Effect of decentralising childhood tuberculosis diagnosis to primary health centre versus district hospital levels on disease detection in children from six high tuberculosis incidence countries: an operational research, pre-post intervention study.

Background: Childhood tuberculosis (TB) remains underdiagnosed largely because of limited awareness and poor access to all or any of specimen collection, molecular testing, clinical evaluation, and chest radiography at low levels of care. Decentralising childhood TB diagnostics to district hospitals (DH) and primary health centres (PHC) could improve case detection. Methods: We conducted an operational research study using a pre-post intervention cross-sectional study design in 12 DHs and 47 PHCs of 12 districts across Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone and Uganda. The intervention included 1) a comprehensive diagnosis package at patient-level with tuberculosis screening for all sick children and young adolescents <15 years, and clinical evaluation, Xpert Ultra-testing on respiratory and stool samples, and chest radiography for children with presumptive TB, and 2) two decentralisation approaches (PHC-focused or DH-focused) to which districts were randomly allocated at country level. We collected aggregated and individual data. We compared the proportion of tuberculosis detection in children and young adolescents <15 years pre-intervention (01 August 2018-30 November 2019) versus during intervention (07 March 2020-30 September 2021), overall and by decentralisation approach. This study is registered with ClinicalTrials.gov, NCT04038632. Findings: TB was diagnosed in 217/255,512 (0.08%) children and young adolescent <15 years attending care pre-intervention versus 411/179,581 (0.23%) during intervention, (OR: 3.59 [95% CI 1.99-6.46], p-value<0.0001; p-value = 0.055 after correcting for over-dispersion). In DH-focused districts, TB diagnosis was 80/122,570 (0.07%) versus 302/86,186 (0.35%) (OR: 4.07 [1.86-8.90]; p-value = 0.0005; p-value = 0.12 after correcting for over-dispersion); and 137/132,942 (0.10%) versus 109/93,395 (0.11%) in PHC-focused districts, respectively (OR: 2.92 [1.25-6.81; p-value = 0.013; p-value = 0.26 after correcting for over-dispersion). Interpretation: Decentralising and strengthening childhood TB diagnosis at lower levels of care increases tuberculosis case detection but the difference was not statistically significant. Funding source: Unitaid, Grant number 2017-15-UBx-TB-SPEED.

Cost-effectiveness and budget impact of decentralising childhood tuberculosis diagnosis in six high tuberculosis incidence countries: a mathematical modelling study.

Background: The burden of childhood tuberculosis remains high globally, largely due to under-diagnosis. Decentralising childhood tuberculosis diagnosis services to lower health system levels could improve case detection, but there is little empirically based evidence on cost-effectiveness or budget impact. Methods: In this mathematical modelling study, we assessed the cost-effectiveness and budget impact of decentralising a comprehensive diagnosis package for childhood tuberculosis to district hospitals (DH-focused) or primary health centres (PHC-focused) compared to standard of care (SOC). The project was conducted in Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone, and Uganda between August 1st, 2018 and September 30th, 2021. A mathematical model was developed to assess the health and economic outcomes of the intervention from a health system perspective. Estimated outcomes were tuberculosis cases, deaths, disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs). We also calculated the budget impact of nationwide implementation. The TB-Speed Decentralization study is registered with ClinicalTrials.gov, NCT04038632. Findings: For the DH-focused strategy versus SOC, ICERs ranged between $263 (Cambodia) and $342 (Côte d'Ivoire) per DALY averted. For the PHC-focused strategy versus SOC, ICERs ranged between $477 (Cambodia) and $599 (Côte d'Ivoire) per DALY averted. Results were sensitive to TB prevalence and the discount rate used. The additional costs of implementing the DH-focused strategy ranged between $12.8 M (range 10.8-16.4) (Cambodia) and $50.4 M (36.5-74.4) (Mozambique), and between $13.9 M (12.6-15.6) (Sierra Leone) and $134.6 M (127.1-143.0) (Uganda) for the PHC-focused strategy. Interpretation: The DH-focused strategy may be cost-effective in some countries, depending on the cost-effectiveness threshold used for policy making. Either intervention would require substantial early investment. Funding: Unitaid.

Integration of HIV Testing in a Community Intervention for Tuberculosis Screening Among Household Contacts of Patients with Tuberculosis in Cameroon and Uganda.

INTRODUCTION: People living with HIV are considered at higher risk of developing severe forms of tuberculosis (TB) disease. Providing HIV testing to TB-exposed people is therefore critical. We present the results of integrating HIV testing into a community-based intervention for household TB contact management in Cameroon and Uganda. METHODS: Trained community health workers visited the households of index patients with TB identified in 3 urban/semiurban and 6 rural districts or subdistricts as part of a cluster-randomized trial and provided TB screening to all household contacts. Voluntary HIV counseling and testing were offered to contacts aged 5 years or older with unknown HIV status. We describe the cascade of care for HIV testing and the factors associated with the acceptance of HIV testing. RESULTS: Overall, 1983 household contacts aged 5 years or older were screened for TB. Of these contacts, 1652 (83.3%) did not know their HIV status, 1457 (88.2%) accepted HIV testing, and 1439 (98.8%) received testing. HIV testing acceptance was lower among adults than children [adjusted odds ratio (aOR) = 0.35, 95% confidence interval (CI): 0.22 to 0.55], those living in household of an HIV-positive vs HIV-negative index case (aOR = 0.56, 95% CI: 0.38 to 0.83), and contacts requiring a reassessment visit after the initial TB screening visit vs asymptomatic contacts (aOR = 0.20, 95% CI: 0.06 to 0.67) and was higher if living in Uganda vs Cameroon (aOR = 4.54, 95% CI: 1.17 to 17.62) or if another contact of the same index case was tested for HIV (aOR = 9.22, 95% CI: 5.25 to 16.18). CONCLUSION: HIV testing can be integrated into community-based household TB contact screening and is well-accepted.

Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

Cost-effectiveness of community-based household tuberculosis contact management for children in Cameroon and Uganda: a modelling analysis of a cluster-randomised trial.

BACKGROUND: WHO recommends household contact management (HCM) including contact screening and tuberculosis-preventive treatment (TPT) for eligible children. The CONTACT trial found increased TPT initiation and completion rates when community health workers were used for HCM in Cameroon and Uganda. METHODS: We did a cost-utility analysis of the CONTACT trial using a health-system perspective to estimate the health impact, health-system costs, and cost-effectiveness of community-based versus facility-based HCM models of care. A decision-analytical modelling approach was used to evaluate the cost-effectiveness of the intervention compared with the standard of care using trial data on cascade of care, intervention effects, and resource use. Health outcomes were based on modelled progression to tuberculosis, mortality, and discounted disability-adjusted life-years (DALYs) averted. Health-care resource use, outcomes, costs (2021 US$), and cost-effectiveness are presented. FINDINGS: For every 1000 index patients diagnosed with tuberculosis, the intervention increased the number of TPT courses by 1110 (95% uncertainty interval 894 to 1227) in Cameroon and by 1078 (796 to 1220) in Uganda compared with the control model. The intervention prevented 15 (-3 to 49) tuberculosis deaths in Cameroon and 10 (-20 to 33) in Uganda. The incremental cost-effectiveness ratio was $620 per DALY averted in Cameroon and $970 per DALY averted in Uganda. INTERPRETATION: Community-based HCM approaches can substantially reduce child tuberculosis deaths and in our case would be considered cost-effective at willingness-to-pay thresholds of $1000 per DALY averted. Their impact and cost-effectiveness are likely to be greatest where baseline HCM coverage is lowest. FUNDING: Unitaid and UK Medical Research Council.

Effectiveness of a community-based approach for the investigation and management of children with household tuberculosis contact in Cameroon and Uganda: a cluster-randomised trial.

BACKGROUND: Globally, the uptake of tuberculosis-preventive treatment (TPT) among children with household tuberculosis contact remains low, partly due to the necessity of bringing children to health facilities for investigations. This study aimed to evaluate the effect on TPT initiation and completion of community-based approaches to tuberculosis contact investigations in Cameroon and Uganda. METHODS: We did a parallel, cluster-randomised, controlled trial across 20 clusters (consisting of 25 district hospitals and primary health centres) in Cameroon and Uganda, which were randomised (1:1) to receive a community-based approach (intervention group) or standard-of-care facility-based approach to contact screening and management (control group). The community-based approach consisted of symptom-based tuberculosis screening of all household contacts by community health workers at the household, with referral of symptomatic contacts to local facilities for investigations. Initiation of TPT (3-month course of rifampicin-isoniazid) was done by a nurse in the household, and home visits for TPT follow-up were done by community health workers. Index patients were people aged 15 years or older with bacteriologically confirmed, drug-susceptible, pulmonary tuberculosis diagnosed less than 1 month before inclusion and who declared at least one child or young adolescent (aged 0-14 years) household contact. The primary endpoint was the proportion of declared child contacts in the TPT target group (those aged <5 years irrespective of HIV status, and children aged 5-14 years living with HIV) who commenced and completed TPT, assessed in the modified intention-to-treat population (excluding enrolled index patients and their contacts who did not fit the eligibility criteria). Descriptive cascade of care assessment and generalised linear mixed modelling were used for comparison. This study is registered with ClinicalTrials.gov (NCT03832023). FINDINGS: The study included nine clusters in the intervention group (after excluding one cluster that did not enrol any index patients for >2 months) and ten in the control group. Between Oct 14, 2019 and Jan 13, 2022, 2894 child contacts were declared by 899 index patients with bacteriologically confirmed tuberculosis. Among all child contacts declared, 1548 (81·9%) of 1889 in the intervention group and 475 (47·3%) of 1005 in the control group were screened for tuberculosis. 1400 (48·4%) child contacts were considered to be in the TPT target group: 941 (49·8%) of 1889 in the intervention group and 459 (45·7%) of 1005 in the control group. In the TPT target group, TPT was commenced and completed in 752 (79·9%) of 941 child contacts in the intervention group and 283 (61·7%) of 459 in the control group (odds ratio 3·06 [95% CI 1·24-7·53]). INTERPRETATION: A community-based approach using community health workers can significantly increase contact investigation coverage and TPT completion among eligible child contacts in a tuberculosis-endemic setting. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Tuberculosis prevention: current strategies and future directions.

BACKGROUND: An estimated one fourth of the world's population is infected with Mycobacterium tuberculosis, and 5-10% of those infected develop tuberculosis in their lifetime. Preventing tuberculosis is one of the most underutilized but essential components of curtailing the tuberculosis epidemic. Moreover, current evidence illustrates that tuberculosis manifestations occur along a dynamic spectrum from infection to disease rather than a binary state as historically conceptualized. Elucidating determinants of transition between these states is crucial to decreasing the tuberculosis burden and reaching the END-TB Strategy goals as defined by the WHO. Vaccination, detection of infection, and provision of preventive treatment are key elements of tuberculosis prevention. OBJECTIVES: This review provides a comprehensive summary of recent evidence and state-of-the-art updates on advancements to prevent tuberculosis in various settings and high-risk populations. SOURCES: We identified relevant studies in the literature and synthesized the findings to provide an overview of the current state of tuberculosis prevention strategies and latest research developments. CONTENT: We present the current knowledge and recommendations regarding tuberculosis prevention, with a focus on M. bovis Bacille-Calmette-Guérin vaccination and novel vaccine candidates, tests for latent infection with M. tuberculosis, regimens available for tuberculosis preventive treatment and recommendations in low- and high-burden settings. IMPLICATIONS: Effective tuberculosis prevention worldwide requires a multipronged approach that addresses social determinants, and improves access to tuberculosis detection and to new short tuberculosis preventive treatment regimens. Robust collaboration and innovative research are needed to reduce the global burden of tuberculosis and develop new detection tools, vaccines, and preventive treatments that serve all populations and ages.

Acceptability of decentralizing childhood tuberculosis diagnosis in low-income countries with high tuberculosis incidence: Experiences and perceptions from health care workers in Sub-Saharan Africa and South-East Asia.

Decentralizing childhood tuberculosis services, including diagnosis, is now recommended by the WHO and could contribute to increasing tuberculosis detection in high burden countries. However, implementing microbiological tests and clinical evaluation could be challenging for health care workers (HCWs) in Primary Health Centers (PHCs) and even District Hospitals (DHs). We sought to assess the acceptability of decentralizing a comprehensive childhood tuberculosis diagnosis package from HCWs' perspective. We conducted implementation research nested within the TB-Speed Decentralization study. HCWs from two health districts of Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Sierra Leone, and Uganda implemented systematic screening, nasopharyngeal aspirates (NPA) and stool sample collection with molecular testing, clinical evaluation and chest X-ray (CXR) interpretation. We investigated their experiences and perceptions in delivering the diagnostic package components in 2020-21 using individual semi-structured interviews. We conducted thematic analysis, supported by the Theoretical Framework of Acceptability. HCWs (n = 130, 55% female, median age 36 years, 53% nurses, 72% PHC-based) perceived that systematic screening, although increasing workload, was beneficial as it improved childhood tuberculosis awareness. Most HCWs shared satisfaction and confidence in performing NPA, despite procedure duration, need to involve parents/colleagues and discomfort for children. HCWs shared positive attitudes towards stool sample-collection but were frustrated by delayed stool collection associated with cultural practices, transport and distance challenges. Molecular testing, conducted by nurses or laboratory technicians, was perceived as providing quality results, contributing to diagnosis. Clinical evaluation and diagnosis raised self-efficacy issues and need for continuous training and clinical mentoring. HCWs valued CXR, however complained that technical and logistical problems limited access to digital reports. Referral from PHC to DH was experienced as burdensome. HCWs at DH and PHC-levels perceived and experienced decentralized childhood tuberculosis diagnosis as acceptable. Implementation however could be hampered by feasibility issues, and calls for innovative referral mechanisms for patients, samples and CXR.

Management of Tuberculosis Infection: Current Situation, Recent Developments and Operational Challenges.

Tuberculosis infection (TBI) is defined as a state of infection in which individuals host live Mycobacterium tuberculosis with or without clinical signs of active TB. It is now understood as a dynamic process covering a spectrum of responses to infection resulting from the interaction between the TB bacilli and the host immune system. The global burden of TBI is about one-quarter of the world's population, representing a reservoir of approximately 2 billion people. On average, 5-10% of people who are infected will develop TB disease over the course of their lives, but this risk is enhanced in a series of conditions, such as co-infection with HIV. The End-TB strategy promotes the programmatic management of TBI as a crucial endeavor to achieving global targets to end the TB epidemic. The current development of new diagnostic tests capable of discriminating between simple TBI and active TB, combined with novel short-course preventive treatments, will help achieve this goal. In this paper, we present the current situation and recent developments of management of TBI and the operational challenges.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

High performance of systematic combined urine LAM test and sputum Xpert MTB/RIF® for tuberculosis screening in severely immunosuppressed ambulatory adults with HIV.

BACKGROUND: In people with HIV (PWH), the WHO-recommended tuberculosis four-symptom screen (W4SS) targeting those who need molecular rapid test may be suboptimal. We assessed the performance of different tuberculosis screening approaches in severely immunosuppressed PWH enrolled in the guided-treatment group of the STATIS trial (NCT02057796). METHODS: Ambulatory PWH with no overt evidence of tuberculosis and CD4 cell count <100/µL were screened for tuberculosis prior to antiretroviral therapy (ART) initiation with W4SS, chest X-ray, urine lipoarabinomannan (LAM) test and sputum Xpert MTB/RIF® (Xpert). Correctly and wrongly identified cases by screening approaches were assessed overall and by CD4 count threshold (≤50 and 51-99 cells/µL). RESULTS: Of 525 enrolled participants (median CD4 cell count: 28/µL), 48 (9.9%) were diagnosed with tuberculosis at enrollment. Among participants with a negative W4SS, 16% had either a positive Xpert, a chest X-ray suggestive of tuberculosis or a positive urine LAM test. The combination of sputum Xpert and urine LAM test was associated with the highest proportion of participants correctly identified as tuberculosis (95.8%) and non-tuberculosis cases (95.4%), with proportions equally high among participants with CD4 counts above or below 50 cells/µL. Restricting the use of sputum Xpert, urine LAM test or chest X-ray to participants with a positive W4SS reduced the proportion of wrongly and correctly identified cases. CONCLUSIONS: There is a clear benefit to perform both sputum Xpert and urine LAM tests as tuberculosis screening in all severely immunosuppressed PWH prior to ART initiation, and not only in those with a positive W4SS. CLINICAL TRIALS REGISTRATION: NCT02057796.

Mortality and Cause of Death in Children With Presumptive Disseminated Tuberculosis.

BACKGROUND AND OBJECTIVES: Children experience high tuberculosis (TB)-related mortality but causes of death among those with presumptive TB are poorly documented. We describe the mortality, likely causes of death, and associated risk factors among vulnerable children admitted with presumptive TB in rural Uganda. METHODS: We conducted a prospective study of vulnerable children, defined as <2 years of age, HIV-positive, or severely malnourished, with a clinical suspicion of TB. Children were assessed for TB and followed for 24 weeks. TB classification and likely cause of death were assessed by an expert endpoint review committee, including insight gained from minimally invasive autopsies, when possible. RESULTS: Of the 219 children included, 157 (71.7%) were <2 years of age, 72 (32.9%) were HIV-positive, and 184 (84.0%) were severely malnourished. Seventy-one (32.4%) were classified as "likely tuberculosis" (15 confirmed and 56 unconfirmed), and 72 (32.9%) died. The median time to death was 12 days. The most frequent causes of death, ascertained for 59 children (81.9%), including 23 cases with autopsy results, were severe pneumonia excluding confirmed TB (23.7%), hypovolemic shock due to diarrhea (20.3%), cardiac failure (13.6%), severe sepsis (13.6%), and confirmed TB (10.2%). Mortality risk factors were confirmed TB (adjusted hazard ratio [aHR] = 2.84 [95% confidence interval (CI): 1.19-6.77]), being HIV-positive (aHR = 2.45 [95% CI: 1.37-4.38]), and severe clinical state on admission (aHR = 2.45 [95% CI: 1.29-4.66]). CONCLUSIONS: Vulnerable children hospitalized with presumptive TB experienced high mortality. A better understanding of the likely causes of death in this group is important to guide empirical management.

Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study.

BACKGROUND: Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients. METHODS: We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count <200 cells per µL, or HIV clinical stage 3 or 4; group 2). All participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples. FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay on sputum or urine, sputum culture for Mycobacterium tuberculosis, and CD4 count were systematically carried out for all patients. Sensitivity and specificity of FujiLAM and AlereLAM were evaluated against microbiological and composite reference standards. FINDINGS: Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2. Tuberculosis was microbiologically confirmed in 96 (9·4%) of 1022 patients in group 1 and 18 (3·3%) of 542 patients in group 2. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51-69) and AlereLAM sensitivity was 40% (31-49; p<0·001). Among patients with CD4 counts of less than 200 cells per µL, FujiLAM sensitivity was 69% (57-79) and AlereLAM sensitivity was 52% (40-64; p=0·0218). Among patients with CD4 counts of 200 cells per µL or higher, FujiLAM sensitivity was 47% (34-61) and AlereLAM sensitivity was 24% (14-38; p=0·0116). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85-89) and AlereLAM specificity was 86% (95 CI 84-88; p=0·941). FujiLAM sensitivity varied by lot number from 48% (34-62) to 76% (57-89) and specificity from 77% (72-81) to 98% (93-99). INTERPRETATION: Next-generation, higher sensitivity urine-lipoarabinomannan assays are potentially promising tests that allow rapid tuberculosis diagnosis at the point of care for HIV-positive patients. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. FUNDING: ANRS and Médecins Sans Frontières.

Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial.

BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. INTERPRETATION: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition. FUNDING: Unitaid and L'Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis.

High-Dose Rifampicin Regimen for Pulmonary TuberculosisThis randomized, controlled trial tested the efficacy and safety of high-dose rifampicin (1200 or 1800 mg/d) as part of the treatment regimen for pulmonary tuberculosis. Four-month high-dose rifampicin regimens had no dose-limiting side effects but failed to meet noninferiority criteria compared with the standard 6-month control regimen.

Tuberculosis Infection in Children and Adolescents.

The burden of tuberculosis (TB) in children and adolescents remains very significant. Several million children and adolescents are infected with TB each year worldwide following exposure to an infectious TB case and the risk of progression from TB infection to tuberculosis disease is higher in this group compared to adults. This review describes the risk factors for TB infection in children and adolescents. Following TB exposure, the risk of TB infection is determined by a combination of index case characteristics, contact features, and environmental determinants. We also present the recently recommended approaches to diagnose and treat TB infection as well as novel tests for infection. The tests for TB infection have limitations and diagnosis still relies on an indirect immunological assessment of cellular immune response to Mycobacterium tuberculosis antigens using immunodiagnostic testing. It is recommended that TB exposed children and adolescents and those living with HIV receive TB preventive treatment (TPT) to reduce the risk of progression to TB disease. Several TPT regimens of similar effectiveness and safety are now available and recommended by the World Health Organisation.

Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial.

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as "definite," "probable," or "possible" using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health.