Critical Consideration of Tuberculosis Management of Papua New Guinea Nationals and Cross-Border Health Issues in the Remote Torres Strait Islands, Australia.

The international border between Australia and Papua New Guinea (PNG) serves as a gateway for the delivery of primary and tertiary healthcare for PNG patients presenting to Australian health facilities with presumptive tuberculosis (TB). An audit of all PNG nationals with presumptive TB who presented to clinics in the Torres Strait between 2016 and 2019 was conducted to evaluate outcomes for PNG patients and to consider the consistency and equity of decision-making regarding aeromedical evacuation. We also reviewed the current aeromedical retrieval policy and the outcomes of patients referred back to Daru General Hospital in PNG. During the study period, 213 PNG nationals presented with presumptive TB to primary health centres (PHC) in the Torres Strait. In total, 44 (21%) patients were medically evacuated to Australian hospitals; 26 met the evacuation criteria of whom 3 died, and 18 did not meet the criteria of whom 1 died. A further 22 patients who met the medical evacuation criteria into Australia were referred to Daru General Hospital of whom 2 died and 10 were lost to follow-up. The cross-border movement of people from PNG into Australia is associated with an emergent duty of care. Ongoing monitoring and evaluation of patient outcomes are necessary for transparency and justice.

Harnessing new mHealth technologies to Strengthen the Management of Multidrug-Resistant Tuberculosis in Vietnam (V-SMART trial): a protocol for a randomised controlled trial.

INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem globally. Long, complex treatment regimens coupled with frequent adverse events have resulted in poor treatment adherence and patient outcomes. Smartphone-based mobile health (mHealth) technologies offer national TB programmes an appealing platform to improve patient care and management; however, clinical trial evidence to support their use is lacking. This trial will test the hypothesis that an mHealth intervention can improve treatment success among patients with MDR-TB and is cost-effective compared with standard practice. METHODS AND ANALYSIS: A community-based, open-label, parallel-group randomised controlled trial will be conducted among patients treated for MDR-TB in seven provinces of Vietnam. Patients commencing therapy for microbiologically confirmed rifampicin-resistant or multidrug-resistant tuberculosis within the past 30 days will be recruited to the study. Participants will be individually randomised to an intervention arm, comprising use of an mHealth application for treatment support, or a 'standard care' arm. In both arms, patients will be managed by the national TB programme according to current national treatment guidelines. The primary outcome measure of effectiveness will be the proportion of patients with treatment success (defined as treatment completion and/or bacteriological cure) after 24 months. A marginal Poisson regression model estimated via a generalised estimating equation will be used to test the effect of the intervention on treatment success. A prospective microcosting of the intervention and within-trial cost-effectiveness analysis will also be undertaken from a societal perspective. Cost-effectiveness will be presented as an incremental cost per patient successfully treated and an incremental cost per quality-adjusted life-year gained. ETHICS: Ethical approval for the study was granted by The University of Sydney Human Research Ethics Committee (2019/676). DISSEMINATION: Study findings will be disseminated to participants and published in peer-reviewed journals and conference proceedings. TRIAL REGISTRATION NUMBER: ACTRN12620000681954.

Under-explored 'third dimension' of medical ethics.

In this paper, we nominally propose three dimensions of medical ethics, using the term medical ethics rather than clinical ethics to focus on the professional obligation of paediatricians in and beyond the ward and clinic. We argue there exists a duty to children along the continuum of all three dimensions. In this taxonomy, the first dimension is the obligation of paediatricians to serve the best interests of their individual patients. The second dimension involves public health aspects and communitarian concerns with a focus on utilitarian principles, such as cost-effectiveness and just resource allocation. The third dimension of medical ethics is the obligation we hold in trust to support and respect the well-being of future generations. As our ecological footprint, characterised by climate change and biodiversity collapse, will adversely affect the health of today's children and those yet unborn, paediatricians have a contemporaneous moral obligation to speak out and act as both advocates and activists.

Antibiotic use in children hospitalised with pneumonia in Central Vietnam.

BACKGROUND AND OBJECTIVES: Excessive use of antibiotics has been noted in children with respiratory tract infections in Vietnam, but antibiotic use in hospitalised children is poorly documented. Antibiotic use and direct healthcare costs in children hospitalised with pneumonia in central Vietnam were assessed. METHODS: A prospective descriptive study of children under 5 years old admitted with a primary admission diagnosis of 'pneumonia' to the Da Nang Hospital for Women and Children over 1 year. RESULTS: Of 2911 children hospitalised with pneumonia, 2735 (94.0%) were classified as 'non-severe' pneumonia by the admitting physician. In total, 2853 (98.0%) children received antibiotics. Intravenous antibiotics were given to 336 (12.3%) children with 'non-severe' and 157/176 (89.2%) children with 'severe' pneumonia; those with 'non-severe' pneumonia accounted for 68.2% (336/493) of intravenous antibiotics given. Only 19.3% (95/493) of children on intravenous antibiotics were stepped down to an oral antibiotic. Cefuroxime was the preferred oral agent, and ceftriaxone was the preferred injectable agent. Hospital admission for oral antibiotics in 'non-severe' pneumonia was a major cost driver, with an average direct cost of US$78.9 per patient, accounting for 54.0% of the total hospitalisation cost in the study cohort. In addition, 336 (12.3%) children with non-severe pneumonia received intravenous antibiotics without indication, accounting for a further 23.2% of hospitalisation costs. CONCLUSION: Limiting unnecessary hospitalisation and considering early intravenous to oral step down antibiotic will reduce direct health system costs and morbidity in children with respiratory tract infections in Vietnam.

Epidemiology of tuberculosis in the Western Pacific Region: Progress towards the 2020 milestones of the End TB Strategy.

Since 2015, the End TB Strategy and the Regional Framework for Action on Implementation of the End TB Strategy in the Western Pacific 2016-2020 have guided national tuberculosis (TB) responses in countries and areas of the Region. This paper provides an overview of the TB epidemiological situation in the Western Pacific Region and of progress towards the 2020 milestones of the Strategy. A descriptive analysis was conducted of TB surveillance and programme data reported to WHO and estimates of the TB burden generated by WHO for the period 2000-2018. An estimated 1.8 million people developed TB and 90 000 people died from it in the Region in 2018. Since 2015, the estimated TB incidence rate and the estimated number of TB deaths in the Region decreased by 3% and 10%, with annual reduction rates of 1.0% and 3.4%, respectively. With current efforts, the Region is unlikely to achieve the 2020 milestones and other targets of the Strategy. Major challenges include: (1) wide variation in the geographical distribution and rate of TB incidence among countries; (2) a substantial proportion (23%) of TB cases that remain unreached, undiagnosed or unreported; (3) insufficient coverage of drug susceptibility testing (51%) for bacteriologically confirmed cases and limited use of WHO-recommended rapid diagnostics (11 countries reported < 60% coverage); (4) suboptimal treatment outcomes of TB (60% of countries reported < 85% success), of TB/HIV co-infection (79%) and of multidrug- or rifampicin-resistant TB (59%); (5) limited coverage of TB preventive treatment among people living with HIV (39%) and child contacts (12%); and (6) substantial proportions (35-70%) of TB-affected families facing catastrophic costs. For the Region to stay on track to achieve the End TB Strategy targets, an accelerated multisectoral response to TB is required in every country.

Better than a pound of cure: preventing the development of multidrug-resistant tuberculosis.

Diagnostic and treatment delays contribute to increased death and disability among the 490,000 adults and children who develop multidrug-resistant (MDR) tuberculosis every year. Since the treatment of MDR tuberculosis is complex, costly and often toxic, tuberculosis control programs should prioritize strategies to prevent drug-resistant tuberculosis. Opportunities to limit transmission and prevent disease progression in close contacts of MDR tuberculosis cases are often neglected. Effective MDR tuberculosis preventive strategies could minimize the costs for patients and healthcare systems. This review characterizes the biological basis for the development of MDR tuberculosis, outlines the evidence for strategies to reduce transmission and highlights programmatic approaches to the management of patients infected with drug-resistant strains of Mycobacterium tuberculosis.

Improving access to tuberculosis preventive therapy and treatment for children.

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.

Interventions for increasing the proportion of health professionals practising in rural and other underserved areas.

BACKGROUND: The inequitable distribution of health professionals, within countries, poses an important obstacle to the optimal functioning of health services. OBJECTIVES: To assess the effectiveness of interventions aimed at increasing the proportion of health professionals working in rural and other underserved areas. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, including specialised register of the Cochrane Effective Practice and Organisation of Care Group; March 2014), MEDLINE (1966 to March 2014), EMBASE (1988 to March 2014), CINAHL (1982 to March 2014), LILACS (February 2014), Science Citation Index and Social Sciences Citation Index (up to April 2014), Global Health (March 2014) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (June 2013). We also searched reference lists of all papers and relevant reviews identified, and contacted authors of relevant papers regarding any further published or unpublished work. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before-and-after studies and interrupted time series studies evaluating the effects of various interventions (e.g. educational, financial, regulatory or support strategies) on the recruitment or retention, or both, of health professionals in underserved areas. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts and assessed full texts of potentially relevant studies for eligibility. Two review authors independently extracted data from eligible studies. MAIN RESULTS: For this first update of the original review, we screened 8945 records for eligibility. We retrieved and assessed the full text of 125 studies. Only one study met the inclusion criteria of the review. This interrupted time series study, conducted in Taiwan, found that the implementation of a National Health Insurance scheme in 1995 was associated with improved equity in the geographic distribution of physicians and dentists. We judged the certainty of the evidence provided by this one study very low. AUTHORS' CONCLUSIONS: There is currently limited reliable evidence regarding the effects of interventions aimed at addressing the inequitable distribution of health professionals. Well-designed studies are needed to confirm or refute findings of observational studies of educational, financial, regulatory and supportive interventions that might influence healthcare professionals' decisions to practice in underserved areas. Governments and medical schools should ensure that when interventions are implemented, their impacts are evaluated using scientifically rigorous methods to establish the true effects of these measures on healthcare professional recruitment and retention in rural and other underserved settings.

Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review.

Pneumonia is a major cause of morbidity and mortality in infants and children worldwide, with most cases occurring in tuberculosis-endemic settings. Studies have emphasised the potential importance of Mycobacterium tuberculosis in acute severe pneumonia in children as a primary cause or underlying comorbidity, further emphasised by the changing aetiological range with rollout of bacterial conjugate vaccines in high mortality settings. We systematically reviewed clinical and autopsy studies done in tuberculosis-endemic settings that enrolled at least 100 children aged younger than 5 years with severe pneumonia, and that prospectively included a diagnostic approach to tuberculosis in all study participants. We noted substantial heterogeneity between studies in terms of study population and diagnostic methods. Of the 3644 patients who had culture of respiratory specimens for M tuberculosis undertaken, 275 (7·5%) were culture positive, and an acute presentation was common. Inpatient case-fatality rate for pneumonia associated with tuberculosis ranged from 4% to 21% in the four clinical studies that reported pathogen-related outcomes. Prospective studies are needed in high tuberculosis-burden settings to address whether tuberculosis is a cause or comorbidity of childhood acute severe pneumonia.

Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study.

BACKGROUND: The diagnosis of paediatric tuberculosis is complicated by non-specific symptoms, difficult specimen collection, and the paucibacillary nature of the disease. We assessed the accuracy of a novel immunodiagnostic T-cell activation marker-tuberculosis (TAM-TB) assay in a proof-of-concept study to identify children with active tuberculosis. METHODS: Children with symptoms that suggested tuberculosis were prospectively recruited at the NIMR-Mbeya Medical Research Center in Mbeya, and the Ifakara Health Institute in Bagamoyo, Tanzania, between May 10, 2011, and Sept 4, 2012. Sputum and peripheral blood mononuclear cells were obtained for Mycobacterium tuberculosis culture and performance assessment of the TAM-TB assay. The children were assigned to standardised clinical case classifications based on microbiological and clinical findings. FINDINGS: Among 290 children screened, we selected a subgroup of 130 to ensure testing of at least 20 with culture-confirmed tuberculosis. 17 of 130 children were excluded because of inconclusive TAM-TB assay results. The TAM-TB assay enabled detection of 15 of 18 culture-confirmed cases (sensitivity 83·3%, 95% CI 58·6-96·4). Specificity was 96·8% (95% CI 89·0-99·6) in the cases that were classified as not tuberculosis (n=63), with little effect from latent tuberculosis infection. The TAM-TB assay identified five additional patients with highly probable or probable tuberculosis, in whom M tuberculosis was not isolated. The median time to diagnosis was 19·5 days (IQR 14-45) for culture. INTERPRETATION: The sputum-independent TAM-TB assay is a rapid and accurate blood test that has the potential to improve the diagnosis of active tuberculosis in children. FUNDING: European and Developing Countries Clinical Trials Partnership, German Federal Ministry of Education and Research, and Swiss National Science Foundation.

Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test.

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.

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.

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.

Modelling the cost-effectiveness of strategies to prevent tuberculosis in child contacts in a high-burden setting.

BACKGROUND: WHO recommends isoniazid preventive therapy (IPT) for young children in close contact with an infectious tuberculosis (TB) case. No models have examined the cost effectiveness of this recommendation. METHODS: A decision analysis model was developed to estimate health and economic outcomes of five TB infection screening strategies in young household contacts. In the no-testing strategy, children received IPT based on age and reported exposure. Other strategies included testing for infection with a tuberculin skin test (TST), interferon γ release assay (IGRA) or IGRA after TST. Markov modelling included age-specific disease states and probabilities while considering risk of re-infection in a high-burden country. RESULTS: Among the 0-2-year-old cohort, the no-testing strategy was most cost effective. The discounted societal cost of care per life year saved ranged from US$237 (no-testing) to US$538 (IGRA only testing). Among the 3-5-year-old cohort, strategies employing an IGRA after a negative TST were most effective, but were associated with significant incremental cost (incremental cost-effectiveness ratio >US$233 000), depending on the rate of Mycobacterium tuberculosis infection. CONCLUSION: Screening for M tuberculosis infection and provision of IPT in young children is a highly cost-effective intervention. Screening without testing for M tuberculosis infection is the most cost-effective strategy in 0-2-year-old children and the preferred strategy in 3-5-year-old children. Lack of testing capacity should therefore not be a barrier to IPT delivery. These findings highlight the cost effectiveness of contact tracing and IPT delivery in young children exposed to TB in high-burden countries.

Can social interventions prevent tuberculosis?: the Papworth experiment (1918-1943) revisited.

RATIONALE: There is consensus on the need to address social determinants of tuberculosis (TB) to achieve TB control, but evidence based on interventions is lacking. OBJECTIVES: We reanalyzed data from the sociomedical experiment performed at the Papworth Village Settlement in England, where the impact of stable employment and adequate housing and nutrition on the incidence of TB infection and disease in children living with parents with active TB was documented during 1918-1943. METHODS: Information on 315 children of patients, who lived at Papworth, was abstracted from a published monograph. Overall and age-specific occurrence of TB infection, disease, and deaths among children born in the settlement (village-born cohort) were compared with those of children born outside and admitted later (admitted cohort) to Papworth. MEASUREMENTS AND MAIN RESULTS: The annual risks of infection in the village-born and admitted cohorts were 20 and 24%, respectively. Of 24 children who developed TB disease, only one was village-born. Among children 5 years of age or less, there was zero incidence of TB in the village-born, compared with five cases (1,217/100,000 person-years) among children born outside Papworth. In the admitted cohort, among children 13 years of age and older, the incidence of TB before admission to Papworth was 5,263/100,000 person-years, whereas it was 341/100,000 person-years while living in Papworth. CONCLUSIONS: At Papworth social interventions including adequate nutrition did not reduce TB transmission but did reduce the incidence of TB disease in children living with parents with active TB. These results are relevant today for prevention of TB in children of patients with active TB, particularly with multidrug-resistant TB in high-burden settings.

Scaling up interventions to achieve global tuberculosis control: progress and new developments.

Tuberculosis is still one of the most important causes of death worldwide. The 2010 Lancet tuberculosis series provided a comprehensive overview of global control efforts and challenges. In this update we review recent progress. With improved control efforts, the world and most regions are on track to achieve the Millennium Development Goal of decreasing tuberculosis incidence by 2015, and the Stop TB Partnership target of halving 1990 mortality rates by 2015; the exception is Africa. Despite these advances, full scale-up of tuberculosis and HIV collaborative activities remains challenging and emerging drug-resistant tuberculosis is a major threat. Recognition of the effect that non-communicable diseases--such as smoking-related lung disease, diet-related diabetes mellitus, and alcohol and drug misuse--have on individual vulnerability, as well as the contribution of poor living conditions to community vulnerability, shows the need for multidisciplinary approaches. Several new diagnostic tests are being introduced in endemic countries and for the first time in 40 years a coordinated portfolio of promising new tuberculosis drugs exists. However, none of these advances offer easy solutions. Achievement of international tuberculosis control targets and maintenance of these gains needs optimum national health policies and services, with ongoing investment into new approaches and strategies. Despite growing funding in recent years, a serious shortfall persists. International and national financial uncertainty places gains at serious risk. Perseverance and renewed commitment are needed to achieve global control of tuberculosis, and ultimately, its elimination.

Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action.

The Millennium Development Goal target for tuberculosis control is to halt the spread of tuberculosis by 2015, and begin to reverse the worldwide incidence. After the introduction of standard control practices in 1995, 36 million people were cured and about 6 million deaths were averted. However, substantial scientific advances and innovative solutions are urgently needed together with creative new strategies. Strong international and national political commitment is essential. Urgent action is needed by national governments to fund their own programmes, and for the G8 countries and other donor governments and organisations to support governmental and non-governmental efforts. To foster the global need for urgent action to control the tuberculosis epidemic, The Lancet, in collaboration with the Stop TB Partnership, WHO, Global Fund to Fight AIDS, Tuberculosis and Malaria, and the experts participating in this Series, is launching The Lancet TB Observatory, which will assess and monitor progress in tuberculosis control and research, assess domestic and global financing, regularly disseminate information, and advocate for intensified efforts with stakeholders at all levels.

Use of light-emitting diode fluorescence microscopy to detect acid-fast bacilli in sputum.

BACKGROUND: Fluorescence microscopy offers well-described benefits, compared with conventional light microscopy, for the evaluation of sputum smear samples for tuberculosis. However, its use in resource-limited settings has been limited by the high cost of the excitatory light source. We evaluated the diagnostic performance of fluorescence microscopy, using novel light-emitting diode (LED) technology as an alternative to the conventional mercury vapor lamp (MVP). METHODS: Routinely collected sputum specimens from persons suspected to have tuberculosis who attended community clinics were stained with auramine O and were evaluated using 2 different excitatory light sources (MVP and LED); these specimens were then Ziehl-Neelsen stained and reexamined using light microscopy. Two microscopists independently evaluated all smears. Bacterial culture provided the gold standard. RESULTS: Of the 221 sputum specimens evaluated, 36 (16.3%) were positive for Mycobacterium tuberculosis by culture. Sensitivity and specificity documented for the different modalities were 84.7% and 98.9%, respectively, for the LED assessment; 73.6% and 99.8%, respectively, for the MVP assessment; and 61.1% and 98.9%, respectively, for light microscopy. kappa values for interreader variation were 0.87 for the LED assessment, 0.79 for the MVP assessment, and 0.77 for light microscopy. The mean time to read a negative smear was 1.4 min with fluorescence microscopy and 3.6 min with light microscopy, reflecting a time savings of 61% with fluorescence microscopy. CONCLUSION: LED fluorescence microscopy provides a reliable alternative to conventional methods and has many favorable attributes that facilitate improved, decentralized, diagnostic services.