Current combination antibiotic treatment for drug-susceptible tuberculosis (DS-TB) usually takes 6 months to complete. This long duration can compromise clinical outcomes. Although a 4-month regimen including an optimized dose of rifapentine plus moxifloxacin is non-inferior to standard therapy, rifapentine is hard to source globally and adoption of this regimen has been slow. This trial investigates the efficacy and safety of a 4-month DS-TB treatment including the more readily available rifamycin, rifampicin 35 mg/kg, with or without moxifloxacin 400 mg. This multi-centre phase III randomized open-label clinical trial will be conducted across four African countries (Gabon, Malawi, Mozambique and Tanzania). A total of 414 newly diagnosed consenting adult participants will be block randomized, after stratification by chest radiograph cavitation, to two experimental and one control arm at a ratio of 1:1:1. The first experimental group will receive optimized dose rifampicin (35 mg/kg) with routine weight-banded doses of isoniazid, pyrazinamide, and ethambutol once daily for 4 months. The second experimental group will receive optimized dose rifampicin (35 mg/kg) and moxifloxacin 400 mg once daily alongside routine doses of isoniazid and pyrazinamide. The control group will receive 6-month standard of care therapy: rifampicin (10 mg/kg) plus weight-banded dose of isoniazid, pyrazinamide, and ethambutol for 2 months, followed by the same doses of rifampicin and isoniazid for 4 months. Participants will be followed until the allocation of efficacy (TB-free survival) and safety (proportion of severe adverse events) outcomes. Secondary outcomes will also include the evaluation of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) for microbiological treatment monitoring. This study will evaluate whether 4-month duration multi-drug treatment including an optimized dose of rifampicin with or without moxifloxacin has non-inferior efficacy and safety outcomes compared to standard of care DS-TB therapy in Africa. ClinicalTrials.gov NCT05575518. Registered on 10th October 2022.

BACKGROUND:Spirometry remains the gold standard for assessing pulmonary function. Deep learning models have demonstrated potential for estimating measurements from chest X-rays (CXR). We aim to effectively address anatomical variability and integrate probabilistic reasoning to enhance estimation reliability near diagnostic thresholds. METHODS:We developed a probabilistic machine learning framework to estimate the forced expiratory volume in the first second (FEV1) and the forced vital capacity (FVC) as measured through spirometry. Estimations use morphologically regularized CXRs and anthropometric-normalized peak expiratory flow rate (PEFR) as proxy for volumetric information unavailable in imaging. By estimating FEV1 and FVC z-scores, we decouple appearance from anatomic variability. We demonstrate our method on a multi-national cohort of pulmonary tuberculosis patients exhibiting diverse structural abnormalities and ventilatory impairments. RESULTS:Using ensembles of neural networks, we analyze 982 CXR and spirometry pairs from 568 individuals. The best model achieves an area under curve (AUC) of 0.879 (FEV1; 99%CI 0.876, 0.881) and 0.853 (FVC; 99%CI 0.850, 0.856) in identifying moderate or severe lung-function impairment on a previously unseen test-set, signifying an AUC improvement of 0.144 (FEV1) and 0.118 (FVC) over previous methods. When allowing up to 10% of samples to remain unclassified due to uncertainty, AUC further rises to 0.894 (0.891, 0.896) and 0.857 (0.854, 0.860), respectively. Our method performs robustly across diverse impairment types and CXR pathologies. CONCLUSIONS:Our study shows that decoupling anatomical variability from functional assessment improves lung function estimation. Incorporation of probabilistic modeling improved diagnostic reliability around a decision threshold. Therefore, our system offers a promising approach to practical lung function estimation in settings where spirometry is unavailable.

Diagnosing paediatric tuberculosis (TB) remains challenging. Currently available diagnostic tests have limited accuracy, and most sampling methods are invasive. In 2021, the World Health Organisation (WHO) endorsed the use of molecular WHO-recommended rapid diagnostic tests (mWRDs) with stool as an initial diagnostic tool for paediatric TB. In this study, we evaluated the diagnostic test accuracy (DTA) of stool samples processed with the Stool Processing Kit (SPK), one of three centrifugation-free methods available at the time. We conducted a multi-centre prospective diagnostic validation study in South Africa, Tanzania, Malawi, Mozambique, and India. Children (< 15 years) under investigation for TB provided at least two (induced) sputum samples at enrolment, one stool sample, and one nasopharyngeal aspirate (NPA) if aged < 5 years and a chest x-ray. TB testing included Xpert® MTB/RIF Ultra (Ultra) and culture. Diagnostic classification followed NIH consensus statements. Stool samples were processed using the SPK and tested with Ultra. We calculated DTA in the overall cohort and predefined subgroups of interest. Out of 5313 children screened, 975 were enrolled, and data from 817 children recruited between January 2019 and June 2021 were analysed. The overall microbiological confirmation rate was 203/817 (24.9

Introduction Of 1.2 million children and young adolescents (<15 years) developing tuberculosis (TB) yearly, more than 50% are undiagnosed and unreported to national TB programmes (NTPs) and the World Health Organization (WHO). This is mainly due to poor performance of microbiological tests, limited clinical skills and structural barriers for childhood TB diagnosis at decentralised levels of care. Treatment decision algorithms (TDAs) could improve child TB outcomes but require external validation. We aim to evaluate a comprehensive TDA-based approach for childhood TB screening, diagnosis and treatment decision-making at district hospital (DH) and primary health centre (PHC) levels in Mozambique and Zambia.Methods and analysis Decide TB is a pragmatic, hybrid effectiveness-implementation type 2 cluster-randomised trial with a stepped wedge design. The comprehensive TDA-based approach (intervention) will be implemented under programmatic conditions in four districts in each country (each comprising one DH and six PHCs), randomly selected to switch sequentially from the standard of care to the intervention. Evaluations will assess epidemiological, clinical, economic, social sciences, implementation and health policy endpoints. Aggregated and individual data from children with presumptive TB will be extracted from facility registers and individual data will be collected using an electronic medical record (EMR), both data sources will be entered in national Demographic Health Information System 2 databases. Questionnaires and individual/group interviews (among healthcare workers (HCWs), parents/caregivers and key informants), supervision and mentoring reports and quantitative cost tools will be used.Ethics and dissemination Ethics approval was obtained from national ethics committees in Mozambique (Instituto Nacional de Saúde review board and National Committee for Bioethics in Health) and Zambia (University of Zambia ethical review board and National Health Research Authority); this includes a waiver for analysing data collected by NTPs (no identifiable information reported, intervention with minimal risk) without individual consent from children’s parents/caregivers. Informed consent will be obtained from HCWs, parents/caregivers and key informants. Results will be openly shared with the scientific community, WHO and national and international stakeholders for translation into policy and practice. Procedures for requesting further use of Decide TB data will be publicly available.Trial registration number NCT06593080; PACTR202407866544155.

BACKGROUND:Tuberculosis elimination is constrained by symptom-based and sputum-dependent diagnostic strategies, which miss asymptomatic disease and are difficult to deploy in community settings. Household contacts of people with tuberculosis are a priority population for screening and preventive therapy, but existing tests have poor prognostic ability. We aimed to evaluated host-response assays for screening and prognostic use in household contacts of people with tuberculosis. METHODS:In this prospective, longitudinal, diagnostic and prognostic accuracy study, we recruited people aged 10 years and older who lived with a person diagnosed with tuberculosis in Mozambique, Tanzania, or Zimbabwe. Household contacts who had taken antimycobacterial antibiotics within the past 4 weeks were excluded. Participants had real-time Cepheid Xpert Mycobacterium tuberculosis Host Response (MTB-HR) testing and clinical, radiological, and microbiological tuberculosis screening every 6 months for up to 24 months. The primary outcomes were the diagnostic accuracy of MTB-HR obtained within 30 days of a confirmed or likely tuberculosis diagnosis at any baseline or follow-up visit, and the prognostic ability of MTB-HR for incident tuberculosis using MTB-HR results obtained 1-6 months, 6-12 months, and 1-12 months before incident tuberculosis diagnosis. Tuberculosis diagnoses were established by an endpoint review committee and we assessed discrimination using the area under the receiver operating characteristic (AUROC) curve. The study was registered with ClinicalTrials.gov (NCT04781257) and is completed. FINDINGS:Between March 8, 2021, and March 23, 2023, we screened 2109 household contacts and enrolled 2079 for analysis (1294 [62·2%] female and 785 [37·8%] male). In the diagnostic analysis (41 household contacts with tuberculosis), the AUROC was 0·86 (95% CI 0·79-0·92). The prognostic analysis included 29 people with incident tuberculosis during the 1-6-month interval, 19 people for the 6-12-month interval, and 39 people for the 1-12-month interval, yielding AUROCs of 0·80 (0·71-0·89), 0·64 (0·53-0·76), and 0·71 (0·62-0·79), respectively, at optimised cutoffs. For the 6-month prediction at the optimised cutoff, the positive predictive value was 7·5% (95% CI 4·9-11·4). INTERPRETATION:MTB-HR did not meet the 2025 WHO target product profile criteria for screening or prognostic use; however, its positive predictive value for incident tuberculosis was higher than that of currently used tests. These findings support a potential role for MTB-HR in screening and prevention strategies. FUNDING:The second European and Developing Countries Clinical Trials Partnership (EDCTP2) programme.

BACKGROUND:Studies have demonstrated an inverse log-linear relationship between body mass index (BMI) and tuberculosis incidence. However, a person's BMI is dynamic, and longitudinal changes may be more informative than cross-sectional assessments. We evaluate the association between cross-sectional and changing BMI and risk of tuberculosis and describe longitudinal trajectories in a high-risk cohort. METHODS:ERASE-TB was a prospective longitudinal cohort study of household contacts ≥10 years in Southern Africa (Zimbabwe, Tanzania, and Mozambique), with 6-monthly follow-up up to 24 months. Associations between BMI and tuberculosis were investigated based on baseline (including hemoglobin) and changing BMI, using logistic, Poisson, and Cox models. Prevalent tuberculosis was defined as diagnosis during <30 days after recruitment. Growth mixture modelling was used to model longitudinal latent trajectories. RESULTS:Of 2107 recruited household contacts (621 [29.5%] adolescents and 1310 [62.2%] female), 520 (24.7%) were underweight. There were 21 and 41 people diagnosed with prevalent and incident tuberculosis, of whom 5/21 (23.8%) and 12/41 (29.3%) were underweight. Being underweight and anemic (adjusted hazard ratio: 3.77; 95% confidence interval: 1.50-9.51) and >10% negative change in BMI during follow-up (adjusted incidence rate ratio: 2.27; 95% confidence interval: 0.22-22.9) were associated with increased risk of incident tuberculosis. The association between continuous BMI-for-age Z-scores were nonlinear, with increased risk of tuberculosis with lower BMI. Four latent groups were defined in the growth mixture modelling: increasing, decreasing, and low/high stable BMI. CONCLUSIONS:Declining BMI, regardless of absolute value, is a strong predictor of tuberculosis among household contacts. Longitudinal measurements should be considered in active case finding among tuberculosis-affected households.

BACKGROUND:The conceptualisation of tuberculosis has undergone a paradigm shift from binary states to a spectrum, resulting in the International Consensus for Early TB (ICE-TB) framework. This study aimed to use data from a prospective, observational cohort study and multistate modelling to address the lack of contemporary data to quantify movement between ICE-TB states. METHODS:ERASE-TB was a prospective, observational cohort study evaluating novel diagnostic tests for earlier detection of tuberculosis. Household contacts aged at least 10 years in Zimbabwe, Tanzania, and Mozambique were followed up 6-monthly for 12-24 months with comprehensive tuberculosis investigations at each visit. Those not diagnosed with prevalent tuberculosis, with state classification from at least two timepoints were included. ICE-TB states were defined by use of symptomatology, interferon gamma release assays, chest radiographs, and sputum microbiology. A Markov multistate model based on ICE-TB was applied with one initial state (Mycobacterium tuberculosis non-infection), two intermediate states (M tuberculosis infection and non-infectious disease [asymptomatic-symptomatic]), and one absorbing state (infectious disease [asymptomatic-symptomatic]). Transition probabilities were predicted. FINDINGS:1789 (84·8%) of 2109 recruited household contacts were included. At enrolment, most (1000 [55·9%]) did not have M tuberculosis infection; 674 (37·7%) had M tuberculosis infection, and 115 (6·5%) had non-infectious disease. 34 people developed infectious disease (23 asymptomatic, 11 symptomatic). In the multistate model, the transition probabilities of progressing from M tuberculosis non-infection to M tuberculosis infection and M tuberculosis infection to non-infectious disease were 13% and 3% by month 12. For those in non-infectious disease, the probabilities of regression and progression by month 12 were 85% and 13%, respectively. INTERPRETATION:This study applied the ICE-TB framework to describe movement between states by use of contemporary, granular, longitudinal data. Although most people remained static over time, the non-infectious state was more dynamic, with most people regressing over time. FUNDING:European and Developing Countries Clinical Trials Partnership.

BACKGROUND: Tuberculosis is the main cause of death among hospitalised people living with HIV. Non-sputum-based diagnostics could improve patient outcomes. The EXULTANT trial aims to evaluate an expanded tuberculosis screening strategy among people with HIV in two African countries with a high tuberculosis and HIV burden. METHODS: This pragmatic, individually randomised controlled superiority trial was conducted across 11 hospitals in Tanzania and Mozambique. We consecutively enrolled adults living with HIV (aged ≥18 years) without an existing tuberculosis diagnosis or recent tuberculosis treatment, within 24 h of admission. The intervention group underwent Xpert MTB/RIF Ultra (Xpert Ultra) testing from sputum, stool, and urine, plus lateral flow urine lipoarabinomannan (LF-LAM) testing (Determine TB LAM Ag assay), irrespective of symptoms. The control group followed standard-of-care, symptom-based, WHO-recommended sputum Xpert Ultra and LF-LAM testing. The primary endpoint was the proportion of participants with microbiologically confirmed tuberculosis starting treatment within 72 h. Secondary endpoints included 8-week all-cause mortality and time to tuberculosis diagnosis. The trial is registered at ClinicalTrials.gov (NCT04568967) and is completed. FINDINGS: From Sept 25, 2022, to March 15, 2024, we screened 1534 participants, and randomly assigned 1172 (76·6%) to either the intervention group (n=582) or the control group (n=590). At admission, 715 participants (61·0%) were female, 845 (75·4%) were on antiretroviral therapy (ART), and median CD4 count was 232 cells per μL (IQR 87-490). In the control group, 505 (85·6%) had tuberculosis-compatible symptoms and were eligible for sputum Xpert Ultra testing (306 of them [60·6%] provided a sample) and 538 (91·2%) met WHO criteria for LF-LAM testing. In the intention-to-treat analysis, 93 (16·0%) of 582 participants in the intervention group and 90 (15·3%) of 590 in the control group had microbiologically confirmed tuberculosis and started treatment within 72 h (difference 0·7%, 95% CI -3·4 to 4·8, p=0·73). 8-week all-cause mortality was 25·8% (150 of 582) in the intervention group and 28·8% (170 of 590) in the control group (hazard ratio 0·86, 95% CI 0·69 to 1·07, p=0·18). Median time to tuberculosis treatment initiation was 0·98 days (IQR 0·83-1·92) and 0·92 days (0·79-1·86) in the intervention and control groups, respectively (hazard ratio 1·05, 95% CI 0·82 to 1·33, p=0·72). INTERPRETATION: An expanded screening strategy among people living with HIV admitted to hospital did not increase the proportion of individuals with microbiologically confirmed tuberculosis starting treatment or reduce 8-week mortality. FUNDING: EDCTP2 programme, supported by the EU.

Background:Predictive biomarkers for symptomatic tuberculosis (TB) progression would transform targeted prevention efforts. Although interferon-gamma release assays (IGRAs), including QuantiFERON® TB-Gold Plus (QFT-Plus), have been studied for this purpose, systematic evaluation of the QFT-Plus TB1 and TB2 Interferon-Gamma (IFNγ) concentrations remains limited, particularly in high-burden TB settings. Methods:Baseline TB1 and TB2 IFNγ concentrations from 5246 participants (ages 15-34 years) in TB-endemic regions were analyzed in relation to subsequent TB outcomes over a median of 525 days follow-up (NCT05190146). Participants were categorized as controls (no TB), suspected TB (no microbiological confirmation), or laboratory-confirmed TB, including a subset meeting a stringent case definition (≥2 positive microbiologic tests). Associations between baseline IFNγ concentrations and progression to symptomatic TB were assessed. Results:In the full cohort (IGRA+/- participants), baseline TB2 IFNγ concentrations were significantly higher compared with controls among participants who developed suspected TB (P = .01), laboratory-confirmed TB (P = .01), or met the stringent case definition (P < .0001). In IGRA+ participants, baseline TB2 concentrations were significantly higher than controls in suspected (P = .01) and laboratory-confirmed (P = .02) groups. Associations with baseline TB1 IFNγ concentrations and TB progression were observed for participants meeting the stringent case definition within the full cohort (P = .001). Among stringent definition cases, TB2 concentrations achieved an area under the receiver operating characteristic curve of 0.84, with sensitivity of 80% and specificity of 78%. Conclusions:Quantitative IFNγ concentrations from QFT-Plus, particularly TB2, were associated with progression to symptomatic TB, met or exceeded WHO-recommended sensitivity and specificity thresholds for predictive biomarkers, and may support biomarker-based stratification in TB clinical research.

This scoping review synthesises the current evidence on Video Observed Therapy for people with Tuberculosis (TB). Accessing Directly Observed Therapy (DOT) is associated with out-of-pocket costs, lost income, and stigma. Video Observed Therapy (VOT) is an alternative to DOT. To explore this, as part of a pilot study evaluating VOT amongst people with multi-drug-resistant TB in Mozambique, we did a scoping review to inform a national, multisectoral participatory workshop. We systematically searched five scientific databases and key grey literature repositories and identified 71 records: 49 primary studies, 16 reviews, and six grey literature documents. Data were extracted into four implementation theme categories: Feasibility, Acceptability, Cost, and Effectiveness. Content analysis described implementation successes and challenges, comparing VOT versus DOT. VOT implementation was narratively reported to be feasible, acceptable, with similar effectiveness and lower cost to the health system than DOT, but studies conducted were predominantly from urban and high-income settings. In Low and Middle Income Countries (LMICs), VOT uptake was reported in studies where participants received mobile phones, data packages, and training. The evidence on effectiveness, cost-effectiveness and scalability of VOT in LMICs, where TB burden is highest, remains limited. Further context-specific research, including randomised controlled trials RCTs and implementation studies, is needed to inform VOT adoption in LMICs.

Background:The World Health Organization (WHO) recommends 4-month treatment for children with non-severe pulmonary tuberculosis, outlining eligibility criteria for settings with and without chest X-ray (CXR). We evaluated the diagnostic accuracy of the WHO eligibility criteria in settings without CXR (WHO-criteria) and developed clinical scores to support disease classification. Methods:Using data from an individual participant dataset (IPD; Decide TB) of children with confirmed/unconfirmed tuberculosis from four diagnostic studies (RaPaed-TB, Umoya, TB-Speed HIV, TB-Speed Decentralisation), we assessed the diagnostic accuracy of the WHO-criteria (with/without bacteriological testing) using expert CXR interpretation as a reference. We developed two multivariable logistic regression models with (Score 1) and without (Score 2) bacteriological testing, converted coefficients into integer scores with a threshold of >10 corresponding to a sensitivity ≥70%. Results:Of 2,383 children in the Decide TB IPD, 633 (26.6%) met the eligibility criteria for a 4-month regimen, of whom 116 (18.3%) had radiologically severe disease. With and without bacteriological testing, the WHO-criteria had sensitivities of 30.1% (95%CI: 20.3%-40.2%) and 21.7% (95%CI: 10.4%-34.5%), and specificities of 83.4% (95%CI: 80.2%-86.4%) and 81.9% (95%CI: 78.8%-84.9%), respectively. Score 1 and Score 2 had sensitivities of 41.1% (95%CI: 32.4%-49.5%) and 30.9% (95%CI: 22.6%-40.4%), and specificities of 77.3% (95%CI: 73.6%-80.8%) and 83.0% (95%CI: 79.5%-86.3%), respectively. Using WHO-criteria, 91/116 (78.4%) and 105/116 (90.5%) of children were at risk of undertreatment, compared to 68/116 (58.6%) and 80/116 (68.9%) when using developed scores. Conclusions:Developed scores demonstrated better sensitivity than WHO-criteria, however, performance remained suboptimal. Implementing shorter antituberculosis regimens without CXR remains challenging in children.

Background Timely and appropriate diagnosis and treatment are key to ending tuberculosis (TB). Incorporating users’ preferences when implementing decentralised strategies for diagnosis may facilitate scale-up and impact. This qualitative study embedded within a cluster randomised controlled trial explored the values and preferences of multiple stakeholders regarding a TB diagnostic strategy using the Truenat platform, mycobacterium tuberculosis (MTB) Plus and rifampicin Dx Assays in Mozambique and Tanzania.Methods We conducted semi-structured interviews with people with presumptive TB (n=35), professional users (laboratory technicians, nurses, clinicians, n=19) and national decision-makers (n=5). Direct observations of testing procedures and usability surveys (n=12) were also conducted. Thematic analysis was performed, informed by the Consolidated Framework for Implementation Research.Results Facilities varied in testing capacity, number of cases and time-to-results (from same-day to >2 weeks). Availability and supply of reagents and cartridges were described as an issue by healthcare providers and a potential cause for delayed results. The Truenat platform for detection of TB was considered easy to use (median SUS score 90/100) as well as acceptable and fit to the context where the evaluation was conducted. Truenat’s advantage was appreciated in facilities with limited prior testing capacity (eg, shipping samples, using microscopy), including short time-to-results, reduced need to return to provide more samples and fewer infrastructure needs (compared with GeneXpert). People with presumptive TB preferred the same-day results and rapid initiation of treatment enabled by Truenat testing. Some viewed waiting longer time (>1 day) for the results acceptable if it were to result in increased accuracy. Regarding the diagnostic process, participants valued the support and counselling from the healthcare workers.Conclusions The Truenat platform and TB assays were perceived as easy to use by health providers, and as acceptable and feasible across stakeholder groups. Its implementation in decentralised settings was considered a preferred alternative to off-site Xpert testing for TB in Mozambique and Tanzania.Trial registration number NCT04568954.

BackgroundAccurate detection of tuberculosis (TB) treatment failure and recurrence can improve disease control, but current sputum-based monitoring tools pose significant limitations. This study aimed to identify sputum-independent biomarkers for detecting and predicting TB treatment failure and recurrence.MethodsWithin the Pan-African TB Sequel study, we conducted a matched case-control study with 40 participants who had recurrent TB or treatment failure and 37 successfully treated controls matched by sex, age, and HIV status. Cases were classified as (a) non-converters with persistently positive sputum Mycobacterium tuberculosis (MTB) results during treatment, (b) reverters at the end of treatment (EOT), or (c) recurrence after EOT. Peripheral blood was collected at baseline, months 2, 4, 6, 9, and 12, and at suspected recurrence. MTB-specific T-cell activation markers (CD38, CD27, HLA-DR, Ki67) and transcriptomic signatures (Sweeney3, Risk6, MAMS6) were assessed and compared to the reference standard MTB culture and smear results.ResultsHere, we show that both MTB-specific T-cell activation and transcriptomic signatures detected non-conversion and TB recurrence at month 9 or 12 after treatment initiation. CD38 expression demonstrates 100% sensitive (95% CI: 56.6-100%) and 78% specific (95% CI: 56.5-99.4%) for detecting TB recurrence, with an AUC of 0.98 (95% CI: 91-100%). Among transcriptomic signatures, MAMS6, RISK6, and Sweeney3 achieve 75% sensitivity (95% CI: 50-100%) and 87-93% specificity (95% CI: MAMS6 0-100%, RISK6 0-93%, Sweeney3 0-100%), with comparable AUCs (0.78-0.83). Neither marker detected TB reversion at EOT.ConclusionThese sputum-independent biomarkers effectively identify TB disease, non-conversion and recurrence TB after EOT, whereas their utility in detecting TB reversion during treatment remains limited.

Most tuberculosis diagnostic validation studies use microbiological or combination reference standards to define tuberculosis. We convened an Endpoint Review Committee (ERC) to define outcomes in ERASE-TB, a longitudinal cohort study across three high tuberculosis-burden countries, aimed at validating novel diagnostics for early detection. Herein, we describe processes and outcomes of the ERC. ERASE-TB enrolled 2,109 household contacts of people with tuberculosis who were followed up 6-monthly up to 24 months with clinical, microbiological, and radiological assessments at each visit. Any participants with a chest X-ray suggestive of tuberculosis or a positive Xpert MTB/Rif Ultra were investigated and eligible for endpoint review. For these, the clinical presentation, radiological, and microbiological results were reviewed independently by two study clinicians; any discordant endpoint categorisations were assessed by the ERC (first individually; if discordant, during a consensus meeting). Tuberculosis outcomes relied on predefined definitions (confirmed, likely, possible, unlikely). The ERC comprised four members: a tuberculosis programme manager, clinicians, and a radiologist. Semi-structured interviews (n = 4) with ERC members explored experiences and challenges in tuberculosis classification. A total of 96 clinical summaries underwent review, 55 were agreed internally, with the majority being categorised as confirmed tuberculosis (34/55, 61.8%). Among the remaining 41, the ERC members agreed on only 14 (34.1%) classifications, with the majority being classified as confirmed tuberculosis (10/14, 71.4%). The discordant 27 were discussed at the consensus meeting; 9/27 were classified as likely tuberculosis (33.3%), and 7/27 as possible and unlikely (25.9%). Qualitative interviews highlighted the complexity of tuberculosis diagnosis, value of longitudinal measurements, and tensions between decision making for research as compared to clinical purposes. Standardized tuberculosis classification frameworks, longitudinal data, and real-time expert review can improve diagnostic accuracy and comparability across studies. Future research should integrate structured ERC processes prospectively to refine tuberculosis case definitions and ensure robust clinical and research outcomes.

People with tuberculosis (TB) may seek care from healthcare providers without designated TB diagnosis and treatment services. This can lead to missed or delayed diagnosis and erroneous treatment for other diseases before being correctly diagnosed with TB. Such delays can contribute to increased out-of-pocket expenditures and lost income. We described TB treatment initiation pathways, including the type and number of pre-treatment healthcare providers visited, the time to TB treatment initiation, and the associated costs, among adults with pulmonary TB in Maputo, Mozambique. We conducted a cross-sectional survey from December 2017 to January 2020 among adults (≥ 18 years) with pulmonary TB initiating TB treatment in health facilities with TB services in Maputo city and Maputo province, Mozambique. We used a locally adapted version of the World Health Organization’s TB Patient Cost Survey tools to collect health and socioeconomic data including symptoms, type and number of pre-treatment healthcare providers visited, and out-of-pocket costs and lost income. Logistic regression models were used to evaluate the associations of health and socioeconomic variables with the number of pre-treatment healthcare providers visited. Of 416 enrolled participants, 268 (64.4

Background More than half of the BBIBP-CorV vaccines, outside of Pacific Asia, were distributed in Africa. Nevertheless, there are limited data on the immunogenicity of BBIBP-CorV from Africa. We compared the antibody response, after 1 and 2 doses of the BBIBP-CorV vaccine, in individuals seropositive or seronegative to severe acute respiratory syndrome coronavirus 2 prior to vaccination. Methods From March to May 2021, blood samples were obtained at first and second doses of the BBIBP-CorV, and 2 weeks later. Antibody titers against the full-length spike, receptor binding domain and nucleocapsid protein (anti-NC) of severe acute respiratory syndrome coronavirus 2 were measured. Pseudovirus neutralization assays and antibody-dependent cellular cytotoxicity (ADCC) against the D614G, BA.2, and BA.4 variants were also evaluated. Results At the second dose, the immunoglobulin G titers for full-length spike and anti-nucleocapsid protein, the ADCC against BA-2, and the neutralizing activity against the D614G and BA.2 were higher in individuals seropositive to any of the epitopes at the first dose (n = 26) compared to the levels observed 2 weeks later in the seronegative group (n = 25). We did not observe an increase on magnitude of binding antibodies, ADCC, and neutralizing activities, in those seropositive, after the second homologous dose of the BBIBP-CorV vaccine. Conclusions We suggest that 1 dose of the BBIBP-CorV vaccine in seropositive individuals induced better antibodies response including against variant of concerns compared to that observed after 2 doses in seronegative individuals. A further homologous dose of the BBIBP-CorV vaccine, in those who are seropositive, does not improve the antibody response observed after the first dose.

There is a growing body of data describing the high burden of respiratory sequelae seen among tuberculosis survivors, including children, adolescents, and adults. This group of sequelae are known as post-tuberculosis lung disease and include parenchymal damage, airway disease, and pulmonary vascular disease. It is thought that approximately half of pulmonary tuberculosis survivors have ongoing structural pathology, lung function impairment, or respiratory symptoms after the resolution of active disease. Post-tuberculosis lung disease has been associated with adverse patient outcomes, including persistent symptoms and functional impairment, ongoing health seeking, and impacts on income and employment. There is still much to understand about the epidemiology and nature of post-tuberculosis lung disease, but in this Review we focus on strategies for prevention, diagnosis, and care to inform the ongoing work of tuberculosis-affected communities, health-care providers, researchers, and policy makers. We summarise recent data, highlight evidence gaps, and suggest key research priorities for those working in the field.

Background Tuberculosis is a severe disease, not only due to its lethality but also to a significant morbidity occurring in people living with HIV (PLWH). If factors associated to mortality, severe morbidity and unsuccessful treatment related to the host are well identified in PLWH, there is scarce knowledge on factors related to the disease itself such as bacillary load, extent of lung involvement and disease dissemination to other organs. We sought to assess whether tuberculosis-related factors were associated with key patient outcomes in PLWH using data from an international clinical trial. Methods We conducted a secondary analysis of the ANRS 12300 Reflate TB2 international phase III open-label randomized trial that assessed different antiretroviral regimens in PLWH treated for tuberculosis. We evaluated whether bacillary load (smear positivity grade), extent of lung involvement (cavitation on chest x-ray) and disease dissemination (urine LAM positivity) were associated with mortality using Cox proportional hazard models and to severe morbidity and unsuccessful tuberculosis treatment using logistic regressions. Results Of 457 participants included in this study, 90 (20.4%) had grade 2 + or 3 + smear positivity, 39 (10.8%) had cavitation on chest X-ray, and 147 (32.2%) had a positive urinary LAM. Overall, 19 (4.2%) participants died, 113 (24.7%) presented severe morbidity, and 33 (7.2%) had unsuccessful tuberculosis treatment. Factors that remained independently associated with mortality were cavitation on chest x-ray (aHR = 7.92, 95% CI, 1.74–35.94, p = .0073) and LAM positivity (aHR = 5.53, 95% CI, 1.09–28.06, p = .0389). The only factor that remained significantly associated with severe morbidity was LAM positivity (aOR = 2.04, 95% CI, 1.06–3.92, p = .0323). No factor remained significantly associated with unsuccessful tuberculosis treatment. Conclusions In PLWH with tuberculosis enrolled in a trial, tuberculosis disease characteristics related to disease severity were cavitation on chest x-ray and urine LAM positivity. Early identification of these factors could help improve the management of PLWH with tuberculosis and improve their survival.