(First published on 20 March 2019; updated on 24 March 2020, 23 March 2021, 23 March 2022 on the Cochrane Library, and updated 7 November 2022 on the CIDG website)
Tuberculosis continues to cause great suffering worldwide. It is expected that once the data are compiled, tuberculosis will rank second as a cause of death from a single infectious agent after COVID-19. (1) People with tuberculosis are often poor, face stigma and discrimination, and have limited access to health care. Many new tuberculosis cases are associated with five risk factors: undernutrition, HIV infection, alcohol use disorders, smoking, and diabetes.
According to the World Health Organization (WHO), in 2021: (1)
- an estimated 10.6 million people developed tuberculosis, an increase of 4.5% from 2020;
- an estimated 1.6 million people died from tuberculosis, including 187,000 people with HIV;
- of all tuberculosis cases, 6 million (56.5%) were in men, 3.4 million (33.5%) in women, and 1.2 million (11%) in children;
- an estimated 450,000 people developed rifampicin-resistant tuberculosis, an increase of 3.1% from 2020. Rifampicin is the most effective first-line tuberculosis medicine;
- an estimated 66 million lives were saved through tuberculosis diagnosis and treatment between 2000 and 2020.
The COVID-19 pandemic has had a disastrous effect on all aspects of global health, in particular on tuberculosis diagnosis and treatment In 2021, there was a considerable decrease in the number of people newly diagnosed with tuberculosis and reported to national programmes (notified cases) compared with 2019 owing to disruptions in access to tuberculosis services. (1, 2) The WHO END TB Strategy is a 20-year strategy devised to end the global tuberculosis epidemic. (3) A vital part of this strategy is early diagnosis of tuberculosis, including universal drug susceptibility testing and systematic screening of contacts and high-risk groups. In 2018, the WHO published the first Essential Diagnostics List, and the United Nations (UN) held its first ever High-Level Meeting on ending TB, galvanizing a global commitment to end the disease by 2030. The commitment from the UN High-Level Meeting calls for finding and treating 40 million people with tuberculosis, including 3.5 million children and 1.5 million people with drug-resistant tuberculosis, as well as providing preventive treatment to 30 million individuals by 2022.
The WHO Global Tuberculosis Programme has led the development of guidelines for diagnostic tests that allow for screening for and rapid detection of tuberculosis and drug-resistant tuberculosis. These guidelines were developed using the GRADE approach for rating the certainty of a body of evidence and translating evidence into recommendations. (4-6)
This Special Collection includes selected systematic reviews from Cochrane Infectious Diseases and other international teams that underpin three WHO consolidated guidelines on systematic screening for tuberculosis disease and on rapid diagnostics for tuberculosis detection. (7-9)
Kathryn Lougheed writes, “Untangling ourselves from this foe is not a simple task. How do you kill something that’s spent millions of generations finding ways not to be killed? … Because if we can understand the makings of TB, then maybe we can find a way to unmake it.” (10) We hope this Special Collection of systematic reviews will enable anyone who is interested to find high-quality information on tests for tuberculosis. Then, we will find the way to unmake it.
About this Special Collection
The Special Collection was curated by Mikashmi Kohli, Adrienne Shapiro, and Karen Steingart (Cochrane Infectious Diseases). Nazir Ismail, Alexei Korobitsyn, and Cecily Miller (WHO Global Tuberculosis Programme) contributed to previous versions.
Systematic screening for tuberculosis disease
There are millions of people who remain undiagnosed with tuberculosis for a variety of reasons. Systematic screening for tuberculosis disease is a strategy to find the ‘missing millions’. Systematic screening is defined as “the systematic identification of people at risk for TB disease, in a predetermined target group, by assessing symptoms and using tests, examinations or other procedures that can be applied rapidly. For those who screen positive, the diagnosis needs to be established by one or several diagnostic tests and additional clinical assessments. This term is sometimes used interchangeably with ‘active tuberculosis case-finding’. It should be distinguished from testing for TB infection (with a TB skin test or interferon-g release assay).” (7) Systematic screening for tuberculosis disease can be done for the entire population or targeted at selected risk groups who may be at higher risk of being exposed to tuberculosis, developing tuberculosis disease, or experiencing poor outcomes of the disease.
This Cochrane Review aims to determine the accuracy of questioning people about the presence of one or more symptoms, chest X-ray abnormalities, and various combinations of symptoms and chest X-ray abnormalities for detecting bacteriologically-confirmed pulmonary tuberculosis in HIV-negative people and people with unknown HIV status considered for tuberculosis screening.
This Cochrane Review aims to determine the accuracy of one or more tuberculosis symptoms, chest X-ray findings, and Xpert MTB/RIF for screening for pulmonary tuberculosis in children in groups considered at high-risk for tuberculosis, such as contacts of an individual with tuberculosis disease and children with HIV, and children accessing health care in inpatient or outpatient settings. The authors did not identify any studies evaluating screening with Xpert Ultra. Associated Cochrane Clinical Answers: What is the accuracy of symptom screening for active pulmonary tuberculosis (TB) in children with HIV under five years of age? and What is the accuracy of the WHO four‐symptom screen for active pulmonary tuberculosis (TB) in children with HIV?
This individual participant data meta-analysis assesses the accuracy of screening approaches for people with HIV in the outpatient setting. The authors included cohorts and randomized trials screening adult and adolescent participants irrespective of signs and symptoms of tuberculosis. The primary objective was to compare the sensitivity and specificity of the WHO four-question symptom screen to other screening approaches including C-reactive protein, and combination algorithms including one or more of chest X-ray, symptom screen, C-reactive protein, and Xpert. Subgroups include people on antiretroviral therapy.
This Cochrane Review aimed to estimate the accuracy of Xpert MTB/RIF or Xpert Ultra for screening for pulmonary tuberculosis and rifampicin resistance in people who may or may not have tuberculosis symptoms. The authors identified studies that evaluated the tests in people with HIV, household contacts of a person with tuberculosis, people residing in prisons, and miners, groups considered at high-risk for tuberculosis. The authors did not identify any studies that evaluated the tests in people with diabetes mellitus or in the general population. The settings were community settings or healthcare settings attended for reasons unrelated to tuberculosis. This is a different approach than diagnosing tuberculosis disease in people with signs and symptoms of tuberculosis who seek care in health facilities. Associated Cochrane Clinical Answer: For high‐risk adults, what is the accuracy of Xpert MTB/RIF for the diagnosis of pulmonary tuberculosis (TB) regardless of signs and symptoms?
Computer-aided detection (CAD) software packages have recently been developed to automate the interpretation of digital chest X-ray images and generate a numerical score indicating the likelihood of tuberculosis. This systematic review aims to determine the accuracy of several commercially available CAD technologies for tuberculosis and provides evidence for use of CAD as a triage test. Triage refers to use of the test in persons with symptoms of tuberculosis to exclude a diagnosis of tuberculosis and identify individuals who do not require further diagnostic testing for tuberculosis. This is a different approach from using a test result to diagnose tuberculosis. The authors used multiple approaches to select threshold scores for assessing sensitivity and specificity of each CAD program.
This systematic review assesses the effect of community interventions for tuberculosis screening on outcomes at the population level, including tuberculosis case notification, prevalence, and incidence. This review extends a 2013 systematic review evaluating these same outcomes, integrating evidence from two interval large-scale studies of high-intensity tuberculosis screening among household contacts of people with tuberculosis and multi-country community cluster tuberculosis screening.
In contrast to outcomes of tuberculosis screening that are measured at the population level, such as the prevalence and incidence of tuberculosis, people-important outcomes are those that are measured at the individual level. This systematic review assesses the effect of systematic tuberculosis screening on key people-important outcomes, including time to diagnosis of tuberculosis, treatment outcomes in people with tuberculosis who were identified through screening, mortality, and patient costs. The authors identified studies conducted in selected risk groups and in the general population in settings in South and Southeast Asia and Africa to estimate these key outcomes.
Active case-finding interventions for tuberculosis have a direct effect on identifying people with undiagnosed tuberculosis, but may also have an indirect effect on more widespread tuberculosis case detection. This systematic review assesses the indirect effects of active case-finding by comparing routine case notification rates in communities with and without active case-finding interventions, and comparing the effect of active case-finding interventions on tuberculosis test-seeking behaviour in communities with and without active case-finding interventions.
Diagnosing tuberculosis disease and drug resistance
Rapid, accurate, and accessible diagnostic tests help people with tuberculosis (through earlier diagnosis and the opportunity to begin earlier, appropriate treatment) and public health (through opportunities to interrupt tuberculosis transmission). These benefits are particularly valuable in countries with a high tuberculosis burden. However, sputum smear microscopy remains the primary diagnostic method in many high tuberculosis burden settings, despite being a relatively insensitive test. Microscopy as the initial diagnostic test should be replaced with the WHO-recommended rapid diagnostics described in this Special Collection and the related WHO guidelines.
With the increase of diagnostic tests that have similar purposes, the WHO has introduced a class-based approach to recommendations. Instead of recommending individual products, the WHO now recommends a class that represents a group of products with similar characteristics and performance. For example, the class of molecular WHO-recommended rapid diagnostic tests (mWRDs) includes Xpert MTB/RIF, Xpert MTB/RIF Ultra, Truenat MTB, MTB Plus, and Truenat MTB-RIF Dx, which diagnose both tuberculosis and rifampicin resistance.
In 2021, an estimated 10.6 million people developed tuberculosis disease. Among all tuberculosis cases, 6.7% were among people with HIV. (1) Compared to people without HIV, people with HIV are 18 times more likely to develop tuberculosis disease. (1) Tuberculosis remains a leading cause of hospitalization and in-hospital death among adults and children with HIV, despite increased access to antiretroviral therapy. (11) Reducing deaths of HIV-positive people will require new, sensitive, point-of-care tests, which can be applied in the community and in primary healthcare facilities.
Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis, and are suitable for use in peripheral laboratories. This Cochrane Review compares the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF. Xpert Ultra includes a new result category ‘trace’ with a lower limit of detection for Mycobacterium tuberculosis than Xpert MTB/RIF. This review update extends evidence from the 2019 version and includes new evidence on Xpert Ultra and trace-positive results. Associated Cochrane Clinical Answers: How do Xpert MTB/RIF and Xpert Ultra compare for accuracy in detecting pulmonary tuberculosis (TB) in adults with presumptive pulmonary TB? and How do Xpert MTB/RIF and Xpert Ultra compare for accuracy in detecting rifampicin resistance in adults with presumptive pulmonary tuberculosis (TB)?
In 2021, an estimated 1.2 million children became ill with tuberculosis. (1) Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular WHO-recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. This Cochrane Review is an update to a review first published in 2020, and aims to determine the diagnostic accuracy of Xpert Ultra for detecting pulmonary tuberculosis, tuberculosis meningitis, lymph node tuberculosis, and rifampicin resistance in children with presumed tuberculosis. This review update includes new evidence on Xpert Ultra on sputum, gastric aspirate, stool, and nasopharyngeal aspirate. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents. Associated Cochrane Clinical Answer: What is the accuracy of Xpert Ultra for diagnosing pulmonary tuberculosis (TB) in children, using culture as the reference standard?
Extrapulmonary tuberculosis accounts for a far lower proportion of tuberculosis than pulmonary tuberculosis, but the proportion of extrapulmonary tuberculosis remains underdiagnosed and underreported. This Cochrane Review aims to determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra in extrapulmonary specimens and includes eight forms of extrapulmonary tuberculosis: tuberculous meningitis; pleural tuberculosis; lymph node tuberculosis; bone or joint tuberculosis; genitourinary tuberculosis; peritoneal tuberculosis; pericardial tuberculosis; and disseminated tuberculosis. This review update includes new evidence on Xpert Ultra. Associated Cochrane Clinical Answers: With culture used as the reference standard, what is the accuracy of the Xpert® MTB/RIF assay for detecting extrapulmonary tuberculosis (TB) using cerebrospinal fluid, pleural fluid, lymph node aspirate, or urine? and What is the accuracy of the Xpert® MTB/RIF assay for detecting rifampicin resistance?
The WHO's End TB Strategy stresses universal access to drug susceptibility testing (DST). DST determines whether Mycobacterium tuberculosis bacteria are susceptible or resistant to drugs. In people with rifampicin-resistant tuberculosis it is critically important to perform additional resistance testing to at least isoniazid and the fluoroquinolones in order to guide treatment decisions. Xpert MTB/XDR is a rapid nucleic acid amplification test for detection of tuberculosis and drug resistance in one test suitable for use in peripheral and intermediate level laboratories. This Cochrane Review aims to determine the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people with tuberculosis detected by Xpert MTB/XDR.
Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need. This Cochrane Review aims to synthesize end‐user and professional user perspectives and experiences with low‐complexity nucleic acid amplification tests for detecting tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity.
Tuberculosis is particularly difficult to diagnose in people with HIV, in part because it is often challenging to produce sputum for diagnosis. The biomarker-based lateral flow lipoarabinomannan assay (LF-LAM) test (Alere Determine TB LAM Ag, USA) is recommended by the WHO to help detect tuberculosis in people with HIV. This review update asks if the new evidence justifies the use of LF‐LAM in a broader group of people, and informed updated WHO guidelines on the use of LF‐LAM. This Cochrane Review aims to determine the diagnostic accuracy of LF‐LAM for diagnosing tuberculosis among HIV‐positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV‐positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms). Associated Cochrane Clinical Answers: What is the accuracy of lateral flow urine lipoarabinomannan for detecting tuberculosis (TB) in symptomatic HIV-positive adults? and What is the accuracy of lateral flow urine lipoarabinomannan for detecting tuberculosis (TB) in unselected HIV-positive adults (symptomatic or asymptomatic)?
People with HIV have higher rates of extrapulmonary tuberculosis, and diagnosis is often limited to imaging results. Ultrasound is an imaging test that is widely used as a diagnostic tool in people suspected of having abdominal tuberculosis or disseminated tuberculosis with abdominal involvement. This Cochrane Review aims to determine the diagnostic accuracy of ultrasound examination of the abdomen (abdominal ultrasound) for diagnosing tuberculosis in people with HIV suspected of having tuberculosis in the abdomen or widespread tuberculosis (disseminated tuberculosis) involving the abdomen. Associated Cochrane Clinical Answer: What is the accuracy of abdominal ultrasound (US) for the diagnosis of abdominal tuberculosis (TB) in people with HIV?
Line probe assays are rapid strip-based molecular tests that detect mutations associated with drug resistance. These tests may be performed on a cultured isolate or a clinical specimen, which eliminates delays associated with culture-based detection of tuberculosis drug resistance. Owing to their complexity, line probe assays are most often used in central-level laboratories. This systematic review aims to determine the diagnostic accuracy of several line probe assays (GenoType MTBDRplus and NTM+MDRTB Detection Kit) for detecting tuberculosis and resistance to isoniazid and rifampicin (the two most effective first-line drugs used to treat tuberculosis).
People with drug-resistant tuberculosis require second-line tuberculosis drugs that, compared with first-line tuberculosis drugs, must be taken for longer periods of time and may be associated with more harms. This Cochrane Review update aims to determine the diagnostic accuracy of the line probe assay Genotype MTBDRsl for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs in M tuberculosis complex. Associated Cochrane Clinical Answers: What is the accuracy of GenoType® MTBDRsl version 1 assay for the detection of second-line injectable drug (SLID)-resistant tuberculosis (TB)? and What is the accuracy of GenoType® MTBDRsl version 1 assays for the detection of fluoroquinolone (FQ)-resistant tuberculosis (TB)?
This Cochrane Review assesses the impact of Xpert MTB/RIF testing on health outcomes in people being evaluated for tuberculosis. The authors concluded, “We were unable to confidently rule in or rule out the effect on all‐cause mortality of using Xpert MTB/RIF rather than smear microscopy. Xpert MTB/RIF probably reduces mortality among participants known to be infected with HIV.… Xpert MTB/RIF probably increases both the proportion of treated participants who had bacteriological confirmation, and the proportion with a laboratory‐confirmed diagnosis who were treated.” Of note, this review highlights the challenges of determining the effect on all-cause mortality of using Xpert MTB/RIF rather than smear microscopy. Associated Cochrane Clinical Answer: For people being investigated for tuberculosis (TB), is there RCT evidence that testing with Xpert MTB/RIF leads to improved outcomes versus smear microscopy?
Alere Determine TB LAM Ag is the only lateral flow lipoarabinomannan assay currently recommended by the WHO. This Cochrane Review assesses the effect of Alere Determine TB LAM Ag testing on death and other important health outcomes in people with HIV. The review found that in inpatient settings, the use of LF‐LAM as part of a tuberculosis diagnostic testing strategy likely reduces deaths and probably results in a slight increase in tuberculosis treatment initiation in people with HIV. In outpatient settings, the use of LF‐LAM testing as part of a tuberculosis diagnostic strategy may reduce deaths and may result in a large increase in tuberculosis treatment initiation in people with HIV. Associated Cochrane Clinical Answer: For adults living with HIV and suspected tuberculosis (TB), what are the effects of using lateral flow urine lipoarabinomannan (LF‐LAM) assay for clinical decision‐making?
1. World Health Organization. Global tuberculosis report 2022. Geneva: World Health Organization. https://www.who.int/teams/global-tuberculosis-programme/tb-reports. 2022.
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3. World Health Organization. The END TB Strategy. https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategy. 2015.
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9. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents. Geneva; World Health Organization; September 2022. https://www.who.int/publications/i/item/9789240046764. 2022.
10. Lougheed K. Catching Breath: The Making and Unmaking of Tuberculosis. London (UK): Bloomsbury Publishing; 2017.
11. Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, et al. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. Journal of the International AIDS Society. 2016;19(1):20714.
This publication is associated with the Research, Evidence and Development Initiative (READ-It) project. READ-It (project number 300342-104) is funded by UK aid from the UK government; however, the views expressed do not necessarily reflect the UK government’s official policies. We are grateful to Christopher Gilpin (Global Laboratory Coordinator, Migration Health Division, International Organization for Migration) for contributing to the initial version of this Special Collection.
The Global Fund/Jonas Gratzer