research topics for tuberculosis

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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.

Latest Research and Reviews

A serum B-lymphocyte activation signature is a key distinguishing feature of the immune response in sarcoidosis compared to tuberculosis

Sarcoidosis patients exhibit higher level of serum B cell activation signature compared to tuberculosis, regardless of uveitis manifestation.

• Ikhwanuliman Putera
• Benjamin Schrijver
• Willem A. Dik

Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice

Mycobacterial phthiocerol dimycocerosate (PDIM) inhibits LC3-associated phagocytosis and counters autophagy-dependent restriction of Mycobacterium tuberculosis in non-alveolar macrophages.

• Ekansh Mittal
• G. V. R. Krishna Prasad
• Jennifer A. Philips

Drug resistance and genomic variations among Mycobacterium tuberculosis isolates from The Nile Delta, Egypt

• May S. Soliman
• Chungyi H. Hansen
• Adel M. Talaat

Mycobacterium tuberculosis cough aerosol culture status associates with host characteristics and inflammatory profiles

Using cough-generated aerosol cultures, authors probe the inflammatory markers and epidemiological characteristics of individuals with pulmonary tuberculosis, in association with infection state.

• Videlis Nduba
• Lilian N. Njagi
• David J. Horne

Tuberculosis in otherwise healthy adults with inherited TNF deficiency

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

• Andrés A. Arias
• Anna-Lena Neehus
• Stéphanie Boisson-Dupuis

Analyzing spatial delays of tuberculosis from surveillance and awareness surveys in Eastern China

News and Comment

Recasting resistance to Mycobacterium tuberculosis

Why some individuals ‘resist’ infection with Mycobacterium tuberculosis (Mtb) has been an enigma. Enriched T cell phenotypes have now been linked to ‘resistance’ to Mtb infection and disease across multiple cohorts.

• Jason R. Andrews

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

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Tuberculosis is the leading cause of death from a single infectious agent and remains a global health emergency. In 2018 alone, there were 1.5 million deaths and 10 million new cases globally, among whom half a million had rifampicin resistant TB. The annual rate of decline in TB incidence is still much lower than what would be needed to end the TB epidemic by 2030.

It is critical to identify and overcome barriers to effective implementation of existing strategies and tools, which, if adequately employed, would drastically reduce the TB burden. Implementation research on best strategies for early diagnosis, treatment and prevention of TB, optimized and tailored to various socioeconomic contexts and responsive to local conditions, would help accelerate the decline in TB incidence rates globally. This is particularly essential in resource-limited settings where much remains to be done to achieve universal coverage for TB care. Implementation research on effective approaches that can mobilize sustained community engagement, address social determinants of TB and strengthen political commitment remains an important area to End TB.

WHO’s End TB Strategy, endorsed by the World Health Assembly in May 2014, distinctly recognized TB research as one of its three pillars. Locally owned and conducted implementation TB research within national TB programmes are needed in countries to identify more efficient ways of using existing tools and expeditiously scaling up new tools to End TB.

TDR aims to contribute to the End TB effort by conducting and enhancing capacity for implementation research at national, regional and global levels.    

Active TB drug safety monitoring and management (aDSM)

TDA4Child initiative

African regional research networks for TB control

Calibrating computer-aided detection (CAD) for TB

ShORRT initiative

Impact Grants awarded for implementation research in South-East Asia Region

Even after full TB treatment, many people suffer disability, other illnesses

Improving childhood TB diagnosis in Nigeria and the Democratic Republic of the Congo: the TDA4Child initiative

Strengthening capacities for improving TB drug safety monitoring

Is tuberculosis treatment truly free? Insights from Pakistan

Exploring catastrophic household costs for tuberculosis treatment

Supporting a new regional network in Southern and East Africa for TB control

• 1 (current)

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The ADP Delivering New Health Technologies for TB, Malaria and NTDs

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• Signs and Symptoms
• Causes and Spread
• Testing for Tuberculosis
• Risk Factors
• Clinical Overview
• Clinical Signs and Symptoms
• Bacille Calmette-Guérin (BCG) Vaccine
• Clinical Testing and Diagnosis
• Mantoux Tuberculin Skin Test Toolkit
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• Dear Colleague Letters
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Related Topics:

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• TB Prevention in Healthcare Settings
• Information for Tuberculosis Programs

Tuberculosis Trials Consortium

• Tuberculosis Trials Consortium (TBTC) is a unique collaboration of researchers from CDC, domestic and international public health departments and academic medical centers, and selected Veterans Administration medical centers.
• TBTC’s mission is to conduct programmatically relevant research concerning the diagnosis, clinical management, and prevention of tuberculosis (TB) infection and disease.
• The current research cycle began in January 2021 and will end in December 2030.

CDC assesses the need for and conducts studies of new or existing drugs and regimens used in the prevention and treatment of TB, including:

• Pharmacokinetics, and

Currently, most of these trials and studies are conducted by TBTC.

TBTC’s mission is to conduct programmatically relevant research concerning the diagnosis, clinical management, and prevention of tuberculosis infection and disease.

The work of TBTC:

• Expands clinical and epidemiologic knowledge of TB,
• Integrates research into the care of persons with TB infection and disease,
• Promotes research within local TB programs through collaboration on clinical research of relevance to public health settings, and
• Provides a forum for international collaborative research of importance to both domestic and international TB control.

The CDC oversees, and collaborates in, the work of TBTC. The TBTC CDC team is composed of medical officers, epidemiologists, trialists, health scientists, microbiologists, data analysts, data managers, programmers, data clerks, multiple public health students, administrative support staff, and others. The CDC team supports the TBTC by:

• Functioning as the TBTC's Data and Coordinating Center;
• Participating in protocol development;
• Guiding implementation, analysis, and interpretation of each trial;
• Conducting the central monitoring for all TBTC trials;
• Performing data management;
• Managing drug supplies;
• Establishing site laboratory standards;
• Executing pharmacovigilance for TBTC trials;
• Presenting scientific data at conferences and in author publications; and
• Coordinating administrative, regulatory, and fiscal support for the TBTC.

Several working committees make up the governance of TBTC:

• Steering Committee: made of representatives from all those engaged, makes major decisions for the group
• Executive Affairs Group: serves as the executive arm of the Steering Committee and conducts the Consortium's day-to-day administrative business
• Core Science Group: develops the scientific program of research
• Implementation and Quality Committee: supervises the conduct and quality of ongoing studies
• Publications and Presentations Committee: assures quality and equity in TBTC's reporting of its work
• Advocacy and External Relations Committee: represents the TBTC to outside entities and supports the Consortium's community engagement activities

CDC staff are represented and participate on all committees.

Other Partners

Developing new TB treatment and prevention strategies depends upon collaboration among academics, private sector and government researchers, public health departments, manufacturers of pharmaceuticals, regulatory agencies, and non-governmental organizations. CDC works closely with such organizations as:

• U.S. Food and Drug Administration ,
• National Institutes of Health and its National Institute of Allergy and Infectious Diseases ,
• Global Alliance for TB Drug Development , and
• Other partners within and outside the United States.

Such partnerships build upon the long tradition of collaboration in pursuit of important public health goals.

Research priorities

The current pipeline of new and re-purposed anti-TB drug candidates is the most promising in 40 years. Advances in TB clinical trials science have fostered the progress of these agents, supported by many members of the global TB control community.

With commitment and support from CDC, the TBTC adds importantly to the resources available for these clinical trials and is expected to continue to make useful contributions to TB treatment, prevention, and control.

Current activities include:

Crush-tb/study 38.

• CRUSH-TB (Combination Regimens for Shortening Tuberculosis Treatment)/Study 38 is a phase 2C trial aims to assess the efficacy and safety of several regimens based on novel agents in the treatment of drug-sensitive TB disease.
• The trial compares the effectiveness and safety of new 4-month bedaquiline, moxifloxacin, and pyrazinamide-based regimens to the standard of care 6-month regimen for TB disease.
• ClinicalTrials.gov Identifier: NCT05766267

ASTERoiD/Study 37

• ASTERoidD (Assessment of the Safety, Tolerability, and Effectiveness of Rifapentine Given Daily for Latent TB Infection)/TBTC Study 37 is an open label, multi-center, phase 3 randomized controlled non-inferiority trial that compares the safety and effectiveness of a 6-week regimen of daily rifapentine against the current standard of 12-16 weeks of rifamycin-based treatment for latent TB infection.
• ClinicalTrials.gov Identifier: NCT03474029

TBTC Study 35

• TBTC Study 35 is a Phase I/2 open-label, single arm, exposure-controlled study to determine appropriate dosing of a novel water-dispersible, child-friendly formulation of rifapentine with isoniazid in children aged 0-12 years.
• The trial aims also to assess safety of this formulation in HIV-infected and HIV-uninfected children.
• If successful, the trial will contribute to global availability of a pediatric formulation that can be used to treat latent TB infection in young children.
• ClinicalTrials.gov Identifier: NCT03730181

TBTC Study 31

• TBTC Study 31 was a large trial of a 4-month rifapentine-based regimen for treatment of drug-sensitive TB, conducted in collaboration with the National Institute of Allergy and Infectious Diseases, AIDS Clinical Trials Group (as ACTG A5349), demonstrated non-inferiority of one of two test regimens.
• The trial has concluded, and many analytic activities are currently underway.
• ClinicalTrials.gov Identifier: NCT02410772

TBTC 1993-1998

In 1993-94, CDC announced a competitive solicitation to fund a group of TB researchers and sites capable of conducting TB clinical trials; successful applicants were funded for a period of 5 years. CDC selected sites that:

• Provided access to significant numbers of TB patients,
• Had experience with clinical trials,
• Demonstrated qualifications of the trial team, and
• Submitted robust plans for recruitment, management, and follow-up of patients.

U.S. Public Health Service Study 22

• Planning together, the researchers and CDC decided to conduct first a randomized, clinical trial comparing a once-weekly, rifapentine-based, continuation-phase regimen to the then-standard, twice-weekly, rifampin-based "Denver" regimen, both given for the last 4 months of the 6-month treatment for TB.
• This trial, USPHS Study 22, began in 1995, enrolled 1,075 TB patients from the United States and Canada, and reported final results in 2002.

Creation of TBTC

In 1997-98, CDC and the Study 22 investigators reorganized their collaboration as a structured consortium, creating the TBTC with the adoption of formal by-laws in 1998. The bylaws were updated in 2012 and again in 2021.

TBTC 1999-2009

• In 1999, the TBTC underwent its second competitive process to select the clinical trial sites that would comprise the TBTC during 1999–2009.
• The selection of sites at that time resulted in a consortium of 23 centers located in the United States and Canada.
• In 2003, the consortium gained an international presence by adding sites in Brazil, Spain, and Sub-Saharan Africa.

TBTC 2010-2020

• In 2009, the TBTC underwent its third re-competition.
• During 2010–2020, TBTC’s international presence expanded from a few clinical study sites located outside of North America, to sites in Peru, Spain, South Africa (two sites), Uganda, Kenya, Vietnam, and China (Hong Kong).
• The TBTC 2010–2020 also included U.S. sites in New York, Washington DC, Texas (four sites), Colorado, and Tennessee.

TBTC 2021-2030

• In 2021, CDC announced the sites for the research cycle through December 2030.

Accomplishments

Since its inception, TBTC clinical trials have had significant impact on TB treatment and prevention:

• U.S. Public Health Service Study 22 substantially influenced American Thoracic Society (ATS)/CDC/Infectious Disease Society of America (IDSA) guidelines for treatment of TB disease.
• TBTC Study 23 results have led to modification of CDC's recommendations for treatment of TB and HIV.
• TBTC Studies 26 and 33 led to updates in National Tuberculosis Controllers Association/CDC guidelines for treatment of latent TB infection .
• TBTC Study 31/ACTG A5349 was the first trial to achieve success with a 4-month treatment regimen for active TB; it demonstrated that a four-month daily treatment regimen containing a combination of high-dose rifapentine and moxifloxacin is non-inferior to the standard six-month daily regimen for drug-susceptible TB disease. The results of this study led to CDC's publication of interim guidance for this 4-month regimen and updated WHO treatment guidelines .
• TBTC Study 34 influenced the 2017 ATS/CDC/IDSA guidelines for TB diagnosis .

Future direction

TBTC clinical trials have enrolled more than 16,000 patients and volunteers over the past 20 years. CDC is confident that TBTC will continue to contribute to development of stronger approaches to treatment and prevention of TB over the next decade.

How it's funded

TBTC sites are funded in one of two ways, either through

• Individual contracts with CDC or as
• Part of a sub-network coordinated by investigators at the Washington, D.C. Veterans Affairs (VA) Medical Center.

Every 10 years, both sides of the consortium undergo re-competition. The current cycle began January 2021 and will end in December 2030.

Funding recipients

2021-2030 TBTC sites are located in Australia, Benin, Canada, Haiti, South Africa, Uganda, the United States, and Vietnam.

Case-Kampala

• Principal Investigators (PI): John L. Johnson, MD; Harriet Mayanja-Kizza; Moses L. Joloba

Cornell/Haiti

• PI: Daniel Fitzgerald, MD
• PI: Jean William Pape, MD
• PI: Robert Belknap, MD

McGill/CAB-V

• PIs: Dick Menzies (McGill University); James Johnston (University of British Columbia) and Greg Fox (University of Sydney), including the following:

Canadian sites

• PI: Dick Menzies, MD
• PI: Richard Long, MD
• PI: Sarah Brode, MD
• PI: Dina Fisher, MD
• PI: James Johnston, MD

Australian sites

• PI: Greg Fox, MD
• PI: Jin-Gun Cho, MD
• PI: Harrington Zinta, MD

Vietnam Sites

• PI: Menonli Adjobimey, MD
• PI: Susan Dorman, MD
• PI: Dr. Rodney Dawson (Bio Analytical Research Corporation partnership)
• PIs: Masa Narita, MD and David Horne, MD

Veterans Affairs (VA) Medical Center sites

• PI: Jose Cadena Zuluaga, MD
• PI: Anneke Hesseling, MD
• PIs: Debra Benator, MD (Washington DC VA Medical Center) and Afsoon Robers, MD (George Washington University Medical Center)
• PIs: Benjamin Wu, MD (New York Harbor Healthcare System) and Joseph Burzynski, MD (New York City Bureau of Tuberculosis Control)

Map of TBTC sites for the 2021-2030 cycle

Tuberculosis (TB)

Tuberculosis is caused by bacteria called Mycobacterium tuberculosis . The bacteria usually attack the lungs but can attack any part of the body.

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• v.18(1); 2022 Mar

New developments in tuberculosis diagnosis and treatment

Cara m. gill.

Dept of Respiratory Medicine, Saint James's Hospital, Dublin, Ireland

Lorraine Dolan

Laura m. piggott, anne marie mclaughlin.

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. It is estimated that 25% of the world's population are infected with Mycobacterium tuberculosis , with a 5–10% lifetime risk of progression into TB disease. Early recognition of TB disease and prompt detection of drug resistance are essential to halting its global burden. Culture, direct microscopy, biomolecular tests and whole genome sequencing are approved methods of diagnosis; however, their widespread use is often curtailed owing to costs, local resources, time constraints and operator efficiency. Methods of optimising these diagnostics, in addition to developing novel techniques, are under review. The selection of an appropriate drug regimen is dependent on the susceptibility pattern of the isolate detected. At present, there are 16 new drugs under evaluation for TB treatment in phase I or II clinical trials, with an additional 22 drugs in preclinical stages. Alongside the development of these new drugs, most of which are oral medications, new shorter regimes are under evaluation. The aim of these shorter regimens is to encourage patient adherence, and prevent relapse or the evolution of further drug resistance. Screening for TB infection, especially in vulnerable populations, provides an opportunity for intervention prior to progression towards infectious TB disease. New regimens are currently under evaluation to assess the efficacy of shorter durations of treatment in this population. In addition, there is extensive research into the use of post-exposure vaccinations in this cohort. Worldwide collaboration and sharing of expertise are essential to our ultimate aim of global eradication of TB disease.

Educational aims

• Differentiate between TB infection and TB disease.
• Understand the different methods of diagnosing TB disease and resistance.
• Recognise the different drugs and regimens currently in use for TB disease.
• Be able to discuss risk of TB disease in TB infection, and assist patients in making an informed decision on treatment for TB infection.

Short abstract

Early detection of drug resistance is essential to our goal of global eradication of TB. Tolerable drugs and shorter regimens promote patient adherence. Treating TB infection in vulnerable groups will prevent further global spread of TB disease. https://bit.ly/3oUW0SN

Introduction

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. TB is caused by the bacillus Mycobacterium tuberculosis (Mtb ), which is spread via airborne droplets. Approximately one in four people worldwide demonstrate an immunological response to Mtb infection, which can remain dormant or progress into active disease forms [ 1 ]. Patients infected with TB who have no active signs or symptoms of disease were previously deemed to have latent TB, more recently changed to TB infection [ 2 ]. Whereas patients with active disease are termed to have TB disease. Patients with TB infection have a 5–10% lifetime risk of developing TB disease, which increases in varying states of immunodeficiency up to a 16% annual risk of activation of TB infection into TB disease in HIV patients [ 3 ]. In 2019, there were an estimated 10 million new incident cases of active TB disease worldwide [ 1 ]. Approximately two-thirds of all cases arise in eight countries alone, the vast majority of which have overwhelmed health services with limited resources [ 1 ]. This significant global burden of disease has been recognised by the World Health Organization (WHO) who launched the End TB initiative in 2016. Their aim is to reduce incidence, morbidity and mortality of this disease by improving diagnostic and therapeutic practices, as well as developing preventative strategies, through innovative research and education. By 2035, the goal is to reduce TB mortality by 95% and reduce overall incidence of TB by 90% worldwide [ 4 ]. Owing to the work of our predecessors, it has been estimated that 60 million lives have been saved globally in the 21st century so far [ 5 ].

Effective TB treatment is dependent on:

• Prompt diagnosis of TB and recognition of drug resistance;
• Promoting and ensuring patient adherence to regimens;
• Robust contact tracing and prophylactic treatment of contacts; and
• Screening for TB infection in high-risk groups.

There is ongoing extensive research into developing accurate, timely methods of detecting drug resistance, even in resource poor settings. Many effective, less toxic medications are under development. Furthermore, methods of promoting and ensuring drug adherence are being reviewed. In addition, there is vital research ongoing in proactive areas of TB prevention, such as screening for, and treatment of, TB infection and developing efficacious vaccines to halt the spread of this killer disease.

The aim of this article is to: review current practice in the diagnosis and treatment of TB; outline new diagnostic techniques under development; discuss new drug therapies and treatment regimens under review; and review the evidence for vaccination.

Improving the efficiency and accuracy of TB diagnosis contributes to treatment efficacy. Pulmonary TB should be suspected when patients present with classical symptoms such as non-resolving cough, haemoptysis, fevers, night sweats and weight loss. Extrapulmonary TB, including TB lymphadenitis, TB meningitis, laryngeal TB, Pott's disease and abdominal TB, presents in a variety of manners. Special consideration should always be given to patients who have potential TB exposure, as well as immunocompromised patients who may present atypically. The diagnosis must be made by confirming the presence of the causative pathogen, Mtb . A variety of methods are employed to confirm the diagnosis. In addition, it is essential that there is emphasis on early detection of potential drug resistance.

Drug resistance is a growing issue that threatens TB care worldwide. Traditionally this was categorised into rifampicin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB). MDR-TB is resistant to both rifampicin (RIF) and isoniazid (INH). Recently definitions have been updated to include pre-XDR-TB, which is TB that fulfils the definition for MDR-TB and RR-TB that is also resistant to any fluoroquinolone (FLQ). The updated definition for XDR-TB is strains that fulfil the definition for MDR-TB/RR-TB which are also resistant to any group A drug (namely levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ) and linezolid (LZD)) [ 6 ]. Replacing the old XDR-TB definition referencing second-line injectable drugs (SLID), it highlights the trend towards use of oral regimens comprising recently developed or repurposed drugs. Despite the importance of early recognition, only 61% of patients with a new diagnosis of bacteriologically confirmed TB disease in 2019 were tested for RIF resistance [ 1 ]. This is in part related to access to diagnostics in resource-limited settings. There are numerous methods currently available, and under development, to determine drug resistance. For these diagnostics to be beneficial on a global scale they need to provide timely, accurate, cost-effective results in centres where access to power, equipment and technical expertise remains limited.

Culture of Mtb in a suitable medium remains the gold standard diagnostic test. The specimen can be cultured in solid ( e.g. Löwenstein–Jensen or Middlebrook 7H11) or liquid media ( e.g. for use with the BACTEC Mycobacterium Growth Indicator Tube (MGIT) 960 system). Sensitivity, specificity, contamination rates and time to detection vary widely amongst both media, with the WHO advocating for dual use of systems where practical. The major benefit of the advent of liquid-based systems is the rapid time to detection, often reducing time to growth by half with a mean time to detection of 12.8 days compared with 25.1–25.5 days for the previously mentioned solid media [ 7 ]. However, sub-optimal laboratory facilities in resource-limited settings often restrict its practical use [ 8 ]. While culture is not recommended for use as a first-line test, it remains an important part of TB diagnostics where persistent culture positivity can predict likelihood of relapse [ 9 ].

Direct microscopy

Direct microscopy is a fast and inexpensive method to identify acid-fast bacilli (AFB), the majority of which are mycobacteria [ 10 ]. Traditionally, Ziehl–Neelsen (ZN) stain was applied and the sample termed “smear positive” or “smear negative”, depending on the presence or absence of AFB. Efficacy is operator dependent, resulting in a broad range of sensitivities and specificities reported in international studies, 25.3–81.6% and 83.4–99%, respectively [ 11 , 12 ]. It is even less sensitive in high-risk groups, such as patients with HIV, and children [ 1 ]. Methods to improve efficacy include use of mercury vapour fluorescence and light-emitting diode (LED) microscopy, which have largely replaced traditional ZN staining [ 13 ]. Education and quality assurance for laboratory technicians is one of the most useful ways to ensure accurate diagnosis, as direct microscopy often remains the only method of diagnosis available in resource-limited settings [ 14 ]. Similar to culture, direct microscopy remains an integral part of monitoring response to treatment, measuring infectiousness, and predicting likelihood of relapse in patients who are smear positive at diagnosis.

Molecular tests

Given the limitations of culture and direct microscopy, the WHO recommends a biomolecular test as the initial diagnostic test in a suspect patient [ 1 ]. Current molecular tests endorsed by WHO include: Xpert MTB/RIF and Xpert MTB/RIF Ultra assays (Cepheid, Sunnyvale, USA); loop-mediated isothermal amplification test (TB-LAMP; Eiken Chemical, Tokyo, Japan); Truenat MTB, MTB Plus and MTBRIF Dx tests (Molbio Diagnostics, Goa, India) and lateral flow urine lipoarabinomannan assay (LF-LAM; Alere Determine TB LAM Ag, Abbott, San Diego, USA).

The WHO currently recommends Xpert (MTB/RIF or MTB/RIF Ultra) or Truenat (MTB or MTB Plus) as the initial diagnostic test of choice in suspected pulmonary TB [ 1 ]. They are cartridge based nucleic acid amplification tests (NAAT) that detect the presence of TB DNA, as well as common mutations associated with RIF resistance along the rpoB gene, within 2 h [ 15 ]. The Xpert MTB/RIF and Xpert MTB/RIF Ultra assays are also endorsed by the WHO for diagnosing extrapulmonary TB and TB in children [ 1 ]. When compared with culture diagnosis, the Xpert assays have demonstrated 89% sensitivity and 99% specificity at diagnosing pulmonary TB in adults [ 16 ]. The Xpert MTB/RIF Ultra assay has a higher sensitivity but lower specificity than the Xpert MTB/RIF assay, owing to its inability to accurately differentiate between dormant and active TB DNA [ 17 , 18 ]. While recommended for use, it is important to remember these assays have reduced sensitivity in certain populations such as children and patients coinfected with HIV, as well as in extrapulmonary TB [ 16 , 19 ]. Moreover, this technology is expensive and requires laboratory facilities with continuous access to power. To overcome this obstacle in resource-limited settings, there are a number of smaller, battery-operated technologies in development. To date, the GeneXpert Omni (Omni; Cepheid) appears to be the most promising potential candidate for widespread use. In a real-world analysis, it has been shown to be a cost-effective method when used in peripheral healthcare settings [ 20 ]. It allows diagnosis to be at/near the point of care, and thus avoids further delays and costs associated with transporting samples to specialised centres.

As well as the Omni, Cepheid is also developing the Xpert MTB/XDR assay. It aims to also detect resistant to INH, FLQ, ethionamide (ETH) and SLID. Similar to other Xpert assays, it is a NAAT that detects 16 clinically relevant mutations associated with resistance in under 90 min [ 21 ]. When compared with phenotypic drug sensitivity testing (pDST), it has a 94% sensitivity and 100% specificity at detecting drug resistance [ 21 ]. There are large scale multicentre clinical trials ongoing to establish its real-world efficacy as a follow-on test to current Xpert MTB/RIF and MTB/RIF Ultra assays, prior to consideration for WHO recommendation. This assay is of paramount importance as the early recognition of drug resistance is a prerequisite to shorter drug regimens, which will be discussed in further detail elsewhere in this review.

While most biomolecular tests are NAAT detecting the presence of Mtb DNA, the LF-LAM test detects a lipopolysaccharide present in mycobacterial cell walls. While not in use in most countries in the developed world, the LF-LAM assay has been recommended for use in HIV-coinfected patients. It is a urinary antigen test that is often employed in resource-limited settings, and is of particular benefit in cases where a sputum sample cannot be obtained. It has a 42% sensitivity in HIV patients with TB symptoms [ 22 ]. However, it cannot distinguish between mycobacterial species, and can cross react with other fungal diseases. As such, it is used as an initial test in peripheral primary care centres in areas of high TB endemicity only, to determine whether symptomatic patients with HIV should be referred for further confirmatory testing [ 23 ].

Line probe assays

Another method of molecular detection of Mtb resistance is line probe assay (LPA). Genotype MTBDR plus and Genotype MTBDR sl (Hain LifeScience GmbH, Nehren, Germany) are used for the detection of Mtb and its associated drug resistance. The WHO approved Genotype MTBDR plus employs a series of steps to detect Mtb and mutations in rpoB and katG , which confer RIF and INH resistance, respectively [ 24 ]. Additionally, it can detect the presence of inhA promoter genes that confer resistance to low dose INH, which are also typically associated with ETH and prothionamide resistance [ 25 ]. This in vitro test delivers results in <6 h [ 26 ]. When compared with traditional culture-based drug sensitivity, it is 78.5% sensitive and 100% specific at detecting RIF and INH resistance [ 27 ]. The WHO endorsed Genotype MTBDR sl 2.0 assay can also detect resistance conferring mutations of FLQ ( gyrA and gyrB ) and SLID ( rrs and eis ) [ 28 ]. Reported sensitivity and specificity are 100% and 98.9% for FLQ, and 89.2% and 98.5% for SLID [ 29 ]. Even more sensitive than NAAT at detecting FLQ resistance, this rapid test could allow for use of FLQ in patients that might otherwise have faced a lengthier regime that potentially required the interim use of SLID. However, these tests are not without limitations including low sensitivity for detecting ethambutol (ETM) and aminoglycoside resistance as demonstrated in a real-world analysis [ 30 ]. Similar in aim to the Xpert MTB/XDR assay, these LPAs provide prompt recognition of drug resistance, so patients can be started on the appropriate regimen and further drug resistance does not have an opportunity to develop while awaiting standard culture-based susceptibility results, nor are patients exposed to burdensome, longer drug regimens with higher potential for toxicity.

Whole genome sequencing (WGS)

While NAAT and LPA tests are rapid, accessible diagnostics, their efficacy at detecting drug resistance is hindered by the inability to detect clinically relevant mutations outside the rifampicin resistance determining region (RRDR) of the rpoB gene [ 31 ]. While 95% of resistant cases arise from mutations in this region, there have been a number of public health crises emerging from missed diagnosis of outbreaks that have arisen from mutations outside it [ 32 ]. One such example is the I491F mutation that has been responsible for an outbreak of MDR-TB in Eswatini and remains a grave public health concern [ 33 ]. Another limitation is the inability to differentiate silent mutations from those that hinder drug efficacy, thus delivering a higher rate of false positive resistance results [ 34 ]. WGS provides a comprehensive review of the entire Mtb genotype with a 96% concordance for culture-based sensitivity testing [ 35 ]. It provides genotypic sensitivity to most drugs required for treatment of MDR-TB [ 36 ]. While full clarification on clinical correlation between genotypic and phenotypic sensitivities remains to be shown, progress has been made in assigning probability of pDST based on genotypic results [ 37 ]. Utility was initially limited in low-income countries by cost and requirement for robust facilities and technical expertise [ 38 ]. However, with ongoing technological advancements in the microfluidic approaches to TB diagnosis, WGS is likely to be available at point of care on a global basis [ 39 ]. For some countries, it remains an important tool not only in case diagnosis, but in formulating public health policy by assisting in tracing TB contact cases in outbreaks [ 40 ]. In the future, with improved knowledge of the genomics involved in TB resistance, WGS is likely to prove revolutionary in tailoring TB treatment to each individual patient based on the particular genome identified by the Mtb strain they have contracted.

Culture-based drug sensitivity testing (DST)

As previously mentioned, the major advantage of liquid culture is rapidity of growth, which has led to more widespread use of liquid broth-based methods such as the MGIT. BACTEC MGIT 960 is a fully automated system that delivers results within 2 weeks [ 41 ]. Culture-based DST remains the gold standard for determining drug resistance at present [ 1 ]. The two approaches currently in use are the critical concentration and minimum inhibitory concentration (MIC). Classically, critical concentration was defined as the lowest concentration of a drug that inhibits growth of 95% of Mtb strain present. Owing to ongoing research, these critical concentrations are regularly updated with a recent reduction in the critical concentration required to determine RIF resistance, allowing for greater concordance between genotypic and phenotypic sensitivity results [ 42 ]. Alternatively, the MIC method is defined as the lowest concentration of a drug that results in complete inhibition of visual growth of the Mtb strain in vitro . Following extensive work completed by national reference laboratories, and international discussion and agreement, a new reference MIC protocol has been set and validated by European consortia [ 43 ].

Computer aided detection for chest radiographs

Given the limitations, in terms of time, cost and infrastructure, to the above testing methods, it has become clear that there need to be affordable, accessible methods of screening available in high-burden areas to assist with risk stratification for allocating further testing. One such proposed method is the use of computer software to digitally interpret chest radiographs, and assign a score indicating the likelihood of TB. The most commonly studied software is CAD4TB, currently on version 6. When compared with NAAT, CAD4TB has been shown to have 90–100% sensitivity, and 23–45% specificity at detecting TB disease [ 44 ]. It performs similarly to expert clinicians and radiologists, with similar pitfalls including disease obscured by musculoskeletal findings and differentiating old scarring from new disease. Its use is intended for high-burden areas, that may lack readily accessible radiological expertise on site to interpret chest radiographs in a timely fashion [ 45 ]. It may assist peripheral health centres to determine which patients require further molecular testing.

Serum biomarkers

Another potential method for triage testing is serum biomarkers. Devising an accurate biomarker that upholds sensitivity across different ethnicities, HIV status and site of TB has proven difficult. However, a nine protein biosignature has recently been discovered which appears to remain efficacious in all of these cohorts. Using fibrinogen, α 2 -macroglobulin, C-reactive protein, matrix metalloproteinase-9, transthyretin, complement factor H, interferon-γ, interferon-γ inducible protein-10 and tumour necrosis factor-α as a host biosignature demonstrated 92% sensitivity and 72% specificity for determining TB from other diseases [ 46 ]. If available on a commercial level, this serum assay could rapidly and effectively determine which patients warranted further testing. It is important to note that most of these biomarkers are markers of inflammation, and as such are widely variable amongst patients and their differing metabolic and disease states. Evaluating serum biomarkers as predictors of response to treatment, potential for relapse and predictors of TB infection versus active disease will be discussed elsewhere.

Alongside research into obtaining accurate and timely diagnostics, there is tremendous work ongoing in developing safe, efficacious, tolerable treatment regimens. The goals of treatment are not only to eradicate disease, but to prevent long-term morbidity arising from either the disease itself or as an adverse effect of the drugs in use. Successful treatment of drug-sensitive TB (DS-TB) has been reported in 85% of patients [ 1 ]. Efficacy in drug-resistant forms is lower at 57% and is likely multifactorial [ 1 ]. To reflect this, there has been a trend towards oral drug regimens, where possible, given research highlighting patient preference and cost-effectiveness of these drugs [ 47 ]. We need to deliver a regimen that will not only aid our global goal of TB eradication, but in a manner that reflects our patients’ wishes, and in doing so, promotes their compliance.

Current treatment

The current medications approved for use in TB treatment, and their notable side-effects are summarised in table 1 .

Current medications in use for TB treatment and their notable side-effects

# : given with pyridoxine prophylaxis to ameliorate risk; ¶ : beta-lactams must be given with Clavulanate for success in TB treatment; however, the only available preparations include Amoxicillin. Information from [ 50 ].

DS-TB tends to follow a standard 6-month regime. This comprises an intensive phase with 2 months treatment consisting of RIF, INH, pyrazinamide (PZA) and ETM, followed by a continuation phase with 4 months treatment of RIF and INH [ 48 ]. If the isolate is susceptible to both RIF and INH, ETM can be stopped. The continuation phase should be extended to 7 months in the presence of: cavitation on the initial chest radiograph; persistent sputum growth at 2 months; or if PZA cannot be used due to monoresistance or drug side-effects. Consideration should also be given to extending this phase to 7 months in patients who are otherwise immunosuppressed, such as patients with HIV, diabetes mellitus, malignancy or medications associated with immunosuppression [ 48 ]. Unfavourable outcomes are most associated with high grade smear positivity (at least 3+) and dependent on the size of cavities, as well as extent of disease on chest radiographs [ 49 ].

Current treatment of drug-resistant TB is more complex and is summarised in table 2 . Most notable is the longer duration of treatment involving combinations of drugs that are often poorly tolerated. There is also minor discordance between the two major international advisory bodies (the WHO and the joint ATS/CDC/ERS/IDSA clinical practice guideline) concerning optimum drug selection and durations. While the WHO recommends only four drugs need to be used in the intensive phase of treatment, the ATS/CDC/ERS/IDSA propose continuing to use five drugs in this phase. The ATS/CDC/ERS/IDSA have proposed this recommendation based on higher success rates in the five-drug group (93.9% versus 89.7%; adjusted odds ratio (aOR) 3.0 versus 1.2; risk difference 8% in both groups). Additionally, they suggest it is likely that one of the drugs may need to be withdrawn due to toxicity [ 50 ]. However, given equivocal risk differences in both groups, the WHO maintain four drugs should be sufficient, providing susceptibilities are known and toxicity is unlikely. De-escalation to a continuation phase comprising three or four drugs is based on similar evidence. Traditionally, MDR-TB required treatment for a total duration of 15–21 months [ 50 ]. Alternatively, it does allow for a shorter 9–12 month all oral regimen for patients who have not previously had more than 1 month of treatment with second-line medications, and in whom FLQ resistance has been ruled out. Additionally, patients should not have extensive disease [ 51 ]. This shorter regimen involves 4 months of six drugs (FLQ, clofazimine (CFZ), ETH, PZA, INH (high dose)), followed by 5 months of FLQ, CFZ, ETH and PZA. BDQ is used concurrently for the first 6 months of this regimen. This conditional recommendation of low certainty evidence was proposed owing to improved success and adherence rates, when compared with shorter regimens containing injectable agents (aOR 1.9 (95% CI 1.6–2.4)) [ 52 ]. (Note, INH is used regardless of susceptibility status).

Current ATS/CDC/ERS/IDSA consolidated guidelines on treating drug-resistant TB

ATS: American Thoracic Society; CDC: US Centers For Disease Control And Prevention; ERS: European Respiratory Society; IDSA: Infectious Diseases Society of America. # : in contrast, the WHO suggests only one of these drugs are required, comprising a 4-drug regimen (see text for full details); ¶ : superscript numbers refer to the order in which the WHO suggests drugs be incorporated into regimes. Information from [ 50 ].

At present, the WHO recommends treatment for RR-TB in line with MDR-TB.

Pre-XDR- and XDR-TB are more difficult to treat, owing to varying patterns of drug resistance and advice should always be sought from national and international expert TB consortia prior to commencing treatment.

New treatment: drugs

At present, there are 16 new drugs in phase I or II clinical trials, and 22 other drugs in discovery or preclinical phases of development, as outlined in figure 1 . Of those drugs undergoing clinical trial, there are 11 drugs of new chemical classes. Of the remaining drugs, TBAJ-587 and TBAJ-876 are diarylquinolines, similar to BDQ, while delpazolid, sutezolid and TBI-223 are oxazolidinones, similar to LZD and cycloserine. At the time of publication, no new drugs have reached phase III trials or been approved for market regulation since the approval of pretomanid (Pa) in 2019. A promising candidate from a new drug class is telacebec. It induces bacterial cell death by inhibiting the mycobacterial cytochrome bc1 complex responsible for ATP synthesis. A proof-of-concept trial has shown increased rates of sputum clearance, with comparable levels of adverse events to currently approved drugs. If results from ongoing clinical trials continue to reflect this, it is likely to be approved as a third new modern drug class with anti-tuberculous activity [ 53 ]. This would be an important achievement as many of the other drugs in development are classified similarly to existing drugs, and as such their use in additive or substitutive places for their relative counterparts will be precluded due to concerns regarding toxicity or resistance. It is also interesting to note that these drugs in development are largely oral preparations, owing to patient preference and thus potential for greater adherence and cure.

New anti-tuberculous drugs currently in development. Data from [ 104 ].

New treatment: routes of delivery

While not a novel idea, interest in inhalation routes has been re-ignited. Numerous methods of drug delivery have been shown to be effective in animals, and additional advantages include reduced dosage and systemic toxicity. However, it would likely have no benefit on extrathoracic disease, nor would it be likely to achieve adequate therapeutic serum concentrations. Similar to the use of nebulised aminoglycosides in non- Mycobacterium tuberculosis , the potential for inhalational therapies to augment TB therapy likely lies as an adjunctive therapy to oral or injectable drug regimens. To date, there has been no data published from similar trials investigating its efficacy in sputum clearance from Mtb disease.

New treatment: regimes

In a disease that has the potential to affect one quarter of the world's population, it is astounding that no advances have been made in progressing the regimen for DS-TB since the mid-20th century. At present, international consensus guidelines continue to endorse standard 6-month regimes for the majority of cases of DS-TB, with varying longer regimens requiring expert opinion for drug-resistant cases. However, much research is being done into assessing shorter regimens with the aim of improving patient adherence and reducing risk of relapse and evolution of drug resistance, as seen in table 3 .

• A shorter 4-month regimen of rifapentine (RFP) in combination with MFX has recently been shown to be non-inferior to the current standard 6-month regimen, as determined by negative smear or culture at 12 months, with no increase in major adverse events [ 54 ].
• The SimpliciTB group have evaluated a 4-month regimen comprising BDQ, Pa, MFX and PZA, in place of the standard 6-month regimen. While it has been said that no drug should ever be kept in reserve, it is unlikely that this regimen will be recommended as first-line therapy for DS-TB, given the need to preserve efficacious drug options for resistant cases [ 55 , 56 ].
• Shorter again with a 2-month regime, the TRUNCATE-TB trial is at recruitment phase. This multi-armed approach will assess combinations of 4–5 currently approved oral anti-tuberculous medications given daily for 8 weeks, with the potential to extend to 12 weeks [ 57 ].
• The RIFASHORT and ReDEFINe studies are evaluating the risk–benefit ratio of higher doses of RIF in DS-TB [ 58 , 59 ]. The evidence base for these ongoing trials has been provided by the HIRIF trial which found an increased rate of sputum clearance, with no associated increase in toxicity, in patients on higher doses of RIF than currently recommended by the WHO [ 60 ].
•   •  The current recommendations for RR-TB have been considered contentious for quite some time. These longer regimens likely expose patients with mono-resistance to unnecessarily long and toxic drug regimens, and also exclude the benefits of INH therapy [ 61 ]. BEAT TB is at the enrolment stage assessing the efficacy of 6 months of BDQ, LZD, delamanid (DLM), LFX and CFZ in comparison to current practices in South Africa [ 62 ].
•   •  The updated STREAM2 study is evaluating a shorter regimen for RR-TB and MDR-TB in a simultaneous multi-armed approach. Their four regimens are based on: current WHO practice; the Bangladesh regime; a 40-week all oral regimen; and a 28-week oral regimen after an 8 week intense regime that also involves INH and kanamycin (Kan) [ 63 , 64 ].
•   •  Results from the NEXT trial completed in December 2020 are awaited. This group compared 6–9 months of LZD, BDQ, LFX, PZA and ETH or INH (high dose) to current standards of care [ 65 ].
•   •  TB-PRACTECAL stopped early due to superior outcomes in the intervention arm, consisting of a 6-month regimen of BDQ, Pa, LZD and MFX. Full results are awaited [ 66 , 67 ].
•   •  SimpliciTB are also evaluating a regimen for RR-TB/MDR-TB consisting of the same drugs as the DS-TB protocol (BDQ, PZA, MFX, Pa) but for 6 months [ 56 ].
•   •  DELIBERATE are completing a phase II safety trial reviewing the safety and pharmacokinetics of combined BDQ and DLM therapy. Given the updated consensus guidelines, these drugs will often be given together and it is essential we have an evidence base for potential harms that may arise throughout the course of treatment [ 68 ].
•   •  endTB, run by Médecins Sans Frontières, are evaluating a multi-armed approach combining varying combinations of an all oral regimen for 39 weeks. Similar to the STREAM2 study, this is the only other multi-armed trial reviewing multiple combinations of novel drugs simultaneously [ 69 ].
•   •  The ZeNix trial is the only trial, at present, that is reviewing treatment regimens for patients with pre-XDR- or XDR-TB. Using BDQ, Pa and either LZD (BPaL) or placebo for a total duration of 26 weeks, their aim is to assess rates of sputum conversion. This trial is also one of the few to follow patients for a significant period post-treatment, and patients with be reviewed for 78 weeks following the end of treatment [ 70 ]. Data from its predecessor the Nix-TB trial has shown 88% favourable outcomes at 24 months following treatment in patients with either MDR- or XDR-TB [ 71 ]. This BPaL regime can currently be used under operational research conditions in patients with MDR-TB, in accordance with WHO guidance [ 51 ].

New drug regimens under evaluation

HD: high dose; RIF: rifampicin; INH: isoniazid; RFP: rifapentine; ETM: ethambutol; PZA: pyrazinamide; MFX: moxifloxacin; LFX: levofloxacin; LZD: linezolid; ETH: ethionamide; BDQ: bedaquiline; DLM: delamanid; Pa: pretomanid; CFZ: clofazamine; Kan: kanamycin; Pro: prothionamide; Pl: Placebo. # : ClinicalTrials.gov identifier. Information from [ 1 , 104 ].

While many of these trials demonstrate promise for an improved approach to TB treatment, it is essential that we see long-term data on their efficacy and relapse rates prior to implementing them on a global scale. The fear is that these patients may have excellent short-term results, but disease recurs soon after with the added potential for drug resistance to develop.

New treatment: adjuncts

In addition to shorter regimens, with new or re-purposed drugs, there is research into methods of modifying the host immune response to improve treatment outcomes and prevent permanent morbidity from TB disease. As previously discussed, upon infection with Mtb the host can either suppress bacillary replication into a latent state, or the host is overwhelmed and active disease develops [ 72 ]. Both deficient and hyperinflammatory states have been associated with TB disease morbidity and mortality, suggesting that tailoring a balanced immune response is of paramount importance to survival [ 73 ]. With evolving knowledge of the pathways and subcellular responses involved, new therapeutic targets are being developed to assist with bacillary quiescence in the so called “host directed therapy” approach [ 74 ]. Numerous drug targets have been suggested, largely centred on modulating macrophage activity [ 75 ]. Proposed adjunctive therapies include vitamin D, everolimus, auranofin and CC-11050, a novel anti-inflammatory compound. Preliminary results from trial data suggest none of these compounds improve rates of sputum conversion; however, patients in receipt of CC-11050 or everolimus had increased recovery of FEV 1 (forced expiratory volume in 1 s) post-treatment, perhaps solidifying the role of a balanced immune response to infection [ 76 ].

New treatment: the future

Going forward, with a combination of new drugs, altered durations and more effective testing of response to treatment, it is likely that each patient will have a tailored approach to TB treatment [ 49 ]. With studies like PredictTB, aiming to determine biomarkers and radiographic appearances that predict response and likelihood of relapse, we will be able to devise a drug combination and duration with greater specificity for each patient [ 77 ]. Similar technology may even assist with developing even more efficacious drugs in early-stage clinical trials [ 78 ]. Additionally, it is essential that any new drug or technology developed is affordable and available to all institutions, most importantly hospitals in low-resource environments, where the majority of the global TB burden persists.

Despite ongoing research, treatment for DS-TB has remained unchanged for decades. This highly effective regimen is often poorly tolerated by patients, and “drug holidays” are frequent during treatment. This, of course, increases the likelihood of relapse and evolution of drug resistance. Moreover, patients with resistant TB have to endure longer regimens with their own associated side-effects. While awaiting the development and approval of less toxic regimens, there are a number of measures we can take to ameliorate adverse effects of treatment and promote patient adherence. It has been shown that comprehensive patient-centred approaches, involving nutritional, financial and psychological support, have higher rates of completion. In addition, patients with increased contact with healthcare workers tended to have lower drop-out rates during treatment [ 79 ]. The evidence base for this is provided by systematic reviews of mostly observational case studies and case cohorts, and as such randomised research in this area is required to determine a formal link.

Directly observed therapy

Directly observed therapy (DOT) has been a standard of care in TB treatment for several years. The premise is that patients are more likely to comply if medication ingestion is witnessed multiple times per week. Current recommendations are that it should be implemented in MDR- or XDR-TB cases, or for patients with complex or vulnerable care needs, such as homelessness, comorbid psychiatric illness or addiction [ 80 ]. There have been conflicting results from systematic reviews on the efficacy of DOT [ 81 , 82 ]. What is known, is that community-based DOT appears to be the most effective strategy, as it is less disruptive for patients and thus their adherence is more likely to be maintained [ 83 ]. In recent years, attention has switched towards the use of smartphone technology. Video observed therapy (VOT) has been suggested as an even less disruptive form of monitoring adherence [ 84 ]. Patients can either upload videos of medication ingestion to a secure platform to be watched at a later date, or it can be taken while on a live feed with their healthcare team. VOT has been shown to have a higher uptake rate and patient preference rating [ 85 ]. While plausible that this will improve adherence, and thus relapse should be less likely, this study was not sufficiently powered to assess this, nor did it follow up on relapse rates at an appropriate interval. A real-world efficacy and cost-effectiveness study is ongoing in a tertiary hospital in Ireland at present [ 86 ].

Prophylaxis

Undoubtedly, a burden of TB infection will persist for years to come. However, we have a chance to prevent many of these patients from progressing to active disease. Screening for TB infection in groups at high risk of progressing to TB disease remains a cost-effective and essential component to the global initiative. Screening via either of the endorsed interferon-γ release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) or traditional tuberculin skin testing is recommended in certain populations. The WHO has advised that clinical judgement is paramount in interpreting these tests, and cautions that a higher rate of false negatives occurs in the most vulnerable populations [ 87 ]. Another essential component of the sustainable development goals is robust public health policy to assist in contact tracing of index cases and early treatment of contacts. In addition, prior to any prophylactic treatment being commenced, it is essential that due caution is taken to rule out the presence of active TB disease.

Currently the WHO advocates for treatment with 4 months of RIF or 6–9 months of INH in cases where the index case is known to be drug sensitive [ 87 ]. A 3-month combination of RIF and INH is also approved, although rarely used due to potential toxicity. Additionally, weekly INH and RFP for 3 months has been shown to demonstrate equal efficacy and toxicity in comparison to 6 months of INH therapy, while higher levels of adherence were noted in the INH/RFP arm [ 88 ]. Moreover, a 1-month regimen of RFP/INH therapy was non-inferior to 9 months INH monotherapy in preventing TB in HIV-infected patients [ 89 ]. However, this regimen has yet to be endorsed by major international consortia.

The recommendations for TB contacts of DS-TB cases who demonstrate evidence of TB infection are as per those above. For contacts of MDR-TB cases, the current recommendation is for 6–12 months treatment with a FLQ with or without a second drug. If a FLQ cannot be used due to resistance in the index case, treatment with ETM and PZA is to be considered [ 87 ]. Regardless of the regimen in use, it is vital that strict adherence is maintained to ensure efficacy and prevent resistance.

At present, the decision to treat is based on the potential for progression to active disease based on similar case profiles. Going forward, we could vastly improve the cost efficacy of this intervention by being able to determine exactly which patients were going to progress to active TB disease or not. It had been hoped the answer would lie in serum transcriptional biomarkers and host response-based gene signatures [ 90 , 91 ]. Recently, a four-protein biomarker panel has shown 67.3% sensitivity and 96.3% specificity at determining active from latent TB [ 92 ]. This subclinical phase of TB disease can be difficult to interpret due to its lower inflammatory profile and person specific confounding factors that influence our immune response. Recent results from transcriptomic studies have been disappointing overall, but may potentially suggest a role for these panels in symptomatic patients with known TB infection and their risk of progression to TB disease in an imminent 6-month period [ 93 ].

Vaccination

Given the current prevalence of TB infection, with the associated lifetime risk of progressing to active disease, it is paramount that we protect future generations from this burden by halting transmission entirely. With greater understanding of the cellular processes involved in Mtb susceptibility and pathogenesis, scientists have been able to identify various potential targets with a role in vaccination. Central to this is the cellular immune response, with a need to upregulate T-helper cell (Th)1, and downregulate Th2 and regulatory T-cell responses [ 94 ]. It appears that Mtb has also recognised the need to adapt to this hypo-inflammatory phenotype with more modern strains displaying shorter latency and higher virulence than previously seen [ 95 ].

The only worldwide approved vaccine against TB remains bacillus Calmette–Guérin (BCG), effectively reducing the risk of severe childhood disease from TB, with an 85% reduction in TB meningitis and miliary TB in those <10 years of age [ 96 ]. It has also been noted that infants innoculated with BCG have increased survival and lower rates of other childhood infections. This observation is likely secondary to BCG's ability to prime innate immunity through epigenetic modification of innate immune cells [ 97 ].

Vaccination can be categorised into preventive pre-exposure, preventive post-exposure or therapeutic [ 98 ]. Vaccines can alternatively be classified according to their biochemical forms: live attenuated, inactivated, protein subunit or recombinant [ 99 ]. With each of these forms, the aim is to target various cells or subcellular components of TB pathogenesis.

MTBVAC, a pre-exposure live attenuated vaccine, has shown promising results from preclinical trials with a higher protection against TB than BCG [ 100 ]. This live vaccine is based on a genetically modified mutant Mtb strain containing deletions in transcription factors important for Mtb growth in macrophages and subsequent virulence.

VPM1002, another live recombinant BCG vaccine, is undergoing phase III studies at present to evaluate its efficacy at not only preventing infection, but in preventing active disease in those already affected [ 101 ]. This vaccine can modify T-cell immune response and enhance Th1 immunity, important in TB disease pathogenesis.

Another promising post-exposure candidate is M72/AS01E, a subunit vaccine, that prevents pulmonary TB in adults already infected with Mtb in 54% of patients, and thus could be a potentially life-saving intervention for one quarter of the world's population [ 102 ]. Also known as Mtb72F this vaccine comprises two immunogenic proteins that promote T-cell proliferation and interferon-γ release [ 103 ].

Further randomised control trials are warranted in a timely manner if the END TB strategy is to be achieved.

The future is bright for TB treatment. Never before has there been such a global effort to develop new technologies and treatment for TB patients. Combining these advancements, it is possible that we will base each patient's treatment on their own protein biosignatures in conjunction with the genomic expression of mutations in the Mtb strain they have been affected with. If we are to achieve our goal of global eradication of TB, it is essential that we continue to collaborate and share our expertise on an international scale to ensure each patient gets the appropriate treatment and support to overcome their TB diagnosis without significant morbidity.

Self- evaluation questions

• b) Biomolecular test ( e.g. Xpert MTB/RIF or Truenat MTB)
• c) Line probe assay ( e.g. Genotype MTBDR plus )
• d) Serum interferon-γ release assay
• a) Linezolid
• b) Second-line injectable drugs ( e.g. amikacin)
• c) Fluoroquinolones ( e.g. moxifloxacin)
• d) Bedaquiline
• Rifampicin (10 mg·kg −1 up to 600 mg maximum) daily for 4 months
• Isoniazid (5 mg·kg −1 up to 300 mg maximum) daily for 6–9 months
• Rifampicin (10 mg·kg −1 up to 600 mg maximum) and Isoniazid (5 mg·kg −1 up to 300 mg maximum) daily for 3 months
• Rifapentine (900 mg if weight >50 kg, adjusted if less) and Isoniazid (15 mg·kg −1 up to 900 mg maximum) weekly for 1 month

Suggested answers

Conflict of interest: C.M. Gill has nothing to disclose.

Conflict of interest: L. Dolan has nothing to disclose.

Conflict of interest: L.M. Piggott has nothing to disclose.

Conflict of interest: A.M. McLaughlin has nothing to disclose.

• Frontiers in Medicine
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Tuberculosis: Recent Updates in Basic Research, Drug Discovery and Treatment

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Pulmonary Tuberculosis (TB) charts among the top ten infectious diseases worldwide, as per the World Health Organization (WHO). Although new treatments (anti-tuberculars and combinatorial therapy) are emerging, these treatments come with significant side-effects. Due to the recent COVID 19 pandemic, TB programs all over the world faced major setbacks, which demands revaluation of goals and assessment of milestones set for ‘End TB Strategy’ program devised by the WHO. This Topic aims to propel clinical as well as basic research in the area of TB treatment, disease management, drug discovery and understanding the metabolic re-modelling of Mycobactrium tuberculosis as a pathogen in response to various drugs. We aspire to reach new heights in diagnosis, treatment and control of the tuberculosis epidemic, worldwide. Potential subtopics for exploration include, but are not limited to: • Investigations of pathogenesis and determinants of TB • Comprehensive investigations into treatment/ drug discovery (and/or development) against pulmonary TB. • Advancements in vaccines, diagnostic methodologies for TB. • Innovative therapeutic approaches for patients with MDR/XDR TB. • Explorations into the molecular and genetic underpinnings of mycobacteria n context with metabolic responses to various drugs/lead molecules.

Keywords : Tuberculosis, Mycobacterium tuberculosis, Drug Discovery, Clinical Trials, Treatment, Disease management, Drug Resistance

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7. TB research and innovation

• 1. COVID-19 and TB
• 2.1 TB incidence
• 2.2 TB mortality
• 2.3 Drug-resistant TB
• 2.4 TB prevalence surveys
• 3.1 Case notifications
• 3.2 Diagnostic testing for TB, HIV-associated TB and drug-resistant TB
• 3.3 TB treatment and treatment coverage
• 3.4 Drug-resistant TB treatment 
• 4. TB prevention
• 5. Financing for TB prevention, diagnostic and treatment services
• 6.1 Universal health coverage
• 6.2 National surveys of costs faced by TB patients and their households
• 6.3 TB determinants
• Civil society engagement
• Innovations
• International funding
• Technical appendices

Tuberculosis (TB) research and innovation is essential to achieve global TB targets for reductions in TB incidence and TB deaths. The targets of the WHO End TB Strategy (1) , adopted in 2014, required a global rate of decline in TB incidence of 17% per year between 2025 and 2035, compared with a baseline level of 2% per year in 2015 and 10% per year by 2025 (the best achieved at national level, historically). It was recognized that such an unprecedented rate of decline from 2025 would require a major technological breakthrough by 2025, such as a new TB vaccine that is effective both before and after exposure to infection (2) . “Intensified research and innovation” is the third pillar of the End TB Strategy. The political declaration at the first UN high-level meeting on TB, held in 2018, included the first global funding target for TB research to be agreed by all UN Member States: US$ 2 billion per year in the period 2018–2022. Although funding has been slowly increasing ( Fig. 7.1 ), the latest published data show that only US$ 915 million was available in 2020  (3) , less than half of the global target.

Fig. 7.1 Funding for TB research, 2015–2020

WHO continues to promote and monitor progress in the development of new TB vaccines, diagnostics and medicines. The diagnostic pipeline has expanded considerably in terms of the number of tests, products or methods in development ( Table 7.1 ). These include molecular tests for the detection of TB disease and drug resistance, interferon gamma release assays (IGRAs) for the detection of TB infection, biomarker-based assays for detection of TB disease, computer-aided detection (CAD) for TB screening using digital chest radiography, and a new class of aerosol-capture technologies for detection of TB disease. Three new antigen-based skin tests for TB infection that perform better than tuberculin skin tests (particularly in terms of specificity) were evaluated and recommended by WHO in 2022; these are the Cy-Tb skin test, Serum Institute of India, India; C-TST, Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China; and Diaskintest, JSC Generium, Russian Federation. WHO plans to evaluate the following tests in the coming year: culture-free, targeted-sequencing solutions to test for drug resistance directly from sputum specimens; broth microdilution methods for drug-susceptibility testing (DST); and new IGRAs to test for TB infection. In September 2022, there were 26 drugs for the treatment of TB disease in Phase I, Phase II or Phase III trials ( Table 7.2 ). These drugs comprise 17 new chemical entities, two drugs that have received accelerated regulatory approval, one drug that was recently approved by the United States (US) Food and Drug Administration under the limited population pathway for antibacterial and antifungal drugs, and six repurposed drugs. Various combination regimens with new or repurposed drugs, as well as host-directed therapies, are in Phase II or Phase III trials.

Table 7.1 An overview of progress in the development of TB diagnostics, September 2022

Table 7.2  The global clinical development pipeline for new anti-TB drugs and drug regimens to treat TB disease, September 2022

In September 2022, at least 22 clinical trials to evaluate drugs and drug regimens for treatment of TB infection were being implemented ( Table 7.3 ). Examples included trials for the prevention of drug-resistant TB among high-risk household contacts of TB patients with multidrug-resistant (MDR) and trials to assess how to optimize the administration of short-course TB preventive treatment (TPT) for very young children and people with HIV.

Table 7.3  The global clinical development pipeline for new drugs and drug regimens to treat TB infection, September 2022

In September 2022, there were 16 vaccine candidates in clinical trials: four in Phase I, eight in Phase II and four in Phase III ( Table 7.4 ). They include candidates to prevent TB infection and TB disease, and candidates to help improve the outcomes of treatment for TB disease. Effective vaccines are critical to achieve annual global and national reductions in TB incidence and mortality that are much faster than those achieved historically. WHO has commissioned a full-value assessment of new TB vaccines to guide investments in late-stage research as well the subsequent introduction and implementation of any that are licensed for use. Preliminary results suggest that vaccine products which meet the preferred product characteristics of new TB vaccines would have substantive and positive health and economic impacts.

Table 7.4  The global clinical development pipeline for new TB vaccines, September 2022

Recent actions by WHO to support TB research and innovation

• Preparations for a high-level summit about how to accelerate progress in the development of new TB vaccines, drawing on lessons learned during the COVID-19 pandemic. It is anticipated that the summit will be held in early 2023.
• Preparation of a report about the health and economic benefits of new TB vaccines, to guide investments in late-stage research as well as the introduction and implementation of new TB vaccines. This will build on a previous publication  (4) and associated journal articles (in preparation).
• In March 2022, convening of a multistakeholder consultation to discuss the emerging needs of Member States for policy guidance, evidence gaps for policy-making, and challenges in the translation of research evidence into policy (7) . The aim is to guide decision-makers who fund and implement research to better focus their research agendas on the priorities of TB programmes and affected populations.
• In May 2022, submission of a progress report to the 75th World Health Assembly on the implementation of the  Global Strategy for TB Research and Innovation (5) .
• Preparation and publication of a consolidated assessment of gaps in TB research that have emerged during the process of reviewing evidence to inform WHO guideline development (6) .
• Continued engagement in meetings of the BRICS TB research network (8) .

Health Organization. Resolution WHA67.1. Global strategy and targets for tuberculosis prevention, care and control after 2015. Geneva: World Health Organization; 2014 ( http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_R1-en.pdf ).

Floyd K, Glaziou P, Houben R, Sumner T, White RG, Raviglione M. Global tuberculosis targets and milestones set for 2016–2035: definition and rationale. Int J Tuberc Lung Dis. 2018;22(7):723–30 ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005124/ ).

Treatment Action Group, Stop TB Partnership. Tuberculosis research funding trends 2005–2020. New York: Treatment Action Group; 2021 ( https://www.treatmentactiongroup.org/wp-content/uploads/2021/12/tb_funding_2021.pdf ).

Gebreselassie N, Hutubessy R, Vekemans J, den Boon S, Kasaeva T, Zignol M. The case for assessing the full value of new tuberculosis vaccines. European Respiratory Journal. 2020;55(3):1902414 ( https://erj.ersjournals.com/content/erj/55/3/1902414.full.pdf ).

Global Strategy for Tuberculosis Research and Innovation (A75/10). Consolidated report by the Director-General. Seventy-fifth World Health Assembly. Geneva: World Health Organization; 2022 ( https://apps.who.int/gb/ebwha/pdf_files/WHA75/A75_10Rev1-en.pdf ).

Evidence and research gaps identified during development of policy guidelines for tuberculosis. Geneva: World Health Organization; 2021 ( https://www.who.int/publications/i/item/9789240040472 ).

Second WHO consultation on the translation of tuberculosis research into global policy guidelines. Geneva: World Health Organization; 2022 ( https://www.who.int/publications/i/item/9789240050907 ).

BRICS TB Research Network. See ( http://bricstb.samrc.ac.za ).

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Peer-reviewed

Research Article

Research Questions and Priorities for Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses

Affiliation McGill University, Montreal, Quebec, Canada

Affiliation Emory University, Atlanta, Georgia, United States of America

Affiliation Stop TB Partnership, World Health Organization, Geneva, Switzerland

* E-mail: [email protected]

• Ioana Nicolau, 
• Daphne Ling, 
• Lulu Tian, 
• Christian Lienhardt, 
• Madhukar Pai

• Published: July 27, 2012
• https://doi.org/10.1371/journal.pone.0042479
• Reader Comments

Systematic reviews are increasingly informing policies in tuberculosis (TB) care and control. They may also be a source of questions for future research. As part of the process of developing the International Roadmap for TB Research, we did a systematic review of published systematic reviews on TB, to identify research priorities that are most frequently suggested in reviews.

Methodology/Principal Findings

We searched EMBASE, MEDLINE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect of TB published between 2005 and 2010. One reviewer extracted data and a second reviewer independently extracted data from a random subset of included studies. In total, 137 systematic reviews, with 141 research questions, were included in this review. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. The three most common research topics were in the area of detection, screening and diagnosis of TB (32.6%), development and evaluation of treatments and therapeutic interventions (23.4%), and TB aetiology and risk factors (19.9%). The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests and drug-resistant TB tests and immunological tests. Other important topics of future research were genetic susceptibility linked to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics.

Conclusions

Systematic reviews are a good source of key research priorities. Findings from our survey have informed the development of the International Roadmap for TB Research by the TB Research Movement.

Citation: Nicolau I, Ling D, Tian L, Lienhardt C, Pai M (2012) Research Questions and Priorities for Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses. PLoS ONE 7(7): e42479. https://doi.org/10.1371/journal.pone.0042479

Editor: Markus M. Heimesaat, Charité, Campus Benjamin Franklin, Germany

Received: April 23, 2012; Accepted: June 26, 2012; Published: July 27, 2012

Copyright: © Nicolau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported in part by the Stop TB Partnership and World Health Organization. Dr Christian Lienhardt from the Stop TB Partnership and WHO provided input in study design and interpretation and revised the manuscript for intellectual content. Additional funding was provided by the European-Developing Countries Clinical Trials Programme (EDCTP; TB-NEAT grant). EDCTP had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Madhukar Pai is a Section Editor with PLoS ONE. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Introduction

Tuberculosis (TB) continues to pose a major threat to global health [1] , and research is a key component of the Global Plan to Stop TB2011-2015 [2] . Research is particularly critical for developing new tools and approaches needed for eliminating TB by 2050 [3] . Recognizing this, the Stop TB Partnership and the World Health Organization's (WHO) Stop TB Department have launched the TB Research Movement, with the aim of boosting TB research and accelerating progress in TB control towards international targets [4] . One of the main outputs of the TB Research Movement in 2011 was the publication of the International Roadmap for Tuberculosis Research [5] in October of 2011. This roadmap outlines all priority areas for investment in TB research and is intended to promote coordination and harmonization of scientific work on TB. Research priorities are identified in the areas of epidemiology; fundamental research; R&D of new diagnostics, drugs and vaccines; and operational and public health research. The ultimate goal is to reach all populations, including people with TB/HIV co-infection or MDR-TB and children, with new and better methods of prevention, diagnosis and treatment [5] .

The process for developing this roadmap has been recently described by Lienhardt and colleagues [4] . Briefly, the research roadmap was developed through a priority ranking exercise conducted by a multidisciplinary group of 50 research experts, a multidisciplinary Delphi consultation, a series of systematic reviews and an open web-based survey [4] .Among the systematic reviews that were commissioned, one was focused on all the TB research agendas that have been published from 1998 to 2010 [6] . As a next step, we were commissioned to review all the published systematic reviews and meta-analyses on TB (in all areas, including drugs, vaccines, diagnostics), to assess what research priorities have been identified in these reviews. The objectives of our systematic review were as follows: (1) to identify all systematic reviews and meta-analyses pertaining to any aspect of tuberculosis from 2005 to 2010, and (2) to assess, compile and rank the research priorities that were identified.

MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for systematic reviews and meta-analyses on TB. The search strategy was developed in consultation with a medical librarian. The search was limited to systematic reviews and meta-analyses published between January 1, 2005 and July 1, 2010, in order to focus on contemporary TB literature and identify research priorities of greatest relevance to current TB control.

The search strategy included the following keywords and MeSH terms: [‘tuberculosis’ (explode) OR ‘ Mycobacterium tuberculosis ’(explode) OR ‘tuberculosis’.ti,ab. OR ‘tuberculos*’.tw] AND [‘meta analysis’ (explode) OR ‘meta analyses’.ti,ab OR ‘meta-analyses’.ti,ab OR ‘meta-analysis’.ti,ab OR ‘metanalys*’.ti,ab OR ‘systematic review’.tw]. The search was not limited to English and the last search was performed on August 18, 2010.

Studies were included if they focused on any aspect of tuberculosis. We included systematic reviews and meta-analyses published in English, French, Spanish, and Italian. The languages included were based on the skill set of our research team. We included systematic review and meta-analyses that had focused on tuberculosis or on a tuberculosis related topic (e.g. BCG), in the title or abstract. We considered a study to be a systematic review or meta-analysis if the authors identified the study as such, or if the title or abstract contained the words “systematic review” or “meta-analysis”. Moreover, studies were regarded as systematic reviews if the authors reported a systematic, explicit approach to identify, select, and synthesize the available evidence.

The first screening of the titles and abstracts obtained following the electronic search was done by one reviewer (IN). Subsequently, the same reviewer (IN) screened the full text articles, determined the eligibility, and decided on the final inclusion of studies in the systematic review. Further, a second reviewer (MP) independently searched, screened and identified studies for the inclusion in the review.

Data abstraction

We developed a data extraction form which was pilot-tested by two reviewers (IN and DL). The reviewers independently piloted the forms until there were no major disagreements in the data extraction process. One reviewer (IN) extracted the data from all the included studies and the second reviewer (DL) extracted data in duplicate for a random subset of 15% of the total number of included articles. Additionally, a third reviewer (LT) independently extracted data for all included studies on the study characteristics section of the data extraction form. Disagreements between the three reviewers were resolved by consensus.

Study characteristics

We extracted data from the text or online supplement of each included systematic review or meta-analysis. Information was collected on two main points: i) the main focus of the systematic review, and ii) questions and priorities identified for future research. The UK Health Research Classification System (HRCS) [7] , developed by the UK Clinical Research Collaboration for the classification and analysis of all types of health research, was used to determine the focus of the included studies as well as the focus of the research questions/priorities. In particular, the HRCS Research Activity Codes [7] were used to assign a category for the main focus of the studies and the research questions/priorities.

The main focus of each included systematic review was determined by extracting keywords from the title and abstract and matching them with the criteria developed by the HRCS. The Codes were divided into eight major categories: (1) Underpinning research; (2) Aetiology; (3) Prevention of disease and conditions, and promotion of well-being; (4) Detection, screening and diagnosis; (5) Development of treatments and therapeutic interventions; (6) Evaluation of treatments and therapeutic interventions; (7) Management of diseases and conditions; and (8) Health and social care services research (see Table 1 for full description). These research categories were used in Tables 2 and 3 , to provide an overarching framework for grouping TB research.

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In the HRCS, each of the eight major categories is further subdivided into five to nine subcategories with definitions for the type of research that belonged to that subcategory. For instance, “(1)Underpinning research” includes five subcategories: (1.1)studies of normal biological development and functioning, including gene, gene products, biological pathways, molecular and cellular structures, and development and characterization of model systems; (1.2) studies that do not address health directly but cover issues such as psychological and socioeconomic processes, individual or group characteristics and behaviours, and social and cultural beliefs; (1.3) research in chemical and physical sciences that may lead to the future development of diagnostic tools or treatments; (1.4) studies that target the development of novel methodologies and measurements including the development of statistical methods, and the development of mapping methodologies; and (1.5)research involving the development and/or distribution of resources for use by the research community, and infrastructure to support research networks. Using the main categories and the subdivisions within each category, we mapped the corresponding TB research areas found in the literature search (refer to Tables 1 and 2 ).

Quantitative data synthesis

Study characteristics were summarized using descriptive statistics. Measures such as total count, frequency, and proportion, were used to summarize data. Data analyses were performed using STATA Version 11.0.

There were a total of 973 records identified through the electronic database search ( Figure 1 ). The first screening of titles and abstracts was done on 680 records. Following the first screening process, 528 records were excluded. The reasons for exclusion are listed in Figure 1 . The full text screening of articles was performed on 152 records. Overall, there were 137 systematic reviews included in our analysis [8] – [144] .

https://doi.org/10.1371/journal.pone.0042479.g001

Characteristics of included TB systematic reviews

The 137 reviews were published in 61 different journals. The majority of reviews (39.4%) were published in journals with impact factors of five or less, and only six (4.3%) reviews were published in journals with a high impact factor (>15). However, a large proportion of the reviews (38.6%) were published in journals that did not have an impact factor. In addition, approximately 24% of the main authors were from the United States and 41% were from four other countries (China, UK, Canada, and Italy). The remaining 34.1% of authors were from 26 different countries.

Out of the 137 reviews, 131 (95.6%) self identified as a systematic review or meta-analysis, which means that they used the term “systematic review” or “meta-analysis” in the title or abstract. Approximately 91% (124) of all reviews were not Cochrane reviews. Among the 13 Cochrane reviews, 9 of them focused on “evaluation of treatments and therapeutic interventions”.

Half of the reviews (67 [48.9%]) reported having a funding source, whereas only 15 reviews (11.0%) reported not being funded and 55 reviews (40.1%) did not report funding status. Most of the reviews (109 [79.6%]) included less than 50 studies in their review and within those reviews, the majority had between 1,000 and 10,000 participants (34/109[31.2%]).

Focus of TB systematic reviews

The main focus of each review was determined using the HRCS as described in the Methods section. The classification categories were subdivided into major tuberculosis research areas as described in Table 2 . The three most common review categories, in decreasing order, were “Detection, screening and diagnosis” with 46/141(32.6%) systematic reviews, “Development and evaluation of treatments and therapeutic interventions” with 33/141(23.4%) systematic reviews and “Aetiology” with 28/141(19.9%) systematic reviews.

Within the category of “Detection, screening and diagnosis”, 17/46 (37%) of the reviews focused on bacteriological diagnostics for active TB, such as improving processing methods of sputum smear microscopy, and assessing the use of nucleic acid amplification tests (NAATs). The two other most common TB research aims were bacteriological diagnostics for MDR-TB (9/46[20%]) and immunological diagnostics (9/46[20%]). More specifically, bacteriological diagnostics for MDR-TB included tests such as line-probe assays, bacteriophage based assays, and colorimetric redox assays. Immunological diagnostics were focused mainly on testing and evaluating interferon-gamma release assays (IGRAs).

In the category “Development and evaluation of treatments and therapeutic interventions”, 10/33 (30%) studies focused on drug resistant tuberculosis treatment, 9/33 (27.3%) studies on evaluating different regimen combinations for tuberculosis treatment, and 6/33(18.2%) on treatment of latent tuberculosis infection (LTBI).

In the category “Aetiology”, 11/28 (39.3%) systematic reviews focused on biological/genetic risk factors such as genetic susceptibility and gene targets,11/28 (39.3%) studies targeted surveillance and distribution of TB/HIV co-infection, MDRTB and HIV, and diabetes and TB, and 5/28(17.9%) focused on travel risk for LTBI and nosocomial TB exposure.

Research priorities

Out of 137 reviews, 103 (75%) identified at least one research question or a research priority. Of these, 48 (46.6%) identified only one research priority, 33 (32.0%) two research priorities, 7 (6.8%) three, 7 (6.8%) four, and 8 (7.8%) five research priorities. None of the reviews identified more than five research priorities.

Table 3 shows the summary of research priorities by category, subdivision, and TB-specific research priority. The three major categories of research priorities/questions were “Detection, screening and diagnosis” responsible for 50/191 (26.2%) of all the identified research priorities, “Aetiology” with 42/191 (22.0%), and “Evaluation of treatments and therapeutic interventions” with 37/191 (19.4%).

In the most common category, “Detection, screening and diagnosis”, the top research priority was the evaluation of bacteriological TB diagnostic tests in 14/50 (28.0%) reviews. Other frequently cited TB research priorities were: evaluation of immunological TB diagnostic tests (6/50 [12.0%]); discovery and development of new TB diagnostic tests (5/50 [10.2%]); and development of new bacteriological MDR-TB diagnostics (5/50 [10.2%]). Two priorities had almost equal importance and were highly prevalent in TB literature. The main priority in that category was to investigate the detection, screening and diagnosis of drug-resistant TB and MDR-TB. Studies called for the need to develop studies that detect resistance from smear positive specimens, determine the accuracy of colorimetric methods, line-probe assays, phage-based assays for rapid screening and nitrate reductase assay (NRA), and find the clinical usefulness of rapid diagnosis of rifampicin-resistant TB. Another frequency priority was to address unresolved research questions on interferon-gamma release assays (IGRAs), discover new antigens with immunodiagnostic potential, and test IGRAs in various populations and settings to establish test reproducibility. Evaluating sputum processing methods and smear microscopy, assessing nucleic acid amplification tests (NAATs), and evaluating tests for extrapulmonary TB (e.g. adenosine deaminase for pleural TB) were commonly cited priorities.

Within the “Aetiology” category, the main TB research priorities were: development of new research methods; better study designs or statistical tools for studying drug resistant TB, MDR-TB, links between HIV and MDR-TB; comparison of diagnostic tests (17/42 [40.5%]); identification of biological and genetic risk factors (15/42 [35.7%]); and evaluation of the role of risk factors such as tobacco and air pollutants (7/42 [16.7%]). The most frequent priority was to examine gene and gene products in relation to TB disease and susceptibility to disease. Key genes such as vitamin D receptor polymorphisms, IL10 gene, and drug-metabolizing enzyme (DME) gene polymorphisms were commonly mentioned for future research. The second most frequent research priority on TB/HIV included recommendations to conduct studies investigating XDR-TB and HIV co-infection, identifying a comprehensive definition of IRIS (immune reconstitution inflammatory syndrome), and investigating sputum processing methods with direct smears in settings with high and low HIV prevalence.

The category “Evaluation of treatments and therapeutic interventions” was the third most frequent. It focused on TB/HIV drug treatments (12/37 [32.4%]), drug-resistant TB treatments (11/37 [29.7%]), new TB drugs and active tuberculosis regimens (8/37[21.6%]). Implementing studies that evaluate new treatments and therapeutic interventions for drug-resistant TB, MDR-TB, and XDR-TB, was a prominent research priority. Such studies would need to examine methods to improve treatment outcomes for patients with XDR TB such as using later-generation fluoroquinolones, discovering methods to tailor treatment regimens for various forms of TB drug resistance, and investigating the use of quality-controlled laboratory testing for all first and second-line drugs that define XDR-TB. Another frequently cited priority was designing trials to evaluate the optimal duration of TB treatment, the influence of level of immunosuppression on effectiveness of TB drugs, and the combination of anti-TB chemoprophylaxis with antiretroviral therapy.

Systematic reviews and meta-analyses are widely acknowledged as a key component of the policy and guideline development process [145] . A large number of systematic reviews have been published in the area of TB diagnostics [146] , and these are increasingly being used for developing guidelines [147] . To this end, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool has increasingly been adopted by policy makers and guideline developers to provide an explicit, comprehensive and transparent process for moving from evidence to recommendations [145] .

Systematic reviews often conclude by making suggestions for the direction of future research, and thus could be a good source for identifying the most important questions for TB research. Our survey collected descriptive information from all eligible systematic reviews and meta-analyses that were subsequently used to generate a list of research priorities in TB which were used for developing the International Roadmap for Tuberculosis Research [5] .

Our systematic search showed that a fairly high number of systematic reviews were published on TB during the period of 2005 to 2010. The findings of our review need to be interpreted along with a recent systematic review by Rylance and colleagues [6] on 33 articles with research agendas on TB. These authors found that the top priority areas for research were new TB drug development (28 articles), diagnosis and diagnostic tests (27), epidemiology (20), health services research (16), basic research (13), and vaccine development and use (13).

In our review of 137 TB systematic reviews, the top three categories for the focus of the research priorities/questions were “Detection, screening and diagnosis” “Aetiology” and “Evaluation of treatments and therapeutic interventions.” TB diagnosis and treatment were among the most important research priorities in both reviews. One possible reason of why TB diagnosis research ranked high on our list could be that our review focused on years 2005 to 2010, a period when major advances have been made in TB diagnostics, especially with IGRAs becoming a very popular subject of research [148] . Also, this time period saw the introduction of several WHO policies on TB diagnostics. Further, the emphasis on new tools in the Global Plan to Stop TB 2006–2015 [149] , along with the creation of product development partnerships such as the Foundation for Innovative New Diagnostics (FIND), AERAS, and Global Alliance for TB Drug Development, may have inspired research on new diagnostics and drugs.

The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests, drug-resistant TB tests and immunological tests, with special focus on IGRA tests. Also, tests for extra-pulmonary TB came up as a frequently cited priority in the Detection of TB category. Other important topics of future research were genetic susceptibility to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics. Many articles cited the need for improved and tailored treatment methods for MDR-TB and XDR-TB.

Although several systematic reviews identified areas for further research, the questions themselves were often framed in a generic way, rather than in a highly focused manner with specific recommendation for action. Future TB systematic reviews will need to be more focused, and propose highly specific, answerable questions that are amenable to well-designed research studies.

Our study has several limitations. Due to the poor overall quality of reporting of the systematic reviews, the findings may not be representative of the general output from the TB research community [150] . The inclusion of eligible studies was limited by the fact that we only reviewed articles in three other languages besides English. We were also unable to search ‘grey’ literature, contact authors, or hand search journals. The review also did not include any unpublished literature. Due to its overarching and generic nature, the Health Research Classification System categories were at times non-specific and difficult to match with specific areas of TB research. Furthermore, it was difficult to classify research priorities into narrow subdivisions since some research priorities could qualify for more than one subdivision. By categorizing research priorities into larger, predefined categories, we lost detailed information on individual research priorities. To remedy this, we condensed each priority and extracted the topic words from it. The topic words were then grouped together to form the summary of repeated priorities/questions and calculate the frequency.

There has been a lot of recent attention and focus on childhood TB, but because our search was last performed in 2010, our analysis may have missed research priorities in this important area.

In summary, our systematic review of published systematic reviews on TB helped identify several key priorities for future TB research. This exercise was useful to describe the landscape of TB research and the overarching TB research themes arising from systematic reviews and meta-analyses conducted over the last 5 years. Their scope is, however, limited, since systematic reviews themselves are influenced by current hot topics or new technologies. They are nevertheless useful in indicating research priorities on areas that receive high attention, either due to recent scientific developments or increasing questions surrounding advancement of knowledge in these very areas. They bring useful additional arguments and information to the broader, deeper and more rigorously conducted process of international research agenda development.

Author Contributions

Conceived and designed the experiments: IN CL MP. Performed the experiments: IN DL LT. Analyzed the data: IN CL MP. Wrote the paper: IN MP.

• 1. World Health Organization (2011) Global tuberculosis control 2011. Geneva: World Health Organization. 1–242 p.
• 2. World Health Organization (2010) Global Plan to Stop Tuberculosis 2011–2015. Geneva: World Health Organization. 1–242 p.
• View Article
• Google Scholar
• 5. Stop TB Partnership & World Health Organization (2011) An international roadmap for tuberculosis research: towards a world free of tuberculosis. Geneva: World Health Organization.
• 7. UK Clinical Research Collaboration (2011) Health Research Classification System (HRCS). London, UK: UKCRC.
• 39. Fraser A, Paul M, Attamna A, Leibovici L (2006) Drugs for preventing tuberculosis in people at risk of multiple-drug-resistant pulmonary tuberculosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd.
• 85. Lutge Elizabeth E, Knight Stephen E, Volmink J (2009) Incentives for improving patient adherence to anti-tuberculosis treatment. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd.
• 136. Vlassov Vasiliy V, Reze Andrey G (2006) Low level laser therapy for treating tuberculosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd.
• 149. Stop TB Partnership (2006) The Global Plan to Stop TB, 2006–2015: Actions for life: towards a world free of tuberculosis. Geneva: World Health Organization (WHO/HTM/STB/2006.35).

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Research Questions and Priorities for Pediatric Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses

Affiliations.

• 1 ICAP at Columbia University, Maputo, Mozambique.
• 2 Atlantic International University, Honolulu, HI, USA.
• 3 Elizabeth Glaser Pediatric AIDS Foundation, Yaoundé, Cameroon.
• 4 Health Alliance International, Abidjan, Côte d'Ivoire.
• 5 Department of Global Health, University of Washington, Seattle, WA, USA.
• PMID: 35178252
• PMCID: PMC8844079
• DOI: 10.1155/2022/1686047

Background: Advancing a research agenda designed to meet the specific needs of children is critical to ending pediatric TB epidemic. Systematic reviews are increasingly informing policies in pediatric tuberculosis (TB) care and control. However, there is a paucity of information on pediatric TB research priorities. Methodology . We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect related to pediatric TB published between 2015 and 2021. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. Findings . In total, 29 systematic reviews, with 84 research questions, were included in this review. The four most common research topics in the area of detection were 43.33% screening and diagnosis of TB, 23.33% evaluation of treatments and therapeutic interventions, 13.34% TB etiology and risk factors, and 13.34% prevention of disease and conditions and promotion of well-being. The research priorities focused mainly on evaluating TB diagnosis by improving yield through enhanced in specimen collection or preparation and evaluating of bacteriological TB diagnostic tests. Other topics of future research were developing a treatment for TB in children, assessing the use of IPT in reducing TB-associated morbidity, evaluating the prioritization of an IPT-friendly healthcare environment, and providing additional guidance for the use of isoniazid in the prevention of TB in HIV-infected children.

Conclusion: There is a need for more systematic reviews on pediatric TB. The review identified several key priorities for future pediatric TB research mainly in the domain of (1) "Detection, screening and diagnosis," "Development of Treatments and Therapeutic Interventions," and "Prevention of Disease and Conditions, and Promotion of Well-Being." These domains are very relevant in the research component of the roadmap towards ending TB in children. It also will serve as an additional action in the WHO End TB strategy.

Copyright © 2022 Thomas Achombwom Vukugah et al.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

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Flow chart of the study selection process.

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Tuberculosis

Tuberculosis (TB) is a contagious disease caused by infection with  Mycobacterium tuberculosis  ( Mtb ) bacteria. It is spread through the air when a person with TB disease of the lungs or throat coughs, speaks or sings, and people nearby breathe in these bacteria and become infected. 

TB typically affects the lungs, but it can also affect other parts of the body, including the kidney, spine and brain. Not everyone infected with TB bacteria becomes sick. People who have latent TB infection have the TB bacteria in their bodies but are not sick and cannot spread the bacteria to others. Individuals with active TB disease, however, are sick and may also be able to transmit the bacteria to others. Many people with latent TB never develop active TB disease. For people with weakened immune systems, such as those living with HIV infection, the risk of developing TB disease is much higher than for those with normal immune systems. Both latent TB infection and active TB disease can be treated. Without treatment, latent TB infection can progress to TB disease, and without proper treatment, TB disease can kill.

Why Is the Study of Tuberculosis a Priority for NIAID?

Tuberculosis is the leading infectious cause of death worldwide. In 2017, 10 million people became ill with TB, and 1.6 million people died of TB disease including 230,000 children, according to the World Health Organization. Over the past 200 years, TB has claimed the lives of more than one billion people---more deaths than from malaria, influenza, smallpox, HIV/AIDS, cholera, and plague combined. Although TB treatment exists, drug resistance is a continued threat.

How Is NIAID Addressing This Critical Topic?

NIAID supports and conducts basic, translational and clinical research to better understand TB and expedite the development of innovative new tools and strategies to improve diagnosis, prevention and treatment of TB. 

NIAID Strategic Plan for Tuberculosis Research, 2024 Update

Tuberculosis is the second leading infectious cause of death worldwide. In the updated strategic plan, NIAID details four strategic priorities that are critical to the development and evaluation of the knowledge and tools needed to end TB globally. 

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Tuberculosis research questions identified through the WHO policy guideline development process

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WHO guideline development groups identify research questions using systematic reviews, economic analyses and stakeholder consultations during policy guidance development to identify urgent research gaps in the policy/implementation interface http://ow.ly/lUUw30nQZRO

High-quality research evidence is critical for improving global health and health equity, and for achieving the World Health Organization (WHO)'s objective of the attainment of the highest possible level of health by all peoples [ 1 ]. This need is most apparent when responding to complex epidemics such as tuberculosis (TB). TB is the leading killer among diseases caused by an infectious agent worldwide, the leading killer of people with HIV infection and a leading cause of death from airborne anti-microbial resistant infections, taking heavy tolls on human lives, communities and health systems at large [ 2 , 3 ]. WHO estimates that TB caused illness in 10 million people and claimed an estimated 1.6 million lives in 2017 alone [ 2 ]. The WHO End TB Strategy, in the context of the Sustainable Development Goals (SDGs), lays ambitious goals and milestones to end the epidemic by reducing incidence and mortality by 80% and 90% in 2030 compared to 2015: such reductions can only be achieved if there are major technological breakthroughs by 2025 [ 4 ].

Critical research is needed to acquire rapid point-of-care TB diagnostics, including for drug resistance; shorter, safer and simpler regimens effective against drug-susceptible and drug-resistant TB, as well as latent TB infection (LTBI) that are appropriate for treatment of TB/HIV co-infection; and a new TB vaccine that is effective both before and after exposure. These require scientific advances in the discovery and development of new biomedical tools, together with innovative delivery mechanisms to effectively adapt and adopt new technologies and optimise the necessary linkages and integrations with other health services and sectors. For this reason, “Intensified research and innovation” has been identified as one of the three essential pillars of the End-TB Strategy. This editorial summarises the research questions identified through recent WHO TB policy guidance to increase the quality of evidence for policy-making. Based on evidence arising from research, WHO is mandated to produce recommendations to guide clinical practice and public health policy for TB prevention and care in response to demand from public health decision makers. WHO guideline development groups (GDGs), which include researchers, the health workforce, civil society, as well as end-users of the guidelines, such as policymakers from government, professional associations and other constituencies, are appointed by WHO to develop policy guidelines [ 5 ]. A GDG meets with the primary objective of agreeing on the scope of recommendations by reviewing evidence, structured according to the standard framework of population, intervention, control, outcomes (PICO). This permits a systematic study of relevant evidence, the formulation of recommendations and the identification of knowledge gaps that need to be addressed through high quality research conducted in various epidemiological, demographic and geographic settings. The research questions highlighted in this document arose because the respective GDGs agreed they were critical for increasing the certainty/strength of existing recommendation, and/or for stimulating the development or optimisation of new recommendations that can lead to improvement in patient health and welfare. This step is an integral part of the WHO guideline development process (see, for example, the discussion section of F alzon et al . [ 6 ]).

Among the major challenges facing global policy guidance development in TB are the shortage of good quality evidence exacerbated, for example, by lack of sufficient clinical trials with direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit; data inaccessibility including for programmatic experiences of benefits and safety of interventions in real world setting; or when the evidence being presented does not address broader questions of values and priorities that go beyond medical interventions ( e.g. acceptability, feasibility, resource distribution and health equity). Evidence obtained from well-designed, large scale multidisciplinary studies with robust testing of interventions are therefore needed to improve the strength of future guidance.

The most up-to-date WHO policy guidance documents for TB prevention and care are summarised in a Compendium of TB Guidelines and Associated Standards [ 7 , 8 ]. Using this compendium as a reference, we compiled a list of 155 research questions across the continuum of TB prevention, diagnosis, treatment and care (also summarised in table 1 ): three related to early detection; 35 related to diagnosis of TB disease, 10 related to the diagnosis and management of latent TB infection, 38 related to treatment of TB disease, including drug-resistant TB; 38 related to the management of TB/HIV and malnutrition; and 31 related to childhood TB management [ 10 ]. Because these research questions are limited in scope to needs identified during guideline development processes, the majority of the questions highlight gaps at the policy/implementation interface ( figure 1 ). Systematically linking such research questions to public health goals requires collaboration among funders, researchers and end users to ensure that funded research represents value for money, not only through the generation of new knowledge but also by contributing to health and economic outcomes. There are several ways of accomplishing that. The National Institute for Health Research Public Health Research Programme (NIHR PHR Programme) in the UK, for example, includes public health decision makers in its decision-making committee, and subsequently, the research it funds has been shown to align with priorities highlighted in national guidelines [ 11 ]. However, this is not the practice across all research funders. An exploratory qualitative study of funding strategy among five high-profile public health research funding organisations showed limited involvement from end users/policymakers in the prioritisation of research questions for funding [ 12 ]. Considering the need for well-funded, timely and high quality research for policy, funders should capitalise on opportunities to strengthen participation of policymakers and other end users in generating priority-driven research funding streams.

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Representation of the research questions documented in World Health Organization tuberculosis (TB) policy guidance documents. BCG: bacille Calmette–Guerin; LTBI: latent TB infection; MDR-TB: multidrug-resistant TB; Hr-TB: isoniazid-resistant TB.

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Research questions from the World Health Organization (WHO) tuberculosis (TB) policy guidance documents

At a time when there are many competing demands on limited resources, the WHO and its partners, countries, civil society and affected communities have a joint responsibility to ensure that TB research investments help achieve the goals and targets of the End TB Strategy and the SDGs. In recognition of this need, a TB resolution adopted at the World Health Assembly in May 2018 requested WHO to develop a global strategy for TB research and innovation, “to make further progress in enhancing cooperation and coordination in respect of tuberculosis research and development” [ 13 ]. Considering the significant funding gap for TB research (USD 1.3 billion gap in 2017 when benchmarked against the targets outlined in the Global Plan to End TB 2016–2020: the Paradigm Shift ), such coordination and collaboration is envisioned to help direct time and resources to the most urgent evidence needs faced by TB policymakers [ 14 – 16 ].

Conflict of interest: N. Gebreselassie has nothing to disclose.

Conflict of interest: D. Falzon has nothing to disclose.

Conflict of interest: M. Zignol has nothing to disclose.

Conflict of interest: T. Kasaeva has nothing to disclose.

• Received November 6, 2018.
• Accepted February 8, 2019.
• The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2019.
• ↵ Constitution of the World-Health-Organization . Public Health Rep 1946 ; 61 : 1268 – 1277 . OpenUrl
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• Migliori GB , et al.
• World Health Organization, TB/HIV Working Group/Stop TB Partnership
• Cartier Y ,
• Creatore MI ,
• Hoffman SJ , et al.
• ↵ Stop TB Partnership. The Global Plan to End TB, 2016–2020: the Paradigm Shift. Geneva, United Nations Office for Project Services/Stop TB Partnership, 2015 .

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Tuberculosis (TB) news, resources and funding for global health researchers

A major cause of death and disability worldwide, tuberculosis is a contagious lung disease that spreads through the air when people infected with it cough, sneeze, talk or spit. TB is caused by a bacterium called Mycobacterium tuberculosis , which usually attacks the lungs, but can affect other parts of the body like the kidney, spine and brain. The disease can be fatal if not treated properly.

According to the World Health Organization, there are almost 2 million TB-related deaths each year, and more than 9 million people around the world become sick with the disease annually. In 2009, almost 10 million children were orphaned as a result of parental deaths caused by TB. The spread of multidrug-resistant TB is a growing global threat, with hundreds of thousands of new cases emerging each year.

TB coinfection with HIV/AIDS is also a serious health issue and a leading cause of death worldwide among people with HIV. Several NIH research and research training programs are helping to reduce the impact of tuberculosis both in the U.S. and overseas.

Grant Awards Related to TB

• View a list of Fogarty grant awards related to tuberculosis (TB) .

Recent News

• Treatment Outcomes for Tuberculosis Infection and Disease Among Persons Deprived of Liberty, Uganda, 2020 Emerging Infectious Diseases , July 2024
• Ambitious clinical trial could bring first TB vaccine in a century Fogarty news, June 4, 2024
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NIH News and Resources

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Updated July 12, 2024

Topic Collection: Implementation and Scale-up of Tuberculosis Preventive Treatment

Implementation and scale-up of tuberculosis preventive treatment.

Guest Editors

• The cost-effectiveness and budget impact of TPT scale-up
• Feasibility and acceptability of approaches to implement and scale-up TPT, particularly those in primary care
• Qualitative research highlighting barriers and facilitators to TPT implementation and scale-up among patients, providers, and policy-makers
• Mixed-methods research leveraging before-and-after designs to evaluate the impact of interventions to implement and/or scale-up TPT
• Cluster randomized trials or prospective studies evaluating interventions that can impact TPT uptake

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What is tuberculosis?

Tuberculosis, or TB, is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease. But people infected with TB bacilli will not necessarily become sick with the disease. The immune system "walls off" the TB bacilli which, protected by a thick waxy coat, can lie dormant for years. When someone's immune system is weakened, the chances of becoming sick are greater.

• Overall, one-third of the world's population is currently infected with the TB bacillus.
• 5-10% of people who are infected with TB bacilli (but who are not infected with HIV) become sick or infectious at some time during their life.
• People with HIV and TB infection are much more likely to develop TB.
• TB is the leading killer of people who are HIV infected.

If properly treated, tuberculosis caused by drug-susceptible strains is curable in virtually all cases. If untreated, more than half the cases may be fatal within five years.

What data does DHS collect about TB?

The DHS collects data on women's and men's knowledge and attitudes concerning TB. Over 90 surveys have included TB questions.

What are the DHS indicators related to TB knowledge and attitudes?

• Percentage who have heard of TB
• Percentage who report that TB is spread through the air by coughing
• Percentage who believe that TB can be cured
• Percentage who would want a family member's TB kept secret

What data does SPA collect about TB?

The Service Provision Assessment ( SPA ) survey collects data on TB diagnostic services, TB treatment, and/or follow-up services and facilities following DOTS (Directly-observed Treatment, Short-course) strategy and any treatment other than DOTS strategy.

Photo credit: © 2008 Anil Gulati, Courtesy of Photoshare. Wall paintings on a TB hospital in Nowgaon, District Chhatarpur, Madhya Pradesh, India, illustrate DOTS tuberculosis medication therapy.

• Stop TB Partnership - resources page
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• The Lancet - special series on TB
• WHO - Status of the global TB epidemic
• WHO - Stop TB Strategy
• World Bank - TB data by country
• CDC - Find TB Resources
• US Global Health Policy (data by topic: TB)
• Tuberculosis Control Assistance Program (2005-2010) toolbox

Exploring Quantitative Biology: A Guide to Research Topics

Welcome to the fascinating world of quantitative biology, where biology, math, and technology blend to help us understand life better. Whether you’re a student, a science enthusiast, or just curious about how biology works at a deeper level, this guide will break down the key research areas in simple terms. Quantitative biology is all about using numbers, patterns, and computer models to figure out how living things behave, and we’re going to explore some of its most exciting topics. Let’s dive in!

What is Quantitative Biology?

Table of Contents

At its core, quantitative biology is the use of mathematical models, statistics, and computational tools to understand biological systems. It combines biology with math, providing a quantitative approach to solving biological problems. Whether predicting how a disease spreads or understanding genetic mutations, quantitative biology allows researchers to gain insights that would be impossible without the power of numbers.

For instance, imagine you’re studying how bacteria develop antibiotic resistance. Using mathematical models, you can predict how quickly resistance will spread in a population, helping scientists develop better treatments.

Why is Quantitative Biology Important?

Quantitative biology plays a vital role in modern science. By blending biological science with quantitative methods, researchers can:

• Understand Complex Biological Systems : From individual cells to entire ecosystems.
• Predict Outcomes : Such as how a disease spreads or how an ecosystem responds to environmental changes.
• Innovate in Medicine and Technology : For example, designing new drugs or genetically engineering crops.
• Make Sense of Large Datasets : With advances in technology, scientists have more data than ever, and quantitative biology helps analyze it.

Key Research Topics in Quantitative Biology

1. systems biology: the blueprint of life.

Systems biology is a key branch of quantitative biology that examines how different parts of a biological system interact to create its overall behavior. It studies biological networks—how genes, proteins, and cells communicate with one another. Using computational modeling, scientists simulate these interactions and predict what might happen if one part of the system changes.

For example, understanding how cancer spreads requires studying how cells interact and multiply. Systems biology helps researchers identify which proteins or genes are involved in these processes, enabling the development of targeted therapies.

Why It Matters:

• Helps in developing new treatments for diseases.
• Provides insights into how cells and organisms function as a whole.

Example Research Question:

• How does a specific protein impact the way cells communicate during growth?

2. Bioinformatics and Genomics: Decoding DNA

Bioinformatics is a field of quantitative biology that applies computational modeling to the study of DNA and genetic data. It plays a central role in genomics, the study of an organism’s entire genetic makeup. Scientists use bioinformatics tools to analyze vast amounts of DNA and gene data, helping them find connections between genes and diseases.

For example, researchers use DNA analysis to identify mutations linked to conditions like diabetes or cancer. The data generated from sequencing entire genomes is immense, and bioinformatics is essential for making sense of it.

• Helps in finding the genetic basis of diseases.
• Enables the development of personalized medicine based on a person’s DNA.
• What genetic mutations are responsible for certain inherited diseases?

3. Population Genetics: Evolution in Action

Population genetics is the study of how gene frequencies change in a population over time. It examines how natural selection, mutations, and genetic drift shape populations’ genetic makeup. Using mathematical models, population geneticists can predict how traits evolve and spread in a group of organisms.

For instance, a population of animals might adapt to a changing environment by developing thicker fur for colder climates. Population genetics helps scientists understand the genetic diversity that drives these changes.

• Helps in conservation efforts by studying how species adapt to environmental changes.
• Provides insights into how diseases or traits evolve within populations.
• How do environmental changes influence the evolution of genetic traits in a population?

4. Biophysics: The Physics Behind Life

Biophysics combines physics with biology to understand the physical principles governing biological processes. It focuses on the molecular dynamics of proteins, DNA, and other cellular components. Scientists use biophysics to study how proteins fold, how cells transmit signals, and how forces within cells affect their behavior.

One crucial area in biophysics is studying protein structure. When proteins fold incorrectly, it can lead to diseases like Alzheimer’s. Understanding these physical processes allows researchers to develop drugs that stabilize proteins and prevent misfolding.

• Helps in understanding diseases caused by misfolded proteins, such as Alzheimer’s and Parkinson’s.
• Provides insights into how cells function on a molecular level.
• How do proteins fold, and what causes them to misfold in diseases?

5. Quantitative Ecology: Modeling Nature

In quantitative ecology, researchers use mathematical tools and environmental modeling to study ecosystems. By simulating how species interact with their environment and each other, ecologists can predict changes in biodiversity due to factors like climate change, pollution, or habitat destruction.

For example, if a new predator is introduced into an ecosystem, it can dramatically alter the populations of prey species. Quantitative ecology models help scientists understand these dynamics and develop strategies to protect endangered species.

• Helps in conservation efforts by modeling how species and ecosystems respond to changes.
• Provides tools for managing ecosystems and protecting biodiversity.
• How does climate change affect the biodiversity of an ecosystem?

6. Neuroscience and Brain Networks: Understanding the Brain

Neuroscience focuses on understanding the structure and function of the brain, and quantitative biology plays a big role here. By studying brain networks and neural circuits, scientists can map out how neurons interact and how information flows through the brain. Neuroscience uses computational models to understand how these networks change when we learn or suffer from disorders like epilepsy.

For instance, researchers use quantitative models to simulate how neural circuits adapt during learning processes, providing insights into memory formation and decision-making.

• Helps in developing new treatments for brain disorders.
• Provides insights into how the brain functions and learns.
• How do neural circuits in the brain adapt when we learn something new?
• 200+ Unique And Interesting Biology Research Topics For Students In 2023
• 200+ Experimental Quantitative Research Topics For STEM Students In 2023

7. Synthetic Biology: Building New Life

Synthetic biology is an exciting field of biotechnology in which researchers design and create new biological systems or organisms. Using principles from genetic engineering, scientists can modify or build DNA sequences to produce new functions, like bacteria that break down plastic or plants that grow faster.

For instance, synthetic biology has been used to engineer yeast cells that can produce medicines like insulin. This type of research is paving the way for sustainable solutions to medical and environmental problems.

• Offers new solutions to environmental and medical challenges.
• Enables the development of genetically modified organisms (GMOs) with useful traits.
• How can we engineer bacteria to produce new antibiotics?

8. Epidemiology and Infectious Disease Modeling: Preventing Outbreaks

In epidemiology, researchers study how diseases spread within populations. By using disease modeling, scientists can predict outbreaks and design public health strategies to prevent the spread of infectious diseases. These models take into account factors like transmission rates, immunity, and social behavior.

For example, during the COVID-19 pandemic, epidemiologists used models to forecast how the virus would spread and what measures, like social distancing, could slow its progression. Public health officials rely on these models to make informed decisions.

• Helps governments and public health officials prepare for and control disease outbreaks.
• Provides insights into the effectiveness of vaccines and other interventions.
• How can we predict the spread of the next pandemic?

How Quantitative Biology Impacts Our Lives

Quantitative biology might sound technical, but it affects everyone. From better healthcare (through personalized medicine and disease modeling) to conservation efforts (by protecting species and ecosystems), the insights from this field shape the world we live in. Whether scientists are predicting how a virus spreads or figuring out how to grow more food in a changing climate, quantitative biology helps tackle global challenges.

Table: Key Research Areas in Quantitative Biology

Conclusion: The Future of Quantitative Biology

As technology continues to advance, quantitative biology will become even more important in solving real-world problems. Whether you’re interested in medicine, ecology, genetics, or any other field, quantitative biology offers exciting opportunities to make a meaningful impact on society . It’s a field that continues to grow, offering new ways to understand and influence the living world.

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Minimum Wages in the 21st Century

This chapter surveys the literature on the impact of minimum wages on low-wage labor markets. We describe and critically review the empirical methods in the new minimum wage literature, particularly those leveraging quasi-experimental variation. We provide a quantitative overview of the most recent evidence on the employment and wage effects of the policy, while also exploring emerging research on its impact on other margins, including amenities, other inputs (such as capital and high-skilled workers), firm entry and exit, output prices and demand, profits, and productivity. This approach allows us to present a comprehensive picture of how minimum wage policies affect firms, workers, and labor markets. We also review the evidence on the policy’s impact on wage inequality and income distribution. Finally, we discuss how these effects can vary depending on the economic context and the level of a country’s development.

We thank Akash Bhatt, Annie McGrew, Jon Piqueras, and Linda Wu for excellent research assistance. We are also grateful to David Card, Christian Dustmann, Larry Katz, Pat Kline, Thomas Lemieux, Alan Manning, Michael Reich, Liyang Sun and the participants of the Conference for the Handbook of Labor Economics, Volume 5 in Berlin for the valuable comments and insights. This research has been funded by the European Union’s Horizon 2020 research and innovation program (grant agreement number 949995). The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.

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Research: How Anxiety Shapes Men’s and Women’s Leadership Differently

• Ivona Hideg,
• Tanja Hentschel,

A study of 137 leaders and their direct reports during the early stages of Covid-19 shows that men were more likely to resort to abusive behavior during stressful moments.

One of the oldest erroneous gender stereotypes is that women are too emotional to be effective leaders, especially in uncertain times. Contrary to this belief, research on 137 leader-report pairs in Europe during the early stages of the Covid-19 pandemic indicates that women may actually be less likely to let their emotions negatively influence their leadership behaviors compared to men. During this time, women leaders reported higher anxiety levels but did not translate these emotions into abusive behaviors, unlike their male counterparts who exhibited more hostile supervision when anxious. Women typically engaged in family-supportive behaviors regardless of their emotional state. The research emphasizes the importance of recognizing the unique strengths women bring to leadership roles, especially their capacity to lead compassionately and prioritize others, but also notes that caring leadership behaviors are evaluated differently based on the gender of the leader. The study calls for more inclusive research that addresses diverse gender identities and cultural contexts.

One of the oldest and most persistent gender stereotypes is that women are too emotional. This stereotype hurts women’s leadership prospects as they are seen as less fit for leader roles because they are perceived to be more likely to make irrational, emotion-driven decisions than men.

• IH Ivona Hideg is Professor of Organisation Studies at the Saïd Business School, University of Oxford, and the Ann Brown Chair of Organization Studies in the Schulich School of Business, York University. Previously, she was a research fellow with the  Women and Public Policy Program at Harvard Kennedy School , she served as an Associate Editor at  Academy of Management Journal and is currently serving as Past Chair of the Canadian Society for Industrial & Organizational Psychology .  Her main program of research includes workplace equity, diversity and inclusion with a focus on gender, but she also examines issues surrounding race, language, and socio-economic background diversity.
• TH Tanja Hentschel is an Associate Professor of Organizational Behavior at the Amsterdam Business School, University of Amsterdam . She received her PhD from the Technical University of Munich and was a research fellow at the Department of Psychology, New York University . Tanja is an editorial board member of Journal of Business and Psychology . Her research focuses primarily on (gender) stereotypes, biases, leadership, and career choices.
• WS Winny Shen is an Associate Professor of Organization Studies at the Schulich School of Business, York University. She is currently an Associate Editor at Journal of Occupational Health Psychology and Journal of Business and Psychology . Her program of research focuses on issues of leadership, diversity and inclusion, and worker health and well-being, and has appeared in leading psychology and management journals.

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Are you in the American middle class? Find out with our income calculator

About half of U.S. adults (52%) lived in middle-income households in 2022, according to a Pew Research Center analysis of the most recent available government data. Roughly three-in-ten (28%) were in lower-income households and 19% were in upper-income households.

Our calculator below, updated with 2022 data, lets you find out which group you are in, and compares you with:

• Other adults in your metropolitan area
• U.S. adults overall
• U.S. adults similar to you in education, age, race or ethnicity, and marital status

Find more research about the U.S. middle class on our topic page .

Our latest analysis shows that the estimated share of adults who live in middle-income households varies widely across the 254 metropolitan areas we examined, from 42% in San Jose-Sunnyvale-Santa Clara, California, to 66% in Olympia-Lacey-Tumwater, Washington. The share of adults who live in lower-income households ranges from 16% in Bismarck, North Dakota, to 46% in Laredo, Texas. The share living in upper-income households is smallest in Muskegon-Norton Shores, Michigan (8%), and greatest in San Jose-Sunnyvale-Santa Clara, California (41%).

How the income calculator works

The calculator takes your household income and adjusts it for the size of your household. The income is revised upward for households that are below average in size and downward for those of above-average size. This way, each household’s income is made equivalent to the income of a three-person household. (Three is the whole number nearest to the  average size of a U.S. household , which was 2.5 people in 2023.)

Pew Research Center does not store or share any of the information you enter.

We use your size-adjusted household income and the cost of living in your area to determine your income tier. Middle-income households – those with an income that is two-thirds to double the U.S. median household income – had incomes ranging from about $56,600 to $169,800 in 2022. Lower-income households had incomes less than $56,600, and upper-income households had incomes greater than $169,800. (All figures are computed for three-person households, adjusted for the cost of living in a metropolitan area, and expressed in 2022 dollars.)

The following example illustrates how cost-of-living adjustment for a given area was calculated: Jackson, Tennessee, is a relatively inexpensive area, with a  price level in 2022 that was 13.0% less than the national average. The San Francisco-Oakland-Berkeley metropolitan area in California is one of the most expensive, with a price level that was 17.9% higher than the national average. Thus, to step over the national middle-class threshold of $56,600, a household in Jackson needs an income of only about $49,200, or 13.0% less than the national threshold. But a household in the San Francisco area needs an income of about $66,700, or 17.9% more than the U.S. threshold, to be considered middle class.

The income calculator encompasses 254 of 387 metropolitan areas in the United States, as defined by the Office of Management and Budget  . If you live outside of one of these 254 areas, the calculator reports the estimates for your state.

The second part of our calculator asks about your education, age, race or ethnicity, and marital status. This allows you to see how other adults who are similar to you demographically are distributed across lower-, middle- and upper-income tiers in the U.S. overall. It does not recompute your economic tier.

Note: This post and interactive calculator were originally published Dec. 9, 2015, and have been updated to reflect the Center’s new analysis.   Former Senior Researcher Rakesh Kochhar and former Research Analyst Jesse Bennett also contributed to this analysis.

The Center recently published an analysis of the distribution of the  American population across income tiers . In that analysis, the estimates of the overall shares in each income tier are slightly different, because it relies on a separate government data source and includes children as well as adults.

Pew Research Center designed this calculator as a way for users to find out, based on our analysis, where they appear in the distribution of U.S. adults by income tier, as well as how they compare with others who match their demographic profile.

The data underlying the calculator come from the 2022 American Community Survey (ACS). The ACS contains approximately 3 million records, or about 1% of the U.S. population.

In our analysis, “middle-income” Americans are adults whose annual household income is two-thirds to double the national median, after incomes have been adjusted for household size. Lower-income households have incomes less than two-thirds of the median, and upper-income households have incomes more than double the median. American adults refers to those ages 18 and older who reside in a household (as opposed to group quarters).

In 2022, the  national  middle-income range was about $56,600 to $169,800 annually for a household of three. Lower-income households had incomes less than $56,600, and upper-income households had incomes greater than $169,800. (Incomes are calculated in 2022 dollars.) The median adjusted household income used to derive this middle-income range is based on household heads, regardless of their age.

These income ranges vary with the cost of living in metropolitan areas and with household size. A household in a metropolitan area with a higher-than-average cost of living, or one with more than three people, needs more than $56,600 to be included in the middle-income tier. Households in less expensive areas or with fewer than three people need less than $56,600 to be considered middle income. Additional details on the methodology are available in our  earlier analyses .

• Income & Wages
• Middle Class

Richard Fry is a senior researcher focusing on economics and education at Pew Research Center .

Income inequality is greater among Chinese Americans than any other Asian origin group in the U.S.

Is college worth it, 7 facts about americans and taxes, methodology: 2023 focus groups of asian americans, 1 in 10: redefining the asian american dream (short film), most popular.

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ABOUT PEW RESEARCH CENTER  Pew Research Center is a nonpartisan, nonadvocacy fact tank that informs the public about the issues, attitudes and trends shaping the world. It does not take policy positions. The Center conducts public opinion polling, demographic research, computational social science research and other data-driven research. Pew Research Center is a subsidiary of The Pew Charitable Trusts , its primary funder.

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