People-centred care versus clinic-based DOT for continuation phase TB treatment in Armenia: a cluster randomized trial.

BACKGROUND: WHO's directly observed therapy (DOT) strategy for tuberculosis (TB) treatment depends upon a well-organized healthcare system. This study sought to evaluate the effectiveness of self-administered drug intake supported by a family member versus in-clinic DOT. METHODS: This open-label, nationally-representative stratified cluster randomized controlled non-inferiority trial with two parallel equal arms involved drug-susceptible pulmonary TB patients in the continuation treatment phase. We randomly assigned outpatient-TB-centres (52 clusters) to intervention and control arms. The intervention included an educational/counseling session to enhance treatment adherence; weekly visits to outpatient-TB-centres to receive medication, and daily SMS medication reminders and phone calls to track adherence and record side effects. Controls followed clinical DOT at Outpatient-TB-centres. Both groups participated in baseline and 4-5 months follow-up surveys. The trial's non-inferiority comparisons include: treatment success as the clinical (primary) outcome and medication adherence (self-reported), knowledge, depressive symptoms, stigma, quality of life, and social support as non-clinical (secondary) outcomes. RESULTS: Per-protocol analysis showed that the intervention (n = 187) and control (n = 198) arms achieved successful treatment outcome of 92.0 and 92.9%, respectively, indicating that the treatment success in the intervention group was non-inferior to DOT. Knowledge, depression, stigma, quality of life, and social support also showed non-inferiority, demonstrating substantial improvement over time for knowledge (change in the intervention = 1.05: 95%CL (0.49, 1.60); change in the control = 1.09: 95%CL (0.56, 1.64)), depression score (change in the intervention = - 3.56: 95%CL (- 4.99, - 2.13); change in the control = - 1.88: 95% CL (- 3.26, - 0.49)) and quality of life (change in the intervention = 5.01: 95%CL (- 0.64, 10.66); change in the control = 7.29: 95%CL (1.77, 12.81)). The intervention resulted in improved treatment adherence. CONCLUSIONS: This socially empowering alternative strategy might be a preferable alternative to DOT available to patients in Armenia and in other countries. Further research evaluating cost effectiveness of the intervention and generalizability of the results is warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02082340, March 10, 2014.

Factors contributing to drug-resistant tuberculosis treatment outcome in five countries in the Eastern Europe and Central Asia region.

Drug-resistant tuberculosis (DR-TB) is a global challenge and a major contributor of death from anti-microbial resistance. With the main aim to determine factors contributing to treatment outcomes observed among DR-TB patients in the countries in Eastern Europe and Central Asia (EECA), a multi-method study was conducted in: Azerbaijan, Belarus, Romania, Tajikistan and Ukraine. Both quantitative and qualitative methodologies were used for data collection and analysis. The quantitative approaches included a desk review of documents related to the DR-TB responses and an analysis of clinical records of DR-TB patients in selected health facilities of the five countries. Qualitative methods included in-depth interviews with national TB programme (NTP) managers, other healthcare providers and non-governmental organizations (NGOs) workers, as well as interviews and Focus Group Discussions (FGDs) with DR-TB patients. The desk review of 38 reports identified as the main challenges to address DR-TB financial and/or management issues and adverse events of the medicines. The most common recommendations related to treatment outcome focussed on general programme management, treatment regimen composition, clinical management and social support for the patients. In all the five countries the NTPs still have a vertical structure. Some integration into the primary health care system (PHC) already exists but further involvement of PHC facilities is feasible and recommended. Interviews with stakeholders indicated that alcoholism and homelessness and a lack of appropriate response to these issues remain as major challenges for a sub-set of patients. Civil society groups, NGOs and communities are substantially engaged in providing different services to DR-TB patients, especially in Ukraine, Romania and Tajikistan. Data from clinical records of 212 patients revealed that independent risk factors for unfavourable treatment outcome (death, loss to follow-up, failure) were culture-positivity at two months of treatment, history of treatment with second-line drugs and homelessness. More powerful, less toxic and shorter oral treatment regimens as well as comprehensive patient support are needed to improve treatment outcome of patients with DR-TB.

Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe.

Evidence-based guidance is needed on 1) how tuberculosis (TB) infectiousness evolves in response to effective treatment and 2) how the TB infection risk can be minimised to help countries to implement community-based, outpatient-based care.This document aims to 1) review the available evidence on how quickly TB infectiousness responds to effective treatment (and which factors can lower or boost infectiousness), 2) review policy options on the infectiousness of TB patients relevant to the World Health Organization European Region, 3) define limitations of the available evidence and 4) provide recommendations for further research.The consensus document aims to target all professionals dealing with TB (e.g TB specialists, pulmonologists, infectious disease specialists, primary healthcare professionals, and other clinical and public health professionals), as well as health staff working in settings where TB infection is prevalent.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

Childhood multidrug-resistant tuberculosis in the European Union and European Economic Area: an analysis of tuberculosis surveillance data from 2007 to 2015.

BackgroundConfirming tuberculosis (TB) in children and obtaining information on drug susceptibility is essential to ensure adequate treatment. We assessed whether there are gaps in diagnosis and treatment of multidrug-resistant (MDR) TB in children in the European Union and European Economic Area (EU/EEA), quantified the burden of MDR TB in children and characterised cases. Methods: We analysed surveillance data from 2007 to 2015 for paediatric cases younger than 15 years. Results: In that period, 26 EU/EEA countries reported 18,826 paediatric TB cases of whom 4,129 (21.9%) were laboratory-confirmed. Drug susceptibility testing results were available for 3,378 (17.9%), representing 81.8% of the confirmed cases. The majority (n = 2,967; 87.8%) had drug-sensitive TB, 249 (7.4%) mono-resistant TB, 64 (1.9%) poly-resistant TB, 90 (2.7%) MDR TB and eight (0.2%) had extensively drug-resistant (XDR) TB. MDR TB was more frequently reported among paediatric cases with foreign background (adjusted odds ratio (aOR) = 1.73; 95% confidence interval (95% CI): 1.12-2.67) or previous TB treatment (aOR: 6.42; 95% CI: 3.24-12.75). Successful treatment outcome was reported for 58 of 74 paediatric MDR TB cases with outcome reported from 2007 to 2013; only the group of 5-9 years-olds was significantly associated with unsuccessful treatment outcome (crude odds ratio (cOR) = 11.45; 95% CI: 1.24-106.04). Conclusions: The burden of MDR TB in children in the EU/EEA appears low, but may be underestimated owing to challenges in laboratory confirmation. Diagnostic improvements are needed for early detection and adequate treatment of MDR TB. Children previously treated for TB or of foreign origin may warrant higher attention.

Psychosocial support interventions to improve treatment outcomes for people living with tuberculosis: a mixed methods systematic review and meta-analysis.

Background: People with tuberculosis (TB) face multi-dimensional barriers when accessing and engaging with care. There is evidence that providing psychosocial support within people-centered models of care can improve TB outcomes, however, there is limited consensus on what works. It remains important for such interventions to be rigorously assessed, and mixed methods systematic reviews are one way of synthesising data for policy makers to be able to access such evidence. Mixed methods reviews take a complexity perspective, with qualitative data being used to contextualise the quantitative findings and giving an insight into how interventions are contingent on variations in design and context. Methods: Five electronic databases were searched from January 1 2015 to 14 January 2023 for randomised controlled trials, quasi-experimental trials, cohort studies and qualitative studies of interventions providing psychosocial support (material and/or psychological-based support) to adults with any clinical form of active TB. Studies with inpatient treatment as the standard of care were excluded. Quantitative studies reporting pre-specified standard TB outcomes were eligible. In line with established mixed methods review methodology, a convergent parallel-results synthesis design was followed: quantitative and qualitative syntheses were distinct and carried out using appropriate methods. A convergent coding matrix was then used to integrate the results. The protocol was registered on PROSPERO (CRD42021235211). Findings: Twenty-three studies of interventions were included (12 quantitative, 10 qualitative, and 1 mixed methods study) were included. Most studies were conducted in low-and middle-income countries with a high-burden of TB. Three explanatory and contextual middle-range theories from the integration of qualitative and quantitative data were developed: effective interventions provide multi-dimensional support; psychological-based support is transformative but there is insufficient evidence that it improves treatment outcomes on its own; intervention delivery shapes a logic of care. Interpretation: This review takes a complexity perspective to provide actionable and timely insight to inform the design and implementation of locally-appropriate and people-centered psychosocial support interventions within national TB programmes. Funding: There was no funding source for this study.

Impact of COVID-19 on diagnosis of tuberculosis, multidrug-resistant tuberculosis, and on mortality in 11 countries in Europe, Northern America, and Australia. A Global Tuberculosis Network study.

OBJECTIVES: Although evidence is growing on the overall impact of the COVID-19 pandemic on tuberculosis (TB) services, global studies based on national data are needed to better quantify the extent of the impact and the countries' preparedness to tackle the two diseases. The aim of this study was to compare the number of people with new diagnoses or recurrence of TB disease, the number of drug-resistant (DR)-TB, and the number of TB deaths in 2020 vs 2019 in 11 countries in Europe, Northern America, and Australia. METHODS: TB managers or directors of national reference centers of the selected countries provided the agreed-upon variables through a validated questionnaire on a monthly basis. A descriptive analysis compared the incidence of TB and DR-TB and mortality of the pre-COVID-19 year (2019) vs the first year of the COVID-19 pandemic (2020). RESULTS: Comparing 2020 vs 2019, lower number of TB cases (new diagnosis or recurrence) was notified in all countries (except USA-Virginia and Australia), and fewer DR-TB notifications (apart from France, Portugal, and Spain). The deaths among TB cases were higher in 2020 compared to 2019 in most countries with three countries (France, The Netherlands, USA-Virginia) reporting minimal TB-related mortality. CONCLUSIONS: A comprehensive evaluation of medium-term impact of COVID-19 on TB services would benefit from similar studies in multiple settings and from global availability of treatment outcome data from TB/COVID-19 co-infected patients.

History of prevention, diagnosis, treatment and rehabilitation of pulmonary sequelae of tuberculosis.

Tuberculosis (TB), known as the White Plague' is of great significance to humanity for the magnitude of morbidity and mortality it has generated over centuries from the very start of human civilization. In this Review, we will describe the history of prevention (vaccination and management of TB infection), diagnosis, treatment and pulmonary rehabilitation of post-treatment sequelae. The article leads the reader through the main discoveries which paved the way to the modern approach to TB prevention and care. The history of Bacille Calmette-Guérin (BCG) vaccine and of the diagnosis and treatment of TB infection are presented, together with that of diagnosis and treatment of TB disease. Pivotal was in 1882 the discovery by Robert Koch of the aetiological agent of TB, and his pioneering work in culturing the bacillus and developing tuberculin. Also of enormous importance was, in 1895, the discovery of the X-rays by Wilhelm Conrad Röntgen, discovery which paved the way to the development of the modern imaging technologies. To complement this, the more recent history of rehabilitation of post-treatment sequelae is summarized, given the importance this issue has on patients' wellbeing and Quality of Life.

Drug resistant TB - latest developments in epidemiology, diagnostics and management.

AIM: The aim of this review is to inform the reader on the latest developments in epidemiology, diagnostics and management. EPIDEMIOLOGY: Drug-resistant Tuberculosis (DR-TB) continues to be a current global health threat, and is defined by higher morbidity and mortality, sequelae, higher cost and complexity. The WHO classifies drug-resistant TB into 5 categories: isoniazid-resistant TB, rifampicin resistant (RR)-TB and MDR-TB, (TB resistant to isoniazid and rifampicin), pre-extensively drug-resistant TB (pre-XDR-TB) which is MDR-TB with resistance to a fluoroquinolone and finally XDR-TB that is TB resistant to rifampicin, plus any fluoroquinolone, plus at least one further priority A drug (bedaquiline or linezolid). Of 500,000 estimated new cases of RR-TB in 2020, only 157 903 cases are notified. Only about a third of cases are detected and treated annually. DIAGNOSTICS: Recently newer rapid diagnostic methods like the GeneXpert, whole genome sequencing and Myc-TB offer solutions for rapid detection of resistance. TREATMENT: The availability of new TB drugs and shorter treatment regimens have been recommended for the management of DR-TB. CONCLUSION: Despite advances in diagnostics and treatments we still have to find and treat two thirds of the drug resistant cases that go undetected and therefore go untreated each year. Control of TB and elimination will only occur if cases are detected, diagnosed and treated promptly.

Delamanid-containing regimens and multidrug-resistant tuberculosis: A systematic review and meta-analysis.

INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening condition needing long poly-chemotherapy regimens. As no systematic reviews/meta-analysis is available to comprehensively evaluate the role of delamanid (DLM), we evaluated its effectiveness and safety. METHODS: We reviewed the relevant scientific literature published up to January 20, 2022. The pooled success treatment rate with 95% confidence intervals (CI) was assessed using a random-effect model. We assessed studies for quality and bias, and considered P<0.05 to be statistically significant. RESULTS: After reviewing 626 records, we identified 25 studies that met the inclusion criteria, 22 observational and 3 experimental, with 1276 and 411 patients, respectively. In observational studies the overall pooled treatment success rate of DLM-containing regimens was 80.9% (95% CI 72.6-87.2) with no evidence of publication bias (Begg's test; P >0.05). The overall pooled treatment success rate in DLM and bedaquiline-containing regimens was 75.2% (95% CI 68.1-81.1) with no evidence of publication bias (Begg's test; P >0.05). In experimental studies the pooled treatment success rate of DLM-containing regimens was 72.5 (95% CI 44.2-89.8, P <0.001, I2: 95.1%) with no evidence of publication bias (Begg's test; P >0.05). CONCLUSIONS: In MDR-TB patients receiving DLM, culture conversion and treatment success rates were high despite extensive resistance with limited adverse events.

Tuberculosis, COVID-19 and hospital admission: Consensus on pros and cons based on a review of the evidence.

The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World Health Organization documents, based on Global Tuberculosis Network (GTN) expert opinion. The core published documents and guidelines on the topic have been reviewed. The proportion of new TB cases admitted to hospital ranges between 50% and 100% while for multidrug-resistant (MDR) TB patients it ranges between 85 and 100% globally. For TB patients with COVID-19 the proportion of cases admitted is 58%, probably reflecting different scenarios related to the diagnosis of COVID-19 before, after or at the same time of the active TB episode. The hospital length of stay for drug-susceptible TB ranges from 20 to 60 days in most of countries, ranging from a mean of 10 days (USA) to around 90 days in the Russian Federation. Hospitalization is longer for MDR-TB (50-180 days). The most frequently stated reasons for recommending hospital admission include: severe TB, infection control concerns, co-morbidities and drug adverse events which cannot be managed at out-patient level. The review also provides suggestions on hospital requirements for safe admissions as well as patient discharge criteria, while underlining the relevance of patient-centred care through community/home-based care.

Screening for Tuberculosis in Migrants: A Survey by the Global Tuberculosis Network.

Tuberculosis (TB) does not respect borders, and migration confounds global TB control and elimination. Systematic screening of immigrants from TB high burden settings and-to a lesser degree TB infection (TBI)-is recommended in most countries with a low incidence of TB. The aim of the study was to evaluate the views of a diverse group of international health professionals on TB management among migrants. Participants expressed their level of agreement using a six-point Likert scale with different statements in an online survey available in English, French, Mandarin, Spanish, Portuguese and Russian. The survey consisted of eight sections, covering TB and TBI screening and treatment in migrants. A total of 1055 respondents from 80 countries and territories participated between November 2019 and April 2020. The largest professional groups were pulmonologists (16.8%), other clinicians (30.4%), and nurses (11.8%). Participants generally supported infection control and TB surveillance established practices (administrative interventions, personal protection, etc.), while they disagreed on how to diagnose and manage both TB and TBI, particularly on which TBI regimens to use and when patients should be hospitalised. The results of this first knowledge, attitude and practice study on TB screening and treatment in migrants will inform public health policy and educational resources.

Prioritising children and adolescents in the tuberculosis response of the WHO European Region.

In 2017, in recognition of the challenges faced by Member States in managing childhood and adolescent tuberculosis (TB) at a country level, the WHO Regional Office for Europe held a Regional Consultation. In total, 35 countries participated in the consultations representing both high- and low-incidence Member States. Here, we provide an overview of the existing World Health Organization (WHO) documents and guidelines on childhood and adolescent TB and describe the outcomes of this regional meeting. National childhood and adolescent TB guidelines are available in 25% of Member States, while 33% reported that no such guidelines are at hand. In the majority of countries (83%), childhood and adolescent TB is part of the National Strategic Plan. The most pressing challenges in managing paediatric TB comprise the lack of adequate drug formulations, the difficult diagnosis, and treatment of presumed latent TB infection. Investments into childhood and adolescent TB need to be further advocated to achieve the End TB goals set by WHO to eliminate TB by 2030.

Computed tomography of the inner ear: size of anatomical structures in the normal temporal bone and in the temporal bone of patients with Menière's disease.

The purpose of the study was to obtain reference values for the sizes of anatomical structures of the inner ear on computed tomography (CT) images and to compare these values with those obtained from patients with Menière's disease. CT images of the temporal bone of 67 patients without inner ear pathology and 53 patients with Menière's disease have been evaluated. CT was performed in the sequential mode (1-mm slice thickness, 120 kV, 125 mA). Anatomical structures, such as the length and the width of the cochlea and of the vestibule, the height of the basal turn, the length and the width of the cochlear, the vestibular and the singular aqueduct and the internal auditory meatus and the diameter of the semicircular canals, were measured, using a dedicated postprocessing workstation. Reference values from the control group could be obtained. In the patients with Menière's disease, the length and the width of the vestibular aqueduct were smaller, compared with the values from the control group. The values obtained from the control group can serve as reference values for adult patients. The different sizes of anatomical structures of the control group and of patients suffering from Menière's disease suggest that functional impairment might be related to subtle morphological changes.