TB to decrease internal stigma. At the interpersonal level, support clubs and family-centred counselling were suggested to dispel TB-related myths and foster support. At the institutional level, health worker stigma reduction training informed by TB survivor perspectives was recommended. Consideration of how integration of TB/HIV care services may exacerbate TB/HIV intersectional stigma and ideas for restructured service delivery models were suggested to decrease anticipated and enacted stigma. At the community level, participants recommended awareness-raising events led by TB survivors, including TB information in school curricula. At the policy level, solutions focused on reducing the visibility generated by a TB diagnosis and resultant stigma in health facilities and shifting tasks to community health workers. Conclusions: Decreasing TB stigma requires a multi-level approach. Co-developing a person-centred intervention with affected communities is feasible and generates stigma intervention components that are directed and implementable. Such community-informed intervention components should be prioritised by TB programs, including integrated TB/HIV care services.

Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru.

Introduction: Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy. Methods: We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors. Results: In the triage cohort (n=387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n=191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort. Conclusions: qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs.

"This is an illness. No one is supposed to be treated badly": Community-based stigma assessments in South Africa to inform TB stigma intervention design.

Background: Though TB-related stigma is a recognized barrier to care, interventions are lacking and gaps remain in understanding the drivers and experiences of TB-related stigma. We undertook community-based mixed methods stigma assessments to inform stigma intervention design. Methods: We adapted the Stop TB Partnership stigma assessment tool, and trained three peer research associates (PRAs; two TB survivors, one community health worker) to conduct surveys with people with TB (PWTB, n=93) and caregivers of children with TB (n=24) at peri-urban and rural clinic sites in Khayelitsha, Western Cape, and Hammanskraal, Gauteng Province, South Africa. We descriptively analyzed responses for each stigma experience (anticipated, internal, and enacted), calculated stigma scores, and undertook generalized linear regression analysis. We further conducted 25 in-depth interviews with PWTB (n=22) and caregivers TB (n=3). Using inductive thematic analysis, we performed open coding to identify emergent themes, and selective coding to identify relevant quotes. Themes were organised using the CARD (Constraints, Actions, Risks and Desires) framework. Results: Surveys revealed at least one-third of PWTB and one-quarter of caregivers report experiences of anticipated, internal, and/or enacted stigma, which affected engagement throughout the care cascade. Participants in rural locations (compared to peri-urban) reported higher anticipated, internal, and enacted stigma (ß-coefficient 0.72, 0.71, and 0.74). Interview participants described how stigma experiences, including HIV intersectional stigma, act individually and in concert as key constraints to impede care, and underpins failure to disclose a TB diagnosis, isolation, and exclusion. Stigma resilience arose through understanding that TB can affect anyone and should not diminish self-worth. Risks of stigma, driven by fears related to disease severity and infectiousness, led to care disengagement and impaired psychological wellbeing. Participants desired counselling, identifying a specific role for TB survivors as peer counsellors, and community education. Conclusions: Stigma is highly prevalent and negatively impacts TB care and the well-being of PWTB, warranting its assessment as a primary outcome indicator rather than intermediary contributor to poor cascade outcomes. Multicomponent stigma interventions are needed, including counselling for PWTB and education for health workers and communities. Such interventions must incorporate contextual differences based on gender or setting, and use survivor-guided messaging to foster stigma resilience.

Female Genital Tuberculosis.

Female genital tuberculosis (FGTB) is an important cause of morbidity and infertility worldwide. Mycobacterium tuberculosis most commonly spreads to the genital tract from a focus elsewhere in the body and affects the bilateral fallopian tubes and/or endometrium. Many patients with FGTB have indolent disease and are only diagnosed after evaluation for infertility. Women may present with menstrual irregularities, lower abdominal or pelvic pain, or abnormal vaginal discharge. Given the low sensitivity of diagnostic tests, various composite reference standards are used to diagnose FGTB, including some combination of endoscopic findings, microbiological or molecular testing, and histopathological evidence in gynecological specimens. Early treatment with a standard regimen of a 2-month intensive phase with isoniazid, rifampin, ethambutol, and pyrazinamide, followed by a 4-month continuation phase with isoniazid and rifampin, is recommended to prevent irreversible organ damage. However, even with treatment, FGTB can lead to infertility or pregnancy-related complications, and stigma is pervasive.

Reimagining the status quo: How close are we to rapid sputum-free tuberculosis diagnostics for all?

Rapid, accurate, sputum-free tests for tuberculosis (TB) triage and confirmation are urgently needed to close the widening diagnostic gap. We summarise key technologies and review programmatic, systems, and resource issues that could affect the impact of diagnostics. Mid-to-early-stage technologies like artificial intelligence-based automated digital chest X-radiography and capillary blood point-of-care assays are particularly promising. Pitfalls in the diagnostic pipeline, included a lack of community-based tools. We outline how these technologies may complement one another within the context of the TB care cascade, help overturn current paradigms (eg, reducing syndromic triage reliance, permitting subclinical TB to be diagnosed), and expand options for extra-pulmonary TB. We review challenges such as the difficulty of detecting paucibacillary TB and the limitations of current reference standards, and discuss how researchers and developers can better design and evaluate assays to optimise programmatic uptake. Finally, we outline how leveraging the urgency and innovation applied to COVID-19 is critical to improving TB patients' diagnostic quality-of-care.

Predicting Airborne Infection Risk: Association Between Personal Ambient Carbon Dioxide Level Monitoring and Incidence of Tuberculosis Infection in South African Health Workers.

BACKGROUND: High rates of tuberculosis (TB) transmission occur in hospitals in high-incidence countries, yet there is no validated way to evaluate the impact of hospital design and function on airborne infection risk. We hypothesized that personal ambient carbon dioxide (CO2) monitoring could serve as a surrogate measure of rebreathed air exposure associated with TB infection risk in health workers (HWs). METHODS: We analyzed baseline and repeat (12-month) interferon-γ release assay (IGRA) results in 138 HWs in Cape Town, South Africa. A random subset of HWs with a baseline negative QuantiFERON Plus (QFT-Plus) underwent personal ambient CO2 monitoring. RESULTS: Annual incidence of TB infection (IGRA conversion) was high (34%). Junior doctors were less likely to have a positive baseline IGRA than other HWs (OR, 0.26; P = .005) but had similar IGRA conversion risk. IGRA converters experienced higher median CO2 levels compared to IGRA nonconverters using quantitative QFT-Plus thresholds of ≥0.35 IU/mL (P < .02) or ≥1 IU/mL (P < .01). Median CO2 levels were predictive of IGRA conversion (odds ratio [OR], 2.04; P = .04, ≥1 IU/mL threshold). Ordinal logistic regression demonstrated that the odds of a higher repeat quantitative IGRA result increased by almost 2-fold (OR, 1.81; P = .01) per 100 ppm unit increase in median CO2 levels, suggesting a dose-dependent response. CONCLUSIONS: HWs face high occupational TB risk. Increasing median CO2 levels (indicative of poor ventilation and/or high occupancy) were associated with higher likelihood of HW TB infection. Personal ambient CO2 monitoring may help target interventions to decrease TB transmission in healthcare facilities and help HWs self-monitor occupational risk, with implications for other airborne infections including coronavirus disease 2019.

Addressing TB-related mortality in adults living with HIV: a review of the challenges and potential solutions.

Tuberculosis (TB) is the leading cause of death in people living with HIV (PLHIV) globally, causing 208,000 deaths in PLHIV in 2019. PLHIV have an 18-fold higher risk of TB, and HIV/TB mortality is highest in inpatient facilities, compared with primary care and community settings. Here we discuss challenges and potential mitigating solutions to address TB-related mortality in adults with HIV. Key factors that affect healthcare engagement are stigma, knowledge, and socioeconomic constraints, which are compounded in people with HIV/TB co-infection. Innovative approaches to improve healthcare engagement include optimizing HIV/TB care integration and interventions to reduce stigma. While early diagnosis of both HIV and TB can reduce mortality, barriers to early diagnosis of TB in PLHIV include difficulty producing sputum specimens, lower sensitivity of TB diagnostic tests in PLHIV, and higher rates of extra pulmonary TB. There is an urgent need to develop higher sensitivity biomarker-based tests that can be used for point-of-care diagnosis. Nonetheless, the implementation and scale-up of existing tests including molecular World Health Organization (WHO)-recommended diagnostic tests and urine lipoarabinomannan (LAM) should be optimized along with expanded TB screening with tools such as C-reactive protein and digital chest radiography. Decreased survival of PLHIV with TB disease is more likely with late HIV diagnosis and delayed start of antiretroviral (ART) treatment. The WHO now recommends starting ART within 2 weeks of initiating TB treatment in the majority of PLHIV, aside from those with TB meningitis. Dedicated TB treatment trials focused on PLHIV are needed, including interventions to improve TB meningitis outcomes given its high mortality, such as the use of intensified regimens using high-dose rifampin, new and repurposed drugs such as linezolid, and immunomodulatory therapy. Ultimately holistic, high-quality, person-centered care is needed for PLHIV with TB throughout the cascade of care, which should address biomedical, socioeconomic, and psychological barriers.

The role of counselling in tuberculosis diagnostic evaluation and contact tracing: scoping review and stakeholder consultation of knowledge and research gaps.

BACKGROUND: Tuberculosis (TB) care cascade analyses show large gaps at early stages, including care-seeking and diagnostic evaluation, where promising interventions to decrease attrition are urgently needed. Person-centered care is prioritized in the World Health Organization's End TB strategy; yet little is known about how it is delivered and can be optimized. Recommendations for counselling, a core component of person-centered care, are largely limited to its role in improving TB treatment adherence. The role of counselling to close key diagnostic gaps in the care cascade is poorly understood. METHODS: We conducted a scoping review to identify evidence on the use of counselling at TB diagnosis, for both people with presumptive TB and index patients to promote patient retention and contact tracing. Using search terms for TB, diagnosis and counselling, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data and conducted a quality assessment. We used thematic analysis to identify key themes. RESULTS: After screening 1785 articles, we extracted data from 15 studies and determined that the major themes best corresponded to the following gaps in the TB care cascade: care-seeking, pre-diagnosis, and pre-treatment. Studies were conducted across varied settings including pharmacies, primary health centres, and clinics, primarily in high TB incidence countries. No study directly evaluated the impact of counselling on outcomes such as treatment initiation or retention in care. Included studies suggested counselling may play an important role in improving the uptake of diagnostic testing and contact tracing. Barriers to counselling included time and personnel requirements. Stakeholder consultation emphasized the importance of high-quality counselling as a core tenet of TB care. CONCLUSION: Data on the impact of counselling to improve TB case detection are absent from the literature. The shift towards person-centred care for TB presents an opportunity to incorporate counselling during earlier stages of the TB care cascade; however, evidence-based approaches are needed. Implementation research is needed to operationalize and evaluate counselling to strengthen high-quality TB care delivery.

Chest X-ray Analysis With Deep Learning-Based Software as a Triage Test for Pulmonary Tuberculosis: An Individual Patient Data Meta-Analysis of Diagnostic Accuracy.

BACKGROUND: Automated radiologic analysis using computer-aided detection software (CAD) could facilitate chest X-ray (CXR) use in tuberculosis diagnosis. There is little to no evidence on the accuracy of commercially available deep learning-based CAD in different populations, including patients with smear-negative tuberculosis and people living with human immunodeficiency virus (HIV, PLWH). METHODS: We collected CXRs and individual patient data (IPD) from studies evaluating CAD in patients self-referring for tuberculosis symptoms with culture or nucleic acid amplification testing as the reference. We reanalyzed CXRs with three CAD programs (CAD4TB version (v) 6, Lunit v3.1.0.0, and qXR v2). We estimated sensitivity and specificity within each study and pooled using IPD meta-analysis. We used multivariable meta-regression to identify characteristics modifying accuracy. RESULTS: We included CXRs and IPD of 3727/3967 participants from 4/7 eligible studies. 17% (621/3727) were PLWH. 17% (645/3727) had microbiologically confirmed tuberculosis. Despite using the same threshold score for classifying CXR in every study, sensitivity and specificity varied from study to study. The software had similar unadjusted accuracy (at 90% pooled sensitivity, pooled specificities were: CAD4TBv6, 56.9% [95% confidence interval {CI}: 51.7-61.9]; Lunit, 54.1% [95% CI: 44.6-63.3]; qXRv2, 60.5% [95% CI: 51.7-68.6]). Adjusted absolute differences in pooled sensitivity between PLWH and HIV-uninfected participants were: CAD4TBv6, -13.4% [-21.1, -6.9]; Lunit, +2.2% [-3.6, +6.3]; qXRv2: -13.4% [-21.5, -6.6]; between smear-negative and smear-positive tuberculosis was: were CAD4TBv6, -12.3% [-19.5, -6.1]; Lunit, -17.2% [-24.6, -10.5]; qXRv2, -16.6% [-24.4, -9.9]. Accuracy was similar to human readers. CONCLUSIONS: For CAD CXR analysis to be implemented as a high-sensitivity tuberculosis rule-out test, users will need threshold scores identified from their own patient populations and stratified by HIV and smear status.

Analysing interventions designed to reduce tuberculosis-related stigma: A scoping review.

Stigma is a critical barrier for TB care delivery; yet data on stigma reduction interventions is limited. This review maps the available literature on TB stigma reduction interventions, using the Health Stigma and Discrimination framework and an implementation analysis to identify research gaps and inform intervention design. Using search terms for TB and stigma, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data, conducted a quality assessment, and assessed implementation. Results were categorized by socio-ecological level, then sub-categorized by the stigma driver or manifestation targeted. After screening 1865 articles, we extracted data from nine. Three studies were implemented at the individual and interpersonal level using a combination of TB clubs and interpersonal support to target internal and anticipated stigma among persons with TB. Two studies were implemented at the interpersonal level using counselling or a video based informational tool delivered to households to reduce stigma drivers and manifestations. Three studies were implemented at the organizational level, targeting drivers of stigma among healthcare workers (HW) and enacted stigma among HWs. One study was implemented at the community level using an educational campaign for community members. Stakeholder consultation emphasized the importance of policy level interventions and education on the universality of risk to destigmatize TB. Review findings suggest that internal and anticipated TB stigma may be addressed effectively with interventions targeted towards individuals using counselling or support groups. In contrast, enacted TB stigma may be better addressed with information-based interventions implemented at the organizational or community level. Policy level interventions were absent but identified as critical by stakeholders. Implementation barriers included the lack of high-quality training and integration with mental health services. Three key gaps must be addressed in future research: consistent stigma definitions, standardized stigma measurement, and measurement of implementation outcomes.

FAST tuberculosis transmission control strategy speeds the start of tuberculosis treatment at a general hospital in Lima, Peru.

OBJECTIVE: To evaluate the effect of the FAST (Find cases Actively, Separate safely, Treat effectively) strategy on time to tuberculosis diagnosis and treatment for patients at a general hospital in a tuberculosis-endemic setting. DESIGN: Prospective cohort study with historical controls. PARTICIPANTS: Patients diagnosed with pulmonary tuberculosis during hospitalization at Hospital Nacional Hipolito Unanue in Lima, Peru. METHODS: The FAST strategy was implemented from July 24, 2016, to December 31, 2019. We compared the proportion of patients with drug susceptibility testing and tuberculosis treatment during FAST to the 6-month period prior to FAST. Times to diagnosis and tuberculosis treatment were also compared using Kaplan-Meier plots and Cox regressions. RESULTS: We analyzed 75 patients diagnosed with pulmonary tuberculosis through FAST. The historical cohort comprised 76 patients. More FAST patients underwent drug susceptibility testing (98.7% vs 57.8%; OR, 53.8; P < .001), which led to the diagnosis of drug-resistant tuberculosis in 18 (24.3%) of 74 of the prospective cohort and 4 (9%) of 44 of the historical cohort (OR, 3.2; P = .03). Overall, 55 FAST patients (73.3%) started tuberculosis treatment during hospitalization compared to 39 (51.3%) controls (OR, 2.44; P = .012). FAST reduced the time from hospital admission to the start of TB treatment (HR, 2.11; 95% CI, 1.39-3.21; P < .001). CONCLUSIONS: Using the FAST strategy improved the diagnosis of drug-resistant tuberculosis and the likelihood and speed of starting treatment among patients with pulmonary tuberculosis at a general hospital in a tuberculosis-endemic setting. In these settings, the FAST strategy should be considered to reduce tuberculosis transmission while simultaneously improving the quality of care.

"If I've got latent TB, I would like to get rid of it": Derivation of the CARD (Constraints, Actions, Risks, and Desires) Framework informed by South African healthcare worker perspectives on latent tuberculosis treatment.

BACKGROUND: Healthcare workers (HWs) have at least twice the risk of tuberculosis (TB) compared to the general population. There is growing emphasis on latent TB infection (LTBI) in high-risk populations. Yet we know little about HWs' perspectives of LTBI testing and treatment to inform implementation in high-incidence settings. We developed a qualitative networked approach to analyze HWs' perspectives on LTBI testing and treatment. METHODS: We conducted 22 in-depth interviews with nurse and physician stakeholders, who had been recruited as part of a larger study evaluating TB transmission risk in HWs at Tygerberg Hospital, Cape Town, South Africa. We performed open coding to identify emergent themes and selective coding to identify relevant text citations. We used thematic analysis to inductively derive the CARD (Constraints, Actions, Risks, Desires) framework. RESULTS: All HWs desired to avoid developing TB but few felt this was actionable. Despite LTBI knowledge gaps, safety and cost concerns, most HWs reported hypothetical willingness to take LTBI treatment. The CARD framework showed that desire and action related to LTBI testing and treatment was clearly framed by the interactions between constraints, administrative action, and risk. The surprise HWs described on receiving a negative LTBI (Quantiferon-Plus) result suggests LTBI testing may recalibrate HWs' perceptions regarding the futility of actions to reduce their TB risk. CONCLUSIONS: LTBI testing and treatment are acceptable to HWs and could counteract the perceived inevitability of occupational TB infection that currently may limit risk reduction action. This should be coupled with administrative leadership and infrastructural support. The CARD analytic framework is a helpful tool for implementation scientists to understand current practices within complex health systems. Application of CARD could facilitate the development of contextually-relevant interventions to address important public health problems such as occupational TB.

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV.

BACKGROUND: Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point-of-care test and the only lateral flow lipoarabinomannan assay (LF-LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF-LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF-LAM (AlereLAM) on mortality and other patient-important outcomes. OBJECTIVES: To assess the impact of the use of LF-LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF-LAM (AlereLAM) on other patient-important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021. SELECTION CRITERIA: Randomized controlled trials that compared a diagnostic intervention including LF-LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed-effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random-effects model. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub-Saharan Africa and assessed the impact of diagnostic strategies that included LF-LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision-making in adults living with HIV. Inpatient settings  In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 0.85, 95% CI 0.76 to 0.94; 5102 participants, 2 trials; moderate-certainty evidence). That is, people living with HIV who received LF-LAM had 15% lower risk of mortality. The absolute effect was 34 fewer deaths per 1000 (from 14 fewer to 55 fewer). In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy probably results in a slight increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 1.26, 95% CI 0.94 to 1.69; 5102 participants, 2 trials; moderate-certainty evidence).  Outpatient settings In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality in people living with HIV at six months compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.89, 95% CI 0.71 to 1.11; 2972 participants, 1 trial; low-certainty evidence). Although this trial did not detect a difference in mortality, the direction of effect was towards a mortality reduction, and the effect size was similar to that in inpatient settings.  In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may result in a large increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (RR 5.44, 95% CI 4.70 to 6.29, 3022 participants, 1 trial; low-certainty evidence). Other patient-important outcomes Assessment of other patient-important and implementation outcomes in the trials varied. The included trials demonstrated that a higher proportion of people living with HIV were able to produce urine compared to sputum for tuberculosis diagnostic testing; a higher proportion of people living with HIV were diagnosed with tuberculosis in the group that received LF-LAM; and the incremental diagnostic yield was higher for LF-LAM than for urine or sputum Xpert MTB/RIF. AUTHORS' CONCLUSIONS: In inpatient settings, the use of LF-LAM as part of a tuberculosis diagnostic testing strategy likely reduces mortality and probably results in a slight increase in tuberculosis treatment initiation in people living with HIV. The reduction in mortality may be due to earlier diagnosis, which facilitates prompt treatment initiation. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality and may result in a large increase in tuberculosis treatment initiation in people living with HIV. Our results support the implementation of LF-LAM to be used in conjunction with other WHO-recommended tuberculosis diagnostic tests to assist in the rapid diagnosis of tuberculosis in people living with HIV.