Tuberculosis (TB) causes more deaths globally than any other infectious disease and is a top 10 cause of death worldwide. When it is detected early and effectively treated, TB is largely curable, but in 2017, around 1.6 million people died of tuberculosis, including 300,000 people living with HIV.[1] Early diagnosis of TB, including universal drug susceptibility testing and systematic screening of contacts and high-risk groups, is a pillar of the World Health Organization (WHO) "End TB" strategy.
The global effort against TB is currently being ramped up as the world enters a new era in the fight against TB. In May 2018, the WHO published the first Essential Diagnostics List, and in September 2018, the United Nations held its first ever High-Level Meeting on TB, galvanizing a global commitment to end the disease by 2030. The High-Level Meeting was the culmination of intensive joint work and collaboration that began with the WHO Global Ministerial Conference on Ending TB in Moscow in November 2017.
The next five years will be critical to ensure this momentum is translated into an accelerated response to End TB. The commitment from the UN High-Level Meeting to finding and treating 40 million people with TB, including 3.5 million children and 1.5 million people with drug-resistant TB, as well as providing preventive treatment to 30 million individuals by 2022, should help to focus efforts.
The WHO Global TB Programme has, for the last decade, led the development of guidelines for diagnostic tests that allow for early and rapid detection of TB and drug-resistant TB. However, sputum smear microscopy remains the primary diagnostic technique in many high TB burden settings, despite being a relatively insensitive test. Microscopy as the initial diagnostic test should be replaced with WHO-recommended rapid diagnostics described in this Special Collection.
This Special Collection, curated by Cochrane contributors, includes Cochrane Reviews from the Cochrane Infectious Diseases Group and other systematic reviews from other international teams. It highlights how Cochrane evidence contributes within a wider landscape of TB evidence and guidelines. The Collection also describes key WHO guidelines on TB diagnostics, and their underpinning systematic reviews, some which are published within the WHO Guideline itself.
This Special Collection covers:
· Early detection of TB
· Diagnosis of active TB disease and TB drug resistance
· Diagnosis of TB in people living with HIV
· Diagnosis of TB in children
· Diagnosis of latent TB infection.
You can browse the full list of Cochrane Reviews related to diagnosing TB, and you can read WHO's Compendium of WHO guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis.[2] You may also find it useful to refer to the Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines on diagnosis of tuberculosis, which are based on comprehensive evidence syntheses.[3]
In her recent book, Catching Breath: The Making and Unmaking of Tuberculosis, 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".[4] We hope this Special Collection of WHO guidelines and systematic reviews on TB diagnosis will enable anyone who is interested to find high-quality information easily and improve understanding of TB diagnosis. Then, we will find the way to unmake it. It's time.
This Special Collection is curated by Karen Steingart (Editor, Cochrane Infectious Diseases), Christopher Gilpin (Senior Scientist, Laboratories, Diagnostics & Drug Resistance Unit, Global TB Programme, World Health Organization), Mikashmi Kohli (Author, Cochrane Infectious Diseases), and Paul Garner (Co-ordinating Editor, Cochrane Infectious Diseases).
Early detection of TB
Early detection of TB helps reduce the severity of illness and minimize the spread of infection. The WHO, along with its partners, developed a guideline on screening for active TB. Key principles of the guideline are to prioritize risk groups and avoid indiscriminate mass screening. People with very high risk of TB or severe consequences of delayed TB diagnosis should be prioritized first. The WHO defines screening for active TB as “the systematic identification of people with suspected active TB, in a predetermined target group, using tests, examinations or other procedures that can be rapidly applied”.
Symptom‐ and chest‐radiography screening for active pulmonary tuberculosis in HIV‐negative adults and adults with unknown HIV status Free access
This Cochrane protocol outlines a review in progress, which will assess the sensitivity and specificity 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 microbiologically-confirmed active pulmonary TB in HIV-negative people and people with unknown HIV status considered for TB screening. A report from some initial analyses of these studies was used in the development of a WHO guideline: Systematic screening for active tuberculosis: principles and recommendations.
Diagnosis of active TB disease and TB drug resistance
Rapid, accurate, and accessible diagnostic tests provide obvious benefits for patients (earlier diagnosis and the opportunity to begin earlier, appropriate treatment) and for public health (opportunities to interrupt TB transmission), especially in countries with a high TB burden.
Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults Open access
The Xpert MTB/RIF assay is a rapid, automated, nucleic acid amplification test. It is the only WHO-recommended diagnostic test that simultaneously detects TB and rifampicin resistance, in persons with signs and symptoms of TB, and it is suitable for use at lower levels of the health system. This Cochrane Review assessed the diagnostic accuracy of Xpert MTB/RIF for active pulmonary TB in adults. This work is associated with the WHO guideline Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children.
Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study
This diagnostic accuracy study comparing Xpert MTB/RIF Ultra (Ultra), the newest generation of the test, with Xpert MTB/RIF, informed the WHO Technical Consultation. The study found Ultra to be non-inferior to Xpert MTB/RIF for the detection of TB and rifampicin resistance. This means that Ultra is at least as good as Xpert MTB/RIF. Ultra had higher sensitivity than Xpert MTB/RIF, in particular in smear-negative, culture-positive specimens and in specimens from HIV-positive patients. However, the increase in sensitivity was accompanied by a decrease in specificity. Ultra and Xpert MTB/RIF had similar accuracy for rifampicin resistance. The current WHO recommendations for the use of Xpert MTB/RIF now also apply to the use of Ultra as the initial diagnostic test for all adults and children with signs and symptoms of TB and in the testing of selected extrapulmonary specimens (cerebrospinal fluid, lymph nodes, and tissue specimens). See: WHO Meeting Report of a Technical Expert Consultation: non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF.
Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis
Extrapulmonary TB accounts for 15% to 20% of TB cases, but the percentage is increasing. This review assessed the diagnostic accuracy of Xpert MTB/RIF for detection of extrapulmonary TB. This review informed the WHO recommendations on the use of Xpert MTB/RIF in the testing of selected extrapulmonary specimens (cerebrospinal fluid, lymph nodes, and tissue specimens). See Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children and WHO Meeting Report of a Technical Expert Consultation: non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF.
Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance Open access
This Cochrane Review assessed the diagnostic accuracy of Xpert MTB/RIF in extrapulmonary specimens and included eight forms of extrapulmonary TB: tuberculous meningitis; pleural TB; lymph node TB; bone or joint TB; genitourinary TB; peritoneal TB, pericardial TB; and disseminated TB. Earlier versions of this review were used by the Indian Government's Revised National Tuberculosis Control Program in drawing up national guidelines for detection and management of extrapulmonary tuberculosis: Index-TB Guidelines: guidelines for extra-pulmonary tuberculosis for India.[5]
Accuracy of line probe assays for the diagnosis of pulmonary and multidrug-resistant tuberculosis: a systematic review and meta-analysis
Line probe assays are rapid molecular diagnostic tests for detecting TB and TB drug resistance. Owing to their complexity, line probe assays are used in reference and regional laboratories and take longer to run than the Xpert MTB/RIF assay. However, unlike Xpert MTB/RIF, which only detects rifampicin resistance, these assays have the ability to detect isoniazid resistance in addition to rifampicin resistance. Rifampicin and isoniazid are two of the most effective and widely-used anti-TB drugs that form part of the standardized first-line regimen for drug-susceptible TB. This review assessed the diagnostic accuracy of line probe assays for detection of TB and resistance to rifampicin and isoniazid, and it informed a WHO process to develop updated guidelines on the use of these tests: The use of molecular line probe assays for the detection of resistance to isoniazid and rifampicin.
GenoType® MTBDRsl assay for resistance to second‐line anti‐tuberculosis drugs Open access
People with drug-resistant TB require second-line TB drugs that, compared with first-line TB drugs, must be taken for longer and may be associated with more harms. Detecting TB drug resistance quickly is important for improving health, reducing deaths, and decreasing the spread of drug-resistant TB. Genotype MTBDRsl is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs in Mycobacterium tuberculosis complex. MTBDRslbelongs to a category of molecular genetic tests called line probe assays. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. This updated review informed a WHO process to develop updated guidelines for using MTBDRsl: The use of molecular line probe assays for the detection of resistance to second-line anti-tuberculosis drugs.
Commercial serological tests, which detect antibodies against Mycobacterium tuberculosis in the blood, could provide a way to diagnose TB in resource-limited countries. There has been uncertainty, however, about the accuracy of these tests. This review assessed the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB, and is associated with the WHO guideline on Commercial serodiagnostic tests for diagnosis of tuberculosis.
A systematic review of biomarkers to detect active tuberculosis
This review, including 443 studies, summarizes evidence on proposed biomarkers and biosignatures. Please note, this content is not Open Access. Supporting data can be found at Bm2Dx: The Biomarker Database.
Diagnosis of TB in people living with HIV
Globally in 2017, an estimated 10 million people developed TB disease, including an estimated 920,000 people living with HIV.[1] TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV, despite increased access to antiretroviral therapy.[6] According to the WHO, around 50% of all people with HIV-associated TB did not reach care. Reducing deaths in HIV-positive people will require new, sensitive, point-of-care tests, which can be applied in the community and in primary healthcare facilities.
Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies
This review aimed at identifying a standardized TB screening rule for use with HIV-positive people living in resource-limited settings. The rule would distinguish people who are unlikely to have TB from those who require further evaluation for TB disease. The related WHO guideline is Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.
Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV‐positive adults Open access
Non-sputum-based point-of-care TB tests are highly desirable to narrow the diagnostic gap and ensure timely treatment. A urine specimen is easy to collect and store, and lacks the infection control risks associated with collection of a sputum specimen. The urine-based lateral flow lipoarabinomannan (LF-LAM) assay Alere LAM is a commercially available point-of-care test for active TB. This Cochrane Review assessed the diagnostic accuracy of urine Alere LAM assay for active TB disease (pulmonary and extrapulmonary TB) in people living with HIV. Since 2015, new evidence has emerged that might justify the use of the test in a broader group of people living with HIV. The WHO has initiated an updated review of the evidence and associated guidance. Current WHO guideline: The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV.
Symptom screening for active tuberculosis in pregnant women living with HIV Free access
This protocol outlines a systematic review to assess the accuracy of the four-symptom screen (cough, fever, night sweats, or weight loss) for identifying active TB in pregnant women living with HIV who are screened in an outpatient or community setting.
Diagnosis of TB in children
According to the WHO, globally in 2017, an estimated one million children under 15 years of age developed TB and 230,000 children (including children with HIV-associated TB) died from the disease,[1] although many believe these estimates are too low. The diagnosis of TB in children relies on clinical, epidemiological, radiological, and laboratory information. Child TB disease is typically paucibacillary (TB disease caused by a smaller number of bacteria) and young children cannot voluntarily produce sputum specimens. Therefore, even under ideal clinical and laboratory conditions, only 30% to 40% of children with TB are microbiologically confirmed. Childhood TB needs to be lifted "out of the shadows".[7] New TB tests are urgently needed for children.
Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis
This review assessed the diagnostic accuracy of Xpert MTB/RIF assay compared with microscopy for pulmonary TB in children and informed the WHO recommendations on the use of Xpert MTB/RIF in children. The related WHO guidelines are Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and childrenand WHO Meeting Report of a Technical Expert Consultation: non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF.
Diagnosis of latent TB Infection
Around one-fourth to one-third of the world’s population is infected with Mycobacterium tuberculosis, though most people do not feel ill, do not have signs or symptoms of TB disease, and cannot spread TB to others. The related WHO guideline is: Latent TB infection: updated and consolidated guidelines for programmatic management. The guideline defines latent TB infection as "a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB". People with TB infection have a 5% to 15% risk of progressing to active TB disease in their lifetime, with the risk of progression being highest in the first two years after acquiring TB infection. The key principle in developing these updated guidelines was "individual benefit should outweigh risk as the mainstay of recommendations on latent TB infection testing and treatment".
Sensitivity and specificity of WHO's recommended four-symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis
This review investigated the use of the WHO-recommended four-symptom screen, specifically for persons on antiretroviral therapy.
Predictive value of interferon-gamma release assays for incident active tuberculosis: a systematic review and meta-analysis
This review aimed to assess whether interferon-gamma release assays can predict the development of active TB and whether the ability of interferon-gamma release assays for prediction was higher than that of the tuberculin skin test.
Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis
This review aimed to assess whether the use of interferon-gamma release assays could improve the identification of HIV-positive people who could benefit from isoniazid preventive therapy.
References
1. World Health Organization. Global tuberculosis report 2018. www.who.int/tb/publications/global_report (accessed 15 March 2019).
2. World Health Organization. Compendium of WHO guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis. 2nd Edition. WHO: 2018. Available at www.who.int/tb/publications/Compendium_WHO_guidelines_TB_2017
3. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children. Clinical Infectious Diseases 2017;64:111-5. https://doi.org/10.1093/cid/ciw778
4. Lougheed K. Catching Breath: The Making and Unmaking of Tuberculosis. London (UK): Bloomsbury Publishing, 2017.
5. Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A, et al. Index-TB guidelines: guidelines on extrapulmonary tuberculosis for India. Indian Journal of Medical Research 207;145(4):448-63. www.ncbi.nlm.nih.gov/pmc/articles/PMC5663158
6. 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. https://doi.org/10.7448/IAS.19.1.20714
7. Goosby E. Out of the shadows: shining a light on children with tuberculosis. International Journal of Tuberculosis and Lung Disease 2015;19 Suppl 1:S1-2. https://doi.org/10.5588/ijtld.15.0411
Acknowledgements
Karen Steingart, Christopher Gilpin, Mikashmi Kohli, and Paul Garner drafted the text and selected the reviews. 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.
Image credit
The Global Fund/Jonas Gratzer
Contact
Cochrane Editorial and Methods Department (emd@cochrane.org)
This article was first published on the Cochrane Library website