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Tuberculosis (TB) remains a leading cause of death from an infectious disease worldwide, partly due to a lack of effective strategies to screen and triage individuals with potential TB. Whole blood RNA signatures have been tested as biomarkers for TB, but have failed to meet the World Health Organizations (WHO) optimal target product profiles (TPP). Here, we use RNA sequencing and machine-learning to investigate the utility of plasma cell-free RNA (cfRNA) as a host-response biomarker for TB in cohorts from Uganda, Vietnam and Philippines. We report a 6-gene cfRNA signature, which differentiates TB-positive and TB-negative individuals with AUC = 0.95, 0.92, and 0.95 in test, training and validation, respectively. This signature meets WHO TPPs (sensitivity: 97.1% [95% CI: 80.9-100%], specificity: 85.2% [95% CI: 72.4-100%]) regardless of geographic location, sample collection method and HIV status. Overall, our results identify plasma cfRNA as a promising host response biomarker to diagnose TB.

BackgroundSputum-based testing is a barrier to increasing access to molecular diagnostics for tuberculosis (TB). Many people with TB are unable to produce sputum, and sputum processing increases assay complexity and cost. Tongue swabs are emerging as an alternative to sputum, but performance limits are uncertain.MethodsFrom June 2022 to July 2023, we enrolled 397 consecutive adults with cough >2 weeks at 2 health centers in Kampala, Uganda. We collected demographic and clinical information, sputum for TB testing (Xpert MTB/RIF Ultra and 2 liquid cultures), and tongue swabs for same-day quantitative polymerase chain reaction (qPCR) testing. We evaluated tongue swab qPCR diagnostic accuracy versus sputum TB test results, quantified TB targets per swab, assessed the impact of serial swabbing, and compared 2 swab types (Copan FLOQSWAB and Steripack spun polyester).ResultsAmong 397 participants, 43.1% were female, median age was 33 years, 23.5% were diagnosed with human immunodeficiency virus, and 32.0% had confirmed TB. Sputum Xpert Ultra and tongue swab qPCR results were concordant for 98.2% (95% confidence interval [CI]: 96.2-99.1) of participants. Tongue swab qPCR sensitivity was 92.6% (95% CI: 86.5 to 96.0) and specificity was 99.1% (95% CI: 96.9 to 99.8) versus microbiological reference standard. A single tongue swab recovered a 7-log range of TB copies, with a decreasing recovery trend among 4 serial swabs. Swab types performed equivalently.ConclusionsTongue swabs are a promising alternative to sputum for molecular diagnosis of TB, with sensitivity approaching sputum-based molecular tests. Our results provide valuable insights for developing successful tongue swab-based TB diagnostics.

RATIONALE: The causal relationship between undernutrition and response to anti-tuberculosis (TB) treatment and TB treatment outcomes among people with retreatment TB is understudied. OBJECTIVE: To evaluate the effect of undernutrition on treatment success and sputum smear conversion among people with retreatment drug-susceptible TB in Kampala, Uganda. METHODS: We conducted a quasi-experimental study utilizing propensity score weighting among people with retreatment drug-susceptible TB aged ≥ 15 years treated between 2012 and 2022 in Kampala. The primary exposure was undernutrition assessed using the mid-upper arm circumference at the time of TB diagnosis. The primary outcome was treatment success defined as cure or treatment completion at month 6. Sputum smear conversion was the secondary outcome and was measured as a change in sputum smear status from positive to negative at months 2, 5, and 6. We estimated the causal effect of undernutrition on the outcomes using a propensity-score weighted modified Poisson regression model with robust error variance. MEASUREMENTS AND MAIN RESULTS: Of the 605 participants, 432 (71.4 %) were male, 215 (35.5 %) were aged 25-34 years, 427 (70.6 %) had bacteriologically confirmed pulmonary TB, 133 (22.0 %) were undernourished and 398 (65.8 %) achieved treatment success. Of participants with bacteriologically confirmed pulmonary TB, 232 (59.0 %), 327 (59.3 %), and 360 (97.6 %) achieved sputum smear conversion at months 2, 5, and 6, respectively. Undernutrition reduced treatment success (RR 0.42, 95 % CI 0.32-0.55) as well as sputum smear conversion at months 2 (RR 0.45, 95 % CI 0.42-0.49) and 5 (RR 0.46, 95 % CI 0.43-0.51) but not month 6 (RR 0.99, 95 % CI 0.97-1.02). CONCLUSION: Undernutrition negatively impacts treatment outcomes. Therefore, nutritional assessment should be an integral component of TB care, with nutritional counseling and support offered to those undernourished to optimize their TB treatment response and outcomes.

BackgroundDigital adherence technologies have been widely promoted as a means to improve tuberculosis medication adherence. However, uptake of these technologies has been suboptimal by both patients and health workers. Not surprisingly, studies have not demonstrated significant improvement in treatment outcomes. ObjectiveThis study aimed to optimize a well-known digital adherence technology, 99DOTS, for end user needs in Uganda. We describe the findings of the ideation phase of the human-centered design methodology to adapt 99DOTS according to a set of design principles identified in the previous inspiration phase. Methods99DOTS is a low-cost digital adherence technology wherein tuberculosis medication blister packs are encased within an envelope that reveals toll-free numbers that patients can call to report dosing. We identified 2 key areas for design and testing: (1) the envelope, including the form factor, content, and depiction of the order of pill taking; and (2) the patient call-in experience. We conducted 5 brainstorming sessions with all relevant stakeholders to generate a suite of potential prototype concepts. Senior investigators identified concepts to further develop based on feasibility and consistency with the predetermined design principles. Prototypes were revised with feedback from the entire team. The envelope and call-in experience prototypes were tested and iteratively revised through focus groups with health workers (n=52) and interviews with patients (n=7). We collected and analyzed qualitative feedback to inform each subsequent iteration. ResultsThe 5 brainstorming sessions produced 127 unique ideas that we clustered into 6 themes: rewards, customization, education, logistics, wording and imagery, and treatment countdown. We developed 16 envelope prototypes, 12 icons, and 28 audio messages for prototype testing. In the final design, we altered the pill packaging envelope by adding a front flap to conceal the pills and reduce potential stigma associated with tuberculosis. The flap was adorned with either a blank calendar or map of Uganda. The inside cover contained a personalized message from a local health worker including contact information, pictorial pill-taking instructions, and a choice of stickers to tailor education to the patient and phase of treatment. Pill-taking order was indicated with colors, chevron arrows, and small mobile phone icons. Last, the call-in experience when patients report dosing was changed to a rotating series of audio messages centered on the themes of prevention, encouragement, and reassurance that tuberculosis is curable. ConclusionsWe demonstrated the use of human-centered design as a promising tool to drive the adaptation of digital adherence technologies to better address the needs and motivations of end users. The next phase of research, known as the implementation phase in the human-centered design methodology, will investigate whether the adapted 99DOTS platform results in higher levels of engagement from patients and health workers, and ultimately improves tuberculosis treatment outcomes.

Interventional researchers face many design challenges when assessing intervention implementation in real-world settings. Intervention implementation requires holding fast on internal validity needs while incorporating external validity considerations (such as uptake by diverse subpopulations, acceptability, cost, and sustainability). Quasi-experimental designs (QEDs) are increasingly employed to achieve a balance between internal and external validity. Although these designs are often referred to and summarized in terms of logistical benefits, there is still uncertainty about (a) selecting from among various QEDs and (b) developing strategies to strengthen the internal and external validity of QEDs. We focus here on commonly used QEDs (prepost designs with nonequivalent control groups, interrupted time series, and stepped-wedge designs) and discuss several variants that maximize internal and external validity at the design, execution and implementation, and analysis stages.

BackgroundNon-sputum-based triage tests for tuberculosis are a priority for ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay.MethodsWe conducted a prospective diagnostic accuracy study among outpatients with presumed tuberculosis in outpatient clinics in Viet Nam, India, the Philippines, Uganda, and South Africa. Eligible participants were aged 18 years or older and reported cough lasting at least 2 weeks. We excluded those receiving tuberculosis treatment in the preceding 12 months and those who were unwilling to consent. Xpert HR was performed on capillary or venous blood. Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial culture. We performed receiver operating characteristic (ROC) analysis to identify the optimal cutoff value for the Xpert HR to achieve the target sensitivity of 90% or more while maximising specificity, then calculated diagnostic accuracy using this cutoff value. This study was prospectively registered with ClinicalTrials.gov, NCT04923958.FindingsBetween July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2 weeks of cough were identified, of whom 1499 adults (686 [45·8%] females and 813 [54·2%] males) had valid Xpert HR and reference standard results. 329 (21·9%) had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC curve of 0·89 (95% CI 0·86-0·91). The optimal cutoff value was less than or equal to -1·25, giving a sensitivity of 90·3% (95% CI 86·5-93·3; 297 of 329) and a specificity of 62·6% (95% CI 59·7-65·3; 732 of 1170). Sensitivity was similar across countries, by sex, and by subgroups, although specificity was lower in people living with HIV (45·1%, 95% CI 37·8-52·6) than in those not living with HIV (65·9%, 62·8-68·8; difference of 20·8%, 95% CI 13·0-28·6; p

The COVID-19 pandemic brought diagnostics into the spotlight in an unprecedented way not only for case management but also for population health, surveillance, and monitoring. The industry saw notable levels of investment and accelerated research which sparked a wave of innovation. Simple non-invasive sampling methods such as nasal swabs have become widely used in settings ranging from tertiary hospitals to the community. Self-testing has also been adopted as standard practice using not only conventional lateral flow tests but novel and affordable point-of-care molecular diagnostics. The use of new technologies, including artificial intelligence-based diagnostics, have rapidly expanded in the clinical setting. The capacity for next-generation sequencing and acceptance of digital health has significantly increased. However, 4 years after the pandemic started, the market for SARS-CoV-2 tests is saturated, and developers may benefit from leveraging their innovations for other diseases; tuberculosis (TB) is a worthwhile portfolio expansion for diagnostics developers given the extremely high disease burden, supportive environment from not-for-profit initiatives and governments, and the urgent need to overcome the long-standing dearth of innovation in the TB diagnostics field. In exchange, the current challenges in TB detection may be resolved by adopting enhanced swab-based molecular methods, instrument-based, higher sensitivity antigen detection technologies, and/or artificial intelligence-based digital health technologies developed for COVID-19. The aim of this article is to review how such innovative approaches for COVID-19 diagnosis can be applied to TB to have a comparable impact.

BACKGROUND: In India, the prevalence of Latent TB infection (LTBI) is estimated to be around 40%. Various formulations of PPD(Purified protein derivative) are available, for diagnosis of LTBI, which may give variable responses. The commercially available PPD in India is by Arkray Healthcare (TST-Arkray). It is unclear if this product may have a similar sensitivity compared to other internationally accepted tuberculins (TST-Tubersol). OBJECTIVES: To assess the performance of the two TSTs compared to Quantiferon-Gold Plus (QFT-Plus). METHODOLOGY: A blood sample was collected for the QFT-Plus test. Both the TSTs were placed in the right and the left volar aspect of the forearms and 48 hrs later, the subjects came back to the study site for reading. RESULTS: Among the 512 participants who were recruited, 326 subjects were healthcare professionals and 186 subjects were household contacts of patients with tuberculosis. They were tested with both TST-Tubersol and TST-Arkray, 139(27 %) participants tested positive for TST-Tubersol (≥10 mm), whereas 203 participants (40.1 %)tested positive for TST-Arkray. There was moderate agreement between the two tests with k = 0.58. Also, there was only poor agreement between both the TSTs with QFT Plus(kappa = 0.19 for Tubersol and 0.17 for Arkray). With QFT-Plus as gold standard, the sensitivity, specificity, PPV and NPV of TST-Tubersol, ast an induration cut-off of 10 mm was 46.8 %,76.3 %,31.8 % and 85.8 %. respectively and TST- Arkray; 60.6 %, 64 %, 28.5 % and 87.2 % respectively. CONCLUSION: The Indian TST (Arkray Diagnostics) has shown moderate agreement with the internationally accepted Tubersol. Additionally, there was poor agreement between the TSTs and QFT plus test.

IntroductionIn 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.MethodsWe 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.ResultsUniversal 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.ConclusionsScreening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

BackgroundExpanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies.Methods and findingsIn a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings.ConclusionsShort-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers.Trial registrationClinicalTrials.gov NCT03934931.

BACKGROUND: Tuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented. METHODS: We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities. DISCUSSION: This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries. TRIAL REGISTRATION: The trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022.

Digital adherence technologies (DATs) have emerged as an alternative to directly observed therapy (DOT) for supervisions of tuberculosis (TB) treatment. We conducted a meta-analysis of implementation feedback obtained from people with TB and health care workers (HCWs) involved in TB REACH Wave 6-funded DAT evaluation projects. Projects administered standardized post-implementation surveys based on the Capability, Opportunity, Motivation, Behavior (COM-B) model to people with TB and their health care workers. The surveys included questions on demographics and technology use, Likert scale questions to assess capability, opportunity, and motivation to use DAT and open-ended feedback. We summarized demographic and technology use data descriptively, generated pooled estimates of responses to Likert scale questions within each COM-B category for people with TB and health care workers using random effects models, and performed qualitative analysis of open-ended feedback using a modified framework analysis approach. The analysis included surveys administered to 1290 people with TB and 90 HCWs across 6 TB REACH-funded projects. People with TB and HCWs had an overall positive impression of DATs with pooled estimates between 4·0 to 4·8 out of 5 across COM-B categories. However, 44% of people with TB reported taking TB medications without reporting dosing via DATs and 23% reported missing a dose of medication. Common reasons included problems with electricity, network coverage, and technical issues with the DAT platform. DATs were overall perceived to reduce visits to clinics, decrease cost, increase social support, and decrease workload of HCWs. DATs were acceptable in a wide variety of settings. However, there were challenges related to the feasibility of using current DAT platforms. Implementation efforts should concentrate on ensuring access, anticipating, and addressing technical challenges, and minimizing additional cost to people with TB.

BackgroundThe World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L-1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs).MethodsFollowing a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal-external cross-validation to evaluate performance.ResultsWe pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L-1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L-1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively.ConclusionsCRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L-1 cut-off or in a CPM depends on available resources.

BACKGROUND: Implementation science offers a systematic approach to adapting innovations and delivery strategies to new contexts but has yet to be widely applied in low- and middle-income countries. The Fogarty Center for Global Health Studies is sponsoring a special series, Global Implementation Science Case Studies, to address this gap. METHODS: We developed a case study for this series describing our approach and lessons learned while conducting a prospective, multi-modal study to design, implement, and evaluate an implementation strategy for TB contact investigation in Kampala, Uganda. The study included formative, evaluative, and summative phases that allowed us to develop and test an adapted contact investigation intervention involving home-based sample collection for TB and HIV testing. We concurrently developed a multi-component mHealth implementation strategy involving fingerprint scanning, electronic decision support, and automated reporting of test results via text message. We then conducted a household-randomized, hybrid implementation-effectiveness trial comparing the adapted intervention and implementation strategy to usual care. Our assessment included nested quantitative and qualitative studies to understand the strategys acceptability, appropriateness, feasibility, fidelity, and costs. Reflecting on this process with a multi-disciplinary team of implementing researchers and local public health partners, we provide commentary on the previously published studies and how the results influenced the adaptation of international TB contact investigation guidelines to fit the local context. RESULTS: While the trial did not show improvements in contact investigation delivery or public health outcomes, our multi-modal evaluation strategy helped us identify which elements of home-based, mHealth-facilitated contact investigation were feasible, acceptable, and appropriate and which elements reduced its fidelity and sustainability, including high costs. We identified a need for better tools for measuring implementation that are simple, quantitative, and repeatable and for greater attention to ethical issues in implementation science. CONCLUSIONS: Overall, a theory-informed, community-engaged approach to implementation offered many learnings and actionable insights for delivering TB contact investigation and using implementation science in low-income countries. Future implementation trials, especially those incorporating mHealth strategies, should apply the learnings from this case study to enhance the rigor, equity, and impact of implementation research in global health settings.

99DOTS is a low-cost digital adherence technology that allows people with tuberculosis (TB) to self-report treatment adherence. There are limited data on its implementation, feasibility, and acceptability from sub-Saharan Africa. We conducted a longitudinal analysis and cross-sectional surveys nested within a stepped-wedge randomized trial at 18 health facilities in Uganda between December 2018 and January 2020. The longitudinal analysis assessed implementation of key components of a 99DOTS-based intervention, including self-reporting of TB medication adherence via toll-free phone calls, automated text message reminders and support actions by health workers monitoring adherence data. Cross-sectional surveys administered to a subset of people with TB and health workers assessed 99DOTS feasibility and acceptability. Composite scores for capability, opportunity, and motivation to use 99DOTS were estimated as mean Likert scale responses. Among 462 people with pulmonary TB enrolled on 99DOTS, median adherence was 58.4% (inter-quartile range [IQR] 38.7-75.6) as confirmed by self-reporting dosing via phone calls and 99.4% (IQR 96.4-100) when also including doses confirmed by health workers. Phone call-confirmed adherence declined over the treatment period and was lower among people with HIV (median 50.6% vs. 63.7%, p3 consecutive doses. Surveys were completed by 83 people with TB and 22 health workers. Composite scores for capability, opportunity, and motivation were high; among people with TB, composite scores did not differ by gender or HIV status. Barriers to using 99DOTS included technical issues (phone access, charging, and network connection) and concerns regarding disclosure. 99DOTS was feasible to implement and highly acceptable to people with TB and their health workers. National TB Programs should offer 99DOTS as an option for TB treatment supervision.

BackgroundMitigating financial barriers to tuberculosis (TB) diagnosis and treatment is a core priority of the global TB agenda. We evaluated the impact of a cash transfer intervention on completion of TB testing and treatment initiation in Uganda.MethodsWe conducted a pragmatic complete stepped wedge randomised trial of a one-time unconditional cash transfer at 10 health centres between September 2019 and March 2020. People referred for sputum-based TB testing were enrolled to receive UGX 20 000 (∼USD 5.39) upon sputum submission. The primary outcome was the number initiating treatment for micro-bacteriologically confirmed TB within 2 weeks of initial evaluation. The primary analysis included cluster-level intent-to-treat and per-protocol analyses using negative binomial regression.Results4288 people were eligible. The number diagnosed with TB initiating treatment was higher in the intervention period versus the pre-intervention period (adjusted rate ratio (aRR)=1.34) with a 95% CI of 0.62-2.91 (p=0.46), indicating a wide range of plausible true intervention effects. More were referred for TB testing (aRR=2.60, 95% CI 1.86-3.62; p

BackgroundDecentralised molecular testing for tuberculosis could reduce missed diagnoses and losses to follow-up in high-burden settings. The aim of this study was to evaluate the cost and cost-effectiveness of the Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) study strategy, a multicomponent strategy including decentralised molecular testing for tuberculosis, in Uganda.MethodsWe conducted a costing and cost-effectiveness analysis nested in a pragmatic cluster-randomised trial of onsite (decentralised) versus hub-and-spoke (centralised) testing for tuberculosis with Xpert MTB/RIF Ultra (Xpert) in 20 community health centres in Uganda. We collected empirical data on the cost of the XPEL-TB strategy (decentralised Xpert testing, workflow redesign, and performance feedback) and routine tuberculosis testing (onsite smear microscopy with specimen transport for centralised Xpert testing) from the health system perspective. Time-and-motion studies were performed to estimate activity-based service costs. Cost-effectiveness was assessed as the incremental cost (2019 US$) per tuberculosis diagnosis and per 14-day treatment initiation.FindingsThe XPEL-TB study ran from Oct 22, 2018, to March 1, 2020. Effectiveness and cost-effectiveness outcomes were assessed from Dec 1, 2018, to Nov 30, 2019 and included 4867 women and 3139 men. On a per-test basis, the cost of decentralised ($20·46, range $17·85-25·72) and centralised ($18·20, range $16·58-24·25) Xpert testing was similar. However, decentralised testing resulted in more patients receiving appropriate Xpert testing, so the per-patient cost of decentralised testing was higher: $20·28 (range $17·68-25·48) versus $9·59 (range $7·62-14·34). The XPEL-TB strategy was estimated to cost $1332 (95% uncertainty range $763-5558) per incremental tuberculosis diagnosis and $687 ($501-1207) per incremental patient initiating tuberculosis treatment within 14 days. Cost-effectiveness was reduced in sites performing fewer than 150-250 tests annually.InterpretationThe XPEL-TB strategy facilitated higher rates of Xpert testing for tuberculosis at a similar per-test cost and modest incremental cost per tuberculosis diagnosis and treatment initiation. Decentralised Xpert testing, with appropriate implementation supports, should be scaled up to clinics with sufficient testing volume to support a single-module device.FundingThe National Heart, Lung, and Blood Institute.

IntroductionIn 2014, the WHO published high-priority target product profiles (TPPs) for new tuberculosis (TB) diagnostics to align end-user needs with test targets and specifications; nevertheless, no TB test meets these targets to date. The COVID-19-driven momentum in the diagnostics world offers an opportunity to address the long-standing lack of innovation in the field of TB diagnostics. This scoping review aims to summarise point-of-care (POC) molecular and antigen tests for COVID-19 diagnosis that, when applied to TB, potentially meet WHO TPPs. This summary of currently available innovative diagnostic tools will guide the development of novel TB diagnostics toward the WHO-set targets.Methods and analysisWe will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension Scoping Reviews recommendations. MEDLINE (via PubMed), bioRxiv, MedRxiv and other publicly available in vitro diagnostic test databases were searched on 23 November 2022. POC antigen or molecular tests developed for SARS-CoV-2 detection that meet the eligibility criteria will be included in the review. Developer description, test description, operation characteristics, pricing information, performance and commercialisation status of diagnostic tests identified will be extracted using a predefined standardised data extraction form. Two reviewers will independently perform the screening and data extraction. A narrative synthesis of the final data will be provided.Ethics and disseminationNo ethical approval is required because individual patient data will not be included. The findings will be published in open-access scientific journals.

To reach the millions of people with tuberculosis (TB) undiagnosed each year, there is an important need to provide people-centered screening and testing services. Despite people-centered care being a key pillar of the WHO END-TB Strategy, there have been few attempts to formally characterize and integrate the preferences of people most affected by TB - including those who have increased exposure to TB, limited access to services, and/or are at increased risk for TB - into new tools and strategies to improve screening and diagnosis. This perspective emphasizes the importance of preference research among people most affected by TB, provides an overview of qualitative preference exploration and quantitative preference elicitation research methods, and outlines how preferences can be applied to improve the acceptability, accessibility, and appropriateness of TB screening and testing services via four key opportunities. These include the following: (1) Defining the most preferred features of novel screening, triage, and diagnostic tools, (2) exploring and prioritizing setting-specific barriers and facilitators to screening and testing, (3) understanding what features of community- and facility-based strategies for improving TB detection and treatment are most valued, and (4) identifying the most relevant and resonant communication strategies to increase individual- and community-level awareness and demand. Preference research studies and translation of their findings into policy/guidance and operationalization have enormous potential to close the existing gaps in detection in high burden settings by enhancing the people-centeredness and reach of screening and diagnostic services to people most affected by TB who are currently being missed and left behind.

Social protection interventions have the potential to accelerate progress towards global tuberculosis (TB) targets. We piloted a screening and linkage program at four community health centers (HC) to enroll adults seeking TB diagnostic evaluation services into existing government-supported social protection programs in Uganda. From May-December 2021, health center staff were asked to screen adults being evaluated for TB for eligibility for government-supported social protection programs, and to refer eligible people to a sub-county community development office (CDO) responsible for enrolling community members into government-supported social protection programs. Linkage was facilitated with a transportation reimbursement via mobile money and referral documentation confirming program eligibility. We assessed feasibility using programmatic data and conducted post-intervention surveys to understand experiences with the linkage program. Of 855 people undergoing TB evaluation, 655 (76%) adults met criteria for at least one government-supported social protection program. 25 (4%) of those were not interested in referral; the rest were referred to their local CDO. While 386 (61%) of the 630 participants reported to the CDO seeking social protection enrolment, only 122 (32%) of those were ultimately enrolled into a social protection scheme, representing only 19% (n = 655) of those eligible. In surveys conducted among 97 participants, 46 of the 60 (77%) people who reported that they sought enrollment at the CDO were not enrolled into a social protection program. Reasons provided for non-enrollment among these 46 participants were either unknown (n = 25, 54%) or due to operational challenges at the CDO including a lack of human resources or available groups to join in the social protection program (n = 20, 43%). 61 survey participants (63%) indicated that they would not have sought social protection enrollment without the referral program. Overall, we found that most adults seeking TB diagnostic evaluation are eligible for and interested in obtaining government-supported social protection. We found facilitated linkage from HCs to CDOs offering social protection services to be feasible, however ultimate enrollment into programs was limited. Additional research is needed to identify strategies to improve access to existing social protection programs for eligible TB-affected individuals. Trial Registration: Pan African Clinical Trials Registry (PACTR201906852160014).

BackgroundIntensive adherence counseling (IAC) is the global standard of care for people living with human immunodeficiency virus (PLHIV) who have unsuppressed VL after ≥ 6 months of first-line anti-retroviral therapy (ART). We investigated whether the number of IAC sessions is associated with suppressed VL among PLHIV in Kampala, Uganda.MethodsWe conducted a nested case-control study among PLHIV with unsuppressed VL after ≥ 3 IAC sessions (cases) and a 2:1 random sample of PLHIV with suppressed VL after ≥ 3 IAC sessions (controls). Unsuppressed VL was defined as VL ≥ 1000 copies/ml. We performed multivariable logistic regression to identify factors that differed significantly between cases and controls.ResultsDemographic and clinical characteristics were similar among the 16 cases and 32 controls including mean age, sex, baseline CD4 count, VL before IAC, and WHO clinical stage. Only the number of IAC sessions differed significantly between cases and controls in unadjusted (p = 0.012) and adjusted (p = 0.016) analyses. Each unit increase in IAC session was associated with unsuppressed VL (Adjusted odds ratio 5.09; 95% CI 1.35-19.10).ConclusionsVL remained unsuppressed despite increasing IAC frequency. The fidelity to standardized IAC protocol besides drug resistance testing among PLHIV with unsuppressed VL before IAC commencement should be examined.

BackgroundHouseholds of children with tuberculosis (TB) experience financial and social hardships, but TB-specific social protection initiatives primarily focus on adults.MethodsWe conducted a single-arm, pilot study of multi-component supportive benefits for children with pulmonary TB in Kampala, Uganda. At diagnosis, participants received in-kind coverage of direct medical costs, a cash transfer, and patient navigation. Caregivers were surveyed before diagnosis and 2 months into TB treatment on social and financial challenges related to their child's illness, including estimated costs, loss of income and dissaving practices.ResultsWe included 368 children from 321 households. Pre-diagnosis, 80.1% of caregivers reported that their child's illness negatively impacted household finances, 44.1% of caregivers missed work, and 24% engaged in dissaving practices. Catastrophic costs (> 20% annual income) were experienced by 18.4% (95% CI 13.7-24.0) of households. School disruption was common (25.6%), and 28% of caregivers were concerned their child was falling behind in development. Two months post-diagnosis, 12 households (4.8%) reported being negatively affected by their child's TB disease (difference -75.2%, 95% CI -81.2 to -69.2, p

Intensive adherence counseling (IAC) is recommended for people living with HIV (PLHIV) with viral load (VL) ≥1,000 copies/ml after ≥6 months of anti-retroviral therapy (ART). We evaluated the effect of IAC on VL suppression and all-cause mortality among PLHIV on first-line ART with VL ≥1,000 copies/ml after ≥6 months of ART in Kampala, Uganda using regression discontinuity design, a quasi-experimental method for effect estimation when interventions depend on a cut-off. PLHIV just above VL ≥1,000 copies/ml cut-off who received ≥3 IAC sessions formed the intervention group while those just below the cut-off who received routine psychosocial support constituted the control group. Primary outcome was repeat VL suppression defined as VL

BackgroundNewer molecular testing platforms are now available for deployment at lower-level community health centers. There are limited data on facility- and health worker-level factors that would promote successful adoption of such platforms for rapid tuberculosis (TB) testing and treatment initiation. Our study aimed to assess readiness to implement onsite molecular testing at community health centers in Uganda, a high TB burden country in sub-Saharan Africa.MethodsTo understand implementation readiness, we conducted a qualitative assessment guided by the Consolidated Framework for Implementation Research (CFIR) at 6 community health centers in central and eastern Uganda between February and April 2018. We conducted 23 in-depth, semi-structured interviews with health workers involved in TB care at each health center to assess TB-related work practices and readiness to adopt onsite molecular testing using the GeneXpert Edge platform. Interviews were transcribed verbatim and coded for thematic analysis.ResultsParticipants (N=23) included 6 nurses/nursing assistants, 6 clinicians, 6 laboratory directors/technicians, 1 medical officer, 2 health center directors, and 2 other health workers involved in TB care. Health workers described general enthusiasm that on-site molecular testing could lead to greater efficiencies in TB diagnosis and treatment, including faster turn- around time for TB test results, lack of need for trained laboratory technicians to interpret results, and reduced need to transport sputum specimens to higher level facilities. However, health workers also expressed concerns about implementation feasibility. These included uncertainty about TB infection risk, safety risks from disposal of hazardous waste, a lack of local capacity to provide timely troubleshooting and maintenance services, and concerns about the security of GeneXpert devices and accessories. Health workers also expressed the need for backup batteries to support testing or charging when wall power is unstable.ConclusionOur study generated a nuanced understanding of modifiable contextual barriers and led to direct revisions of implementation strategies for onsite molecular testing. The findings highlight that novel diagnostics should be implemented along with health system co-interventions that address contextual barriers to their effective uptake. Pre-implementation assessment of stakeholder perspectives, collaborative work processes, and institutional contexts is essential when introducing innovative technology in complex health care settings.

Tuberculosis (TB) education seeks to increase patient knowledge about TB, while TB counselling seeks to offer tailored advice and support for medication adherence. While universally recommended, little is known about how to provide effective, efficient, patient-centred TB education and counselling (TEC) in low-income, high HIV-TB burden settings. We sought to characterise stakeholder perceptions of TEC in a public, primary care facility in Kampala, Uganda, by conducting focus group discussions with health workers and TB patients in the TB and HIV clinics. Participants valued TEC but reported that high-quality TEC is rarely provided, because of a lack of time, space, staff, planning, and prioritisation given to TEC. To improve TEC, they recommended adopting practices that have proven effective in the HIV clinic, including better specifying educational content, and employing peer educators focused on TEC. Patients and health workers suggested that TEC should not only improve TB patient knowledge and adherence, but should also empower and assist all those undergoing evaluation for TB, whether confirmed or not, to educate their households and communities about TB. Community-engaged research with patients and front-line providers identified opportunities to streamline and standardise the delivery of TEC using a patient-centred, peer-educator model.

ObjectiveTo assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting.Design/methodsWe conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/μl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption.ResultsAmong 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant.ConclusionPrevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

BackgroundC-reactive protein (CRP) has shown promise as a triage tool for pulmonary tuberculosis (TB) in adults living with the human immunodeficiency virus. We performed the first assessment of CRP for TB triage in children.MethodsSymptomatic children less than 15 years old were prospectively enrolled in Kampala, Uganda. We completed a standard TB evaluation and measured CRP using a point-of-care assay. We determined the sensitivity and specificity of CRP to identify pulmonary TB in children using 10 mg/L and 5 mg/L cut-off points and generated a receiver operating characteristic (ROC) curve to determine alternative cut-offs that could approach the target accuracy for a triage test (≥90% sensitivity and ≥70% specificity).ResultsWe included 332 children (median age 3 years old, interquartile range [IQR]: 1-6). The median CRP level was low at 3.0 mg/L (IQR: 2.5-26.6) but was higher in children with Confirmed TB than in children with Unlikely TB (9.5 mg/L vs. 2.9 mg/L, P-value = .03). At a 10 mg/L cut-off, CRP sensitivity was 50.0% (95% confidence interval [CI], 37.0-63.0) among Confirmed TB cases and specificity was 63.3% (95% CI, 54.7-71.3) among children with Unlikely TB. Sensitivity increased to 56.5% (95% CI, 43.3-69.0) at the 5 mg/L cut-off, but specificity decreased to 54.0% (95% CI, 45.3-62.4). The area under the ROC curve was 0.59 (95% CI, 0.51-0.67), and the highest sensitivity achieved was 66.1% at a specificity of 46.8%.ConclusionsCRP levels were low in children with pulmonary TB, and CRP was unable to achieve the accuracy targets for a TB triage test.

BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (

Rapid screening of tuberculosis by evaluation of associated volatile organic biomarkers in breath is a promising technology that is significantly faster and more convenient than traditional sputum culture tests. Methyl nicotinate (MN) and methyl p-anisate (MPA) have been isolated as potential biomarkers for mycobacterium tuberculosis and have been found in the breath of patients with active pulmonary tuberculosis. A novel approach to detection of these biomarkers in liquid droplets (e.g. from breath condensate) using inexpensive screen-printed electrodes is presented. Previous modelling studies suggest that these biomarkers complex with certain transition metals of particular valence state. This interaction can be exploited by mixing the biomarker sample into an electroactive solution (EAS) containing the functional metal ion and observing the change electrochemically. The study focuses on low biomarker concentrations, determined to be clinically relevant based on preliminary GC-MS studies of the levels found in patient breath. It was found that both the cyclic voltammogram and square wave voltammogram of copper(II) change significantly when as little as 0.1 mM MN is added to the solution, with analysis times of less than 2 min. Copper(II) exhibits three separate peaks during square wave voltammetry. The location and area of each peak are affected differently as the concentration of MN increases, suggesting a reaction with specific oxidation states of the metal. In this way, a "fingerprint" method can be used to identify biomarkers once their known interaction is established.

Tuberculosis (TB) remains a significant cause of mortality worldwide. Metagenomic next-generation sequencing has the potential to reveal biomarkers of active disease, identify coinfection, and improve detection for sputum-scarce or culture-negative cases. We conducted a large-scale comparative study of 428 plasma, urine, and oral swab samples from 334 individuals from TB endemic and non-endemic regions to evaluate the utility of a shotgun metagenomic DNA sequencing assay for tuberculosis diagnosis. We found that the composition of the control population had a strong impact on the measured performance of the diagnostic test: the use of a control population composed of individuals from a TB non-endemic region led to a test with nearly 100% specificity and sensitivity, whereas a control group composed of individuals from TB endemic regions exhibited a high background of nontuberculous mycobacterial DNA, limiting the diagnostic performance of the test. Using mathematical modeling and quantitative comparisons to matched qPCR data, we found that the burden of Mycobacterium tuberculosis DNA constitutes a very small fraction (0.04 or less) of the total abundance of DNA originating from mycobacteria in samples from TB endemic regions. Our findings suggest that the utility of a minimally invasive metagenomic sequencing assay for pulmonary tuberculosis diagnostics is limited by the low burden of M. tuberculosis and an overwhelming biological background of nontuberculous mycobacterial DNA.

IntroductionHigh levels of treatment adherence are critical for achieving optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.MethodsWe conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.ResultsOf 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%) extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n = 483), a moderate adherence group (n = 93) and a low adherence group (n = 20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90-6.12) and final (aOR 2.71, 95% 1.73-4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9% vs. 65.4% correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).ConclusionsAdherence patterns are strongly predictive of DR TB treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.

BackgroundOne in five patients diagnosed with TB in Uganda are not initiated on TB treatment within two weeks of diagnosis. We evaluated a multifaceted intervention for improving TB treatment initiation among patients diagnosed with TB using Xpert® MTB/RIF testing in Uganda.MethodsThis was a pre-post interventional study at one tertiary referral hospital. The intervention was informed by the COM-B model and included; i) medical education sessions to improve healthcare worker knowledge about the magnitude and consequences of pretreatment loss to follow-up; ii) modified laboratory request forms to improve recording of patient contact information; and iii) re-designed workflow processes to improve timeliness of sputum testing and results dissemination. TB diagnostic process and outcome data were collected and compared from the period before (June to August 2019) and after (October to December 2019) intervention initiation.ResultsIn September 2019, four CME sessions were held at the hospital and were attended by 58 healthcare workers. During the study period, 1242 patients were evaluated by Xpert® MTB/RIF testing at the hospital (679 pre and 557 post intervention). Median turnaround time for sputum test results improved from 12 hours (IQR 4-46) in the pre-intervention period to 4 hours (IQR 3-6) in the post-intervention period. The proportion of patients started on treatment within two weeks of diagnosis improved from 59% (40/68) to 89% (49/55) (difference 30%, 95% CI 14%-43%, p

Since 2012, the World Health Organization has recommended household contact investigation as an evidence-based intervention to find and treat individuals with active tuberculosis (TB), the most common infectious cause of death worldwide after COVID-19. Unfortunately, uptake of this recommendation has been suboptimal in low- and middle-income countries, where the majority of affected individuals reside, and little is known about how to effectively deliver this service. Therefore, we undertook a systematic process to design a novel, theory-informed implementation strategy to promote uptake of contact investigation in Uganda, using the COM-B (Capability-Opportunity-Motivation-Behavior) model and the Behavior Change Wheel (BCW) framework. We systematically engaged national, clinic-, and community-based stakeholders and collectively re-examined the results of our own formative, parallel mixed-methods studies. We identified three core behaviors within contact investigation that we wished to change, and multiple antecedents (i.e., barriers and facilitators) of those behaviors. The BCW framework helped identify multiple intervention functions targeted to these antecedents, as well as several policies that could potentially enhance the effectiveness of those interventions. Finally, we identified multiple behavior change techniques and policies that we incorporated into a multi-component implementation strategy, which we compared to usual care in a household cluster-randomized trial. We introduced some components in both arms, including those designed to facilitate initial uptake of contact investigation, with improvement relative to historical controls. Other components that we introduced to facilitate completion of TB evaluation-home-based TB-HIV evaluation and follow-up text messaging-returned negative results due to implementation failures. In summary, the Behavior Change Wheel framework provided a feasible and transparent approach to designing a theory-informed implementation strategy. Future studies should explore the use of experimental methods such as micro-randomized trials to identify the most active components of implementation strategies, as well as more creative and entrepreneurial methods such as human-centered design to better adapt the forms and fit of implementation strategies to end users.

Cough assessment is central to the clinical management of respiratory diseases, including tuberculosis (TB), but strategies to objectively and unobtrusively measure cough are lacking. Acoustic epidemiology is an emerging field that uses technology to detect cough sounds and analyze cough patterns to improve health outcomes among people with respiratory conditions linked to cough. This field is increasingly exploring the potential of artificial intelligence (AI) for more advanced applications, such as analyzing cough sounds as a biomarker for disease screening. While much of the data are preliminary, objective cough assessment could potentially transform disease control programs, including TB, and support individual patient management. Here, we present an overview of recent advances in this field and describe how cough assessment, if validated, could support public health programs at various stages of the TB care cascade.

BackgroundThe WHO END TB strategy targets to place at least 90% of all patients diagnosed with Tuberculosis (TB) on appropriate treatment. In Uganda, approximately 20% of patients diagnosed with TB are not initiated on TB treatment. We sought to identify the patient and health system level barriers to and facilitators for TB treatment initiation in Uganda.MethodsWe conducted the study at ten public health facilities (three primary care, four district and three tertiary referral hospitals). We carried out in-depth interviews with patients diagnosed with TB and key informant interviews with health managers. In addition, we held focus group discussions with healthcare workers involved in TB care. Data collection and thematic analysis of transcripts was informed by the Capability, Opportunity, Motivation and Behavior (COM-B) model. We identified relevant intervention functions using the Behavior Change Wheel.ResultsWe interviewed 79 respondents (31 patients, 10 health managers and 38 healthcare workers). Common barriers at the health facility level included; lack of knowledge about the proportion of patients not initiated on TB treatment (psychological capability); difficulty accessing sputum results from the laboratory as well as difficulty tracing patients due to inadequate recording of patient addresses (physical opportunity). At the patient level, notable barriers included long turnaround time for sputum results and lack of transport funds to return to health facilities (physical opportunity); limited TB knowledge (psychological capability) and stigma (social opportunity). The most important facilitators identified were quick access to sputum test results either on the date of first visit (same-day diagnosis) or on the date of first return and availability of TB treatment (physical opportunity). We identified education, restructuring of the service environment to improve sputum results turnaround time and enablement to improve communication of test results as relevant intervention functions to alleviate these barriers to and enhance facilitators for TB treatment initiation.ConclusionWe found that barriers to treatment initiation existed at both the patient and health facility-level across all levels of the (Capability, Opportunity and Motivation) model. The intervention functions identified here should be tested for feasibility.

BackgroundEffective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease.MethodsWe conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions.ResultsA total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40).ConclusionsA multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.).

BackgroundA 12-dose, once-weekly regimen of isoniazid and rifapentine (3HP) is effective in preventing tuberculosis (TB) among people living with HIV (PLHIV). We sought to identify potential barriers to and facilitators of acceptance and completion of 3HP treatment from the perspective of people living with HIV (PLHIV) and health workers in a routine HIV care setting in Kampala, Uganda.MethodsWe conducted semi-structured interviews with 25 PLHIV and 10 health workers at an HIV/AIDS clinic in Kampala, Uganda. For both groups, we explored their understanding and interpretations of TB and TB preventive therapy (TPT), and perceptions about social and contextual factors that might influence the willingness of PLHIV to initiate and complete 3HP. We analyzed the data using an inductive thematic approach and aligned the emergent themes to the Behavior Change Wheel framework to identify sources of behavior and targeted behavior change interventions.ResultsFacilitators of acceptance and completion of 3HP treatment among PLHIV were fear of contracting TB, awareness of being at risk of getting TB, willingness to take TPT, trust in health workers, and the perceived benefits of directly observed therapy (DOT) and self-administered therapy (SAT) 3HP delivery strategies. Barriers included inadequate understanding of TPT, fear of potential side effects, concerns about the effectiveness of 3HP, and the perceived challenges of DOT or SAT. Among health workers, perceived facilitators included knowledge that TB is a common cause of mortality for PLHIV, fear of getting TB, and trust in the health workers by PLHIV, the advantages of once-weekly 3HP dosing, and the benefits of DOT and SAT 3HP delivery strategies. Health worker-reported barriers for PLHIV included inadequate understanding of TB and benefits of TPT, TB-associated stigma, potential side effects pill burden, and challenges of DOT and SAT 3HP delivery strategies. Lack of experience in the use of digital technology to monitor patient care was identified as a health worker-specific barrier. Identified intervention functions to address the facilitators or barriers included education, persuasion, environmental restructuring, enablement, and training.ConclusionsUsing a formative qualitative and comprehensive theoretical approach, we identified key barriers, facilitators, and appropriate interventions, including patient education, enhancing trust, and patient-centered treatment support that could be used to optimize the delivery of 3HP to PLHIV in our setting. These interventions are likely generalizable to other clinical interventions in similar populations in sub-Saharan Africa and other TB high-burden settings.

BackgroundPolicies implemented to slow transmission of COVID-19 are expected to have disrupted delivery of routine health services, including tuberculosis (TB) care.MethodsWe analyzed daily counts of drug-susceptible (DS)-TB case notifications from all health facilities affiliated with the Philippines National TB Program (NTP) before and after implementation of community quarantine (January 1-December 31, 2020). Using an interrupted time series design, we assessed the immediate and sustained effects of community quarantine on TB case reporting. Using 2019 WHO estimates of national TB incidence, treatment, and mortality rates for the Philippines, we modeled excess mortality from TB, assuming a national decline in TB case reporting were extended for 12 months, followed by a return to pre-community quarantine trends.ResultsThe analysis included 192,918 DS-TB case notifications from 2,986 facilities located in 113 provinces and highly urbanized cities across 17 regions and covered 49 observations days before and 174 days after community quarantine implementation. We found an significant drop and steeper decline in daily TB case notifications after the implementation of community quarantine, resulting in 44.6% (95% CI 38.3-50.1) fewer daily TB case notifications 60 days after implementation of community quarantine. During 2020, DS-TB case notifications never returned to pre-quarantine levels. Assuming a 12-month disruption of TB case reporting, we estimate there will be 56.3% increase in TB-related deaths in the Philippines.ConclusionModified delivery of TB prevention and care should be prioritized alongside efforts to combat COVID-19.

ObjectivesWe assessed attitudes and perceptions and willingness to accept (WTA) varying incentive structures for completing tuberculosis (TB) diagnostic evaluation among patients in Uganda.MethodsWe surveyed 177 adult patients undergoing TB evaluation at 10 health centers between September 2018 and March 2019. We collected household sociodemographic information and assessed attitudes and perceptions of incentives. We surveyed patients regarding their willingness to complete TB diagnostic evaluation in exchange for incentives ranging in value from 500 Ugandan shillings (USh) to 25 000USh (~$0.15-$6.75). We compared associations between WTA and patient characteristics using ordered logistic regression.ResultsParticipant willingness to return to the health center to complete TB diagnostic evaluation increased proportionally with incentive amount. The median participant accepted between 2000 and 5000 USh. Cash (52%) and transportation vouchers (34%) were the most popular incentive types. Half of respondents preferred unconditional incentives; for a multiday evaluation, 84% preferred conditioning incentive receipt upon returning to the health center. In multivariate models, we found the pairwise difference between the third and lowest income quartile (aOR = 2.38, 95% CI: 1.20-4.69; P = .01), younger age, and difficulty returning to the health center to be significantly associated with WTA higher incentive thresholds.ConclusionsIn Uganda, incentives such as cash transfers or transportation vouchers are an acceptable intervention for facilitating adherence to TB diagnostic evaluation. Household income is associated with preferred incentive structure and amount, especially for those at the cusp of the poverty threshold who are more likely to prefer unconditional and higher valued incentives. Targeted and context-specific socioeconomic supports for at-risk patients are needed to optimize outcomes.

Rapid and consistent protein identification across large clinical cohorts is an important goal for clinical proteomics. With the development of data-independent technologies (DIA/SWATH-MS), it is now possible to analyze hundreds of samples with great reproducibility and quantitative accuracy. However, this technology benefits from empirically derived spectral libraries that define the detectable set of peptides and proteins. Here, we apply a simple and accessible tip-based workflow for the generation of spectral libraries to provide a comprehensive overview on the plasma proteome in individuals with and without active tuberculosis (TB). To boost protein coverage, we utilized nonconventional proteases such as GluC and AspN together with the gold standard trypsin, identifying more than 30,000 peptides mapping to 3309 proteins. Application of this library to quantify plasma proteome differences in TB infection recovered more than 400 proteins in 50 min of MS acquisition, including diagnostic Mycobacterium tuberculosis (Mtb) proteins that have previously been detectable primarily by antibody-based assays and intracellular proteins not previously described to be in plasma.

ObjectivePathways are succinct, operational versions of evidence-based guidelines. Studies have demonstrated pathways improve quality of care for children hospitalized with asthma, but we have limited information on other key factors to guide hospital leaders and clinicians in pathway implementation efforts. Our objective was to evaluate the adoption, implementation, and reach of inpatient pediatric asthma pathways.MethodsThis was a mixed-methods study of hospitals participating in a national collaborative to implement pathways. Data sources included electronic surveys of implementation leaders and staff, field observations, and chart review of children ages 2-17 years admitted with a primary diagnosis of asthma. Outcomes included adoption by hospitals, pathway implementation factors, and reach of pathways to children hospitalized with asthma. Quantitative data were analyzed using descriptive statistics and multivariable regression. Qualitative data were analyzed using thematic content analysis.ResultsEighty-five hospitals enrolled; 68 (80%) adopted/completed the collaborative. These 68 hospitals implemented pathways with overall high fidelity, implementing a median of 5 of 5 core pathway components (Interquartile Range [IQR] 4-5) in a median of 5 months (IQR 3-9). Implementation teams reported a median time cost of 78 h (IQR: 40-120) for implementation. Implementation leaders reported the values of pathway implementation included improvements in care, enhanced interdisciplinary collaboration, and access to educational resources. Leaders reported barriers in modifying electronic health records (EHRs), and only 63% of children had electronic pathway orders placed.ConclusionsHospitals implemented pathways with high fidelity. Barriers in modifying EHRs may have limited the reach of pathways to children hospitalized with asthma.

BackgroundNew, sensitive diagnostic tests facilitate identification and investigation of milder forms of tuberculosis (TB) disease. We used community-based TB testing with the Xpert MTB/RIF Ultra assay ("Ultra") to characterize individuals with previously undiagnosed TB and compare them to those from the same community who were diagnosed with TB through routine care.MethodsWe offered community-based sputum Ultra testing to adult residents of a well-defined area (population 34 000 adults) in Kampala, Uganda, via door-to-door screening and venue-based testing, then used detailed interview and laboratory testing to characterize TB-positive individuals. We compared these individuals to residents diagnosed with pulmonary TB at local health facilities and a representative sample of residents without TB (controls).ResultsOf 12 032 residents with interpretable Ultra results, 113 (940 [95% confidence interval {CI}, 780-1130] per 100 000) tested positive, including 71 (63%) positive at the lowest (trace) level. A spectrum of TB disease was observed in terms of chronic cough (93% among health facility-diagnosed cases, 77% among residents with positive community-based Ultra results at levels above trace, 33% among trace-positive community participants, and 18% among TB-negative controls), TB symptom prevalence (99%, 87%, 60%, and 38%, respectively), and C-reactive protein (75th percentile: 101 mg/L, 28 mg/L, 6 mg/L, and 4 mg/L, respectively). Community-diagnosed cases were less likely than health facility-diagnosed cases to have human immunodeficiency virus coinfection or previous TB. The specificity of Ultra was 99.4% (95% CI, 99.2%-99.5%) relative to a single spot sputum culture.ConclusionsPeople with undiagnosed prevalent TB in the community have different characteristics than those diagnosed with pulmonary TB in health facilities. Newer diagnostic tests may identify a group of people with early or very mild disease.

BackgroundGlobally, several diabetes prevention interventions have been shown to be cost-effective, yet they have had limited adaptation, implementation, and evaluation in the Caribbean and among Caribbean-descent individuals, where the burden of type 2 diabetes is high. We report on the protocol for the Lifestyle Intervention with Metformin Escalation (LIME) study - an evidence-based diabetes prevention intervention to reduce the incidence of diabetes among Caribbean-descent individuals with prediabetes.MethodsLIME is a hybrid type-I effectiveness-implementation quasi-experimental study taking place in 4 clinical sites in Barbados, Trinidad, the U.S. Virgin Islands, and Puerto Rico. LIME targets individuals who self-identify as Caribbean or Caribbean-descent and have high-risk prediabetes with a hemoglobin A1c (HbA1c) between 6 and 6.4%. Eligible participants in the intervention arm are enrolled in a six-week lifestyle modification workshop. Six months later, individuals who have not lost at least 5% of their bodyweight or continue to have an HbA1c of 6% or higher are prescribed metformin medication. In total, participants are followed for one year. The primary effectiveness outcome is proportion of individuals who lower their HbA1c below 6%.DiscussionLIME is a unique diabetes prevention intervention for Caribbean and Caribbean-descent individuals. LIME utilizes a tailored lifestyle change curriculum, incorporates appropriate metformin prescribing when lifestyle change alone is insufficient, targets the highest-risk individuals with prediabetes, and is based in a clinical setting to ensure sustainability.