Celso Khosa

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.

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.

Introduction: In 2023, almost 200,000 children under 15 years died from tuberculosis, most without appropriate treatment. Treatment decision algorithms (TDAs), developed to facilitate rapid anti-tuberculosis treatment initiation in children, were recommended by the World Health Organization (WHO) in 2022, conditional on validation in different cohorts and settings. We performed a retrospective external evaluation of WHO TDAs using an individual participant dataset (IPD). Methods and findings: The IPD comprised four paediatric cohorts, restricted to children with presumptive pulmonary TB < 10 years, and including children in high-risk groups (children living with HIV “CLHIV”, children with severe acute malnutrition “SAM”, and children n = 740, Umoya: n = 474, TB-Speed HIV: n = 204, TB-Speed Decentralisation: n = 468), the median age was 2.9 years (interquartile range [IQR]:1.3,5.5), 741 (39.3%) were <2 years, 382 (20.3%) were CLHIV, and 284 (15.1%) had SAM. 281 (14.9%) had confirmed tuberculosis, 672 (35.6%) were classified as unconfirmed tuberculosis (clinically diagnosed, microbiological investigations negative), and 933 (49.5%) as unlikely tuberculosis. For TDAs A and B, algorithm sensitivity was 84.3% (95% CI: 74.8, 90.6) and 90.6% (95% CI: 83.8, 94.7), respectively, with a specificity of 50.6% (95% CI: 30.4, 70.7) and 30.8% (95% CI: 21.5, 42.0), respectively. For TDA A, estimated sensitivity in children in high-risk groups was lower than those with low-risk (83.0%, 95% CI: 79.4%, 86.1%; versus 88.0%, 95% CI: 84.8%, 90.6%), while having a gain in specificity (50.0%, 95% CI: 44.9%, 55.1%; versus 36.6%, 95% CI: 32.7%, 40.7%). Trends were similar for TDA B. As for limitations, most diagnostic tuberculosis studies in children, including two of those included in the IPD, are performed at secondary or tertiary hospitals with higher levels of healthcare and thus the target population might differ somewhat from the IPD, potentially limiting the generalisability of our results. Conclusions: This retrospective external evaluation of WHO TDAs in a large IPD shows high sensitivity but sub-optimal specificity for both TDAs, in line with the meta-analyses that generated the algorithms. Prospective studies that evaluate the entire TDA, including triage step are needed. Additionally, the integration of novel diagnostic tools within the TDAs should aim to enhance the accuracy, especially the specificity.

Tuberculosis (TB) remains a major public health issue across the world and national TB guidelines are an important resource for diagnosis and treatment. This scoping review aimed to analyze how countries with the highest TB burdens approach the integration of comorbidity and risk factor screening, diagnosis and treatment, TB recurrence, and post-TB lung disease (PTLD) diagnosis and management, within their TB guidelines. We used the Arksey and O’Malley methodological framework to conduct a scoping review of TB guidelines among the WHO list of highest-TB burden countries. We identified drug-susceptible, drug-resistant, and consolidated guidelines through web searches and personal contacts within TB programs. We translated guidelines into English as needed and systematically extracted, recorded, and reviewed the guidelines to aggregate and describe our findings. Among the 49 countries with the highest TB burden, we successfully identified, translated, and analyzed 43 guidelines (24 drug-sensitive, 9 drug-resistance, and 10 consolidated) from 34 countries. Recommendations for screening varied by comorbidity or risk factor with the four most recommended being HIV/AIDS (100%), pregnancy (73%) and liver disease (59%) and mental health (59%). Recommendations for linkage to care were more infrequent and also varied with the top four being HIV (88%), liver disease (47%), diabetes (44%), and mental health (44%). Only 27 (79%) countries specified diagnostic tests to assess for TB recurrence among individuals presenting with symptoms post-TB treatment, with 25 recommending GeneXpert MTB/RIF. Notably, only 7 (21%) countries mentioned PTLD in their guidelines, with wide variations in their specific recommendations regarding screening, diagnosis, and management. Our findings highlight the lack of detailed guidance on how to properly diagnose and refer patients to appropriate care for various comorbidities or risk factors which may significantly impact microbiological and clinical TB treatment outcomes, including PTLD and ultimately point to an important opportunity for improvement in future guidelines.

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.

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 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.

Introduction: Task-shifting of tuberculosis (TB) rapid molecular testing from laboratory technicians to nurses could help decentralizing TB diagnosis at Primary Health Centers (PHC) and allow in-ward testing to shorten treatment decision for very sick patients. We assessed the feasibility of XpertMTB/RIF Ultra (Ultra) testing on nasopharyngeal aspirate (NPA) by nurses in children with presumptive TB at PHCs and in hospitalized children with severe pneumonia within the TB-Speed project in seven countries. Methods: Of 23 PHCs and 15 paediatric wards, 9 and 4 respectively had nurses trained to perform Ultra using the battery-operated GeneXpert Edge. Laboratory technicians performed the testing in the other sites. We compared proportion of samples tested, invalid or error results, TB detection yield, Turnaround Time (TAT) between sample reception and result at PHC, and between sample collection and result delivery to clinicians in paediatric wards between nurses and laboratory technicians. External Quality Assessment (EQA) and site support supervision assessed performances. Self-administered questionnaire and semi-structured individual interviews assessed nurses’ perceptions. Results: Ultra was done in 253/254 (99.6%) and 258/258 (100%) samples for PHC and hospital nurses vs 895/897 (99.8%) and 874/874 (100%) for laboratory technicians, respectively. At PHC, the TAT was below 1h30 for 158/252 (62.7%) samples tested by nurses vs 677/893 (75.8%) by laboratory technicians, p<0.001. Ultra results were available to clinicians within 3h in 201/258 (77.9%) samples for nurses vs 464/874 (53.1%) for laboratory technicians in hospitals, p<0.001. EQA results <87.5% was more common for PHC nurses than PHC laboratory technicians or hospital nurses. Technical difficulties, lack of practice and workload were the main challenges, and training and supervision the main facilitators reported by nurses. Conclusion: Task shifting of Ultra testing from laboratory technicians to nurses under close supervision could support decentralisation of TB diagnosis and shorten time to treatment decision for very sick patients. Key Messages: What is already known on this topic: Centralisation of childhood tuberculosis cares in many high burden and low middle income countries (LMICs) contribute to the important gap of childhood tuberculosis diagnosis. In 2022, WHO recommended the decentralisation of childhood tuberculosis diagnosis to increase access. The rapid tuberculosis molecular XpertMTB/RIF Ultra test recommended by WHO can be deployed at primary health care level but there is still limited data on its use at this level of care and no data for settings without a laboratory. Another diagnostic challenge is the diagnostic delay, which can be fatal in very sick children. There is no data on in-ward Xpert Ultra testing to shorten diagnostic delays in very sick children. What this study adds: As part of the TB-Speed operational research in 6 countries, we trained nurses from primary health centres without laboratory to perform Xpert Ultra tests on nasopharyngeal aspirate sample, using the GeneXpert Edge equipment. With close supervision and sufficient training, task-shifting of NPA Xpert Ultra testing from laboratory technicians to nurses was feasible and well accepted. Similarly, in order to reduce diagnostic delays in very sick children, we trained hospital nurses to perform in-ward Xpert Ultra tests on nasopharyngeal aspirate in 6 countries. Nurses were able to achieve similar performance as laboratory technicians and the time to treatment decision was shorter when Xpert Ultra testing was done by nurses as compared to laboratory technician. To our knowledge this is the first study assessing Xpert Ultra testing by nurses in high tuberculosis burden and LMICs. How this study might affect research, practice or policy: It is our hope that results from this study will foster the development of content and context specific approach of task-shifting to increase access and quality of healthcare services for TB diagnosis within the same labour force especially in LMICs.