Improving lung health in low-income and middle-income countries: from challenges to solutions.

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage.

Implementing the End TB Strategy in the Western Pacific Region: Translating vision into reality.

The End TB Strategy aims to end the global tuberculosis (TB) epidemic by 2035 in line with the sustainable development goals targets and has been implemented in the World Health Organization (WHO) Western Pacific Region since 2015. Significant progress has been made in implementing this strategy. However, several challenges still remain. In 2016, an estimated 1.8 million people developed TB in the region, and of these about 20% were missed by national TB programmes. The gap in diagnosis and enrolment as well as treatment completion is greater with drug-resistant TB. Many TB-affected families face catastrophic costs due to the disease. Sustaining financing for TB care is a long-term challenge in many countries. This article emphasizes targeted interventions in high-risk populations, including systematic screening and patient-centred TB care. Several other approaches including improving TB diagnostic tools and algorithm, and engaging all care providers are suggested to find missing TB patients. Drug-resistant TB requires additional resourcing for laboratories, enrolment and patient support. Specific measures are required at different levels to mitigate financial burden due to TB including linking TB to overall social protection schemes. The Moscow Ministerial conference in 2017 and upcoming United Nations (UN) 2018 high-level meeting provide an opportunity to raise TB higher on the global agenda, forge partnerships and move towards universal health coverage.

Developments in Impact Assessment of New Diagnostic Algorithms for Tuberculosis Control.

A modified presentation of the impact assessment framework is proposed that improves accessibility while continuing to provide a checklist of the evidence needed to support policy decisions on the implementation of new tools for the diagnosis of tuberculosis.

Clinical Impact of the Line Probe Assay and Xpert® MTB/RIF Assay in the Presumptive Diagnosis of Drug-Resistant Tuberculosis in Brazil: A Pragmatic Clinical Trial.

BACKGROUND: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert. METHODS: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months. RESULTS: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81). CONCLUSIONS: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month.

Why tobacco control should be a priority agenda item of Joint External Monitoring Missions for TB control?

INTRODUCTION: Tobacco smoking is a significant risk factor for developing tuberculosis (TB), contributing to diagnostic delays, poor treatment outcomes and an increased risk of death and relapse. The World Health Organization (WHO) has reported that TB rates could decline by as much as 20% if smoking were eliminated. Tobacco smoking was a risk factor in at least 860,000 TB cases in 2018, and has been documented as one of the leading contributors to TB in India, Indonesia, Myanmar, Nepal and Philippines. METHODS: Joint External Monitoring Missions (JEMM) are arranged by WHO to review the progress, challenges and plans for national TB control programs and provide guidance for improvement of policies, planning and implementation. During May and June 2021, JEMM reports from five South-East Asian countries that had a JEMM in 2019 and early 2020 were reviewed. Reports reviewed from India, Indonesia, Myanmar, Nepal and the Philippines. Any mention of the association of TB and smoking, TB and tobacco use, impact of tobacco use/smoking on TB outcomes, current practices and challenges of TB and tobacco in the TB control program and proposed actions were documented. RESULTS: Of the five country JEMM, Myanmar's did not recognise the impact of smoking tobacco on TB at all, and only one of the five countries, India, identified a very limited number of current TB-Tobacco practises including that a collaborative framework for TB/tobacco was in place. Nepal's 2019 JEMM acknowledged that there was no smoking cessation within the TB Control program and health providers were not aware about the brief advice and smoking cessation program. The Philippines and Myanmar reported neither current practices nor challenges in implementing tobacco intervention in TB control programs. CONCLUSION: Given the importance of tobacco smoking as a key risk factor for TB, assessing its burden on the national TB epidemic should be included as one of the key indicators in the JEMM framework. Key interventions include brief cessation support through regular TB services and the use of Nicotine Replacement Therapy (NRT) and other medications as part of a comprehensive package of care for people with TB to improve the quality of the services they receive. Multisectoral efforts to stop smoking also contribute the non-communicable disease agenda as well as protecting against poor outcomes for COVID-19. The support of TB programs to integrate tobacco control is critical and will contribute to national TB control program targets that support WHO's End TB Strategy.

Turning threats into opportunities: how to implement and advance quality TB services for people with HIV during the COVID-19 pandemic and beyond.

INTRODUCTION: Until COVID-19, tuberculosis (TB) was the leading infectious disease killer globally, disproportionally affecting people with HIV. The COVID-19 pandemic is threatening the gains made in the fight against both diseases. DISCUSSION: Although crucial guidance has been released on how to maintain TB and HIV services during the pandemic, it is acknowledged that what was considered normal service pre-pandemic needs to improve to ensure that we rebuild person-centred, inclusive and quality healthcare services. The threat that the pandemic may reverse gains in the response to TB and HIV may be turned into an opportunity by pivoting to using proven differentiated service delivery approaches and innovative technologies that can be used to maintain care during the pandemic and accelerate improved service delivery in the long term. Models of care should be convenient, supportive and sufficiently differentiated to avoid burdensome clinic visits for medication pick-ups or directly observed treatments. Additionally, the pandemic has highlighted the chronic and short-sighted lack of investment in health systems and the need to prioritize research and development to close the gaps in TB diagnosis, treatment and prevention, especially for children and people with HIV. Most importantly, TB-affected communities and civil society must be supported to lead the planning, implementation and monitoring of TB and HIV services, especially in the time of COVID-19 where services have been disrupted, and to report on legal, policy and gender-related barriers to access experienced by affected people. This will help to ensure that TB services are held accountable by affected communities for delivering equitable access to quality, affordable and non-discriminatory services during and beyond the pandemic. CONCLUSIONS: Successfully reaching the related targets of ending TB and AIDS as public health threats by 2030 requires rebuilding of stronger, more inclusive health systems by advancing equitable access to quality TB services, including for people with HIV, both during and after the COVID-19 pandemic. Moreover, services must be rights-based, community-led and community-based, to ensure that no one is left behind.

[The International Standards for Tuberculosis Care (ISTC): what is the importance for Japan?].

In 2005, the World Health Assembly resolved that all Member States should ensure that all persons with tuberculosis (TB) "have access to the universal standard of care based on proper diagnosis, treatment and reporting consistent with the DOTS strategy..." The purpose of the International Standards for Tuberculosis Care (ISTC) is to define the widely accepted level of care of persons either suspected of, or diagnosed with, TB by all health practitioners, especially those in the private sector, who often lack guidance and systematic evaluation of outcomes provided by government programs. Since their publication in 2006 on World TB Day, the standards have been endorsed by the major international health organizations as well as many country-level professional societies. The intention is to complement local and national control polices consistent with those of the World Health Organization: they are not intended to replace local guidelines, but are written to accommodate local differences in practice. The ISTC comprise seventeen evidence-based standards on tuberculosis diagnosis and treatment, as well as the responsibility of the public health sector. These are based on the basic principles of TB care: prompt and accurate diagnosis, standardized treatment regimens of proven efficacy, appropriate treatment support and supervision, monitoring of response to treatment and the carrying out of essential public health responsibilities. The relevance of the ISTC to the Japanese context is highlighted, in terms of when persons should be suspected of TB; the appropriate diagnostic modalities, including the use of chest radiographs; the advantages of fixed dose combinations; the importance of follow-up laboratory tests to document response to treatment, the importance of recordkeeping and reporting to public health authorities, the value of HIV testing of TB patients and the use of anti-retrovirals for those dually infected; and the assessment of drug resistance and the appropriate treatment of multidrug-resistant tuberculosis. Finally, some proposals were made on the way forward for Japan.

Building a Multi-Institutional and Interdisciplinary Team to Develop a Zoonotic Tuberculosis Roadmap.

Tuberculosis (TB), as the major infectious disease in the world, has devastating consequences for not only humans, but also cattle and several wildlife species. This disease presents additional challenges to human and veterinary health authorities given the zoonotic nature of the pathogens responsible for the disease across species. One of the main public health challenges regarding zoonotic TB (ZTB) caused by Mycobacterium bovis is that the true incidence of this type of TB in humans is not known and is likely to be underestimated. To effectively address challenges posed by ZTB, an integrated One Health approach is needed. In this manuscript, we describe the rationale, major steps, timeline, stakeholders, and important events that led to the assembling of a true integrated multi-institutional and interdisciplinary team that accomplished the ambitious goal of developing a ZTB roadmap, published in October, 2017. It outlines key activities to address the global challenges regarding the prevention, surveillance, diagnosis, and treatment of ZTB. We discuss and emphasize the importance of integrated approaches to be able to accomplish the short (year 2020) and medium term (year 2025) goals outlined in the ZTB roadmap.

Zoonotic tuberculosis in human beings caused by Mycobacterium bovis-a call for action.

Mycobacterium tuberculosis is recognised as the primary cause of human tuberculosis worldwide. However, substantial evidence suggests that the burden of Mycobacterium bovis, the cause of bovine tuberculosis, might be underestimated in human beings as the cause of zoonotic tuberculosis. In 2013, results from a systematic review and meta-analysis of global zoonotic tuberculosis showed that the same challenges and concerns expressed 15 years ago remain valid. These challenges faced by people with zoonotic tuberculosis might not be proportional to the scientific attention and resources allocated in recent years to other diseases. The burden of zoonotic tuberculosis in people needs important reassessment, especially in areas where bovine tuberculosis is endemic and where people live in conditions that favour direct contact with infected animals or animal products. As countries move towards detecting the 3 million tuberculosis cases estimated to be missed annually, and in view of WHO's end TB strategy endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of tuberculosis by 2035, we call on all tuberculosis stakeholders to act to accurately diagnose and treat tuberculosis caused by M bovis in human beings.

Clinical Impact of the Line Probe Assay and Xpert® MTB/RIF Assay in the Presumptive Diagnosis of Drug-Resistant Tuberculosis in Brazil: A Pragmatic Clinical Trial

ABSTRACT Background: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert. Methods: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months. Results: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81). Conclusions: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month.

Trends in drug-resistant Mycobacterium tuberculosis in New York City, 1991-2003.

BACKGROUND: Two drug-resistance surveys showed a very high prevalence of drug resistance among isolates obtained from patients with tuberculosis in 1991 and 1994 in New York, New York. METHODS: A cross-sectional survey in April 1997 and a survey of incident cases in April-June 2003 were conducted. The trend in the proportion of drug resistance in the 4 surveys was examined separately for prevalent and incident cases. Risk factors for drug resistance in incident cases were also assessed. RESULTS: The number of patients was 251 in the 1997 survey and 217 in the 2003 survey. Among prevalent cases, the percentage of cases with resistance to any antituberculosis drug decreased from 33.5% in 1991 to 23.8% in 1994 and to 21.5% in 1997 (P < .001, by test for trend); cases of multidrug-resistant tuberculosis also decreased significantly, from 19% in 1991 to 6.8% in 1997 (P < .001, by test for trend). Among incident cases in the 4 surveys, the decrease in resistance to any antituberculosis drugs was not statistically significant; however, the decrease in multidrug-resistant tuberculosis (from 9% in 1991 to 2.8% in 2003) was statistically significant (P = .002, by test for trend). However, in 2003, a worrisome increase in incident cases of multidrug-resistant tuberculosis (an increase of 23%) was seen among previously treated patients with pulmonary tuberculosis not born in the United States. Human immunodeficiency virus infection, a strong predictor for drug resistance in 1991 and 1994, was not associated with drug resistance in subsequent surveys. CONCLUSIONS: Intensive case management, including directly observed therapy, adherence monitoring, and periodic medical review to ensure appropriate treatment for each patient, should be sustained to prevent acquired drug resistance.

Implementation and Operational Research: Programmatic Feasibility of Dried Blood Spots for the Virological Follow-up of Patients on Antiretroviral Treatment in Nord Kivu, Democratic Republic of the Congo.

BACKGROUND: As part of its policy to shift monitoring of antiretroviral therapy (ART) to primary health care (PHC) workers, the Ministry of Health of the Democratic Republic of Congo (DRC) tested the feasibility of using dried blood spots (DBS) for viral load (VL) quantification and genotypic drug resistance testing in off-site high-throughput laboratories. METHODS: DBS samples from adults on ART were collected in 13 decentralized PHC facilities in the Nord-Kivu province and shipped during program quarterly supervision to a reference laboratory 2000 km away, where VL was quantified with a commercial assay (m2000rt, Abbott). A second DBS was sent to a World Health Organization (WHO)-accredited laboratory for repeat VL quantification on a subset of samples with a generic assay (Biocentric) and genotypic drug resistance testing when VL >1000 copies per milliliter. FINDINGS: Constraints arose because of an interruption in national laboratory funding rather than to technical or logistic problems. All samples were assessed by both VL assays to allow ART adjustment. Median DBS turnaround time was 37 days (interquartile range: 9-59). Assays performed unequally with DBS, impacting clinical decisions, quality assurance, and overall cost-effectiveness. Based on m2000rt or generic assay, 31.3% of patients were on virological failure (VF) and 14.8% presented resistance mutations versus 50.3% and 15.4%, respectively. CONCLUSION: This study confirms that current technologies involving DBS make virological monitoring of ART possible at PHC level, including in challenging environments, provided organizational issues are addressed. Adequate core funding of HIV laboratories and adapted choice of VL assays require urgent attention to control resistance to ART as coverage expands.

Liquid vs Solid Culture Medium to Evaluate Proportion and Time to Change in Management of Suspects of Tuberculosis-A Pragmatic Randomized Trial in Secondary and Tertiary Health Care Units in Brazil.

BACKGROUND: The use of liquid medium (MGIT960) for tuberculosis (TB) diagnosis was recommended by WHO in 2007. However, there has been no evaluation of its effectiveness on clinically important outcomes. METHODS AND FINDINGS: A pragmatic trial was carried out in a tertiary hospital and a secondary health care unit in Rio de Janeiro City, Brazil. Participants were 16 years or older, suspected of having TB. They were excluded if only cerebral spinal fluid or blood specimens were available for analysis. MGIT960 technique was compared with the Lowenstein-Jensen (LJ) method for laboratory diagnosis of active TB. Primary outcome was the proportion of patients who had their initial medical management changed within 2 months after randomisation. Secondary outcomes were: mean time for changing the procedure, patient satisfaction with the overall treatment and adverse events. Data were analysed by intention-to-treat. Between April 2008 and September 2011, 693 patients were enrolled (348 to MGIT, 345 to LJ). Smear and culture results were positive for 10% and 15.7% of participants, respectively. Patients in the MGIT arm had their initial medical management changed more frequently than those in the LJ group (10.1% MGIT vs 3.8% LJ, RR 2.67 95% CI 1.44-.96, p = 0.002, NNT 16, 95% CI 10-39). Mean time for changing the initial procedure was greater in LJ group at both sites: 20.0 and 29.6 days in MGIT group and 52.2 and 64.3 in LJ group (MD 33.5, 95% CI 30.6-36.4, p = 0.0001). No other important differences were observed. CONCLUSIONS: This study suggests that opting for the MGIT960 system for TB diagnosis provides a promising case management model for improving the quality of care and control of TB. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN79888843.

Effectiveness of isoniazid treatment for latent tuberculosis infection among human immunodeficiency virus (HIV)-infected and HIV-uninfected injection drug users in methadone programs.

Injection drug users (IDUs) were heavily affected by the tuberculosis (TB) resurgence in New York City in the 1990s. We assessed the effectiveness of screening for latent TB infection in methadone users and of selective treatment with isoniazid. Risk for future TB was classified as low or high on the basis of tuberculin, anergy, and HIV test results. The cohort of 2212 IDUs was followed up for a median of 4.2 years; 25 IDUs, of whom 20 (80%) were infected with human immunodeficiency virus (HIV), developed TB. In an adjusted Cox proportional hazards model of high-risk IDUs, the risk of TB was associated with HIV infection (HR 10.3; 95% CI, 3.4-31.3); receipt of <6 months of isoniazid therapy (HR 7.6; 95% CI, 1.02-57.1); a CD4+ T lymphocyte count of <200 cells/mm3 (HR 6.6; 95% CI, 1.7-25.9); and tuberculin positivity (HR 4.0; 95% CI, 1.6-10.2). Treatment with isoniazid was beneficial in HIV-infected, tuberculin-positive IDUs.

Prevalence of tuberculin skin test positivity and conversions among healthcare workers in New York City during 1994 to 2001.

OBJECTIVE: To determine the prevalence of and risk factors for tuberculin skin test positivity and conversion among New York City Department of Health and Mental Hygiene employees. DESIGN: Point-prevalence survey and prospective cohort analysis. Sentinel surveillance was conducted from March 1, 1994, to December 31, 2001. PARTICIPANTS: HCWs in high-risk and low-risk settings for occupational TB exposure. RESULTS: Baseline tuberculin positivity was 36.2% (600 of 1,658), 15.5% (143 of 922) among HCWs born in the United States, and 48.5% (182 of 375) among HCWs not born in the United States. There were 36 tuberculin conversions during 2,754 observation-years (rate, 1.3 per 100 person-years). For HCWs born in the United States, the risk for tuberculin conversion was greater in high-risk occupational settings compared with low-risk settings (OR, 5.7; CI95, 1.7-19.2; P < .01). HCWs not born in the United States and those employed at the Office of the Chief Medical Examiner (OCME) were at high risk for baseline tuberculin positivity (OR, 3.2; CI95, 1.7-5.8; P < .001); OCME HCWs (OR, 4.7; CI95, 2.3-9.4; P < .001), those of Asian ethnicity (OR, 4.3; CI95, 1.4-13.5; P < .01), and older HCWs (OR, 1.0; CI95, 1.0-1.1; P < .05) were at a higher risk for conversion. CONCLUSIONS: Although the prevalence of tuberculin positivity decreased after the peak of the recent TB epidemic in New York City, the conversion rate among HCWs in high-risk occupational settings for TB exposure was still greater than that among HCWs in low-risk settings. Continued surveillance of occupational TB infection is needed, especially among high-risk HCWs.

Assessing new strategies for TB diagnosis in low- and middle-income countries.

In this manuscript, we report the current situation of tuberculosis globally and in Brazil, the need for new strategies toward tuberculosis control, focusing on new diagnostic technologies. Critical comments are given on the state of the art regarding the evaluation of new health technologies, degree of scientific evidence needed, evaluation of clinical impact, cost-effectiveness of incorporation into the health system and the social impact.