Publications
208 results found
Chiang SS, Graham SM, Schaaf HS, et al., 2023, Clinical standards for drug-susceptible TB in children and adolescents., International Journal of Tuberculosis and Lung Disease, Vol: 27, Pages: 584-598, ISSN: 1027-3719
BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.
Patankar S, Cruz AT, Douglas-Jones B, et al., 2023, Making the Case for All-Oral, Shorter Regimens for Children with Drug-Resistant Tuberculosis., Am J Respir Crit Care Med, Vol: 208, Pages: 130-131
Garcia-Prats AJ, Hoddinott G, Howell P, et al., 2023, Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis., Lancet Infect Dis, Vol: 23, Pages: 778-780
Swanepoel J, van der Zalm MM, Preiser W, et al., 2023, SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study, BMC Infectious Diseases, Vol: 23, Pages: 1-10, ISSN: 1471-2334
BackgroundThe 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.MethodsAn 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.ResultsThere 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).ConclusionsOur 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 investigat
Palmer M, Seddon JA, van der Zalm MM, et al., 2023, Optimising computer aided detection to identify intra-thoracic tuberculosis on chest x-ray in South African children, PLOS Global Public Health, Vol: 3, Pages: 1-15, ISSN: 2767-3375
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 tub
Buonsenso D, Seddon JA, Esposito S, et al., 2023, QuantiFERON-TB Gold Plus Performance in Children: A Narrative Review., Pediatr Infect Dis J, Vol: 42, Pages: e158-e165
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.
Gunasekera K, Seddon J, 2023, Development and validation of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis, The Lancet Child & Adolescent Health, Vol: 7, Pages: 336-346, ISSN: 2352-4642
BackgroundMany 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.MethodsFor 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.FindingsOf 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having
Cruz AT, Seddon JA, 2023, Vulnerable Children With Presumptive Tuberculosis: When Will This Population Be Prioritized?, Pediatrics, Vol: 151
Nightingale R, Carlin F, Meghji J, et al., 2023, Post-TB health and wellbeing., Int J Tuberc Lung Dis, Vol: 27, Pages: 248-283
TB affects around 10.6 million people each year and there are now around 155 million TB survivors. TB and its treatments can lead to permanently impaired health and wellbeing. In 2019, representatives of TB affected communities attending the '1st International Post-Tuberculosis Symposium´ called for the development of clinical guidance on these issues. This clinical statement on post-TB health and wellbeing responds to this call and builds on the work of the symposium, which brought together TB survivors, healthcare professionals and researchers. Our document offers expert opinion and, where possible, evidence-based guidance to aid clinicians in the diagnosis and management of post-TB conditions and research in this field. It covers all aspects of post-TB, including economic, social and psychological wellbeing, post TB lung disease (PTLD), cardiovascular and pericardial disease, neurological disability, effects in adolescents and children, and future research needs.
Channon-Wells S, Vito O, McArdle AJ, et al., 2023, Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study, The Lancet Rheumatology, Vol: 5, Pages: e184-e199, ISSN: 2665-9913
BackgroundMultisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.MethodsThe Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370.FindingsWe enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologica
Marcy O, Wobudeya E, Font H, et al., 2023, 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., Lancet Infect Dis, Vol: 23, Pages: 341-351
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&midd
Chiang SS, Waterous PM, Atieno VF, et al., 2023, Caring for Adolescents and Young Adults With Tuberculosis or at Risk of Tuberculosis: Consensus Statement From an International Expert Panel., J Adolesc Health, Vol: 72, Pages: 323-331
BACKGROUND:: Despite being a preventable and treatable disease, tuberculosis (TB) is a leading cause of death among young people globally. Each year, an estimated 1.8 million adolescents and young adults (AYAs; 10–24 years old) develop TB. In 2019, an estimated 161,000 AYAs died of the disease. AYAs have unique developmental, psychosocial, and healthcare needs, but these needs have been neglected in both TB care and research agendas. In order to improve outcomes in this age group, the specific needs of AYAs must be considered and addressed. METHODS:: Through a consensus process, an international panel of 34 clinicians, researchers, TB survivors, and advocates with expertise in child/adolescent TB and/or adolescent health proposed interventions for optimizing AYA engagement in TB care. The process consisted of reviewing the literature on TB in AYAs; identifying and discussing priority areas; and drafting and revising proposed interventions until consensus, defined a priori, was reached. RESULTS:: The panel acknowledged the dearth of evidence on best practices for identifying and managing AYAs with TB. The final consensus statement, based on expert opinion, proposes nine interventions to reform current practices that may harm AYA health and well-being, and nine interventions to establish high-quality AYA-centered TB services. CONCLUSION:: AYA-specific interventions for TB care and research are critical for improving outcomes in this age group. In the absence of evidence on best practices, this consensus statement from an international group of experts can help address the needs of AYA with TB or at risk for TB.
Nicholson T, Seddon J, Osman M, 2023, A systematic review of risk factors for mortality among tuberculosis patients in South Africa, Systematic Reviews, Vol: 12, Pages: 1-16, ISSN: 2046-4053
BackgroundTuberculosis (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.MethodsWe 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.ResultsWe 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 in
Cardoso Pinto A, Shariq S, Ranasinghe L, et al., 2023, Reasons for reductions in routine childhood immunisation uptake during the COVID-19 pandemic in low- and middle-income countries: a systematic review, PLOS Global Public Health, Vol: 3, Pages: 1-17, ISSN: 2767-3375
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 me
Waderman DT, Palmer M, Purchase S, et al., 2022, Toward a conceptual framework of the acceptability of tuberculosis treatment in children using a theory generative approach, PLOS Global Public Health, Vol: 2, ISSN: 2767-3375
To describe an early-stage holistic framework towards evaluating factors that impact the overall acceptability of TB treatment along the TB care cascade in children. We developed a conceptual framework utilising a theory generative approach. Domains were developed through review of existing definitions and analysis of existing qualitative data undertaken in acceptability studies of TB treatment in children. Clarity of domain definitions was achieved through iterative refinement among the research team. Three domains, each comprising several dimensions, were identified to holistically evaluate treatment acceptability: (1) usability, which involves the alignment between the requirements of treatment use and caregivers’ and children’s ability to integrate TB treatment into their everyday routines, (2) receptivity, which describes the end-user’s perception and expectations of treatment and its actual use, and (3) integration, which describes the relationship between available health services and caregivers/children’s capacity to make use of those services. Our framework addresses the gaps in current research which do not account for the influence of caregivers’ and children’s contexts on TB treatment uptake and overall acceptability. This approach may support the development of more standard, holistic measures to improve TB treatment delivery and experiences and future research in children.
Swanepoel J, Zimri K, van der Zalm MM, et al., 2022, Understanding the biology, morbidity and social contexts of adolescent tuberculosis: a prospective observational cohort study protocol (Teen TB), BMJ Open, Vol: 12, ISSN: 2044-6055
Introduction: A considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with the 5–10 years old age group, are incompletely understood. Despite the pressing clinical and public health need to better understand and address adolescent TB, research in this field remains limited.Methods and analysis: Teen TB is an ongoing prospective observational cohort study that aims to better understand the biology, morbidity and social context of adolescent TB. The study plans to recruit 50 adolescents (10–19 years old) with newly diagnosed microbiologically confirmed pulmonary TB disease and 50 TB-exposed controls without evidence of TB disease in Cape Town, South Africa, which is highly endemic for TB. At baseline, cases and controls will undergo a detailed clinical evaluation, chest imaging, respiratory function assessments and blood collection for viral coinfections, inflammatory cytokines and pubertal hormone testing. At 2 weeks, 2 months and 12 months, TB disease cases will undergo further chest imaging and additional lung function testing to explore the patterns of respiratory abnormalities. At week 2, cases will complete a multicomponent quantitative questionnaire about psychological and social impacts on their experiences and longitudinal, in-depth qualitative data will be collected from a nested subsample of 20 cases and their families.Ethics and dissemination: The study protocol has received ethical approval from the Stellenbosch University Health Research Ethics Committee (N19/10/148). The study findings will be disseminated through peer-reviewed publications, academic conferences and formal presentations to health professionals. Results will also be made available to participants and caregivers.
Saal C-L, Springer P, Seddon JA, et al., 2022, Risk factors of poor developmental outcome in children with tuberculous meningitis, CHILDS NERVOUS SYSTEM, ISSN: 0256-7040
van wyk S, Nliwasa M, Seddon J, et al., 2022, Drug-resistant tuberculosis case-finding strategies: a scoping review protocol, JMIR Research Protocols, Vol: 11, Pages: 1-7, ISSN: 1929-0748
Background:Transmission of drug-resistant tuberculosis (DR-TB) is ongoing. Finding individuals with DR-TB and initiating treatment as early as possible is important to improve patient clinical outcomes and to break the chain of transmission to control the pandemic. To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB to inform research, policy, and practice have not been conducted, and it is unknown whether enough research exists to conduct such reviews. It is unknown whether case-finding strategies are similar for DR-TB and drug-susceptible TB and whether we can draw on findings from drug-susceptible reviews to inform decisions on case-finding strategies for DR-TB.Objective:This protocol aims to describe the available literature on case-finding for DR-TB and to describe case-finding strategies.Methods:We will screen systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that specifically sought to improve DR-TB case detection. We will exclude studies that invited individuals seeking care for TB symptoms, those including individuals already diagnosed with TB, or laboratory-based studies. We will search the academic databases including MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL, Epistemonikos, and PROSPERO with no language or date restrictions. We will screen titles, abstracts, and full-text articles in duplicate. Data extraction and analyses will be performed using Excel (Microsoft Corp).Results:We will provide a narrative report with supporting figures or tables to summarize the data. A systems-based logic model, developed from a synthesis of case-finding strategies for drug-susceptible TB, will be used as a framework to describe different strategies, resulting pathways, and enhancements of pathways. The search will be conducted at the end of 2021. Title and abstract screening, f
Meier S, Seddon JA, Maasdorp E, et al., 2022, Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis, PLoS One, Vol: 17, ISSN: 1932-6203
Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.
Ranasinghe L, Achar J, Groschel M, et al., 2022, The global impact of COVID-19 on childhood tuberculosis: analysis of notification data, The Lancet Global Health, Vol: 10, Pages: e1774-e1781, ISSN: 2214-109X
Background:There is concern that the Coronavirus Disease-19 (COVID-19) pandemic has damaged global childhood tuberculosis management. Quantifying changes in child tuberculosis notifications could support more targeted interventions to restore child tuberculosis services.Methods: Annual case notification data reported to the World Health Organization (WHO) by 215 countries were used to calculate annual notification counts for 2014-2020 stratified by age groups (0-4, 5-14 and 15+ years) and sex. We used time series modelling to predict notification counts for 2020, and calculated differences from observed 2020 notifications at WHO region level and country-level for the 30 high tuberculosis-burden countries. We assessed association between these differences and the Oxford Government Response Tracker, a measure of COVID-19 social impact. Findings:Before 2020, annual notification counts increased across all age groups and WHO regions. More males than females 0-4 years were notified in all years and WHO regions. In 2020, global notifications for children 0-4 years were 35.4% lower than predicted (95% prediction interval [PI] -30.3 to -39.9), compared to 27.7% lower (95% PI: -23.4 to -31.5) in children 5-14 years and 18.8% lower (95%PI; -15.4 to -21.9) in 15+ years. The difference between predicted and observed notifications for 2020 were greater in males (-30.9%; 95%PI: -24.8 to -36.1) than females (-24.5%; 95%PI: -18.1 to –29.9%). No association was seen between severity of COVID-19 restrictions and change in notifications.Interpretation:Our findings suggest that COVID-19 has substantially impacted child tuberculosis services with the youngest children most affected. Although children suffered fewer severe health consequences from COVID-19 infection, they have been disproportionately affected by the consequences of the pandemic on tuberculosis care. As countries rebuild health systems post-COVID-19, it is vital that childhood tuberculosis services are placed centr
Garcia-Prats AJ, Starke JR, Waning B, et al., 2022, New Drugs and Regimens for Tuberculosis Disease Treatment in Children and Adolescents, JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY, Vol: 11, Pages: S101-S109, ISSN: 2048-7193
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Martinez L, Cords O, Liu Q, et al., 2022, Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis, LANCET GLOBAL HEALTH, Vol: 10, Pages: E1307-E1316, ISSN: 2214-109X
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Solomons RS, van Toorn R, Cresswell FV, et al., 2022, Update on the Treatment of Pediatric Tuberculous Meningitis, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 41, Pages: E393-E395, ISSN: 0891-3668
Nel Van Zyl K, Whitelaw A, Hesseling A, et al., 2022, Fungal diversity in the gut microbiome of young South African children, BMC Microbiology, Vol: 22, ISSN: 1471-2180
Background. The fungal microbiome, or mycobiome, is a poorly described component of the gut ecosystem and little is known about its structure and development in children. In South Africa, there have been no culture-independent evaluations of the child gut mycobiota. This study aimed to characterise the gut mycobiota and explore the relationships between fungi and bacteria in the gut microbiome of children from Cape Town communities. Methods. Stool samples were collected from children enrolled in the TB-CHAMP clinical trial. Internal transcribed spacer 1 (ITS1) gene sequencing was performed on a total of 115 stool samples using the Illumina MiSeq platform. Differences in fungal diversity and composition in relation to demographic, clinical, and environmental factors were investigated, and correlations between fungi and previously described bacterial populations in the same samples were described.Results. Taxa from the genera Candida and Saccharomyces were detected in all participants. Differential abundance analysis showed that Candida spp. were significantly more abundant in children younger than 2 years compared to older children. The gut mycobiota was less diverse than the bacterial microbiota of the same participants, consistent with the findings of other human microbiome studies. The variation in richness and evenness of fungi was substantial, even between individuals of the same age. There was significant association between vitamin A supplementation and higher fungal alpha diversity (p = 0.047), and girls were shown to have lower fungal alpha diversity (p = 0.003). Co-occurrence between several bacterial taxa and Candida albicans was observed.Conclusions. The dominant fungal taxa in our study population were similar to those reported in other paediatric studies; however, it remains difficult to identify the true core gut mycobiota due to the challenges set by the low abundance of gut fungi and the lack of true gut colonising species. The connection between the
Cardoso Pinto A, Ranasinghe L, Dodd P, et al., 2022, Disruptions to routine childhood vaccinations in low- and middle-Income countries during the COVID-19 pandemic: a systematic review, Frontiers in Pediatrics, Vol: 10, ISSN: 2296-2360
BackgroundThe COVID-19 pandemic has disrupted routine childhood vaccinations worldwide with low- and middle-income countries (LMICs) most affected. This study aims to quantify levels of disruption to routine vaccinations in LMICs. MethodsA systematic review (PROSPERO CRD42021286386) was conducted of MEDLINE, Embase, Global Health, CINAHL, Scopus and MedRxiv, on the 11th of February 2022. Primary research studies published from January 2020 onwards were included if they reported levels of routine paediatric vaccinations before and after March 2020. Study appraisal was performed using NHLBI tool for cross-sectional studies. Levels of disruption were summarised using medians and interquartile ranges. ResultsA total of 39 cross-sectional studies were identified. These showed an overall relative median decline of 10.8% (interquartile range [IQR] -27.6%, -1.4%) across all vaccines. Upper-middle-income countries (upper-MICs) (-14.3%; IQR -24.3%, -2.4%) and lower-MICs (-18.0%; IQR 48.6%, 4.1%) showed greater declines than low-income countries (-3.1%; IQR -12.8%, 2.9%), as did vaccines administered at birth (-11.8%; IQR -27.7%, -3.5%) compared to those given after birth (-8.0%; IQR -28.6%, -0.4%). Declines during the first three months of the pandemic ( 8.1%; IQR -35.1%, -1.4%) were greater than during the remainder of 2020 (-3.9%; IQR 13.0%, 11.4%) compared to baseline. ConclusionThere has been a decline in routine paediatric vaccination, greatest in MICs and for vaccines administered at birth. Nations must prioritise catch-up programmes alongside public health messaging to encourage vaccine uptake.
Wademan D, Goddinott G, Purchase S, et al., 2022, Practical and psychosocial challenges faced by caregivers influence the acceptability of multidrug-resistant tuberculosis preventive therapy for young children, PLoS One, Vol: 17, Pages: 1-18, ISSN: 1932-6203
Drug-resistant (DR) strains of Mycobacterium tuberculosis (M. tb) are increasingly recognised as a threat to global tuberculosis (TB) control efforts. Identifying people with DR-TB exposure/ infection and providing TB preventive therapy (TPT) is a public health priority. TB guidelines advise the evaluation of household contacts of newly diagnosed TB cases, with the provision of TPT to vulnerable populations, including young children (<5 years). Many children become infected with TB through exposure in their household. Levofloxacin is under evaluation as TPT in children exposed to M. tb strains with resistance to rifampicin and isoniazid (multidrug-resistant TB; MDR-TB).Prior to opening a phase 3 prevention trial in children <5 years exposed to MDR-TB, the pharmacokinetics and safety of a novel formulation of levofloxacin given daily was evaluated as part of a lead-in study. We conducted an exploratory qualitative study of 10 caregivers’ experiences of administering this formulation. We explored how the acceptability of levofloxacin as TPT is shaped by the broader impacts of MDR-TB on the overall psychological, social, and financial wellbeing of caregivers, many of whom also had experienced MDR-TB.Caregivers reported that the novel levofloxacin formulation was acceptable. However, caregivers described significant psychosocial challenges in the process of incorporating TPT administration to their children into their daily lives, including financial instability, withdrawal of social support and stigma. When caregivers themselves were sick, these challenges became even more acute. Although new child-friendly formulations can ameliorate some of the pragmatic challenges related to TPT preparation and administration, the overall psychosocial burden on caregivers responsible for administering TPT remains a major determinant of effective MDR-TB prevention in children.
Kaforou M, Broderick C, Vito O, et al., 2022, Transcriptomics for child and adolescent tuberculosis, Immunological Reviews, Vol: 309, ISSN: 0105-2896
Tuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is estimated that 70 million children (<15 years) are currently infected with Mtb, with 1.2 million each year progressing to disease. Of these, a quarter die. The risk of progression from Mtb infection to disease and from disease to death is dependent on multiple pathogen and host factors. Age is a central component in all these transitions. The natural history of TB in children and adolescents is different to adults, leading to unique challenges in the development of diagnostics, therapeutics, and vaccines. The quantification of RNA transcripts, encoded in the genome in specific cells or in the peripheral blood, using high-throughput methods, such as microarray analysis or RNA sequencing, are emerging technologies. RNA sequencing can shed light into the host immune response to Mtb during infection and disease, as well as understanding treatment response, disease severity and vaccination, in a global hypothesis-free manner. Additionally, gene expression profiling can be used for biomarker discovery, to diagnose disease, predict future disease progression and to monitor response to treatment. Here, we review the role of transcriptomics in children and adolescents, focussed mainly on work done in blood, to understand disease biology and to discriminate disease states to assist clinical decision-making. In recent years, studies with a specific paediatric and adolescent focus have identified blood gene expression markers with diagnostic or prognostic potential that meet or exceed the current sensitivity and specificity targets for diagnostic tools. Diagnostic and prognostic gene expression signatures identified through high-throughput methods are currently being translated into diagnostic tests.
Dodd P, Mafirakureva N, Seddon J, et al., 2022, The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study, The Lancet Global Health, Vol: 10, Pages: e1034-e1044, ISSN: 2214-109X
Background:Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done.Methods:We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy.Findings:Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000–252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940–2790), costing an additional US$63 million (74–95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540–6890) and an additional 1240 deaths (970–1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product f
Groschel MI, van den Boom M, Dixit A, et al., 2022, Management of childhood MDR-TB in Europe and Central Asia: report of a Regional WHO meeting, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 26, Pages: 433-440, ISSN: 1027-3719
Lopez-Varela E, Abulfathi AA, Strydom N, et al., 2022, Drug concentration at the site of disease in children with pulmonary tuberculosis, Journal of Antimicrobial Chemotherapy, Vol: 77, Pages: 1710-1719, ISSN: 0305-7453
BackgroundCurrent TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB.ObjectivesTo determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB.MethodsWe quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions.ResultsIsoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions.ConclusionsDespite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.
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