Holistic acceptability of an adult levofloxacin formulation in children and adolescents on a tuberculosis preventive treatment trial.

Drug-resistant tuberculosis (TB) is threatening global TB control. Although formulations designed for children are a priority, adult levofloxacin formulations are widely used in TB treatment and prevention. TB-CHAMP was a cluster-randomised, placebo-controlled trial evaluating the efficacy and safety of 24 weeks of daily levofloxacin to prevent TB in child and adolescent household contacts of adults with infectious multidrug-resistant TB. Nested in-depth longitudinal qualitative work was conducted in a subset of children and their caregivers to understand broader experiences of treatment acceptability. We conducted 41 interviews with 8 caregivers of children <6 years, and with 6 older children responding for themselves. Children who could not swallow the adult formulation whole, found the tablet unpalatable, although they learnt to tolerate the taste over time. Most caregivers and children came from families with substantial experience of TB, but felt they knew little about TB preventive therapy. Many families experienced challenging socio-economic circumstances. Poor acceptability was mitigated by sympathetic study personnel, assistance with transport and financial compensation. The adult formulation of levofloxacin was disliked by many younger children but was acceptable to children able to swallow the tablet whole. In addition to using acceptable drug formulations, TB preventive treatment implementation models should include patient education and should accommodate patients' socioeconomic challenges.

The inclusion of children and adolescents in tuberculosis diagnostic development and evaluation-a consensus statement.

The diagnosis of paediatric tuberculosis remains a challenge due to the non-specificity of symptoms and the paucibacillary nature of tuberculosis in children. However, in the development of new tuberculosis diagnostics, the unique needs of children and adolescents are rarely considered in the design process, with delays in evaluation and approval. No clear guidance is available on when and how to include children and adolescents in tuberculosis diagnostic development and evaluation. To address this gap, we conducted a Delphi consensus process with 42 stakeholders, including one qualitative and two quantitative rounds. Consensus was achieved on 20 statements, with agreement that the needs and perspectives of children, adolescents, and their caregivers should be incorporated throughout diagnostic design and evaluation. Opportunities exist for the early use of well characterised samples and prospective enrolment of children and adolescents in tuberculosis diagnostic evaluation, with consideration of the type of test, expected benefit, and potential risks. Pathogen-based tests might be initially optimised and assessed in adults and adolescents, but parallel evaluation in children is needed for host-based tests. Late-stage evaluation and implementation studies should examine combination testing and integration into clinical algorithms. The statements support collaboration between developers, researchers, regulators, and users to widen and accelerate the diagnostic pipeline for paediatric tuberculosis.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

Effectiveness of preventive treatment among different age groups and Mycobacterium tuberculosis infection status: a systematic review and individual-participant data meta-analysis of contact tracing studies.

BACKGROUND: Tuberculosis is a preventable disease. However, there is debate regarding which individuals would benefit most from tuberculosis preventive treatment and whether these benefits vary in settings with a high burden and low burden of tuberculosis. We aimed to compare the effectiveness of tuberculosis preventive treatment in exposed individuals of differing ages and Mycobacterium tuberculosis infection status while considering tuberculosis burden of the settings. METHODS: In this systematic review and individual-participant meta-analysis, we investigated the development of incident tuberculosis in people closely exposed to individuals with tuberculosis. We searched for studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase. We restricted our search to cohort studies; case-control studies and outbreak reports were excluded. Two reviewers evaluated titles, abstracts, and full text articles for eligibility. At each stage, two reviewers discussed discrepancies and re-evaluated articles until a consensus was reached. Individual-participant data and a pre-specified list of variables, including characteristics of the exposed contact, the index patient, and environmental characteristics, were requested from authors of all eligible studies; contacts exposed to a drug-resistant tuberculosis index patient were excluded. The primary study outcome was incident tuberculosis. We estimated adjusted hazard ratios (aHRs) for incident tuberculosis with mixed-effects Cox regression models with a study-level random effect. We estimated the number-needed-to-treat (NNT) to prevent one person developing tuberculosis. Propensity score matching procedures were used in all analyses. This study is registered with PROSPERO (CRD42018087022). FINDINGS: After screening 25 358 records for eligibility, 439 644 participants from 32 cohort studies were included in the individual-participant data meta-analysis. Participants were followed for 1 396 413 person-years (median of 2·7 years [IQR 1·3-4.4]), during which 2496 people were diagnosed with incident tuberculosis. Overall, effectiveness of preventive treatment was 49% (aHR 0·51 [95% CI 0·44-0·60]). Participants with a positive tuberculin-skin-test (TST) or IFNγ release assay (IGRA) result at baseline benefitted from greater protection, regardless of age (0·09 [0·05-0·17] in children younger than 5 years, 0·20 [0·15-0·28] in individuals aged 5-17 years, and 0·17 [0·13-0·22] in adults aged 18 years and older). The effectiveness of preventive treatment was greater in high-burden (0·31 [0·23-0·40]) versus low-burden (0·58 [0·47-0·72]) settings. The NNT ranged from 9 to 34 depending on age among participants with a positive TST or IGRA in both high-burden and low-burden settings; among all contacts (regardless of TST or IGRA test result), the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings. INTERPRETATION: Our findings suggest that a risk-targeted strategy prioritising contacts with evidence of M tuberculosis infection might be indicated in low-burden settings, and a broad approach including all contacts should be considered in high-burden settings. Preventive treatment was similarly effective among contacts of all ages. FUNDING: None.

Continuous wave terahertz detection using 1550 nm pumped nonlinear photoconductive GaAs metasurfaces.

Terahertz (THz) continuous wave (CW) spectroscopy systems can offer extremely high spectral resolution over the THz band by photo-mixing high-performance telecommunications-band (1530-1565 nm) lasers. However, typical THz CW detectors in these systems use narrow band-gap photoconductors, which require elaborate material growth and generate relatively large detector noise. Here we demonstrate that two-step photon absorption in a nano-structured low-temperature grown GaAs (LT-GaAs) metasurface which enables switching of photoconductivity within approximately one picosecond. We show that LT-GaAs can be used as an ultrafast photoconductor in CW THz detectors despite having a bandgap twice as large as the telecommunications laser photon energy. The metasurface design harnesses Mie modes in LT GaAs resonators, whereas metallic electrodes of THz detectors can be designed to support an additional photonic mode, which further increases photoconductivity at a desired wavelength.

Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise.

The current active-latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

Enhanced active case finding of drug-resistant tuberculosis in Namibia: a protocol for the hotspots, hospitals, and households (H3TB) study.

INTRODUCTION: Namibia is a high tuberculosis (TB)-burden country with an estimated incidence of 460/100 000 (around 12 000 cases) per year. Approximately 4.5% of new cases and 7.9% of previously treated TB cases are multidrug resistant (MDR) and 47% of patients with MDR-TB are HIV coinfected. Published data suggest a clustering of MDR-TB transmission in specific areas. Identifying transmission clusters is key to implementing high-yield and cost-effective interventions. This includes knowing the yield of finding TB cases in high-transmission zones (eg, community hotspots, hospitals or households) to deliver community-based interventions. We aim to identify such transmission zones for enhanced case finding and evaluate the effectiveness of this approach. METHODS AND ANALYSIS: H3TB is an observational cross-sectional study evaluating MDR-TB active case finding strategies. Sputum samples from MDR-TB cases in three regions of Namibia will be evaluated by whole genome sequencing (WGS) in addition to routine sputum investigations (Xpert MTB/RIF, culture and drug susceptibility testing). We will collect information on household contacts, use of community spaces and geographical map intersections between participants, synthesising these data to identify transmission hotspots. We will look at the feasibility, acceptability, yield and cost of case finding strategies in these hotspots, and in households of patients with MDR-TB and visitors of hospitalised patients with MDR-TB. A compartmental transmission dynamic model will be constructed to evaluate the impact and cost-effectiveness of the strategies if scaled. ETHICS AND DISSEMINATION: Ethics approval was obtained. Participants will give informed consent. H3TB will capitalise on a partnership with the Ministry of Health and Social Services to follow up individuals diagnosed with MDR-TB and integrate WGS data with innovative contact network mapping, to allow enhanced case finding. Study data will contribute towards a systems approach to TB control. Equally important, it will serve as a role model for similar studies in other high-incidence settings.

Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < -1.64). Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity. Funding: EDCTP, National Institute of Health, Medical Research Council, BMBF.

Human Cytomegalovirus Immunoglobulin G Response and Pulmonary Tuberculosis in Adolescents: A Case-Control Study.

Background: Emerging evidence suggests a link between infection with herpes viruses, particularly human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), and progression to tuberculosis disease. Methods: An unmatched case-control study was conducted among adolescents aged 10-19 years enrolled in an observational study (Teen TB) between November 2020 and November 2021, in Cape Town, South Africa. Fifty individuals with pulmonary tuberculosis and 51 healthy tuberculosis-exposed individuals without tuberculosis were included. Demographics and clinical data were obtained, and serum samples collected at enrolment were tested for HCMV immunoglobulin G (IgG) and EBV nuclear antigen (EBNA) IgG using 2 automated enzyme immunoassays. Odds ratios were estimated using unconditional logistic regression. Results: The median age of 101 participants was 15 years (interquartile range, 13-17 years); 55 (54%) were female. All participants were HCMV IgG seropositive, and 95% were EBNA IgG seropositive. Individuals with tuberculosis had higher HCMV IgG titers than healthy controls (P = .04). Individuals with upper-tertile HCMV IgG titers had 3.67 times greater odds of pulmonary tuberculosis than those with IgG titers in the lower tertile (95% confidence interval, 1.05-12.84; P = .04). There was a trend for increasing odds of pulmonary tuberculosis with increasing titers of HCMV IgG (P = .04). In contrast, there was no association between tuberculosis and higher EBNA IgG values. Conclusions: There is a high prevalence of sensitization to HCMV and EBV among adolescents in this high-tuberculosis-burden setting. Higher HCMV IgG titers were associated with pulmonary tuberculosis in adolescents.

SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study.

BACKGROUND: The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic has had an impact on the global tuberculosis (TB) epidemic but evidence on the possible interaction between SARS-CoV-2 and TB, especially in children and adolescents, remains limited. We aimed to evaluate the relationship between previous infection with SARS-CoV-2 and the risk of TB in children and adolescents. METHODS: An unmatched case-control study was conducted using SARS-CoV-2 unvaccinated children and adolescents recruited into two observational TB studies (Teen TB and Umoya), between November 2020 and November 2021, in Cape Town, South Africa. Sixty-four individuals with pulmonary TB (aged < 20 years) and 99 individuals without pulmonary TB (aged < 20 years) were included. Demographics and clinical data were obtained. Serum samples collected at enrolment underwent quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) testing using the Abbott SARS-CoV-2 IgG II Quant assay. Odds ratios (ORs) for TB were estimated using unconditional logistic regression. RESULTS: There was no statistically significant difference in the odds of having pulmonary TB between those who were SARS-CoV-2 IgG seropositive and those who were seronegative (adjusted OR 0.51; 95% CI: 0.23-1.11; n = 163; p = 0.09). Of those with positive SARS-CoV-2 serology indicating prior infection, baseline IgG titres were higher in individuals with TB compared to those without TB (p = 0.04) and individuals with IgG titres in the highest tertile were more likely to have pulmonary TB compared to those with IgG levels in the lowest tertile (OR: 4.00; 95%CI: 1.13- 14.21; p = 0.03). CONCLUSIONS: Our study did not find convincing evidence that SARS-CoV-2 seropositivity was associated with subsequent pulmonary TB disease; however, the association between magnitude of SARS-CoV-2 IgG response and pulmonary TB warrants further investigation. Future prospective studies, evaluating the effects of sex, age and puberty on host immune responses to M. tuberculosis and SARS-CoV-2, will also provide more clarity on the interplay between these two infections.

Optimising computer aided detection to identify intra-thoracic tuberculosis on chest x-ray in South African children.

Diagnostic tools for paediatric tuberculosis remain limited, with heavy reliance on clinical algorithms which include chest x-ray. Computer aided detection (CAD) for tuberculosis on chest x-ray has shown promise in adults. We aimed to measure and optimise the performance of an adult CAD system, CAD4TB, to identify tuberculosis on chest x-rays from children with presumptive tuberculosis. Chest x-rays from 620 children <13 years enrolled in a prospective observational diagnostic study in South Africa, were evaluated. All chest x-rays were read by a panel of expert readers who attributed each with a radiological reference of either 'tuberculosis' or 'not tuberculosis'. Of the 525 chest x-rays included in this analysis, 80 (40 with a reference of 'tuberculosis' and 40 with 'not tuberculosis') were allocated to an independent test set. The remainder made up the training set. The performance of CAD4TB to identify 'tuberculosis' versus 'not tuberculosis' on chest x-ray against the radiological reference read was calculated. The CAD4TB software was then fine-tuned using the paediatric training set. We compared the performance of the fine-tuned model to the original model. Our findings were that the area under the receiver operating characteristic curve (AUC) of the original CAD4TB model, prior to fine-tuning, was 0.58. After fine-tuning there was an improvement in the AUC to 0.72 (p = 0.0016). In this first-ever description of the use of CAD to identify tuberculosis on chest x-ray in children, we demonstrate a significant improvement in the performance of CAD4TB after fine-tuning with a set of well-characterised paediatric chest x-rays. CAD has the potential to be a useful additional diagnostic tool for paediatric tuberculosis. We recommend replicating the methods we describe using a larger chest x-ray dataset from a more diverse population and evaluating the potential role of CAD to replace a human-read chest x-ray within treatment-decision algorithms for paediatric tuberculosis.

Reasons for reductions in routine childhood immunisation uptake during the COVID-19 pandemic in low- and middle-income countries: A systematic review.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in a substantial decline in routine immunisation coverage in children globally, especially in low- and middle-income countries (LMICs). This study summarises the reasons for disruptions to routine child immunisations in LMICs. A systematic review (PROSPERO CRD42021286386) was conducted following PRISMA 2020 guidelines. Six databases were searched: MEDLINE, Embase, Global Health, CINAHL, Scopus and MedRxiv, on 11/02/2022. Observational and qualitative studies published from January 2020 onwards were included if exploring reasons for missed immunisations during the COVID-19 pandemic in LMICs. Study appraisal used National Heart, Lung, and Blood Institute and Critical Appraisal Skills Programme tools. Reasons for disruption were defined with descriptive codes; cross-sectional (quantitative) data were summarised as mean percentages of responses weighted by study population, and qualitative data were summarised narratively. A total of thirteen studies were included describing reasons behind disruptions; 7 cross-sectional (quantitative), 5 qualitative and 1 mixed methods. Seventeen reasons for disruptions were identified. In quantitative studies (total respondents = 2,853), the most common reasons identified were fear of COVID-19 and consequential avoidance of health centres (41.2%, SD ±13.3%), followed by transport challenges preventing both families and healthcare professionals from reaching vaccination services (11.1% SD ±16.6%). Most reasons stemmed from reduced healthcare-seeking (83.4%), as opposed to healthcare-delivery issues (15.2%). Qualitative studies showed a more even balance of healthcare-seeking (49.5%) and healthcare-delivery issues (50.5%), with fear of COVID-19 remaining a major identified issue (total respondents = 92). The most common reasons for disruption were parental fear of COVID-19 and avoidance of health services. Health systems must therefore prioritise public health messaging to encourage vaccine uptake and recovery of missed immunisations.

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.

A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

QuantiFERON-TB Gold Plus Performance in Children: A Narrative Review.

This review summarizes studies evaluating the performance of the QuantiFERON-TB Gold Plus (QFT-Plus) interferon-gamma release assay (IGRA) test for Mycobacterium tuberculosis ( Mtb ) infection in children. Literature searching was conducted using PubMed, MEDLINE and Embase (January 2017 to December 2021) and the terms "children" or "pediatric" and "IGRAs" or "QuantiFERON-TB Gold Plus." Selected studies (N = 14; 4646 subjects) enrolled children with Mtb infection, tuberculosis (TB) disease or healthy children with household TB contacts. Agreement between QFT-Plus and tuberculin skin test (TST) (kappa values) ranged from -0.201 (no agreement) to 0.83 (almost perfect agreement). Assay sensitivity of QFT-Plus (against reference standard of microbiologically confirmed TB disease) was 54.5%-87.3%, with no reported difference in children less than 5 versus greater than or equal to 5 years of age. In individuals less than or equal to 18 years of age, the rate of indeterminate results was 0%-33.3% (2.6% in children <2 years). IGRAs may overcome the limitations of TST in young, Bacillus Calmette-Guérin-vaccinated children.