tuberculosis research articles

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Tuberculosis articles from across Nature Portfolio

Tuberculosis (TB) is an infectious disease caused by strains of bacteria known as mycobacteria. The disease most commonly affects the lungs and can be fatal if not treated. However, most infected individuals show no disease symptoms. One third of the world’s population is thought to have been infected with TB.

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Prevalence of pulmonary tuberculosis and HIV infections and risk factors associated to tuberculosis in detained persons in Antananarivo, Madagascar

• Fanjasoa Rakotomanana
• Anou Dreyfus
• Rindra V. Randremanana

The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova

Chitwood et al. report on the rapid expansion of a Ural-lineage multidrug resistant strain of Mycobacterium tuberculosis in Moldova. This strain has an estimated reproduction number more than two times greater than otherwise similar drug susceptible strains.

• Melanie H. Chitwood
• Caroline Colijn
• Benjamin Sobkowiak

Genomic insights into anthropozoonotic tuberculosis in captive sun bears ( Helarctos malayanus ) and an Asiatic black bear ( Ursus thibetanus ) in Cambodia

• Kirsty Officer
• Timothy M. Walker
• Bethany Jackson

TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection

Toll-interacting protein (TOLLIP) prevents inflammation and lipid accumulation in alveolar macrophages to limit integrated stress response activation, macrophage necrosis and promote control of Mycobacterium tuberculosis .

• Sambasivan Venkatasubramanian
• Courtney R. Plumlee
• Javeed A. Shah

Multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis that is resistant to several first-line drugs. MDR-TB is an increasing public health challenge. In this Primer, Dheda et al. summarize the epidemiology and mechanisms, and discuss diagnosis, management and quality of life of patients with MDR-TB.

• Keertan Dheda
• Fuad Mirzayev
• Christoph Lange

Molecular docking, molecular dynamics simulations and binding free energy studies of interactions between Mycobacterium tuberculosis Pks13, PknG and bioactive constituents of extremophilic bacteria

• Kudakwashe Nyambo
• Kudzanai Ian Tapfuma
• Vuyo Mavumengwana

News and Comment

Restocking the tuberculosis drug arsenal

After many lean years, important progress has been made in updating the anti-tuberculosis drug armamentarium; a new drug that targets bacterial protein synthesis is one of several that could help transform the treatment of this neglected and deadly disease.

• Eric L. Nuermberger
• Richard E. Chaisson

Digital intervention improves tuberculosis treatment outcomes

An intervention that incorporates electronic pill boxes and remote adherence monitoring improved treatment success in patients with tuberculosis in Tibet — making this a promising strategy for low-resource settings.

• Karen O’Leary

A spotlight on the tuberculosis epidemic in South Africa

Tuberculosis is the leading cause of death from a single infectious agent, with over 25% of these occurring in the African region. Multi-drug resistant strains which do not respond to first-line antibiotics continue to emerge, putting at risk numerous public health strategies which aim to reduce incidence and mortality. Here, we speak with Professor Valerie Mizrahi, world-leading researcher and former director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, regarding the tuberculosis burden in South Africa. We discuss the challenges faced by researchers, the lessons that need to be learnt and current innovations to better understand the overall response required to accelerate progress.

Presumed ocular tuberculosis – need for caution before considering anti-tubercular therapy

• Rohan Chawla
• Urvashi B. Singh
• Pradeep Venkatesh

Transforming tuberculosis diagnosis

Diagnosis is the weakest aspect of tuberculosis (TB) care and control. We describe seven critical transitions that can close the massive TB diagnostic gap and enable TB programmes worldwide to recover from the pandemic setbacks.

• Madhukar Pai
• Puneet K. Dewan
• Soumya Swaminathan

B cells and T follicular helper-like cells within lung granulomas are required for TB control

We show a crucial protective function for T follicular helper (T FH )-like cells localized within granuloma-associated lymphoid tissue for Mycobacterium tuberculosis control in mouse models of tuberculosis. Antigen-specific B cells contribute to this strategic localization and the maturation of cytokine-producing T FH -like cells.

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Tuberculosis

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• PMID: 30212088
• Bookshelf ID: NBK525174
• DOI: 10.1596/978-1-4648-0524-0_ch11

Despite 90 years of vaccination and 60 years of chemotherapy, tuberculosis (TB) remains the world’s leading cause of death from an infectious agent, exceeding human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) for the first time (WHO 2015b, 2016a). The World Health Organization (WHO) estimates that there are about 10.4 million new cases and 1.8 million deaths from TB each year. One-third of these new cases (about 3 million) remain unknown to the health system, and many are not receiving proper treatment.

Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory route and most commonly affects the lungs, but can damage any tissue. Only about 10 percent of individuals infected with Mtb progress to active TB disease within their lifetime; the remainder of persons infected successfully contain their infection. One of the challenges of TB is that the pathogen persists in many infected individuals in a latent state for many years and can be reactivated to cause disease. The risk of progression to TB disease after infection is highest soon after the initial infection and increases dramatically for persons co-infected with HIV/AIDS or other immune-compromising conditions.

Treatment of TB disease requires multiple drugs for many months. These long drug regimens are challenging for both patients and health care systems, especially in low- and middle-income countries (LMICs), where the disease burden often far outstrips local resources. In some areas, the incidence of drug-resistant TB, requiring even longer treatment regimens with drugs that are more expensive and difficult to tolerate, is increasing.

Diagnosis in LMICs is made primarily by microscopic examination of stained smears of sputum of suspected patients; however, smear microscopy is capable of detecting only 50–60 percent of all cases (smear-positive). More sensitive methods of diagnosing TB and detecting resistance to drugs have recently become available, although they are more expensive. The time between the onset of disease and when diagnosis is made and treatment is initiated is often protracted, and such delays allow the transmission of disease. Although bacille Calmette–Guérin (BCG) remains the world’s most widely used vaccine, its effectiveness is geographically highly variable and incomplete. Modeling suggests that more effective vaccines will likely be needed to drive tuberculosis toward elimination in high-incidence settings.

The basic strategy to combat TB has been, for 40 years, to provide diagnosis and treatment to individuals who are ill and who seek care at a health facility. The premise is that, if patients with active disease are cured, mortality will disappear, prevalence of disease will decline, transmission will decline, and therefore incidence should decline. The reality in many countries is more complex, and overall the decline in incidence (only about 1.5 percent per year) has been unacceptably slow.

Chemotherapy for TB is one of the most cost-effective of all health interventions (McKee and Atun 2006). This evidence has been central to the global promotion of the WHO and Stop TB Partnership policy of directly observed therapy, short course (DOTS) strategy, the package of measures combining best practices in the diagnosis and care of patients with TB (UN General Assembly 2000). The DOTS strategy to control tuberculosis promotes standardized treatment, with supervision and patient support that may include, but is far broader than, direct observation of therapy (DOT), where a health care worker personally observes the patient taking the medication (WHO 2013a).

Thanks in part to these efforts and national and international investments, much progress has been made in TB control over the past several decades. Between 1990 and 2010, absolute global mortality from TB declined 18.7 percent, from 1.47 million to 1.20 million (Lozano and others 2012) and by 22 percent between 2000 and 2015 (WHO 2016a). By 2015, an estimated 49 million lives had been saved (WHO 2016a). The internationally agreed targets for TB, embraced in the United Nations (UN) Millennium Development Goals (MDGs), sought “to halt and reverse the expanding incidence of tuberculosis by 2015,” and this target has been met to some extent in all six WHO regions and in most, but not all, of the world’s 22 high-burden countries (WHO 2014c).

Despite progress, major gaps persist. Although the Sustainable Development Goals (SDGs) seek to end the tuberculosis epidemic altogether (WHO 2015a, 2015c), the decline in incidence has been disappointing. One of every three TB patients remains “unknown to the health system,” many are undiagnosed and untreated, and case detection and treatment success rates remain too low in the high-burden countries. Ominously, rates of multidrug-resistant (MDR) TB—defined as resistance to the two major TB drugs, isoniazid and rifampicin—are rising globally (WHO 2011a) with the emergence of extensively drug-resistant (XDR) TB, resistant to many second-line drugs, as well as strains resistant to all current drugs (Dheda and others 2014; Udwadia and others 2012; Uplekar and others 2015). These are now primarily the result of transmission rather than inadequate treatment (Shah and others 2017).

Moreover, the TB problem has become more pressing because of co-infection with HIV/AIDS. While globally HIV/AIDS and TB co-infection represents only 11 percent of the total TB burden, in some areas of Sub-Saharan Africa with a high burden of TB, as many as three-quarters of TB patients are co-infected with HIV/AIDS. In those countries, efforts to control TB are overwhelmed by the rising number of TB cases occurring in parallel with the HIV/AIDS epidemic. And after decades of steady decline, the incidence of TB is also increasing in some high-income countries (HICs), mainly as the result of outbreaks in vulnerable groups (WHO 2015b).

If the ultimate goal of controlling an infectious disease is to interrupt transmission, turning the tide on TB will require early and accurate case detection, rapid commencement of and adherence to effective treatment that prevents transmission, and, where possible, preventive treatment of latent TB. It is universally understood that new strategies and more effective tools and interventions will be required to reach post-2015 targets (Bloom and Atun 2016; WHO 2015a). These interventions must be not only cost-effective, but also affordable and capable of having an impact on a very large scale.

TB control will need three new advances—development of new point-of-care diagnostics, more effective drug regimens to combat drug-susceptible and drug-resistant TB, and more effective vaccines. As argued in this chapter, these require new strategies and tools that include moving away from the traditional DOTS passive case finding and toward more active case finding in high-burden regions; service delivery that is targeted to the most vulnerable populations and integrated with other services, especially HIV/AIDS services; and care that is based at the primary health care and community levels. Specifically, in high-burden countries, many individuals with TB are asymptomatic, such that waiting for patients to become sick enough to seek care has not been sufficient to reduce transmission and incidence markedly (Bates and others 2012; Mao and others 2014; Willingham and others 2001; Wood and others 2007). A more active and aggressive approach is needed that tackles health system barriers to effective TB control.

The strategies for controlling TB recommended by the WHO have evolved significantly over time. In the early formulations, the central tenets of the global TB control strategy were clinical and programmatic in nature, focusing principally on the delivery of standardized drug regimens; the underlying assumption was that the problem could be solved largely by existing biomedical tools (Atun, McKee, and others 2005; Schouten and others 2011). Yet, in many LMICs, health system weaknesses in governance, financing, health workforce, procurement and supply chain management, and information systems have impeded TB control (Elzinga, Raviglione, and Maher 2004; Marais and others 2010; Travis and others 2004) and not been adequately addressed by TB control efforts. The current global TB strategy, formulated as the End TB Strategy, is the most comprehensive ever, with three major pillars:

Integrated, patient-centered care and prevention

Social and political action to address determinants of disease

Recognition of the urgent need for research to provide new tools (WHO 2015a).

Health systems are important and need to be strengthened. As with other health interventions, the success of tuberculosis treatment and control in a country is often determined by the strength of its health system (McKee and Atun 2006; WHO 2003). A health system can be defined in many ways, perhaps best as “all the activities whose primary purpose is to promote, restore, or maintain health” (WHO 2000, 5).

In a sense, the major risk factor for acquiring TB is breathing. Thus, people of all social and economic statuses are at risk. While TB disproportionately affects the poor, the narrative that TB is a disease only of the poor is misleading and counterproductive, if it leads either to further stigmatization of the disease or to the view that middle- and high-income countries need not worry about the disease. In the case of co-infection with HIV/AIDS, evidence suggests that HIV/AIDS is often more prevalent in better-off populations in Africa that suffer high rates of TB.

The analytical framework underlying this chapter defines key functions of the health system, ultimate goals, and contextual factors that affect the health system (figure 11.1). It builds on the WHO framework (WHO 2000) as well as health system frameworks developed by Frenk (1994), Hsiao and Heller (2007), and Roberts and others (2004), and national accounts (OECD, Eurostat, and WHO 2011). It also draws on earlier studies by Atun (2012); Atun and Coker (2008); Atun, Samyshkin, and others (2006); Samb and others (2009); and Swanson and others (2012).

The four key health system functions represented in the framework are as follows:

Governance and organization. The policy and regulatory environment; stewardship and regulatory functions of the ministry of health and its relation to other levels of the health system; and structural arrangements for insurers and purchasers, health care providers, and market regulators

Financing. The way funds are collected, funds and risks are pooled, finances are allocated, and health care providers are remunerated

Resource management. The way resources—physical, human, and intellectual—are generated and allocated, including their geographic and needs-based allocation

Service delivery. Both population- and individual-level public health interventions and health care services provided in community, primary health care, hospitals, and other health institutions.

Each of these functions is influenced by the economic, demographic, legal, cultural, and political context.

As the framework suggests, health system goals include better health, financial protection, and user satisfaction. Personal health services and public health interventions should be organized to achieve an appropriate balance of equity (including reducing out-of-pocket [OOP] expenditures and impoverishment of individuals and families), efficiency, effectiveness (that is, the extent to which interventions are evidence based and safe), responsiveness, equity, and client satisfaction (as perceived by the users of services).

This chapter is organized as follows. First, we provide a detailed discussion of the global burden of disease and clinical context, followed by a review of approaches to diagnosis, treatment, and prevention. The aim throughout is to approach TB through a health system lens and, in the latter part of the chapter, to provide recommendations for improving delivery strategies and strengthening health systems, including care, supply chain, and information systems. Because the current tools for combating TB are seriously inadequate, we conclude with sections on critical research and development and economic analyses of new interventions for diagnosis, treatment, and vaccines. Throughout, emphasis is placed on data or modeling of the economic costs and benefits, where available, of current or possible future interventions to combat this disease.

The chapter recommends moving toward active case finding in high-burden countries; greater investments in health systems; community-based rather than hospital-based service delivery; and greater support for research on new tools—that is, developing better diagnostics, treatment regimens, and vaccines. Most of these approaches were included in earlier WHO policies, but were not emphasized. They are now part of the WHO’s End TB Strategy, with which this report is fully consistent (WHO 2015a, 2015c).

© 2017 International Bank for Reconstruction and Development / The World Bank.

• Historical Trends, Current Burden, and Global Response
• Infection and Disease in Individuals and Populations
• TB Diagnosis and Screening
• TB Treatment
• TB Prevention
• Turning the Tide Against TB
• Research and Development
• Financing for TB Programs
• Economic Analyses and Cost-Effectiveness
• Extended Cost-Effectiveness Analysis of Universal Public Financing of TB Treatment
• Summary and Recommendations

Publication types

ORIGINAL RESEARCH article

Aberrant adaptive immune response underlies genetic susceptibility to tuberculosis.

• 1 BostonGene Laboratory, Waltham, United States
• 2 Abu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab Emirates
• 3 Pirogov Russian National Research Medical University, Moscow, Moscow Oblast, Russia
• 4 Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow , Russia, Moscow, Moscow Oblast, Russia
• 5 Institute of Clinical Molecular Biology, Faculty of Medicine, University of Kiel, Kiel, Schleswig-Holstein, Germany
• 6 Central Tuberculosis Research Institute (RAMS), Moscow, Moscow Oblast, Russia
• 7 Central European Institute of Technology (CEITEC), Brno, Olomouc, Czechia

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Mycobacterium tuberculosis (Mtb) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibility and resistance. C57BL/6 mice are relatively TBresistant, whereas I/St mice are prone to develop severe TB, partly due to the MHC-II allelic variant that shapes suboptimal CD4 + T cell receptor repertoire. We investigated the repertoires of lunginfiltrating helper T cells and B cells at the peak of anti-Mtb immune responses in both strains. We found that lung CD4 + T cell repertoires of infected C57BL/6 but not I/St mice contained convergent TCR clusters with functionally confirmed Mtb specificity. Transcriptomic analysis revealed a more prominent Th1 signature in C57BL/6, and expression of pro-inflammatory IL-16 in I/St lunginfiltrating helper T cells. The two strains also showed distinct Th2 signatures. Furthermore, the humoral response of I/St mice was delayed, less focused, and dominated by IgG/IgM isotypes, whereas C57BL/6 mice generated more Mtb antigen-focused IgA response. We conclude that the inability of I/St mice to produce a timely and efficient anti-Mtb adaptive immune responses arises

Keywords: TCR repertoire, Tuberculosis, TB-susceptible mouse strain, CD4 + T cells, B cells, Immunoglobulins, Transcriptomic signatures

Received: 02 Feb 2024; Accepted: 11 Apr 2024.

Copyright: © 2024 Tsareva, Shelyakin, Shagina, Myshkin, Merzlyak, Kriukova, Apt, Linge, Chudakov and Britanova. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Irina Linge, Central Tuberculosis Research Institute (RAMS), Moscow, 107564, Moscow Oblast, Russia Olga Britanova, Institute of Clinical Molecular Biology, Faculty of Medicine, University of Kiel, Kiel, 24105, Schleswig-Holstein, Germany

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Tuberculosis can have a lasting impact on the lung health of successfully treated individuals

by European Society of Clinical Microbiology and Infectious Diseases

New research being presented at this year's ESCMID Global Congress (formerly ECCMID) in Barcelona, Spain (27–30 April) has found compelling evidence that tuberculosis (TB) can have a lasting impact on the lungs of individuals who have been successfully treated for the disease.

TB survivors have smaller lungs with narrower airways and slower air flow, the analysis of data on tens of thousands of individuals from around the world found.

"This damage could have a profound effect on long-term health, reduce quality of life and affect ability to work and carry out day-to-day tasks," says lead researcher Dr. Sharenja Ratnakumar, of St George's, University of London, London, UK.

"And, with growing numbers of people being successfully treated for TB, the finding strongly indicates that post-TB lung disease is an under-recognized global challenge."

TB can be cured with antibiotics and, worldwide, an estimated 155 million people are alive today as a result of successful diagnosis and treatment of the bacterial infection.

However, although significant progress has been made in combating TB in recent decades, the number of new diagnoses has increased since the COVID-19 pandemic. Some 7.5 million were diagnosed globally in 2022—the highest number since monitoring began in 1995 and above the pre-COVID baseline of 7.1 million in 2019, according to WHO's 2023 Global Tuberculosis Report.

The burden is highest in sub-Saharan Africa and south east Asia but even low incidence countries such as the UK are seeing diagnoses increase. According to provisional data from the UK Health Security Agency, there were 4,850 new diagnoses in England in 2023. This is above pre-COVID levels and represents a rise of more than 10% on 2022, when there were 4,380 diagnoses.

Previous research has found that between 18% and >80% of survivors will be left with lung damage that reduces their quality of life and life expectancy but data on the size and type of respiratory impairment is scarce. To find out more, Dr. Ratnakumar and colleagues carried out a systematic review and meta-analysis of existing research on the topic.

The Medline, Embase and CINAHL databases were searched from 1/01/00 to 31/01/23 for studies that compared the lung function of individuals with a history of TB with that of healthy controls.

The meta-analysis included data on 75,631 individuals from 15 studies conducted in 17 countries with varying TB incidence and income levels.

The 7,377 TB survivors had an average age range of 11–65 years. Many of the studies were skewed towards a younger population (<50years) from mainly low- and middle-income countries.

Four measures of lung function were included in the analysis: forced expiratory volume in 1 second (FEV1, the volume of air can be forcefully exhaled in one second); forced vital capacity (FVC, the volume of air that can be forcefully exhaled in a single breath); FEV1/FVC ratio; FVC as a percentage of the predicted value (compares the volume to the average of a healthy person of the same age, sex and height).

The study found that, compared to the healthy controls, the participants with prior TB had significantly lower results on all four measures of lung function, with FEV1 more affected than FVC.

Dr. Ratnakumar says, "FEV1 was 230 milliliters lower compared to healthy controls and FVC was 140 milliliters lower. A decrease in FEV1 of 100 milliliters is considered clinically significant and is associated with an increased risk of cardiovascular and respiratory disease."

The results as a whole point to the TB survivors having smaller lungs (restrictive disease) and narrower airways with slower air flow (obstructive disease). This means that the breaths they take are smaller and take longer; breathing is less efficient and less able to respond to increased ventilatory demands such as during exercise.

Analysis of data from five of the studies showed the TB survivors to have 65% higher odds of airflow obstruction (AFO) than the healthy controls.

The results suggest TB can leave a lasting and widespread impact on the lungs, especially in terms of how the airways are structured. This valuable insight can help guide rehabilitation strategies and, in the longer term, aid in the development of new therapies, say the researchers.

Dr. Ratnakumar explains, "Our results strongly indicate that post-tuberculosis lung disease is an under-recognized global challenge—and one that has significant implications for clinical practice and policy.

"The focus, until now, has been on the treatment of acute TB, but even when treatment is successful, individuals can be left with significant lung damage.

"This can cause breathlessness that can affect their ability to work and go about their day-to-day lives and reduces their quality of life.

"This legacy of TB has been overlooked for too long and it is vital it is recognized.

"With an estimated 74 million lives saved through tuberculosis treatment between 2000 and 2020 and a rising life expectancy , there is an urgent need for evidence-based recommendations on the diagnosis, treatment and management of post-tuberculosis lung disease.

"Our study also provides compelling evidence that the long-term care of individuals with post-tuberculosis lung disease should be an explicit component of the WHO's End TB strategy."

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TB Epidemiologic Studies Consortium

The TB Epidemiologic Studies Consortium (TBESC) was established to strengthen, focus, and coordinate tuberculosis (TB) programmatic research. Since 2001, CDC has funded TBESC external partners to conduct epidemiologic and operational research to find better approaches to TB control and prevention.

TB Trials Consortium

The  TB Trials Consortium (TBTC) is a collaboration of North American and international clinical investigators whose mission is to conduct programmatically relevant research concerning the diagnosis, clinical management, and prevention of TB infection and disease.

Behavioral and Social Science Research

Behavioral and social science research has the potential to make a tremendous impact on TB elimination efforts. This research is needed to 1) understand how behaviors of both patients and providers affect TB-related care seeking, diagnosis, treatment success, and prevention; and 2) understand how other social, cultural, and environmental influences affect health seeking and treatment outcomes related to TB.

Epidemiologic and Economic Modeling

Modeling epidemics and economics of disease provide useful information on how to prevent the greatest amount of disease with existing resources. In 2014, CDC funded a 5-year cooperative agreement, the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) Epidemiologic and Economic Modeling Agreement (NEEMA) , to support modeling activities to inform and, ultimately, improve the effectiveness of public health programs and activities supported by NCHHSTP.

• NEEMA Funded Projects by Topic Area – Tuberculosis
• NEEMA Published Papers – Tuberculosis
• NEEMA Abstracts- Tuberculosis

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• Scoping Review
• Open access
• Published: 25 May 2023

Global prevalence of drug-resistant tuberculosis: a systematic review and meta-analysis

• Nader Salari 1 , 2 ,
• Amir Hossein Kanjoori 3 ,
• Amin Hosseinian-Far 4 ,
• Razie Hasheminezhad 3 ,
• Kamran Mansouri 5 &
• Masoud Mohammadi   ORCID: orcid.org/0000-0002-5722-8300 6  

Infectious Diseases of Poverty volume  12 , Article number:  57 ( 2023 ) Cite this article

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Tuberculosis is a bacterial infectious disease, which affects different parts of a human body, mainly lungs and can lead to the patient’s death. The aim of this study is to investigate the global prevalence of drug-resistant tuberculosis using a systematic review and meta-analysis.

In this study, the PubMed, Scopus, Web of Science, Embase, ScienceDirect and Google Scholar repositories were systematically searched to find studies reporting the global prevalence of drug-resistant tuberculosis. The search did not entail a lower time limit, and articles published up until August 2022 were considered. Random effects model was used to perform the analysis. The heterogeneity of the studies was examined with the I 2 test. Data analysis was conducted within the Comprehensive Meta-Analysis software.

In the review of 148 studies with a sample size of 318,430 people, the I 2 index showed high heterogeneity ( I 2  = 99.6), and accordingly random effects method was used to analyze the results. Publication bias was also examined using the Begg and Mazumdar correlation test which indicated the existence of publication bias in the studies ( P  = 0.008). According to our meta-analysis, the global pooled prevalence of multi-drug resistant TB is 11.6% (95% CI : 9.1–14.5%).

Conclusions

The global prevalence of drug-resistant tuberculosis was found to be very high, thus health authorities should consider ways to control and manage the disease to prevent a wider spread of tuberculosis and potentially subsequent deaths.

Tuberculosis (TB) is one of the most common infectious diseases, which is the main cause of widespread mortality, especially among people living with HIV (PLHIV) [ 1 , 2 ]. The disease is caused by a type of bacteria called Mycobacterium TB [ 3 ]. Different types of TB are multi drug-resistant (MDR), pre-extensively drug-resistant (Pre-XDR), and extensively drug-resistant (XDR) [ 4 ]. TB usually affects the lungs, however it can also affect other parts of the body, such as the kidneys and the brain [ 4 ].

There were an estimated 450,000 incident cases of MDR in 2021, up 3.1% from 437,000 in 2020, three countries accounted for 42% of global cases in 202: India (26%), the Russian Federation (8.5%), and Pakistan (7.9%) [ 5 ]. A study by Baya et al., reported that the average age of patients was 39.31 ± 14.64 years, whilst 62.6% of patients were less than 40 years old. Patients were predominantly male 76.2%, and 77.1% were married [ 6 ]. Additionally, the prevalence of latent MDR TB has been reported in some countries of Eastern Europe and Central Asia, such as China (6 million people), India (4 million people), and Russia (1.8 million people) [ 4 , 5 , 6 ].

According to the existing literature, risk factors of tuberculosis include demographic characteristics such as gender, age, place of residence, education, marital status, bad habits such as alcohol abuse and smoking, and concomitant infections including diabetes mellitus, HIV, Acid-Fast Bacilli (AFB) smear, pulmonary space, history of tuberculosis, and history of anti-tuberculosis treatment are significant risk factors for MDR TB [ 7 ].

TB often impacts patients with other diseases such as diabetes, HIV, and chronic obstructive pulmonary disease (COPD) [ 7 ]. Cough or fever for > 2 weeks, weight loss, or hemoptysis are among the symptoms of TB which are also associated with lack of health insurance, tuberculin skin test, diagnosis through a process not entailing screening, and ethnicities other than Asian [ 8 ]. Complications of this disease include bronchial stenosis, severe airway obstruction, pneumonia, and hemoptysis, the most common of which is liver damage [ 9 , 10 ]. Vocal cord paralysis, associated with laryngeal TB, can also be found among the patients [ 10 ]. To treat TB, a combination of isoniazid, rifampin, ethambutol, and pyrazinamide, followed by a combination of isoniazid and rifampin are used [ 9 ].

Several studies have been conducted on the prevalence of drug-resistant tuberculosis worldwide. These studies have reported different rates, yet their reported results are heterogeneous and are not aligned. The aim of this systematic review and meta-analysis is to pool the reported results of the existing studies and offer a scientifically consistent prevalence for drug resistant TB. The findings of our study can provide useful insights to health policymakers to devised appropriate interventions, with a view to reducing the subsequent complications from the disease.

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The keywords of prevalence, drug-resistant tuberculosis, burden, outbreak and their combination using the (AND) and (OR) operators, were used to search the PubMed, Google Scholar, Science Direct, Embase, Scopus and Web of Science databases. The search was conducted with no lower time limit and until August 2022. The reference lists within the identified studies were also manually searched to ensure the comprehensive of the collected articles. The information of the identified studies was transferred into the EndNote reference management software, and studies that had reported the prevalence of drug-resistant tuberculosis by continent and were satisfying the inclusion criteria, were selected for final analysis.

Inclusion and exclusion criteria

The following criteria were used to keep an identified study in the systematic review and for meta-analysis: Studies that reported the prevalence of drug-resistant tuberculosis (including cross-sectional, case–control, and cohort studies), Studies with their full-text available, Studies that provided sufficient data (sample size, prevalence), Studies written and published in English. In contrary, the following criteria resulted in excluding identified articles: Case report studies, case series studies, duplicate studies and meta-analysis studies.

Study selection

Similarly, selection of studies was conducted in accordance with the PRISMA guidelines. Initially, articles that were duplicates in different databases were excluded, and only one copy was retained. Subsequently, the initial screening of articles was conducted through reviewing the titles and abstracts, and irrelevant articles were omitted based on the inclusion and exclusion criteria. Then their full text of articles was reviewed in line with the inclusion and exclusion criteria, and at this stage further irrelevant studies were removed. To avoid any potential bias, all the steps of reviews and data extraction were conducted by two reviewers independently. In cases where there was a difference of opinion between two reviewers, the review of the article was finalized by a third reviewer.

Quality evaluation

To evaluate the quality of articles, a checklist appropriate to observational studies was selected. The Strengthening the Reporting of Observational Studies in Epidemiology checklist (STROBE) consists of six scales including: title, abstract, introduction, methods, results, and discussion. In total, this instruction consists of 32 subscales. These 32 subscales denote different methodological aspects of the study, i.e., title, statement of the problem, study objectives, type of study, statistical population of the study, sampling method, determining the appropriate sample size, definition of variables and procedures, study data collection tools, statistical analysis methods and findings. Consider that the fulfilment of each of the subscales award a point, and based on this, articles with scores of 16 and above were considered to be of medium and high methodological quality articles respectively. Articles with a score below 16 were considered to be of poor quality and were therefore excluded from our study.

Data extraction

Data extraction was completed by two researchers using a different pre-prepared checklist. This checklist included: first author's name, year of publication, study location, sample size, age group of men and women, global prevalence of drug-resistant tuberculosis, and research instruments.

Statistical analysis

The extracted information were structured and were inputted into Comprehensive Meta-Analysis software (Version 2, Biostat, Inc., 14 North Dean Street, Englewood, NJ 07631 USA). The heterogeneity of the studies was then assessed using the I 2 test. In order to check the publication bias, the Begg’s test was used at a significance level of 0.1, and associated Funnel plots were drawn.

Following the initial search, 5109 articles were identified from the databases. An additional 60 related articles were also included following manual searches. Information of all identified articles were then transferred into the EndNote reference management software. Throughout the PRISMA’s identification stage, 2491 articles were excluded due to being repeated in various databases, and only one copy was retained. In the screening stage, the title and abstract of the studies were reviewed and 1964 further articles were excluded based on the inclusion and exclusion criteria. In the eligibility evaluation phase, 323 articles were omitted, after examination of the full text of the articles. As part of quality evaluation, and through the evaluation of the full text of the articles and based on the scores obtained from the STROBE checklist, studies with poor methodological quality were removed, and finally 148 studies were kept for analysis. All included studies were cross-sectional and most of the reviewed studies were conducted in Africa (continent). The information related to the 148 included studies is presented in Fig.  1 and Additional file 1 : Tables S1 to S6 [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 ].

PRISMA flow diagram for study selection

Multi drug-resistant TB

In the review of 148 studies that had studied multi drug resistant TB (sample size of 318,430 people), the I 2 test showed a high heterogeneity ( I 2  = 99.6), and accordingly, random effects method was used to analyze the results. Considering the meta-analysis, the global pooled prevalence of multi-drug resistant TB was found to be 11.6% (95% CI : 9.1–14.5%). Test of publication bias in the studies through the Begg and Mazumdar correlation test showed the existence of publication bias among the studies ( P = 0.008) (Table 1 ) (Figs. S1, S2 in Additional file 2 ).

Isoniazid resistant TB

In 98 studies with a focus on Isoniazid resistant TB (sample size of 102,260 people), the I 2 heterogeneity test showed a high heterogeneity ( I 2  = 99.03), and accordingly, random effects method was used to analyze the results. Considering the meta-analysis, the pooled global prevalence of isoniazid resistant TB was found to be 15.7% (95% CI : 13.7–17.9%). The study of publication bias in the studies through the Begg and Mazumdar correlation test showed the existence of publication bias in the studies ( P  = 0.02) (Table 1 ) (Figs. S3, S4 in Additional file 2 ).

Rifampin resistant TB

In the review of 109 studies that had researched rifampin resistant TB (sample size of 215,660 people), the I 2 heterogeneity test showed a high heterogeneity ( I 2  = 98.9), and similarly, random effects method was used to analyze the results. Based on the meta-analysis, the pooled global prevalence of rifampin- resistant TB was found as 9.4% (95% CI : 7.8–11.2%). The study of publication bias in the studies through the Begg and Mazumdar correlation test indicated the existence of publication bias in the studies ( P  = 0.00045) (Table 1 ) (Figs. S5, S6 in Additional file 2 ).

Single drug resistant TB

In the review of 35 studies with a focus on single drug resistant TB (sample size of 45,147 people), the I 2 heterogeneity test showed a high heterogeneity ( I 2  = 98.5). Hence, random effects method was used to analyze the results. Considering the meta-analysis results, the pooled global prevalence of single drug resistant TB was found as 11.8% (95% CI : 9.2–15.2%). The study of publication bias in the studies through the Begg and Mazumdar correlation test showed the absence of publication bias in the studies ( P  = 0.139) (Table 1 ) (Figs. S7, S8 in Additional file 2 ).

Extensive drug resistant TB

In the review of 56 studies on extensive drug resistant TB (sample size of 350,420 people), the I 2 heterogeneity test showed high heterogeneity ( I 2  = 98.8), and therefore, random effects method was used to analyze the results. Considering the meta-analysis results, the pooled global prevalence of extensive drug resistant TB was found to be 2.5% (95% CI : 2–3%). The study of publication bias using the Begg and Mazumdar correlation test indicated the absence of publication bias in the studies ( P  = 0.938) (Table 1 ) (Figs. S9, S10 in Additional file 2 ).

Information in Table 2 outlines the subgroup analysis of the types of tuberculosis resistance among patients by gender, and by TB type. Accordingly, male patients have a higher prevalence in multi-drug resistant TB, Isoniazid resistant TB and Rifampin-resistant TB, compared to female patients, with prevalence of 20% (95% CI : 11.9–31.8%), 17.5% (95% CI : 9.6–29.8%), and 12.7% (95% CI : 5.7–25.9%) respectively. Given that the articles did not report gender-segregated data for single drug-resistant TB and extensively drug-resistant TB, the authors could not include these results in the subgroup analysis.

Tuberculosis is a very common infection with a bacterial agent called Mycobacterium [ 22 , 45 , 180 , 181 , 182 ]. MDR-TB is a strain of Tuberculosis (TB) that is resistant to at least two of the most important anti-tuberculosis drugs (INH and RIF) [ 180 , 181 , 182 , 183 , 184 , 185 ].

This systematic review and meta-analysis was conducted to identify and review existing research works that had examined prevalence of different types of TB. It was also aimed to obtain pooled prevalence of TB types globally. Accordingly, we did not find a specific study on the prevalence of drug-resistant tuberculosis at the global level, despite the fact that there are many articles that have reported the prevalence of this disease at country level, or at most in a continent.

Considering the reported results of an all included studies, the global pooled prevalence of different types of drug-resistant tuberculosis, namely MDR, Isoniazid (INH), Rifampcin (RIF), and XDR were calculated as 11.6%, 15.7%, 9.4%, and 2.5%, respectively.

Eastern European countries, the Russia and Central Asian countries, and parts of China have a high rate of MDR-TB infection [ 184 , 186 ]. In the study by Kindu Alem Mola et al., the authors reported that the level of MDR-TB in East Africa is higher than other regions globally [ 187 ]. In this work, based on the relevant reports from the World Health Organization (WHO) in 2015, the prevalence of global MDR TB in new and previous TB cases were 3.5% and 20.5%, respectively, while countries in southern regions of Africa have greater rates [ 187 , 188 ].

The main reasons for the emergence of MDR TB globally numerous [ 187 ], and they are mostly related to living conditions [ 189 ], lifestyle [ 190 ], previous medical history [ 111 , 191 ], history of diabetes [ 192 , 193 ] and Human Immunodeficiency Viruses (HIV) infection [ 194 ]. A study conducted in Ethiopia shows that HIV infection is one of the most important factors associated with MDR TB [ 187 , 195 ]. In addition, HIV patients, due to the length of hospitalization in hospitals with poorer hygiene and infection control, are more exposed to MDR TB and hence the rate of infection is higher among these patients [ 187 ]. In another study by Al-Derraji et al. [ 187 , 196 ], the incidence of MDR TB among HIV-positive patients was reported to be 20% higher compared to that of HIV-negatives [ 187 ].

In densely populated and poor families, the spread of TB disease is also more prevalent [ 187 ]. According to the literature, unhealthy or poor lifestyles which entail alcohol abuse, smoking, drug use, etc. are the main risk factors related to the spread of MDR TB [ 187 ]. It was also stated that smokers, especially men, are more likely to be infected with MDR TB compared to female smokers [ 187 , 197 , 198 , 199 ].

According to an article by Jilani Talha et al., tuberculosis complications are usually seen more among elderly patients, young children, people with severe respiratory disorders or patients who do not receive proper treatment. Accordingly, patients who do not receive proper treatment are more exposed to tuberculosis complications. Some of these complications are acute respiratory distress syndrome, extensive lung destruction, empyema, pneumothorax, disseminated tuberculosis infection (including tuberculosis meningitis), bronchiectasis, fibrothorax, aspergilloma, and hemoptysis [ 200 ].

According to a study conducted by Jilani et al., with a focus on treating active tuberculosis, a combination of drugs is required during the two intensive and the continuous phases; the first-line drugs that are the most common regimen for tuberculosis treatment include: (1) isoniazid, (2) rifampin, (3) ethambutol, and (4) pyrazinamide [ 200 ].

The intensive phase in the treatment of Tuberculosis includes the combination of the above 4 drugs that are prescribed for 2 months, yet the continuation phase includes the combination of isoniazid and rifampin for an additional 4 months. The second line drugs include: (1) Injectable aminoglycoside: streptomycin, amikacin, kanamycin; (2) Injectable polypeptides: viomycin and capreomycin; (3) Fluoroquinolones: levofloxacin, gatifloxacin, ofloxacin and moxifloxacin, and (4) Para-amino salicylic acid, ethionamide, cycloserine, prothionamide, trazodone, linezolid [ 200 ].

In a study conducted, the side effects of each anti-tuberculosis drug were described as follows: (1) Isoniazid: liver damage (fatigue, nausea, lethargy, abdominal pain, and vomiting), skin rash, numbness, headache and tingling of limbs; (2) Rifampin: jaundice, arthralgia (joint stiffness), and fever; (3) Ethambutol: visual impairment including blurred or reduced vision and blindness, liver damage, headache, and nausea, and (4) Pyrazinamide: nausea, painful or swollen joints, and liver damage [ 200 ]. According to the reported results of the same study, the highest prevalence of multi-drug resistant tuberculosis was reported in males.

Considering the ratio of infections among males vs females, one study reported that the split between males and females with multi-drug resistant tuberculosis was 70.4% and 29.6% respectively [ 201 ], In a study conducted in patients with resistant tuberculosis in Ghana, the ratio of males and females was 69.6% and 30.4% respectively [ 202 ], whilst in another study conducted in Egypt, the ratio of males and females was reported as 67.5% and 32.5%, respectively [ 203 ]. Moreover, in a similar research work conducted in Ethiopia 65.3% male and 34.7% female has multi drug resistant TB [ 204 ].

Our study shows that different strains of Tuberculosis, including drug-resistant TBs, have a high prevalence. On the other hand, these strains can be treated, and there are similar strategies and interventions to control existing and new infections. Considering the complications that this disease may cause, its control and management are vital, since it would be possible to reduce the Tuberculosis induced mortality rate through controlling its different strains.

The main limitation of the present meta-analysis is related to the significant publication bias among the identified studies, and therefore, the results should be considered with caution. Moreover, it is recommended that future meta-analysis studies in this field are conducted using more keywords and databases to potentially eliminate this bias.

According to the results of the present study, the global prevalence of multidrug-resistant, mono drug-resistant, isoniazid, and rifampicin tuberculosis are 11.6%, 11.8%, 15.7%, and 9.4%, respectively. The results of this study can offer some consistency to the heterogeneous results from studies conducted around the world and provide reliable insights to health policymakers. Such insights would be instrumental to devise appropriate preventive, therapeutic and diagnostic measures.

Availability of data and materials

Datasets are available through the corresponding author upon reasonable request.

Abbreviations

Drug susceptibility testing

Whole genome sequencing

Restriction fragment length polymorphism

Decontamination and Ziehl–Neelsen

Chest X-ray

Antimicrobial susceptibility testing

Confidence interval

Tuberculosis

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Acknowledgements

We would like to thank the support provided by the Student Research Committee of Kermanshah University of Medical Sciences.

By Deputy for Research and Technology, Kermanshah University of Medical Sciences (IR) (50002460). This deputy has no role in the study process.

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NS and RH and AK contributed to the design, MM statistical analysis, participated in most of the study steps. MM and RH and AHF prepared the manuscript. AK and RH and KM assisted in designing the study, and helped in the interpretation of results. All authors have read and approved the content of the manuscript. All authors read and approved the final manuscript.

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Supplementary Information

Additional file 1: table s1..

Summary of Characteristics of Included Studies of Prevalence of MDR-TB. TableS2. Summary of Characteristics of Included Studies of Prevalence of Isoniazid Resistant-TB . Table S3. Summary of Characteristics of Included Studies of Prevalence of Rifampcin Resistant-TB. Table S4. Summary of Characteristics of Included Studies of Prevalence of Single Drug Resistant-TB. Table S5. Summary of characteristics of included studies of prevalence of XDR-TB. TableS6. Summary of characteristics of included studies of prevalence of pre-XDR TB.

Additional file 2: Figure S1.

Forest plot of the global prevalence ofmulti-drug resistant TB based on the random effects method. Figure S2. Funnel plotof publication bias in reviewed studies. Figure S3. Forest plot of global prevalence of isoniazid resistant TB based on randomeffects method. Figure S4. Funnel plot of publication biasin reviewed studies. Figure S5. Forest plot ofglobal prevalence of rifampin-resistant TB based on random effects method. FigureS6. Funnel plot of publication bias in reviewed studies. FigureS7. Forest plot of globalprevalence of single drug resistant TB based on random effects method. FigureS8. Funnel plot of publication bias in reviewed studies. Figure S9. Forest plot of global prevalence of extensively drugresistant TB based on random effects method. Figure S10. Funnel Plot of Publication Bias in ReviewedStudies.

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Salari, N., Kanjoori, A.H., Hosseinian-Far, A. et al. Global prevalence of drug-resistant tuberculosis: a systematic review and meta-analysis. Infect Dis Poverty 12 , 57 (2023). https://doi.org/10.1186/s40249-023-01107-x

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Increased tuberculosis case detection in Tanzanian children and adults using African giant pouched rats

• Tefera B. Agizew 1 , 2 ,
• Joseph Soka 1 ,
• Cynthia D. Fast 1 , 2 ,
• Stephen Mwimanzi 1 ,
• Gilbert Mwesiga 1 ,
• Nashon Edward 1 ,
• Marygiven Stephen 1 ,
• Reheme Kondo 1 ,
• Robert Burny 3 ,
• Christophe Cox 1 , 2 &
• Negussie Beyene 1 , 2 , 4  

BMC Infectious Diseases volume  24 , Article number:  401 ( 2024 ) Cite this article

Metrics details

African giant pouched rats, trained by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO), have demonstrated their ability to detect tuberculosis (TB) from sputum. We assessed rat-based case detection and compared the mycobacterium bacillary load (MTB-load) in children versus adults.

From January–December 2022, samples were collected prospectively from 69 Directly Observed Therapy (DOT) facilities’ presumed TB patients. Using an average of five rats, APOPO re-evaluated patients with bacteriologically negative (sputum-smear microscopy or Xpert MTB/RIF) results. Rat-positive samples were tested using concentrated smear light-emitting diode microscopy to confirm TB detection before treatment initiation. The rats’ identification of pulmonary TB is based on smelling TB-specific volatile organic compounds (VOCs) in sputum. Using STATA, Chi-square for odds ratio and confidence interval was calculated and evaluated: (1) the yield of rat-based TB detection compared to that of the health facilities; (2) rat-based TB detection in children versus adults; and (3) rats’ ability to detect TB across MTB-loads and between children and adults.

From 35,766 patients, 5.3% (1900/35,766) were smear-positive and 94.7% (33,866/35,766) were smear or Xpert-negatives at DOTS facility. Of those with negative results, 2029 TB cases were detected using rats, contributing to 52% (2029/3929 of total TB identified), which otherwise would have been missed. Compared to DOT facilities, rats were six-fold more likely to detect TB among Acid Fast Bacilli (AFB) 1+/scanty [90% (1829/2029) versus 60% (1139/1900), odds ratio, OR = 6.11, 95% confidence interval, CI: 5.14–7.26]; twice more likely to identify TB cases among children [71% (91/129) versus 51% (1795/3542), OR = 2.3, 95% CI: 1.59–3.42]; and twice more likely to identify TB cases among children with AFB 1+/scanty than adults with the same MTB-load [5% (86/1703) versus 3% (28/1067), OR = 2.0, 95% CI: 1.28–3.03].

Conclusions

Rats contributed over half of the TB cases identified in program settings, and children, especially those with a lower MTB-load, were more likely to be diagnosed with TB by rats. The chemical signatures, VOCs, were only available for adults, and further research describing the characteristics of VOCs in children versus adults may pave the way to enhance TB diagnosis in children.

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Introduction

Despite the curable and preventable nature of tuberculosis (TB), about 10.6 million people fell ill with it and 1.6 million died in 2021 [ 1 ]. The African region accounts for nearly one-third of the estimated global burden of TB, and TB remains a public health problem in sub-Saharan African countries, Tanzania included. TB is declining by only 5% on average annually in Tanzania [ 1 ]. With this current rate of decline, considerable gaps persist in finding and treating TB cases timely, as a result of which achieving reduced TB transmission and TB cases per the END TB target may not be possible in the near future [ 2 ]. Therefore, scaling up of cheaper, faster, and more sustainable diagnostic tests to find more TB patients, especially those missed in routine program settings, is essential.

Over the years, African giant pouched rats ( Cricetomys ansorgei ), trained by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) to identify TB by smell, have demonstrated their ability to detect TB from sputum [ 3 , 4 , 5 ]. The trained rats have very high sample throughput, as they can screen 100 sputum samples in 20 minutes [ 6 ]. The rats’ identification of pulmonary TB is based on smelling TB-specific volatile organic compounds (VOCs) in sputum specimens [ 5 ]. By the end of 2022, APOPO’s TB Detection Programs had screened 870,777 sputum samples from 517,264 presumptive TB patients and found 26,084 newly diagnosed TB patients in three high-TB burden countries (Ethiopia, Mozambique, and Tanzania). At APOPO, we have generally done this by re-evaluating (second-line TB screening) sputum samples initially tested and declared bacteriologically negative by sputum-smear microscopy (smear) or Xpert MTB/RIF [ 4 ]. Before treatment initiation, all TB patients identified using rats are confirmed using the national standard diagnostics.

Due to the low bacillary load and lesser sensitivity of the available diagnostic methods, including culture, diagnosing TB in children is difficult, leaving them undiagnosed and therefore untreated [ 7 ]. Using APOPO rats, Mgode et al. reported on the diagnosis of TB in children (0–14 years) in 2018. They discovered 39% (208/539) contributions among pediatric TB cases reported, which translates to 62.8% additional cases (incremental yield) by rats to DOT facilities TB case detection [ 8 ]. There is limited data on rats’ abilities to detect TB in children versus adults. Other than the above report, all the previous studies were focused on adults [ 9 , 10 ]. In this study, we aim to evaluate: (1) the yield of rat-based TB case detection compared to that of the health facilities; (2) rat-based TB case detection in children versus adults; and (3) rats’ ability to detect TB across Mycobacterium TB bacillary loads (MTB-load) and between children and adults.

Study settings and designs

We conducted a prospective study using routinely collected data on presumptive TB patients enrolled in the national TB program’s routine care at 69 (58 Dar es Salaam, 11 Dodoma) DOT facilities from 1st of January to 31st of December 2022 in Tanzania.

Study population

The study population includes all individuals of all ages, including children, men, and women, who presented with symptoms of TB at study sites.

Tuberculosis screening

At the health facility visit, children (0–14 years old) and adults (15 years and above, hereafter referred to as adults) were screened for TB symptoms. Per the national TB guidelines, adults were screened for 4 TB symptoms (cough, fever, night sweats, and weight loss) of two or more weeks duration. Children were screened for weight loss or failure to thrive (no weight gain > 3 months), cough for ≥2 weeks, fever for ≥2 weeks, fatigue or reduced playfulness for ≥2 weeks, and profuse night sweats for ≥2 weeks [ 11 ]. Presumptive TB cases were defined when patients were screened positive for one or more of the TB symptoms using the above guide.

APOPO tuberculosis detection model using rats

APOPO sample collection, a rat-based assessment procedure, and a TB detection model using rats were reported in previous APOPO publications (Fig.  1 ) [ 3 , 12 ]. In summary, smear, which has very good specificity but very poor sensitivity, especially in sub-Saharan African settings [ 13 ], remains the most commonly used TB diagnostic method in low- and middle-income countries [ 4 ]. At APOPO, samples from smear- or Xpert MTB/RIF-negative presumptive TB patients are screened using detection rats, and rat-positive samples are confirmed using light-emitting diode fluorescence smear microscopy (LED-FM), yielding an annual average of a 40% increase (incremental yield) in smear-positive case detection [ 3 ]. Therefore, APOPO envisages targeting and reaching the missed TB cases to maximize TB case detection and treatment coverage. In this study, five rats on average sequentially evaluated the samples placed under 10 sniffing holes in the floor in a of rectangular chamber (205 cm long, 55 cm wide, and 55 cm high). The details of the evaluation setup have been reported elsewhere [ 14 ].

APOPO tuberculosis detection model using rats. Reproduced with permission [ 12 ]

Data collection

Data were collected using standardized case report forms (CRF) between January and December 2022. An APOPO-developed TB Laboratory Information System (TB-LIMS) was used to record the data. Logic checks were used to find inconsistencies, which were then verified against the original CRF after being discovered. Consistencies and missing data were, whenever possible, fixed by reviewing patient charts.

Statistical analysis

Data were analyzed using STATA statistical software 15 [ 15 ]. A Chi-square for odds ratio was calculated to analyze the demographic and laboratory parameters of the patients, and rats’ TB detection over the DOT facilities and compared the increase by MTB-load in children versus adults. We employed an odds ratio and a 95% confidence interval, and statistical significance was determined by P values less than 0.05.

From a total of 35,766 patients, 46,048 samples were screened between January and December 2022; Among these patients 5.3% (1900/35,766) were smear-positive and 94.7% (33,866/35,766) were smear or Xpert-negatives at DOTS facility (Fig.  2 a). Figure  2 b shows children and adults, respectively, were 8% (2508/33,243) and 92% (30,735/33,243). Among presumptive TB patients 2523, and 258 TB patients were not included for the odds ratio analysis due to missing age. Bacteriologically confirmed (smear at DOT facilities and rats’ detection verified by smear) cumulative TB cases were 11% (3929/35,766), whereas 5% (129/2508) and 12% (3542/30,735) were among children and adults, respectively. The median age was 36 years (interquartile range, 26–47 years), and 68% (2680/3903) were males (Fig. 2 b and Table  1 ).

A Rat indication and tuberculosis cases after LED smear confirmation among presumptive tuberculosis patients in Tanzania study sites from January to December 2022. Note: *Since the samples were not tested by culture, 17.8% does not truly represent sensitivity. Since the LED smear is not good enough in sensitivity, nor does 81.9% represent a true false positive. B Presumptive tuberculosis and bacteriologically confirmed tuberculosis cases in Tanzania study sites from January to December 2022. Note: *Children versus adults bacteriologically confirmed TB: 5% (129/2508) versus 12% (3542/30,735), odds ratio 0.42, 95% confidence interval: 0.35–0.50, p value, 0.001

TB detection using rats

Of the 3929 TB cases, APOPO rats’ detection contributed 52% (2029/3929) of the TB cases reported as smear-positive TB at DOT facilities that otherwise would have been missed by routine program. Compared to DOT facilities, the detection rats were six-fold more likely to detect TB among patients with Acid Fast Bacilli (AFB) smear 1+ or scanty [90% (1829/2029) versus 60% (1139/1900), odds ratio, OR = 6.11, 95% confidence interval, CI: 5.14–7.26]. The odds of identifying TB cases by rat among children were two-fold higher than adults [71% (91/129) versus 51% (1795/3542), OR = 2.3, 95% CI: 1.59–3.42] (Table 1 ). Furthermore, the odds of identifying TB cases by rats among children with AFB 1+ or scanty smear were two-fold higher than those among adults with the same MTB-load range [5% (86/1703) versus 3% (28/1067), OR = 2.0, 95% CI: 1.28–3.03] (Tables 2 and 3 and Figs.  3 and 4 ).

Tuberculosis cases among children and adults identified using rats by Mycobacterium bacillary load

Tuberculosis cases detected by smear microscopy at DOTs and by rats at APOPO and confirmed by LED smear microscopy in Tanzania study sites from January to December 2022

Tuberculosis detection by smear at DOTs and by rats at APOPO confirmed by LED smear by Mycobacterium tuberculosis bacillary load

Higher proportions of AFB Scanty were identified among TB diagnosed by rats and confirmed by LED smear than those diagnosed at DOT, and this was similar among children and adults (Fig. 4 ).

On average, 2.36 (3459/1466), 3.40 (1233/363), 3.68 (545/148), and 3.75 (195/52) rats from a set of five rats indicated TB in those with AFB Scanty, 1+, 2+, and 3+, respectively More rats were able to identify TB as the MTB-load increased (Fig.  5 ).

Average rat indication by Mycobacterium Tuberculosis bacillary load

Discussions

For more than a decade, APOPO-trained African giant pouched rats have been used to re-evaluate (second-line screening) sputum samples tested by smear under routine program conditions [ 3 , 4 ], and this has allowed us to compare the effect of rats on pulmonary TB case finding against DOT facilities. In the present study, rats demonstrated a 52% contribution in the detection of TB cases among patients who presented to routine DOT facilities with symptoms of TB and were diagnosed with TB. Rats were six times more likely than DOT facilities to uncover TB in patients with AFB smear 1+ or scanty, and this finding is similar to a previous study (five times more likely), though the latter was only applicable to children [ 4 ]. It is worth noting that if verification tests following the sputum samples’ rat indication as positive had been confirmed by molecular WHO-recommended rapid diagnostics, such as Xpert MTB/RIF Untra or Truenat, or by culture, which can detect TB with much lower concentrations of mycobacterium in a sample than concentrated LED microscopy, the contribution of rats would have been higher. Rats’ contribution has implications for Tanzania’s efforts to eliminate TB, especially as those who were identified using rats were deemed TB negative (missed TB cases) in the context of the standard TB diagnostic procedures and would have been left untreated otherwise.

We described elsewhere how rats can discriminate Mycobacterium TB by sniffing a variety of VOCs [ 3 , 5 ]. According to a recent meta-analysis (53,181 samples from 24,600 patients in seven studies), the sensitivity and specificity of TB screening using rats were 81.3 and 73.4%, respectively [ 16 ]. In our report, we further analyzed the rats’ responses to different MTB-loads with respect to their impact on children and adults with pulmonary TB.

TB detection using rats among children and adults

Comparing the effect of TB detection using rats in children to that in adults, rats were more than twice as likely to identify TB in children compared to adults, even though the likelihood of TB diagnosis among children with presumptive TB was lower by 58%. It should be noted that the increased TB detection among children was not only higher, but it was also significantly higher among children with a lesser bacillary load (AFB 1+ or scanty) compared to adults with a similar bacillary load. Our finding suggests that the rat-based technology could be used to improve pediatric TB case detection in high-burden countries such as Tanzania, where children are diagnosed with TB less frequently than adults by the standard of care.

In the previous study, rats contributed 39% (208/539) to pulmonary TB case detection reported in children (0–14 years), which was far less than our finding (71%, p < 0.001 ) [ 8 ].

APOPO’s rat technology has shown further improvement over time toward better rat and rat-handler training techniques, among other possibilities, which may explain the difference between the two reports. APOPO is working to advance its technologies further in this direction, and rats’ performance-rewarding systems are being computerized. The recent fully automated (i.e., controlling indication threshold time, notification of correct identification, reward delivery, and data recording are all computer controlled) rat cage is one step in this process and is currently being evaluated [ 14 ]. If validated, the automated system eliminates the effect of the human factor, i.e., rat handlers, who previously rewarded rats manually by providing food after a rat indicated the sample had TB. With the automated cage, APOPO anticipates improving and speeding up TB detection in Tanzania. In agreement with Mgode et al., our work has implications for developing rat-based TB diagnostic techniques or algorithms among children due to the challenges of detecting TB in this age group, where sputum quality and quantity remain a concern [ 7 , 8 ].

Fewer number of rats is needed to identify TB with a higher bacillary load

The direct relationship between smear positivity and MTB-load was expected [ 17 ]. Interestingly, we also observed that when the bacillary load increased, more and more rats identified TB cases, suggesting that fewer rats were needed to detect TB, and once again, the effect tends to be stronger in children than in adults. The properties of the chemical signature, VOCs, among various age groups have not yet been determined, and the previous report was for adults only [ 5 ]. Our research led us to two hypotheses: (1) children may have distinct or greater VOC characteristics, making it simpler to diagnose TB even when the bacillary load is lower than that of adults; and (2) probably, the less developed physiology may not let them to produce other odors that could be developed by adult patients, which in turn may somehow mask the odor from the characteristic VOCs. These merit additional investigation. On the other hand, sputum quality and quantity have an impact on the accuracy of TB diagnosis by smear or Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) [ 17 , 18 , 19 ], and in the same vein, higher-quality sputum makes it simpler for rats to detect TB.

Our study has some limitations. First, because the data were from a routine program setting, the age of certain TB cases was missing, which prevented them from being further analyzed. Rats were, however, four times more likely to detect TB than DOT among those with missing ages, and It’s likely that the conclusion would remain unchanged if the missing data were included. Second, health workers at various DOT facilities may not have received training before the data collection, and the TB screening and recording procedures may not have been consistent, which may result in inconsistent presumptive patient identification. Third, despite the fact that sputum induction is usual at DOT facilities, it was possible to collect insufficient sputum samples from children, which may have resulted in fewer pediatric TB diagnoses than in adult patients. Finally, for those samples evaluated by rats after the Xpert MTB/RIF negative test result, using the same sample for rats was not possible. Thus, a sister sample was collected and evaluated by rats. In such cases, we cannot rule out the possibility of inter-sample variations, i.e., the sister sample had a chance not to be negative if it was tested by Xpert MTB/RIF before rats’ evaluation.

In conclusion, in our high TB burden settings, APOPO rats led to more than half of the TB cases identified. Children had a higher rate of TB detection, particularly among those with lower bacillary loads. In the present study, rats demonstrated their essential role in TB control efforts, specifically in identifying TB cases that were overlooked in routine program diagnostic settings. Since rats were more easily able to detect TB in children than adults, and the data from prior reports about chemical signatures, VOCs, were only available for adults, further research describing the characteristics of VOCs in children versus adults may pave the way to enhance TB diagnosis in children. Like other TB diagnostic technologies, it’s likely that the quality of the sputum specimen influences the rat’s ability to detect TB by sniffing; therefore, advancements in this area make it simpler for the rats to recognize TB.

Availability of data and materials

The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Although the patient-level data do not include patient names, this IRB decision is in the interest of ensuring patient confidentiality. An individual may email the lead author ( [email protected] ) or the APOPO TB Detection Research Department ( [email protected] ) to request the data.

Abbreviations

Acid fast bacilli

Anti-persoonsmijnen ontmijnende product ontwikkeling

Confidence interval

Case report form

Directly observed therapy

Light-emitting diode fluorescence smear microscopy

Mycobacterium Tuberculosis

South Texas Art Therapy Association

Tuberculosis

Volatile organic compound

Ziehl-Neelsen

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Acknowledgements

The authors gratefully acknowledge the service of the APOPO TB research team, which carried out the day-to-day work of the evaluation of samples from DOT facilities. The authors would also like to thank the Tanzania Ministry of Health, the National TB and Leprosy Program, and health care workers at the collaborating DOT facilities in Dar es Salaam and Dodoma. Patient tracking by MKUTA is much appreciated.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the APOPO project. References in this manuscript to any specific commercial products, process, service, manufacturer, or company do not constitute its endorsement or recommendation by the donors or APOPO.

This research has been supported by Else Kröner-Fresenius-Stiftung (EKFS, Germany), the Light Foundation (Germany), the Polish embassy in Tanzania, and the Directorate General for Development Cooperation (DGD, Belgium), who supported the study financially. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) Tuberculosis Department, Sokoine University of Agriculture, Morogoro, Tanzania

Tefera B. Agizew, Joseph Soka, Cynthia D. Fast, Stephen Mwimanzi, Gilbert Mwesiga, Nashon Edward, Marygiven Stephen, Reheme Kondo, Christophe Cox & Negussie Beyene

Department of Biology, University of Antwerp, Antwerp, Belgium

Tefera B. Agizew, Cynthia D. Fast, Christophe Cox & Negussie Beyene

APOPO, TB Detection Program, Eduardo Mondlane University, Maputo, Mozambique

Robert Burny

APOPO TB Research Project, Armauer Hansen Research Institute, Addis Ababa, Ethiopia

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Contributions

T.A and J.S conceptualized and designed the study and conducted the statistical analysis. S.M, G.M, N.E, M.S., and R.K conducted the fieldwork and laboratory work. T.A, J.S, S.M, C.F, R.B, C.C, and N.B reviewed the collected data and participated in the writing of the results and discussions. All co-authors contributed to the writing and review of the manuscript.

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Correspondence to Tefera B. Agizew .

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Ethics approval and consent to participate.

The study protocol was approved by the Institutional Review Board ( IRB, Ref. nr. NMRI/HQ/R.8c/Vov.I/2066 ) at the Tanzanian National Institute for Medical Research (Dar es Salaam, Tanzania). Following IRB approval, patients were enrolled in the study, and data were collected as part of the national TB program’s routine TB diagnostic care activities. Therefore, the ethical committee waived the need for informed consent for this operational research that involved second-line TB screening following routine care.

Pertaining to the rats, all procedures were conducted with approval from the Institutional Committee for Research Involving Animals of the Sokoine University of Agriculture and in accordance with all relevant guidelines and regulations. The methods and results reported herein adhere to the National Centre for Replacement Refinement & Reduction of Animals in Research ARRIVE 2.0 guidelines. At the conclusion of all experiments, subjects remained housed according to the procedures described above with no animals sacrificed.

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Agizew, T.B., Soka, J., Fast, C.D. et al. Increased tuberculosis case detection in Tanzanian children and adults using African giant pouched rats. BMC Infect Dis 24 , 401 (2024). https://doi.org/10.1186/s12879-024-09313-0

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DOI : https://doi.org/10.1186/s12879-024-09313-0

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Tuberculosis: A Global Health Problem

Tuberculosis (TB) is an ancient disease that has affected mankind for more than 4,000 years ( 1 ). It is a chronic disease caused by the bacillus Mycobacterium tuberculosis and spreads from person to person through air. TB usually affects the lungs but it can also affect other parts of the body, such as brain, intestines, kidneys, or the spine. Symptoms of TB depend on where in the body the TB bacteria are growing. In the cases of pulmonary TB, it may cause symptoms, such as chronic cough, pain in the chest, haemoptysis, weakness or fatigue, weight loss, fever, and night-sweats.

TB remains a leading cause of morbidity and mortality in developing countries, including Bangladesh. With the discovery of chemotherapy in the 1940s and adoption of the standardized short course in the 1980s, it was believed that TB would decline globally. Although a declining trend was observed in most developed countries, this was not evident in many developing countries ( 2 ). In developing countries, about 7% of all deaths are attributed to TB which is the most common cause of death from a single source of infection among adults ( 3 ). It is the first infectious disease declared by the World Health Organization (WHO) as a global health emergency ( 4 ). In 2007, it was estimated globally that there were 9.27 million incident cases of TB, 13.7 million prevalent cases, 1.32 million deaths from TB in HIV-negative and 0.45 million deaths in HIV-positive persons ( 5 ). Asia and Africa alone constitute 86% of all cases ( 5 ). Bangladesh ranked the 6th highest for the burden of TB among 22 high-burden countries in 2007, with 353,000 new cases, 70,000 deaths, and an incidence of 223/100,000 people per year ( 5 ).

Implementation of directly-observed therapy short course (DOTS) has been a ‘breakthrough’ in the control of tuberculosis. In many countries, it has become the cornerstone in the treatment of tuberculosis. The number of countries and the coverage of DOTS within the countries have increased over the years ( 5 ). Over the last 15 years, about 35 million people have been cured, and eight million deaths have been averted with the adoption of DOTS ( 6 ). Implementation of DOTS was started in 1993 in Bangladesh, and it gradually covered the whole country ( 7 ).

Men are more commonly affected than women. The case notifications in most countries are higher in males than in females. There were 1.4 million smear-positive TB cases in men and 775,000 in women in 2004 ( 8 ). The ratio of female to male TB cases notified globally is 0.47:0.67 ( 9 ). The reasons for these gender differences are not clear. These may be due to differences in the prevalence of infection, rate of progression from infection to disease, under-reporting of female cases, or the differences in access to services.

The association between poverty and TB is well-recognized, and the highest rates of TB were found in the poorest section of the community ( 10 ). TB occurs more frequently among low-income people living in overcrowded areas and persons with little schooling ( 11 ). Poverty may result in poor nutrition which may be associated with alterations in immune function. On the other hand, poverty resulting in overcrowded living conditions, poor ventilation, and poor hygiene-habits is likely to increase the risk of transmission of TB ( 12 ).

Various surveys have been conducted to understand the knowledge, attitudes, and practices regarding tuberculosis ( 13 – 14 ). One survey in India reported that most (93%) people had heard of TB but only 20.5% of the people demonstrated sufficient knowledge of TB ( 13 ). This issue of the Journal includes an article by Rundi who explored healthcare-seeking behaviour with regard to TB among the people of Sabah in East Malaysia and the impact of TB on patients and their families ( 15 ). The author used qualitative methods and interviewed patients with TB and their relatives. It was found that most (96%) respondents did not know the cause of TB. TB also affected life-styles of the people. The author emphasized the need to understand the reasons for misconceptions about TB and to address it through health education.

Better understanding of the prevalence of drug resistance against tuberculosis is one of the key elements in the control of TB. Drug resistance, in combination with other factors, results in increased morbidity and mortality due to tuberculosis. Drug-resistant strains of TB is rapidly emerging worldwide ( 16 ). The WHO reported alarming rise of not only multidrug-resistant (MDR) TB but also of XDR TB (extreme drug-resistant TB) globally. Both treatment and management of such cases are well beyond the capacity of any developing country. Globally, there were about 0.5 million cases of MDR TB. In Bangladesh, the MDR rate is 3.5% among new cases and 20% among previously-treated cases ( 5 ). The death rate in MDR cases is high (50–60%) and is often associated with a short span of disease (4–16 weeks) ( 17 ). Several factors have been identified for the development of MDR cases. These include non-adherence to therapy, lack of direct observed treatment, limited or interrupted drug supplies, poor quality of drugs, widespread availability of anti-TB drugs without prescription, poor medical management, and poorly-managed national control programmes ( 18 – 20 ). Continuation of the existing MDR surveillance is important to effectively plan for the treatment of MDR cases and implementation of the DOTS-Plus strategy. It requires rapid, concerted action and close collaboration among government, non-government and private organizations to control MDR tuberculosis ( 21 ).

The diagnosis of TB among children is difficult. Moreover, young children cannot produce sputum. Estimates indicate that children constitute about 10% of all new cases in high-burden areas ( 8 ). Clinical signs and symptoms and scoring system have been used for the diagnosis of TB among children ( 22 ). Various diagnostic techniques have been used for improving the diagnosis among children. These include culture, serodiagnosis, and nucleic acid amplification ( 23 ).

Many countries use BCG vaccine as part of their TB-control programme. The protective efficacy of BCG viccine against all forms of TB is about 50% but it was more in serious forms of infection (64% in cases of tuberculosis meningitis and 78% in disseminated infection) ( 24 ). Several new vaccines against TB are being developed. These vaccines are now being field-tested in different countries in different phases ( 25 ).

There are several challenges which need to be addressed for effective control of TB, particularly in developing countries. These include the development of an effective surveillance system, accelerated identification of cases, expansion of DOTS to hard-to-reach areas, strengthening of DOTS in urban settings, ensuring adequate staff and laboratory facilities, involvement of private practitioners, treatment facilities for MDR cases, identification of TB among children and extra-pulmonary cases, and effective coordination among healthcare providers ( 5 , 26 – 27 ). Moreover, the prevalence of TB is influenced by HIV, and effective control measures are needed for both the diseases.

Further research is warranted to improve diagnostics, develop new drugs and vaccines, simple and effective regimen for simultaneous treatment of TB and HIV, ways to improve programme effectiveness, and better understanding of the relationship between TB and chronic diseases, e.g. diabetes and smoking, and identify social and behavioural factors which limit the detection of cases ( 8 , 28 ).