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Coronavirus disease (COVID-19) negatively impacted tuberculosis (TB) programs which were already struggling to meet End-TB targets globally. We aimed to quantify and compare diagnosis, treatment initiation, treatment success, and losses along this TB care cascade for drug-susceptible TB in Cape Town, South Africa, prior to and during COVID-19. This observational study used routine TB data within two predefined cohorts: pre-COVID-19 (1 October 2018-30 September 2019) and during-COVID-19 (1 April 2020-31 March 2021). The numbers of people diagnosed, treated for TB and successfully treated were received from the Western Cape Provincial Health Data Centre. Pre and post treatment loss to follow up and cascade success rates (proportion of individuals diagnosed with an outcome of treatment success) were calculated and compared across cohorts, disaggregated by sex, age, HIV status, TB treatment history and mode of diagnosis. There were 27,481 and 19,800 individuals diagnosed with drug-susceptible TB in the pre- and during-COVID-19 cohorts respectively, a relative reduction of 28% (95% CI [27.4% - 28.5%]). Initial loss to follow up increased from 13.4% to 15.2% (p<0.001), while post treatment loss increased from 25.2% to 26.1% (p < 0.033). The overall cascade success rate dropped by 2.1%, from 64.8% to 62.7% (p< 0.001). Pre- and during-COVID-19 cascade success rates were negatively associated with living with HIV and having recurrent TB. An already poorly performing TB program in Cape Town was negatively impacted by the COVID-19 pandemic. There was a substantial reduction in the number of individuals diagnosed with drug-susceptible. Increases in pre-and post-treatment losses resulted in a decline in TB cascade success rates. Strengthened implementation of TB recovery plans is vital, as health services now face an even greater gap between achievements and targets and will need to become more resilient to possible future public health disruptions.

Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

In South Africa, low tuberculosis (TB) treatment coverage and high TB case fatality remain important challenges. Following TB diagnosis, patients must link with a primary health care (PHC) facility for initiation or continuation of antituberculosis treatment and TB registration. We aimed to evaluate mortality among TB patients who did not link to a TB treatment facility for TB treatment within 30 days of their TB diagnosis, i.e. who were “initial loss to follow-up (ILTFU)” in Cape Town, South Africa. We prospectively included all patients with a routine laboratory or clinical diagnosis of TB made at PHC or hospital level in Khayelitsha and Tygerberg sub-districts in Cape Town, using routine TB data from an integrated provincial health data centre between October 2018 and March 2020. Overall, 74% (10,208/13,736) of TB patients were diagnosed at PHC facilities and ILTFU was 20.0% (2,742/13,736). Of ILTFU patients, 17.1% (468/2,742) died, with 69.7% (326/468) of deaths occurring within 30 days of diagnosis. Most ILTFU deaths (85.5%; 400/468) occurred in patients diagnosed in hospital. Multivariable logistic regression identified increasing age, HIV positive status, and hospital-based TB diagnosis (higher in the absence of TB treatment initiation and being ILTFU) as predictors of mortality. Although hospitals account for a modest proportion of diagnosed TB patients they have high TB-associated mortality. A hospital-based TB diagnosis is a critical opportunity to identify those at high risk of early and overall mortality. Interventions to diagnose TB before hospital admission, improve linkage to TB treatment following diagnosis, and reduce mortality in hospital-diagnosed TB patients should be prioritised.

[...]medications, including those for TB, are often prescribed in pregnancy without the knowledge required to achieve appropriate doses for optimal therapeutic effect [23,24], and WHO and Centers for Disease Control and Prevention (CDC) recommend conflicting treatment guidelines for drug-susceptible TB (i.e., 6-month regimen, including pyrazinamide versus 9-month regimen, excluding pyrazinamide, respectively) [25,26]. [...]TB diagnosis and treatment response monitoring rely on clinical, more subjective measures in at least 60% of children, as young children cannot spontaneously produce sputum for examination, and paucibacillary disease (sputum smear negative) is diagnosed by culture, the current diagnostic gold standard, in only 30%–40% of cases [55]. [...]child-friendly formulations are important to ensure accurate, acceptable, and palatable doses in young children. [...]data analysis should be stratified by HIV infection/HIV disease status (i.e., HIV-uninfected, HIV-infected with high CD4 count, and HIV-infected with low CD4 count) to reduce concerns about any potential imbalances in subgroup numbers between randomized arms.

Approximately 30,000 children (<15 years) develop multidrug-resistant (MDR) tuberculosis (TB) each year. MDR-TB severely impacts the lives of children and their families, yet data exploring their experiences are limited. We describe the experiences of children routinely treated for MDR-TB and their caregivers throughout their MDR-TB journeys in Cape Town, South Africa. We conducted a series of three in-depth qualitative interviews (48 interviews in total) with 17 children (<15 years) and/or their caregivers between April 2021 and September 2021. We selected children who had been routinely treated for MDR-TB between 2018 and 2021. We applied a deductive, thematic analysis to case summaries with illustrative examples from interviews. Children had negative experiences throughout their MDR-TB journey, before their diagnosis, during the diagnostic process, through treatment, and beyond treatment completion. Children and their caregivers experienced delays in acquiring accurate and timely MDR-TB diagnosis; stating lack of symptom recognition and repeated referrals between health facilities. Once on treatment, caregivers experienced challenges administering MDR-TB medication as children resisted taking their medications due to poor palatability, tolerability, and negative side effects. Some caregivers reported that, beyond treatment, children experienced extended physical challenges such as shortness of breath. Additionally, MDR-TB diagnosis and treatment negatively affected family life, as caregivers adjusted household spending toward foods that facilitated ingestion and mitigated side effects. Caregivers also juggled between attending to their children's MDR-TB care and other household priorities. There are multifactorial challenges experienced by children and their caregivers throughout their MDR-TB journey. Research is needed to develop holistic interventions for child-caregiver-centred psychosocial support to mitigate the negative impact of MDR-TB on children and their caregivers through prevention, earlier diagnosis, and simpler, child-friendly regimens. [1112,3].

Children who are hospitalised for tuberculosis (TB) experience challenges that put them at risk of developing emotional, behavioural, and social difficulties. In this methodological paper, we showcase the development of a narrative intervention toolkit with key components of the resulting version 1.0 tool. The study design was participatory and pragmatic, with researchers working with the routine staff of TB hospital wards, children admitted and their caregivers, to iteratively understand and improve children's experiences of hospitalisation. The project included three phases: (1) a situational analysis to map children and healthcare providers' perspectives on priorities and potential intervention components, (2) co-development of a beta-version of the intervention, and (3) piloting and incremental refinement toward a version 1.0 of the intervention. The intervention toolkit combined a series of activities alongside the story of 'Courageous Curly' to facilitate children's engagement with their own experiences of hospitalisation, including psychosocial and treatment challenges, captured, and described throughout data collection. We found that dividing the story into short chapters facilitated children's engagement with the section of story that is being told on a specific day. Each chapter of the story follows/mimics a different stage children can expect during their treatment journey while hospitalised for TB care. Implementation and evaluation of such interventions can mitigate the psychosocial impact of TB in children and inform policies to improve their overall TB care.

Tuberculosis during pregnancy and treatment outcomes are poorly defined in high prevalence tuberculosis and HIV settings. A prospective cohort study of pregnant and postpartum women identified to be routinely on antituberculosis treatment was conducted at Tygerberg Hospital, Cape Town, South Africa, from January 2011 through December 2011. Maternal tuberculosis disease spectrum and tuberculosis-exposed newborns were characterized by maternal HIV status. Maternal tuberculosis treatment outcomes were documented and a multivariable regression model identified predictors of unfavourable tuberculosis treatment outcomes. Infant outcomes were also described. Seventy-four women with tuberculosis, 53 (72%) HIV-infected, were consecutively enrolled; 35 (47%) were diagnosed at delivery or postpartum and 22 (30%) of women reported previous antituberculosis treatment. HIV-infected women were 5.67 times more likely to have extrapulmonary tuberculosis (95% CI 1.18-27.25, p = 0.03). All 5 maternal deaths were amongst HIV-infected women. Birth outcomes were available for 75 newborns (2 sets of twins, missing data for 1 stillbirth). Of the 75 newborns, 49 (65%) were premature and 44 (59%) were low birth weight (LBW; <2500 grams). All 6 infants who died and the 4 stillbirths were born to HIV-infected women. Unfavourable tuberculosis treatment outcomes were documented in 33/74 (45%) women. Unfavourable maternal tuberculosis outcome was associated with delivery of LBW infants (OR 3.83; 95% CI 1.40-10.53, p = 0.009). A large number of pregnant women with tuberculosis presented at a provincial referral hospital. All maternal and infant deaths occurred in HIV-infected women and their newborns. Maternal tuberculosis treatment outcomes were poor.

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.

The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence. 76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-α2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation. Measurement of the levels of IFN-α2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.

Rifampicin-resistant (RR) tuberculosis (TB) in children is a major global health concern but is often neglected in economics research. Accurate cost estimations across the spectrum of paediatric RR-TB treatment regimens are critical inputs for prioritisation and budgeting decisions, and an existing knowledge gap at local and international levels. This normative cost analysis was nested in a Phase I/II pharmacokinetics, safety, tolerability, and acceptability trial of TB medications in children in South Africa, the Philippines and India. It assessed the pharmaceutical costs of 36 childhood RR-TB regimens using combinations from 16 different medicines in 34 oral formulations (adult and child-friendly) in 11 weight bands in children <15 years of age. The analysis used local and Global Drug Facility pricing, and local and international guideline recommendations, including adaptions of BPaL and BPaLM regimens in adults. Costs varied significantly between regimen length, age/weight banding, severity of disease, presence of fluroquinolone resistance, and different country guideline recommendations. WHO recommended regimen costs ranged 12-fold: from US $232 per course (short regimen in non-severe disease) to US$ 2,761 (long regimen in severe, fluroquinolone-resistant disease). Regimen treating fluoroquinolone-resistant infection cost US $1,090 more than comparable WHO-recommended regimen. Providing child-friendly medicine formulations in <5-year-olds across all WHO-recommended regimens is expected to cost an additional $ 380 (range$212-$ 563) per child but is expected to have wider benefits including palatability, acceptability, adherence, tolerability, and dose accuracy. There were substantial differences in regimen affordability between countries when adjusted for purchasing power and domestic spending on health. Appropriate, effective, and affordable treatment options are an important component of the fight against childhood RR-TB. A comprehensive understanding of the cost and affordability dynamics of treatment options will enable national TB programs and global collaborations to make the best use of limited healthcare resources for the care of children with RR-TB.