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• Children are over-represented among TB deaths; most dying without accessing TB care. • Major gaps persist in TB preventive treatment (TPT) provision and TB case detection. • Reducing the TPT gap requires major upscaling of household contact investigation. • Reducing the TB case detection gap requires acceptance of some over-treatment. • New approaches are required to improve the accuracy of diagnostic (rule-in and rule-out) tests. Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children. [ABSTRACT FROM AUTHOR]

It is estimated that 20 million children are exposed to tuberculosis (TB) each year, making TB a global paediatric health emergency. TB preventative efforts have long been overlooked. With the view of achieving "TB elimination" in "our lifetime", this paper explores challenges and potential solutions in the TB prevention cascade, including identifying children who have been exposed to TB; detecting TB infection in these children; identifying those at highest risk of progressing to disease; implementing treatment of TB infection; and mobilizing multiple stakeholders support to successfully prevent TB. [ABSTRACT FROM AUTHOR]

Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics and pharmacodynamics. We discuss the changing treatment landscape for drug-susceptible and drug-resistant paediatric tuberculosis in both the most common (intrathoracic) and most severe (central nervous system) forms of disease, and address the current knowledge gaps for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that was declared a pandemic by the World Health Organization on 11th March, 2020. Response to this ongoing pandemic requires extensive collaboration across the scientific community in an attempt to contain its impact and limit further transmission. Mathematical modelling has been at the forefront of these response efforts by: (1) providing initial estimates of the SARS-CoV-2 reproduction rate, R0 (of approximately 2-3); (2) updating these estimates following the implementation of various interventions (with significantly reduced, often sub-critical, transmission rates); (3) assessing the potential for global spread before significant case numbers had been reported internationally; and (4) quantifying the expected disease severity and burden of COVID-19, indicating that the likely true infection rate is often orders of magnitude greater than estimates based on confirmed case counts alone. In this review, we highlight the critical role played by mathematical modelling to understand COVID-19 thus far, the challenges posed by data availability and uncertainty, and the continuing utility of modelling-based approaches to guide decision making and inform the public health response. †Unless otherwise stated, all bracketed error margins correspond to the 95% credible interval (CrI) for reported estimates. [ABSTRACT FROM AUTHOR]

Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process. [ABSTRACT FROM AUTHOR]

Summary Children suffer a huge burden of disease in tuberculosis (TB) endemic countries. This disease burden was largely invisible when TB control programmes focused exclusively on adults with sputum smear-positive disease. High-level advocacy and better data have improved visibility, but the establishment of functional paediatric TB programmes remains challenging. The key issues that limit children's access to TB preventive therapy and treatment in endemic areas are briefly discussed. Barriers to preventive therapy include (1) the perceived inability to rule out active disease, (2) fear of creating drug resistance, (3) non-implementation of existing guidelines in the absence of adequate monitoring, and (4) poor adherence with long preventive therapy courses. Barriers to TB treatment include (1) perceived diagnostic difficulties, (2) non-availability of chest radiography, (3) young children presenting to unprepared maternal and child health (MCH) services, and (4) the absence of child-friendly formulations. With drug-resistant disease there is currently no guidance on the use of preventive therapy and treatment is usually restricted to cases with bacteriologically confirmed disease, which excludes most young children from care, even if their likely source case has documented drug-resistant TB. [ABSTRACT FROM AUTHOR]

Pneumonia accounted for 15% of the 6.3 million deaths among children younger than five years in 2013, a total of approximately 935,000 deaths worldwide. Routine vaccination against common childhood illnesses has been identified as one of the most cost-effective strategies to prevent death from pneumonia. Vaccine-preventable or potentially preventable diseases commonly linked with respiratory tract infections include Streptococcus pneumoniae, Haemophilus influenza type-b (Hib), pertussis, influenza, measles, and tuberculosis. Although here have been great strides in the development and administration of effective vaccines, the countries that carry the largest disease burdens still struggle to vaccinate their children and newer conjugated vaccines remain out of reach for many. The Global Vaccine Action Plan (GVAP) has identified priority areas for innovation in research in all aspects of immunisation development and delivery to ensure equitable access to vaccines for all. [ABSTRACT FROM AUTHOR]

Summary Background Mongolia has high and rising rates of multi-drug resistant tuberculosis (MDR-TB). Spatio-temporal and programmatic evidence suggests a major contribution from MDR-TB transmission, but genotypic evidence has not been assessed. Methods All MDR-TB cases identified during 2012 were examined. Demographic and bacteriological data were obtained from the National Tuberculosis Reference Laboratory. Isolates of Mycobacterium tuberculosis from culture-confirmed category 1 treatment failures were genotyped using 24-loci mycobacterium interspersed repetitive unit (MIRU-24) analysis. Results Of the 210 MDR-TB cases identified, 115 (54.8%) were treatment failures (34.8% category 1; 20.0% category 2). Streptomycin resistance was present in 156 (74.3%) cases; including 55/73 (75.3%) category 1 treatment failures who had never been exposed to streptomycin. Among category 1 treatment failures, Beijing lineage strains predominated (88.0%; 59/67 of genotyped isolates). MIRU-24 clustering was documented in 62.7% (42/67) of strains; 55.2% (37/67) remained clustered when drug susceptibility test results were considered. In total 59.5% (25/42) of clustered strains were Beijing lineage and demonstrated in-vitro resistance to all first-line drugs tested. Conclusion The MDR-TB epidemic in Mongolia appears to be driven by primary transmission of Beijing lineage strains resistant to all first-line drugs. Enhanced infection control strategies together with early MDR-TB case detection and appropriate treatment are necessary to limit escalation of the MDR-TB epidemic. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the ability of the Xpert(®) MTB/RIF assay to detect Mycobacterium tuberculosis in whole blood of children with tuberculosis in tuberculosis endemic settings with high rates of HIV infection.Methods: From June 2011 to September 2012 we prospectively enrolled children with symptoms or signs suggestive of tuberculosis at three research centres in Tanzania and Uganda. After clinical assessment, respiratory specimens were collected for microscopy and culture, as well as whole blood for Xpert(®) MTB/RIF. Children were classified according to standardised case definitions.Results: A total of 232 children were evaluated; 14 (6.0%) had culture-confirmed tuberculosis. The Xpert(®) MTB/RIF assay detected M. tuberculosis in 5/232 (2.2%) blood samples with 1 (0.4%) error reading and presumably 1 (0.4%) false-positive result. The sensitivity of the assay in children with culture-confirmed (1/14) versus no tuberculosis (1/117) was 7.1% (95% CI, 1.3-31.5). Three of the five Xpert(®) MTB/RIF positive patients had negative cultures, but were classified as probable tuberculosis cases. Assay sensitivity against a composite reference standard (culture-confirmed, highly probable or probable tuberculosis) was 5.4% (95% CI, 2.1-13.1).Conclusion: Whole blood Xpert(®) MTB/RIF demonstrated very poor sensitivity, although it may enhance the diagnostic yield in select cases, with culture-negative tuberculosis. [ABSTRACT FROM AUTHOR]

The highly cost-effective DOTS strategy helped to bring the global tuberculosis (TB) epidemic under control in many parts of the world; however, the emergence and spread of drug-resistant strains pose a major threat to these gains. Molecular epidemiology studies, together with recent genomic evidence, provide proof that some drug-resistant strains are highly transmissible with documented epidemic spread. The potential for epidemic replacement of drug-susceptible with drug-resistant strains provides strong motivation for renewed emphasis on TB drug and vaccine development. It also reflects the need for enhanced infection control measures in health care and congregate settings, especially in TB endemic areas. The exploration of preventive therapy options for close contacts of patients with infectious drug-resistant TB also warrants further exploration, in an attempt to break the transmission cycle. Increased population mobility and large scale cross-border migration imply that the inexorable rise of drug-resistant TB is not geographically confined; it is a global concern that poses a very real threat to TB endemic and non-endemic settings. Failure to find new solutions will compromise traditional TB control efforts and derail momentum toward future TB elimination. [ABSTRACT FROM AUTHOR]

Summary: Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment. [ABSTRACT FROM AUTHOR]

Summary: Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored. [ABSTRACT FROM AUTHOR]

Summary: WHO estimated that of 9.4 million cases of tuberculosis (TB) worldwide in 2008, 440,000 (3.6%) had multidrug-resistant (MDR)-TB. Childhood TB is estimated at 10-15% of the total burden, but little is known about the burden of MDR-TB in children. Children in close contact with MDR-TB cases are likely to become infected with the same resistant strains and are vulnerable to develop disease. Although MDR-TB is a microbiological diagnosis, children should be treated empirically according to the drug susceptibility result of the likely source case, as often cultures cannot be obtained from the child. MDR-TB treatment in children is guided by the same principles, using the same second-line drugs as in adults, with careful monitoring for adverse effects. Co-infection with HIV poses particular challenges and requires early initiation of antiretroviral therapy. Preventive therapy for high-risk MDR-TB contacts is necessary, but no consensus guidance exists on how best to manage these cases. Pragmatic and effective Infection control measures are essential to limit the spread of MDR-TB. [Copyright &y& Elsevier]

Summary: HIV-associated tuberculous meningitis (TBM) poses significant diagnostic and therapeutic challenges and carries a dismal prognosis. In this review, we present the clinical features and management of HIV-associated TBM, and compare this to disease in HIV-uninfected individuals. Although the clinical presentation, laboratory findings and radiological features of TBM are similar in HIV-infected and HIV-uninfected patients, some important differences exist. HIV-infected patients present more frequently with extra-meningeal tuberculosis and systemic features of HIV infection. In HIV-associated TBM, clinical course and outcome are influenced by profound immunosuppression at presentation, emphasising the need for earlier diagnosis of HIV infection and initiation of antiretroviral treatment. [Copyright &y& Elsevier]

Summary: Childhood tuberculosis (TB) has long been neglected by TB control programmes, as children tend to develop sputum smear-negative disease and rarely contribute to disease transmission. However, children suffer severe TB-related morbidity and mortality in areas with endemic TB and carry a significant proportion of the global disease burden. Apart from improved control of the global TB epidemic, access to accurate diagnosis and effective treatment is essential to reduce the disease burden associated with childhood TB. Access to child friendly anti-TB treatment is improving, but establishing an accurate diagnosis remains a challenge. This review provides an overview of recent advances in the diagnosis of childhood TB, focusing on bacteriological, immunological, radiological and symptom-based approaches. It is possible to establish a fairly accurate diagnosis of either latent infection or active TB in immunocompetent children, even in resource-limited settings, but establishing an accurate diagnosis of TB in HIV-infected (immunocompromised) children remains a major challenge. [Copyright &y& Elsevier]

Abstract: Objectives: Bacille Calmette-Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, poses a risk to human immunodeficiency virus (HIV)-infected children; this risk has not been well quantified. We estimate the risk of disseminated BCG disease in HIV-infected children in a setting highly endemic for tuberculosis and HIV. Design and methods: We conducted a prospective hospital-based surveillance study in the Western Cape Province, South Africa. Clinical and laboratory-confirmed cases of disseminated BCG disease in children <1 year of age from January 2002 to December 2004 at a referral hospital were used as numerator data. Denominator data for calculations of disseminated BCG risk were obtained through estimating the total number of HIV-infected infants receiving BCG based on the known vaccination coverage in the study setting, combined with population data on the total number of children <1 year of age, the known HIV prevalence amongst women attending public antenatal care facilities and different scenarios (5–15%) for the rate of vertical HIV transmission. Results: Nine cases of disseminated BCG disease were identified over the study period, seven of these were in HIV-infected infants. The estimated risk for HIV-infected infants to develop disseminated BCG disease, given a 95% BCG coverage and an HIV prevalence of 12.4–15.4% amongst women, were as follows for different scenarios of vertical HIV transmission: 329–417/100,000 vaccinees (assuming 5% vertical HIV transmission), 164–208/100,000 vaccinees (assuming 10% vertical HIV transmission) and 110–139/100,000 vaccinees (assuming 15% vertical HIV transmission). Conclusions: The risk of disseminated BCG disease is increased several hundred fold in HIV-infected infants compared to the documented risk in HIV-uninfected infants. Data on the protective effect of BCG in HIV-exposed and infected children is lacking. Population- and hospital-based surveillance is vitally important to more accurately estimate the safety and benefits of BCG in HIV-exposed and infected infants. [Copyright &y& Elsevier]

Keywords: Tuberculosis; Children; Paediatric; Adolescents; Women; Pregnancy EN Tuberculosis Children Paediatric Adolescents Women Pregnancy 25 26 2 11/23/20 20201101 NES 201101 Tuberculosis (TB) remains the leading infectious disease killer on the planet. TB preventive therapy (TPT) is an effective measure to prevent disease progression after TB exposure or infection, mainly within the short-term when risk of disease progression is highest, but also to reduce the reservoir of infection from which future disease may arise [5]. In high incidence settings TB transmission frequently occurs outside the household and this should be acknowledged [6], but even if many infections are missed household exposure offers an excellent opportunity for intervention given that TB services are already engaged with the family. [Extracted from the article]

Summary: Objectives: To describe the clinical presentation, delay in diagnosis and treatment initiation, and outcome of culture-confirmed childhood tuberculosis. Methods: Retrospective study of children<13 years of age at Tygerberg Children''s Hospital, Cape Town, South Africa with culture-confirmed tuberculosis seen January 2002–June 2003. Data were collected by review of hospital and clinic records. Results: Culture-confirmed tuberculosis was diagnosed in 184 children, median age 36 months; 26 (14.1%) were diagnosed clinically and treatment was started before admission. Tuberculosis was newly diagnosed in 158 children; 127 (80.4%) were clinically diagnosed and 31 (19.6%) were diagnosed only after culture result was known (culture-diagnosed). The median time from admission to diagnosis was 1 day (1–21 days) for clinically diagnosed, and 73 (34–178 days) for culture-diagnosed children. Treatment was initiated by hospital physicians in all 127 clinically diagnosed and 14/31 culture-diagnosed children. Of the 17 culture-diagnosed children not started on treatment, 4 were subsequently diagnosed on clinical grounds and treated at clinic level, 8 were found in good health, 4 failed to follow-up and 1 neonate died before the culture result was known. Conclusions: In symptomatic children, the vast majority could be confidently diagnosed on clinical grounds. However, culture-confirmation remains valuable to establish drug susceptibility. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Children suffer a huge and often underappreciated burden of disease in tuberculosis (TB) endemic countries. Major hurdles include limited awareness among health care workers, poor integration of TB into maternal and child health approaches, diagnostic difficulties and a lack of child-friendly treatment options. Accurate disease diagnosis is particularly difficult in young and vulnerable children who tend to develop paucibacillary disease and are unable to produce an expectorated sputum sample. In addition, access to chest radiography is problematic in resource-limited settings. Differentiating between TB exposure and M. tuberculosis infection, and especially between M. tuberculosis infection and TB disease is crucial to guide clinical management. TB represents a dynamic continuum from well-contained "latent" infection to incipient and ultimately severe disease. The clinical spectrum of disease in children is broad and can be confused with a myriad of common infections. We provide a pragmatic 4-step approach to diagnose intra-thoracic TB in children and demonstrate how classifying clinical, radiological and laboratory findings into recognised clinical syndromes may provide a more refined diagnostic approach, even in resource-limited settings. [ABSTRACT FROM AUTHOR]

The DOTS strategy assisted global tuberculosis (TB) control, but was unable to prevent the emergence and spread of drug-resistant strains. Genomic evidence confirms the transmission of drug-resistant Mycobacterium tuberculosis strains in many different settings, indicative of epidemic spread. These findings emphasise the need for enhanced infection control measures in health care and congregate settings. Young children in TB endemic areas are particularly vulnerable. Although advances in TB drug and vaccine development are urgently needed, improved access to currently available preventive therapy and treatment for drug resistant TB could reduce the disease burden and adverse outcomes experienced by children. We review new insights into the transmission dynamics of drug resistant TB, the estimated disease burden in children and optimal management strategies to consider. [ABSTRACT FROM AUTHOR]

• Differentiation between relapse and reinfection is critical for TB control. • Comparison of genomic and molecular techniques to detect TB recurrence. • Genome sequencing provide increased resolution but is consistent with molecular methods. • New drug resistance mutations were acquired in cases that experienced relapse. Differentiation between relapse and reinfection in cases with tuberculosis (TB) recurrence has important implications for public health, especially in patients with human immunodeficiency virus (HIV) co-infection. We compared Mycobacterial Interspersed Repeat Unit (MIRU) typing and spoligotyping with whole genome sequencing (WGS) to differentiate between relapse and reinfection in patients (HIV-positive and HIV-negative) with TB recurrence. We also assessed the value of WGS to track acquired drug resistance in those with relapse after successful treatment. Forty-one paired M. tuberculosis isolates collected from 20 HIV-positive and 21 HIV-negative patients were subjected to WGS in addition to spoligotyping and MIRU typing. Phylogenetic and Single Nucleotide Substitution (SNP) clustering analyses were performed to determine whether recurrences were due to relapse or re-infection. Comparison of M. tuberculosis genomes indicated that 95% of TB recurrences in the HIV-negative cohort were due to relapse, while the majority of TB recurrences (75%) in the HIV-positive cohort was due to reinfection (P = 0.0001). New drug resistance mutations were acquired in 5/24 cases (20.8%) that experienced relapse. WGS provided increased resolution, but differentiation between relapse and reinfection was broadly consistent with MIRU and spoligotyping. The high contribution of reinfection among HIV infected patients experiencing TB recurrence warrants further study to explore risk factors for TB exposure. [ABSTRACT FROM AUTHOR]

• Whole genome sequencing identifies more atypical drug resistance mutations. • Additional gains in detecting TB drug resistance is largely lineage associated. • Routine genomic surveillance delivers added value in low incidence TB settings. • Whole genome sequencing provides added value for management of drug resistant TB. Routine whole genome sequencing (WGS) of pathogens is becoming more feasible as sequencing costs decrease and access to benchtop sequencing equipment and bioinformatics pipelines increases. This study examined the added value gained from implementing routine WGS of all Mycobacterium tuberculosis isolates in New South Wales, Australia. Drug resistance markers inferred from WGS data were compared to commercial genotypic drug susceptibility testing (DST) assays and conventional phenotypic DST in all isolates sequenced between 2016 and 2019. Of the 1107 clinical M. tuberculosis isolates sequenced, 29 (2.6%) were multi-drug resistant (MDR); most belonged to Beijing (336; 30.4%) or East-African Indian (332; 30%) lineages. Compared with conventional phenotypic DST, WGS identified an additional 1% of isolates which were likely drug resistant, explained by mutations previously associated with treatment failure and mixed bacterial populations. However, WGS provided a 20% increase in drug resistance detection in comparison with commercial genotypic assays by identifying mutations outside of the classic resistance determining regions in rpoB , inhA , katG, pncA and embB genes. Gains in drug resistance detection were significant (p = 0.0137, paired t -test), but varied substantially for different phylogenetic lineages. In low incidence settings, routine WGS of M. tuberculosis provides better guidance for person-centered management of drug resistant tuberculosis than commercial genotypic assays. [ABSTRACT FROM AUTHOR]

Knowledge that older people are vulnerable to develop tuberculosis is rarely considered in developing country settings. According to 2010 Global Burden of Disease estimates, the majority of tuberculosis-related deaths occurred among people older than 50; most in those aged 65 and above. Older people also contribute a large proportion of Disability-Adjusted Life Years (DALYs); 51% of tuberculosis DALYs occurred in patients aged 50 years and older in East Asia. Tuberculosis age distributions in Africa have been severely skewed by the human immunodeficiency virus (HIV) epidemic, but emerging data suggest increasing disease burdens among older people. Older adults are more likely to develop extra-pulmonary and atypical forms of disease that are often harder to diagnose than conventional sputum smear-positive pulmonary tuberculosis. Their care is complicated by more frequent drug-related adverse events and increased co-morbidity, which may prove difficult to manage in regions where health resources are already constrained. Health systems will have to confront the challenge of an ageing global population and the integrated services required to address their health needs. [ABSTRACT FROM AUTHOR]

• Updated clinical guidance on MDR-TB is needed. • Several new MDR-TB diagnostics have been recently approved by WHO to complement existing tools. • To design a regimen, 4–5 active drugs are needed with a treatment duration up to 24 months. • Post-treatment sequelae might require pulmonary rehabilitation. • LTBI management and infection control are core elements of the MDR-TB public health approach. The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed, including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities. [ABSTRACT FROM AUTHOR]

• In suspected pulmonary tuberculosis (PTB), expensive negative pressure rooms are used for isolation. • Only 16% of patients suspected of PTB had the disease in this cohort. • GeneXpert MTB/RIF (Xpert) is a more rapid test compared to consecutive smear microscopy. • Xpert on pooled sputum is similar to smear microscopy in excluding PTB. • Xpert on pooled sputum would allow for more rapid de-isolation and cost savings. Patients with suspected pulmonary tuberculosis (PTB) are usually placed in respiratory isolation awaiting three sputum smear microscopy results for acid-fast bacilli (3AFB). GeneXpert MTB/RIF (Xpert) on a pooled sample from two sputa may allow for more rapid de-isolation. To compare the sensitivity and negative predictive value (NPV) of Xpert performed on a single pooled sputum sample ('pooled Xpert') to 3AFB, in order to exclude PTB in patients placed in respiratory isolation. Hospital inpatients in respiratory isolation for possible PTB were enrolled prospectively. Three expectorated sputum samples were obtained for smear microscopy. Two of the same samples had 0.5 ml removed from each and pooled for pooled Xpert. The diagnostic accuracy of pooled Xpert and 3AFB were assessed and compared to liquid culture at 8 weeks as the reference standard. Of 56 participants, nine (16.1%) were diagnosed with PTB. Compared to liquid culture, pooled Xpert had a sensitivity of 88.9% (95% confidence interval (CI) 57–99%) and NPV of 97.9% (95% CI 89–99%). 3AFB had a sensitivity of 66.7% (95% CI 35–88%) and NPV of 93.5% (95% CI 83–98%). A single pooled Xpert was non-inferior to 3AFB, with a strong trend towards greater sensitivity and better NPV. These findings support the use of a single pooled Xpert as an effective rapid screening approach for ruling out PTB in low incidence settings. Its value in high incidence settings and optimal combination with smear microscopy and culture warrant further evaluation. [ABSTRACT FROM AUTHOR]

• Tuberculosis preventive treatment is effective and feasible in high-prevalence settings. • Successful scale-up of tuberculosis preventive treatment requires attention to all steps in the 'cascade of care'. • The greatest drop-out typically occurs prior to commencement of therapy. • Programs should adopt a patient-centred approach. • Shorter-course regimens promise to improve treatment completion. • Operational research can help to localise the use of preventive therapy. Latent tuberculosis infection affects one quarter of the world's population, and effective therapies are available. However, scale-up of tuberculosis preventive treatment (TPT) remains limited. We describe strategies to support scale-up of TPT in high-prevalence settings, where the potential benefit for affected individuals is considerable. Patients must be at the centre of policies to scale-up TPT. Addressing the health system requirements for scale-up will ensure that programs can deliver treatment safely, efficiently and sustainably. Further research is required to adapt TPT to local contexts, and develop new shorter treatments that will be suitable for wide-scale deployment. [ABSTRACT FROM AUTHOR]

Summary The importance of addressing the conditions that predispose individuals and populations to develop tuberculosis is increasingly being recognized. Accurate quantification of the protective effect of preventive therapy and the provision of pragmatic guidance for clinical care and public health interventions is important. However, this approach must be nested within a socio-political context that addresses associated disadvantage and inequality. [ABSTRACT FROM AUTHOR]

Highlights • The renewed commitment to Primary Health Care (PHC) presents an opportunity to reconsider latent synergies and novel partnerships for child health and development. • TB and HIV partners need to align better and jointly formulate strategies to scale up pediatric TB and HIV in an integrated MNCH and PHC context. • Integrated, family-centered approaches, implemented at the community and primary care facility level are key for bridging the pediatric TB and HIV gaps. [ABSTRACT FROM AUTHOR]

Background: Case fatality ratios in children with tuberculosis are poorly understood-particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, <15 years) tuberculosis cases.Methods: We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946-80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0-4 years, 5-14 years), and HIV status.Findings: We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1-26·4) overall. The pooled case fatality ratio was significantly higher in children aged 0-4 years (43·6%, 95% CI 36·8-50·6) than in those aged 5-14 years (14·9%, 11·5-19·1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5-1·6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV.Interpretation: Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment.Funding: US National Institutes of Health, Janssen Global Public Health. [ABSTRACT FROM AUTHOR]

Summary Objectives Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model. Methods This model considers two TB strains, one with and one without an MDR phenotype. It was considered that intrinsic transmissibility may be different between the two strains, as may the control response including the detection, treatment failure, and default rates. The outcomes were explored in terms of the incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain. Results and conclusions The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility was modestly reduced (to between 50% and 100% as transmissible as the DS-TB strain). This model suggests that it may take decades or more for strain replacement to occur. It was also found that while the amplification of resistance is the early cause of MDR-TB, this will rapidly give way to person-to-person transmission. [ABSTRACT FROM AUTHOR]

In recent years the State of New South Wales (NSW), Australia, has maintained a low tuberculosis incidence rate with little evidence of local transmission. Nearly 90% of notified tuberculosis cases occurred in people born in tuberculosis-endemic countries. We analyzed geographic, epidemiological and genotypic data of all culture-confirmed tuberculosis cases to identify the bacterial and demographic determinants of tuberculosis hotspot areas in NSW. Standard 24-loci mycobacterium interspersed repetitive unit-variable number tandem repeat (MIRU-24) typing was performed on all isolates recovered between 2009 and 2013. In total 1692/1841 (91.9%) cases with confirmed Mycobacterium tuberculosis infection had complete MIRU-24 and demographic data and were included in the study. Despite some year-to-year variability, spatio-temporal analysis identified four tuberculosis hotspots. The incidence rate and the relative risk of tuberculosis in these hotspots were 2- to 10-fold and 4- to 8-fold higher than the state average, respectively. MIRU-24 profiles of M. tuberculosis isolates associated with these hotspots revealed high levels of heterogeneity. This suggests that these spatio-temporal hotspots, within this low incidence setting, can represent areas of predominantly imported infection rather than clusters of cases due to local transmission. These findings provide important epidemiological insight and demonstrate the value of combining tuberculosis genotyping and spatiotemporal data to guide better-targeted public health interventions. [ABSTRACT FROM AUTHOR]

Summary Dr Thato Mosidi never expected to be diagnosed with tuberculosis (TB), despite widely prevalent exposure and very limited infection control measures. The life-threatening diagnosis of primary extensively drug-resistant TB (XDR-TB) came as an even greater shock. The inconvenient truth is that, rather than being protected, Dr Mosidi and thousands of her healthcare colleagues are at an increased risk of TB and especially drug-resistant TB. In this viewpoint paper we debunk the widely held false belief that healthcare workers are somehow immune to TB disease (TB-proof) and explore some of the key factors contributing to the pervasive stigmatization and subsequent non-disclosure of occupational TB. Our front-line workers are some of the first to suffer the consequences of a progressively more resistant and fatal TB epidemic, and urgent interventions are needed to ensure the safety and continued availability of these precious healthcare resources. These include the rapid development and scale-up of improved diagnostic and treatment options, strengthened infection control measures, and focused interventions to tackle stigma and discrimination in all its forms. We call our colleagues to action to protect themselves and those they care for. [ABSTRACT FROM AUTHOR]

Abstract: Although nucleic acid amplification tests (NAATs) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation NAATs was suboptimal and variable. We conducted a meta-analysis of studies published between 2003 and 2013, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool to evaluate methodological quality. The diagnostic accuracy of newer commercial NAATs was assessed. Pooled estimates of diagnostic accuracy for commercial NAATs measured against a cerebrospinal fluid Mycobacterium tuberculosis culture-positive gold standard were sensitivity 0.64, specificity 0.98, and diagnostic odds ratio 64.0. Heterogeneity was limited; P value = 0.147 and I 2 = 33.85%. The Xpert MTB/RIF® test was evaluated in 1 retrospective study and 4 prospective studies, with pooled sensitivity 0.70 and specificity 0.97. The QUADAS-2 tool revealed low risk of bias, as well as low concerns regarding applicability. Heterogeneity was pronounced among studies of in-house tests. Commercial NAATs proved to be highly specific with greatly reduced heterogeneity compared to in-house tests. Sub-optimal sensitivity remains a limitation. [Copyright &y& Elsevier]

Summary: Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans. [ABSTRACT FROM AUTHOR]

Summary: Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers. [ABSTRACT FROM AUTHOR]

Summary: Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patient''s age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care. [Copyright &y& Elsevier]