The role and value of counsellors in the treatment journeys of people with tuberculosis and their families: Qualitative insights from the South Fly District of Papua New Guinea.

Combined education and counselling can contribute to person-centred care for tuberculosis (TB), improving uptake, adherence, and outcomes of treatment for TB disease and TB infection. Though strongly recommended by the World Health Organization for all people diagnosed with TB, education and counselling is not widely implemented in TB programs around the world. In 2016, a pilot TB education and counselling program, delivered by trained professionals and peers, was initiated to support people on TB treatment in the South Fly District of Papua New Guinea. This article reports on select findings from a qualitative study that examined the socio-cultural dimensions of TB, including treatment support such as education and counselling, in the South Fly District. An assessment on data collected during 128 semi-structured in-depth interviews of the role of counsellors on TB treatment journeys revealed strong participant support for the counsellors and the services they delivered, with particular emphasis on the emotional support provided to address fears and concerns related to TB diagnosis and treatment, and to support treatment adherence; valuable attributes of counsellors; their role as intermediaries between patients and health workers; their provision of biomedical knowledge of TB transmission and disease; and their assistance in addressing stigma and discrimination from family and community. Participants also noted how tackling the socio-structural issues that drive TB transmission in people's homes and communities were beyond the remit of counsellors' work. TB education and counselling should be an essential part of all TB services to provide support and encouragement for people to continue treatment to completion.

Clinical Features, Adverse Events and Treatment Outcomes of Multidrug/Rifampicin-resistant Tuberculosis in Children and Adolescents: An Eight-year Retrospective Cohort Study in Bandung, Indonesia.

BACKGROUND: Data on childhood and adolescent multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in Indonesia are lacking. We aimed to assess clinical features, adverse events (AEs) and treatment outcomes of childhood and adolescent MDR/RR-TB. METHODS: A retrospective cohort study was performed in children and adolescents aged <18 years treated for MDR/RR-TB at Hasan Sadikin General Hospital in Bandung, Indonesia, between June 2016 and March 2024. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for predictors of all-cause mortality. RESULTS: Among 84 included patients, 69 (82%) were adolescents aged 10-17 years, 54 (64%) were female, 54 (64%) were malnourished and 55 (65%) had culture-confirmed disease. Among 69 (82%) patients with known outcomes, 48 (70%) were successfully treated, 14 (20%) died (including 5 pretreatment deaths) and 7 (10%) were lost to follow-up (LTFU) (including 5 pretreatment LTFU). Predictors of all-cause mortality included shortness of breath on admission [aOR: 6.4, 95% confidence interval (CI): 1.3-49.1], high bacillary burden on Xpert MTB/RIF assay (aOR: 17.0, 95% CI: 1.6-260.5) and the presence of lung cavities on chest radiograph (aOR: 4.8, 95% CI: 1.1-23.3). Among 74 patients who initiated treatment, 39 (53%) had at least one grade 1-2 AE, and 4 (5%) had one grade 3-4 AE each, including hepatotoxicity, QT prolongation, hearing loss and rash/hyperpigmentation. CONCLUSION: Younger children were underrepresented among those treated for MDR/RR-TB, indicating reduced access to care. Severe AEs were uncommon during MDR/RR-TB treatment. Baseline indicators of extensive disease were associated with all-cause mortality. The high proportion of pre-treatment mortality and LTFU may reflect complex patient pathways limiting access to care.

Community-Wide Active Case Finding for Tuberculosis: Time to Use the Evidence We Have.

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb) bacteria, is one of the world's deadliest infectious diseases. Despite being the world's oldest pandemic, tuberculosis is very much a challenge of the modern era. In high-incidence settings, all people are at risk, irrespective of whether they have common vulnerabilities to the disease warranting the current WHO recommendations for community-wide tuberculosis active case finding in these settings. Despite good evidence of effectiveness in reducing tuberculosis transmission, uptake of this strategy has been lacking in the communities that would derive greatest benefit. We consider the various complexities in eliminating tuberculosis from the first principles of the disease, including diagnostic and other challenges that must be navigated under an elimination agenda. We make the case that community-wide tuberculosis active case finding is the best strategy currently available to drive elimination forward in high-incidence settings and that no time should be lost in its implementation. Recognizing that high-incidence communities vary in their epidemiology and spatiosocial characteristics, tuberculosis research and funding must now shift towards radically supporting local implementation and operational research in communities. This "preparing of the ground" for scaling up to community-wide intervention centers the local knowledge and local experience of community epidemiology to optimize implementation practices and accelerate reductions in community-level tuberculosis transmission.

Critical assessment of infants born to mothers with drug resistant tuberculosis.

Background: There have been no detailed descriptions of infants born to mothers treated for drug resistant TB in pregnancy. Critical case history assessment is important to identify risks and guide clinical practice. Methods: In a cohort of pregnant women with multidrug or rifampicin resistant (MDR/RR)-TB enrolled between 1 January 2013 and 31 December 2022, we followed mother-infant pairs until the infant was 12 months old. We performed critical case history assessments to explore potential mechanisms of Mycobacterium tuberculosis transmission to the infant, and to describe the clinical presentation and disease trajectories observed in infants diagnosed with TB. Findings: Among 101 mother-infant pairs, 23 (23%) included infants diagnosed with TB disease; 16 were clinically diagnosed and seven had microbiological confirmation (five MDR/RR-TB, two drug-susceptible TB). A positive maternal sputum culture at the time of delivery was significantly associated with infant TB risk (p = 0.023). Of the 12 infants diagnosed with TB in the first three months of life, seven (58%) of the mothers were culture positive at delivery; of whom four reported poor TB treatment adherence. However, health system failures, including failing to diagnose and treat maternal MDR/RR-TB, inadequate screening of newborns at birth, not providing appropriate TB preventive therapy (TPT), and M. tuberculosis transmission from non-maternal sources also contributed to TB development in infants. Interpretation: Infants born to mothers with MDR/RR-TB are at greatest risk if maternal adherence to MDR/RR-TB treatment or antiretroviral therapy (ART) is sub-optimal. In a high TB incidence setting, infants are also at risk of non-maternal household and community transmission. Ensuring maternal TB diagnosis and appropriate treatment, together with adequate TB screening and prevention in all babies born to mothers or households with TB will minimise the risk of infant TB disease development. Funding: South African Medical Research Council.

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

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

Genomic characteristics of prospectively sequenced Mycobacterium tuberculosis from respiratory and non-respiratory sources.

Understanding the differences between Mycobacterium tuberculosis strains isolated from respiratory and non-respiratory sources may inform clinical care and control strategies. We examined demographic and genomic characteristics of all culture-confirmed M. tuberculosis cultures isolated from respiratory and non-respiratory sources in New South Wales, Australia, from January 2017 to December 2021, using logistic regression models. M. tuberculosis strains from 1,831 patients were sequenced; 64.7% were from respiratory, 32.1% from non-respiratory, and 2.2% from both sources. Female patients had more frequent isolation from a non-respiratory source (p = 0.03), and older adults (≧65 years) from a respiratory source (p < 0.0001). Lineage 2 strains were relatively over-represented among respiratory isolates (p = 0.01). Among 39 cases with sequenced isolates from both sources, 43.6% had 1-10 single nucleotide polymorphism differences. The finding that older adults were more likely to have M. tuberculosis isolated from respiratory sources has relevance for TB control given the expected rise of TB among older adults.

Sustained transmission over two decades of a previously unrecognised MPT64 negative Mycobacterium tuberculosis strain in Queensland, Australia: a whole genome sequencing study.

Background: MPT64 is a key protein used for Mycobacterium tuberculosis (MTB) complex strain identification. We describe protracted transmission of an MPT64 negative MTB strain in Queensland, Australia, and explore genomic factors related to its successful spread. Methods: All MPT64 negative strains identified between 2002 and 2022 by the Queensland Mycobacteria Reference Laboratory, and an additional 2 isolates from New South Wales (NSW), were whole genome sequenced. Bayesian modelling and phylogeographical analyses were used to assess their evolutionary history and transmission dynamics. Protein structural modelling to understand the putative functional effects of the mutated gene coding for MPT64 protein was performed. Findings: Forty-three MPT64 negative isolates were sequenced, belonging to a single MTB cluster of Lineage 4.1.1.1 strains. Combined with a UK dataset of the same lineage, molecular dating estimated 1990 (95% HPD 1987-1993) as the likely time of strain introduction into Australia. Although the strain has spread over a wide geographic area and new cases linked to the cluster continue to arise, phylodynamic analysis suggest the outbreak peaked around 2003. All MPT64 negative strains had a frame shift mutation (delAT, p.Val216fs) within the MPT64 gene, which confers two major structural rearrangements at the C-terminus of the protein. Interpretation: This study uncovered the origins of an MPT64 negative MTB outbreak in Australia, providing a richer understanding of its biology and transmission dynamics, as well as guidance for clinical diagnosis and public health action. The potential spread of MPT64 negative strains undermines the diagnostic utility of the MPT64 immunochromatographic test. Funding: This study was funded from an operational budget provided to the Queensland Mycobacterium Reference Laboratory by Pathology Queensland, Queensland Department of Health.

Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.

Disease spectrum and prognostic factors in patients treated for tuberculous meningitis in Shaanxi province, China.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China. Methods: A multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as "confirmed," "probable," or "possible" TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome-assessed using the modified Barthel disability index-were recorded and compared. Findings: A total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 "not TBM." Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298-11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372-10.761), age > 60 years (OR = 3.566; 95%CI: 1.022-12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027-5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score < 12; these patients exhibited less classic meningitis symptoms and signs and had better outcomes compared with those with a TBM score ≥ 12. In this group, signs of disseminated/miliary TB (OR = 12.427; 95%CI: 1.138-135.758) and a higher TBM score (≥15, OR = 8.437; 95%CI: 1.328-53.585) were most strongly associated with death. Conclusion: TBM patients who are older (>60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

Population-wide active case finding as a strategy to end TB.

Tuberculosis (TB) is the leading infectious cause of morbidity and mortality globally. Despite available tools for preventing, finding, and treating TB, many people with TB remain undiagnosed. In high-incidence settings, TB transmission is ubiquitous within the community, affecting both high-risk groups and the general population. In fact, most people who develop TB come from the general population. To disrupt the chain of transmission that sustains the TB epidemic, we need to find and treat everyone with infectious TB as early as possible, including those with minimal symptoms or subclinical TB who are unlikely to present for care. Important elements of an effective active case-finding strategy include effective social mobilisation and community engagement, using sensitive screening tools that can be used at scale, and embracing population-wide screening in high-incidence ('hot spot') areas. We require a better description of feasible delivery models, 'real-life' impact and cost effectiveness to enable wider implementation.

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

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

Management of the infant born to a mother with tuberculosis: a systematic review and consensus practice guideline.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

Therapeutic drug monitoring of liposomal amphotericin B in children. Are we there yet? A systematic review.

INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5-10 mg/kg/day were reported to achieve Cmax/MIC > 25 using an MIC of 1 mg/L. CONCLUSIONS: While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended.

Tuberculosis in elderly Australians: a 10-year retrospective review.

Objective: This report describes the epidemiology of active tuberculosis (TB) in elderly Australians (≥ 65 years) with analysis of the factors associated with TB disease and successful treatment outcomes. Methods: A retrospective study of TB cases reported to the National Notifiable Diseases Surveillance System over a 10-year period from 2011 to 2020 was conducted. Cases were stratified by sex, age, risk factors, drug resistance, treatment type and outcome. Notification rates and incidence rate ratios with 95% confidence intervals were calculated and factors associated with treatment success analysed using multivariable logistic regression. Results: A total of 2231 TB cases among elderly people were reported over the study period, with a 10-year mean incidence rate of 6.2 per 100 000 population. The median age of cases was 75 years (range 65-100 years); most were male (65%) and born overseas (85%). Multivariable analysis found that successful treatment outcome was strongly associated with younger age, while unsuccessful treatment outcome was associated with being diagnosed within the first 2 years of arrival in Australia, ever having resided in an aged-care facility and resistance to fluoroquinolones. Discussion: Compared to other low-incidence settings in the Western Pacific Region, TB incidence in elderly people is low and stable in Australia, with most cases occurring among recent migrants from TB-endemic settings. Continued efforts to reduce TB importation and address migrant health, especially among elderly people, are important.

Assessing risks for bovine and zoonotic tuberculosis through spatial analysis and a questionnaire survey in Fiji - A pilot study.

Mycobacterium bovis causes tuberculosis in cattle and when transmitted to humans typically causes extra-pulmonary tuberculosis (EPTB). Bovine tuberculosis (bTB) has a global distribution and is controlled in most countries to protect animal and public health. Recent studies revealed that bTB is established on dairy farms in Fiji where EPTB cases have been reported in people. The aims of this pilot investigation were to look for putative zoonotic TB (EPTB) cases in people and to evaluate practices that might contribute to the persistence and transmission of M. bovis between cattle and to humans. Existing data sets were shared between the Fiji Ministry of Agriculture and Ministry of Health and a questionnaire-based survey was implemented using One Health principles. Statistically significant co-location and close proximity of EPTB cases and bovine TB affected farms were identified. The bTB infection status of farms was significantly associated with unfenced water sources where cattle grazed. Of 247 households, 65 % shared drinking water sources with cattle and 36 % consumed raw milk without boiling, while 62 % of participants reported backyard slaughter of cattle. Several participants reported current symptoms potentially suggestive of TB (chronic cough) but the impact of smoking and history of previous TB treatment could not be evaluated. Farmers had limited understanding of the practices required to prevent bTB at farm level. Further study is recommended and should include an assessment of lifetime EPTB diagnoses, classification of farms based on more recent bTB test data and molecular typing of mycobacterial isolates from humans, cattle and the environment. A targeted awareness and education approach is required to reduce the future risk of zoonotic TB and to help ensure uptake of recommendations and practices aimed at controlling and preventing bTB.

Critical Review of Tuberculosis Diagnosis in Children from Papua New Guinea Presenting to Health Facilities in the Torres Strait Islands, Australia.

Paediatric tuberculosis can be challenging to diagnose, and various approaches are used in different settings. A retrospective review was conducted on Papua New Guinea (PNG) children with presumptive TB who presented for health care in the Torres Strait Islands, Australia, between 2016 and 2019. We compared diagnostic algorithms including the modified Keith Edwards TB Score, The Union Desk Guide, and the new World Health Organization (WHO) algorithm, with diagnostic practices used in the remote Torres Strait Islands. Of the 66 children with presumptive TB, 7 had bacteriologically confirmed TB. The majority (52%) were under 5 years (median age 61 months), and 45% were malnourished. There was moderate agreement across the diagnostic methods (K = 0.34; 95% CI 0.23-0.46), with the highest concordance observed between The Union Desk Guide and the WHO's algorithm (K = 0.61). Local TB physicians might have over-diagnosed presumed lymph node TB while under-diagnosing TB overall. Enhancing the precision and promptness of paediatric TB diagnosis using practical tools is pivotal to decrease TB-related child mortality, notably in isolated regions like the Torres Strait and the Western Province of PNG.

Finding and treating both tuberculosis disease and latent infection during population-wide active case finding for tuberculosis elimination.

In recognition of the high rates of undetected tuberculosis in the community, the World Health Organization (WHO) encourages targeted active case finding (ACF) among "high-risk" populations. While this strategy has led to increased case detection in these populations, the epidemic impact of these interventions has not been demonstrated. Historical data suggest that population-wide (untargeted) ACF can interrupt transmission in high-incidence settings, but implementation remains lacking, despite recent advances in screening tools. The reservoir of latent infection-affecting up to a quarter of the global population -complicates elimination efforts by acting as a pool from which future tuberculosis cases may emerge, even after all active cases have been treated. A holistic case finding strategy that addresses both active disease and latent infection is likely to be the optimal approach for rapidly achieving sustainable progress toward TB elimination in a durable way, but safety and cost effectiveness have not been demonstrated. Sensitive, symptom-agnostic community screening, combined with effective tuberculosis treatment and prevention, should eliminate all infectious cases in the community, whilst identifying and treating people with latent infection will also eliminate tomorrow's tuberculosis cases. If real strides toward global tuberculosis elimination are to be made, bold strategies are required using the best available tools and a long horizon for cost-benefit assessment.