Management of childhood MDR-TB in Europe and Central Asia: report of a Regional WHO meeting.

BACKGROUND: As the WHO European Region has the highest proportion of multidrug-resistant TB (MDR-TB) among total incident TB cases, many children and adolescents are at risk of MDR-TB infection and disease.METHODS: We performed an electronic survey of clinicians and TB programme personnel who attended the 2020 Regional Consultation on child and adolescent TB organised by the WHO Regional Office. We characterised access to diagnostics and drugs, and practices in the prevention and management of child and adolescent MDR-TB.RESULTS: Children and adolescents are inconsistently represented in national guidelines and budgets; child-friendly drug formulations for MDR-TB treatment are insufficiently available in 57% of countries, and 32% of countries reported paediatric drug stock-outs. The novel drugs, bedaquiline and delamanid, are accessible by respectively 80% and 60% of respondent countries. Respondents were asked how many children were diagnosed with MDR-TB in 2019, and a comparison of this number to modelled estimates of incidence (to identify the case detection gap) and WHO notifications (to identify the case reporting gap) showed substantial differences in both comparisons.CONCLUSIONS: Better representation of this patient group in guidelines and budgets, greater access to drugs and improved reporting are essential to reach TB elimination in this Region.

The effect of systematic screening of the general population on TB case notification rates.

BACKGROUND: Understanding how TB case notification rates (TB-CNR) change with TB screening and their association with underlying TB incidence/prevalence could inform how they are best used to monitor screening impact.METHODS: We undertook a systematic review to identify articles published between 1 January 1980 and 13 April 2020 on TB-CNR trends associated with TB screening in the general-population. Using a simple compartmental TB transmission model, we modelled TB-CNRs, incidence and prevalence dynamics during 5 years of screening.RESULTS: Of 27,282 articles, seven before/after studies were eligible. Two involved population-wide screening, while five used targeted screening. The data suggest screening was associated with initial increases in TB-CNRs. Increases were greatest with population-wide screening, where screening identified a large proportion of notified people with TB. Only one study reported on sustained screening; TB-CNR trends were compatible with model simulations. Model simulations always showed a peak in TB-CNRs with screening. Following the peak, TB-CNRs declined but were typically sustained above baseline during the intervention. Incidence and prevalence decreased during the intervention; the relative decline in incidence was smaller than the decline in prevalence.CONCLUSIONS: Published data on TB-CNR trends with TB screening are limited. These data are needed to identify generalisable patterns and enable method development for inferring underlying TB incidence/prevalence from TB-CNR trends.

Modelling the social and structural determinants of tuberculosis: opportunities and challenges.

INTRODUCTION: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants. OBJECTIVE: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB. METHODS: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting. RESULTS: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socio-economic and nutritional status), and one focused on macro-economic influences. CONCLUSIONS: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes.

The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis.

BACKGROUND: Children (<15 years) are vulnerable to TB disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. OBJECTIVES: Determine the impact of HIV infection and ART on risk of incident TB disease in children. METHODS: We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases ('TB cohorts') and paediatric HIV cohorts reporting TB incidence ('HIV cohorts'). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4%, relative incidence by immunological stage and ART-associated protection from TB. RESULTS: 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% CI 4.5 to 13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95% CI 4.0 to 6.0) times higher in children with severe compared with non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (HR: 0.30; 95% CI 0.21 to 0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a HR of 0.10 (95% CI 0.04 to 0.25). CONCLUSIONS: HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk. TRIAL REGISTRATION NUMBER: CRD42014014276.

Coverage of clinic-based TB screening in South Africa may be low in key risk groups.

The South African Ministry of Health has proposed screening all clinic attendees for tuberculosis (TB). Amongst other factors, male sex and bar attendance are associated with higher TB risk. We show that 45% of adults surveyed in Western Cape attended a clinic within 6 months, and therefore potentially a relatively high proportion of the population could be reached through clinic-based screening. However, fewer than 20% of all men aged 18-25 years, or men aged 26-45 who attend bars, attended a clinic. The population-level impact of clinic-based screening may be reduced by low coverage among key risk groups.

Le Ministère de la Santé d'Afrique du Sud a proposé de dépister la tuberculose (TB) chez tous les patients visitant un centre de santé. Parmi d'autres facteurs, le sexe masculin et la fréquentation des bars sont associés à un risque plus élevé de TB. Nous montrons que 45% des adultes dépistés dans la province du Cap Ouest s'étaient rendus dans un centre de santé au cours des 6 derniers mois et c'est pourquoi une proportion relativement élevée de la population pourrait être atteinte à travers un dépistage en centre de santé. Cependant, moins de 20% de tous les hommes âgés de 18­25 ans, ou des hommes âgés de 26­45 ans qui fréquentent les bars, se rendent dans un centre de santé. L'impact sur la population de ce type de dépistage pourrait donc être réduit par une faible couverture parmi les groupes à risque majeur.

El Ministerio de Salud de Suráfrica propuso una detección sistemática de la tuberculosis (TB) a todas las personas que acudían a los consultorios. Entre los factores asociados con un mayor riesgo de padecer TB están el sexo masculino y la frecuentación de bares. El presente artículo pone de manifiesto que 45% de los adultos encuestados en la Ciudad del Cabo había acudido a un establecimiento de salud en los últimos 6 meses, por lo cual se pudo llegar a una proporción relativamente alta de la población mediante esta detección sistemática. Sin embargo, menos del 20% de todos los hombres entre los 18 y los 25 años, o entre los 26 y los 45 años de edad que frecuenta los bares, acudió a los establecimientos de salud. La repercusión a escala de la población de una detección sistemática realizada en los consultorios podría verse atenuada por una baja cobertura de los grupos más vulnerables.

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete.

Reconstructing disease outbreaks from genetic data: a graph approach.

Epidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. In particular, genetic data coupled with dates and locations of sampled isolates can be used to reconstruct the spatiotemporal dynamics of pathogens during outbreaks. Thus far, phylogenetic methods have been used to tackle this issue. Although these approaches have proved useful for informing on the spread of pathogens, they do not aim at directly reconstructing the underlying transmission tree. Instead, phylogenetic models infer most recent common ancestors between pairs of isolates, which can be inadequate for densely sampled recent outbreaks, where the sample includes ancestral and descendent isolates. In this paper, we introduce a novel method based on a graph approach to reconstruct transmission trees directly from genetic data. Using simulated data, we show that our approach can efficiently reconstruct genealogies of isolates in situations where classical phylogenetic approaches fail to do so. We then illustrate our method by analyzing data from the early stages of the swine-origin A/H1N1 influenza pandemic. Using 433 isolates sequenced at both the hemagglutinin and neuraminidase genes, we reconstruct the likely history of the worldwide spread of this new influenza strain. The presented methodology opens new perspectives for the analysis of genetic data in the context of disease outbreaks.

Approximate disease dynamics in household-structured populations.

We argue that the large-dimensional dynamical systems which frequently occur in biological models can sometimes be effectively reduced to much smaller ones. We illustrate this by applying projection operator techniques to a mean-field model of an infectious disease spreading through a population of households. In this way, we are able to accurately approximate the dynamics of the system in terms of a few key quantities greatly reducing the number of equations required. We investigate linear stability in this framework and find a new way of calculating the familiar threshold criterion for household systems.