Tuberculosis: Laboratory Support of Screening and Diagnosis

Although tuberculosis (TB) is treatable, the disease remains a common cause of morbidity and mortality in many regions of the world, including parts of the United States.1,2 TB may be latent (noninfectious and asymptomatic) or active (infectious and symptomatic) and can progress from latent to active TB.1,2 Notably, latest World Health Organization (WHO) guidelines updated the nomenclature for latent TB to “TB infection” and active TB to “TB disease.”3

Risk factors for TB have been identified (see Sidebar),1 and professional organizations have provided guidelines regarding screening for TB infection.

This article discusses TB, risk factors, and screening guidelines. It also discusses the traditional tuberculin skin test (TST) and more recently developed TB blood tests, as well as the indications for each type of test.

Tuberculosis infection and disease
Tuberculosis is a highly transmittable respiratory infection caused by inhalation of droplets containing the bacterium Mycobacterium tuberculosis.1,2 Approximately 30% of people exposed to M tuberculosis (close contact with a person who has TB disease) develop TB (infection or disease).1,2,4

The prevalence of TB infection in the United States is about 5% overall5 but is much higher in certain populations (eg, 23%-88% among incarcerated persons and 19%-80% among people without homes).5 States with the highest TB case rates (TB disease and TB infection) include Alaska, California, the District of Columbia, Maryland, Texas, New Jersey, and New York.6

Persons with TB infection are asymptomatic and not infectious. Overall, only about 5% to 10% of persons with untreated TB infection will develop TB disease.1 However, the rate is much higher in persons with immunosuppression (eg, due to medications or diseases such as HIV infection).1

TB disease can cause symptoms including cough with or without blood-tinged sputum, general malaise, and intermittent fever.1,2 Although TB infection begins in the lungs, it can spread to the kidneys, spine, and brain. Untreated TB disease can be fatal.1,2,4 Notably, about 80% of TB disease cases progress from TB infection (20% of persons exposed to TB progress directly to TB disease).1

Importantly, treatment of TB infection can prevent or reduce disease progression, transmission, and TB-related morbidity and mortality.1,2 The following sections discuss current screening guidelines for TB infection.
United States Preventive Services Task Force guidelines
In 2016, the United States Preventive Services Task Force (USPSTF) recommended screening for TB infection in asymptomatic adults at increased risk for TB (see Sidebar).5 The recommendations do not apply to symptomatic adults or to children and adolescents. Screening can be done just once if the person has a low risk of future exposure or can be done annually if there is a continuing risk of exposure. Either a TST or a TB blood test can be used (described below). At the time of writing, the USPSTF was in the process of updating their screening guidelines.7

Centers for Disease Control and Prevention guidelines
The Centers for Disease Control and Prevention (CDC) recommends screening for TB infection in persons who are (1) at high risk for exposure to, or infection with, M tuberculosis; and (2) at high risk for developing TB disease once infected with M tuberculosis (see Sidebar).1

The CDC guidelines “encourage” healthcare providers to use a TB blood test to screen for TB infection; a blood test is preferred for persons who have received a bacille Calmette-Guérin (BCG) vaccination and those who are unlikely to return for a follow-up appointment (eg, persons living in a homeless shelter).1 On the other hand, a TST is preferred for children younger than 5 years of age.1 Notably, these guidelines for children are slightly different than the recommendations of the American Academy of Pediatrics (below).8

The CDC is responsible for developing TB screening requirements for people applying for United States permanent residence.9 They require that all applicants ≥2 years of age have a TB blood test; a TST is not acceptable.9 Persons with signs or symptoms of TB disease or known HIV infection require a chest x-ray.9
WHO guidelines
The WHO screening guidelines are similar to those of the CDC and USPSTF but include systematic screening for TB disease in the general population in areas with an estimated TB prevalence of 0.5% or higher.3 TST and TB blood tests are both recommended by the WHO as options to screen for TB infection.10

American Academy of Pediatrics
While not published as formal guidelines, the American Academy of Pediatrics suggests that a TST or a TB blood test is appropriate for children who (1) have a risk factor for TB infection or are at risk for progressing to disease (see Sidebar), (2) are suspected of having TB disease, or (3) have an immunosuppressive disease or are beginning an immunosuppressive therapy.8 Both the TST and TB blood test are acceptable; however, a TST is generally preferred in children <2 years of age; a TB blood test is preferred in children ≥2 years old, especially those who have received the BCG vaccine.8
Screening test selection: TST and TB blood test
Three tests are currently approved by the United States Food and Drug Administration (FDA) for TB infection screening: the traditional TST and 2 blood tests (QuantiFERON®-TB Gold Plus [also FDA cleared] and T-SPOT®.TB).1,11,12

The TST identifies M tuberculosis infection by subcutaneous injection of tuberculin (M tuberculosis antigens).1,13 The area of injection is then examined 48 hours later, and a positive result is indicated by a raised, erythematous, circular area.1,13 Examination of the injection site for a positive or negative result, however, is partially subjective and is dependent on the experience of the observer.1,13

The TB blood tests are interferon-gamma release assays (IGRAs) and are highly sensitive and specific for identifying TB infection.11,12 In brief, T cells become sensitized after exposure to M tuberculosis, and in vitro stimulation of sensitized T cells with high-specificity M tuberculosis antigens causes them to release interferon-gamma.11,12 The presence of interferon-gamma in a blood specimen, determined by objective laboratory methods, indicates infection with M tuberculosis.11,12 Notably, T-SPOT.TB is approved by the FDA for children as young as 2 years old.12

Guidelines recommend using either a TST or a TB blood test to screen for TB infection. A TB blood test has advantages over the TST in some settings; however, a TST is preferred in children under 5 years of age. A comparison of the 2 methods is shown in the Table.
TB Skin Test1,3 TB Blood Test1,3
Tuberculin injected into skin Blood specimen collected from vein
Subjective measurement of test result Objective measurement of test result
Requires 2 visits to the doctor's office Requires 1 visit to the doctor's office
Preferred for children under 5 yearsa
  • Preferred for BCG vaccinated peoplea
  • Preferred for people who cannot, or are unlikely to, return to have a skin test reada
Affected by booster phenomenon: annual or serial testing requires 2 baseline tests if first is negative No booster phenomenon: annual or serial testing requires only 1 baseline test
Can be used during pregnancy Can be used during pregnancy
Can be used in newborns Not FDA approved for children less than 2 years of age
BCG, bacille Calmette-Guérin, a TB vaccine commonly used outside the United States.
a The World Health Organization recommends a TST for children less than 5 years old, while a TB blood test is recommended for persons who have received a BCG vaccination and for people who are unlikely to return for examination of TST results.3

Routine use of both test types (TST and IGRA) in the same person is not generally recommended but can be useful in certain situations (eg, when the initial test is negative but the risk or clinical suspicion of TB infection is high).1,10,13 Importantly, a TST does not cause a false-positive result if a TB blood test is subsequently performed.14

TB disease or TB infection
Neither the TST nor TB blood test can distinguish a TB infection from TB disease.1,4 Diagnosis of TB disease typically requires a medical history and examination by a healthcare provider, and a chest x-ray and sputum examination for acid fast bacilli and sputum culture.1,4

Individuals at increased risk for TB infection and TB disease

Persons at high risk for exposure to, or infection with, M tuberculosis include1
  • Contacts of people known or presumed to have infectious TB disease
  • People who were born in or who frequently travel to countries where TB disease is common, including Mexico, the Philippines, Vietnam, India, China, Haiti, and Guatemala
  • People who currently live or used to live in large group settings where TB is more common, such as homeless shelters, prisons, jails, or nursing homes
  • Healthcare workers who serve patients with TB disease

Persons at high risk for developing TB disease after infection with M tuberculosis include1
  • People living with HIV
  • Children younger than 5 years of age
  • People recently infected with M tuberculosis (within the last 2 years)
  • People receiving immunosuppressive therapy
  • People with a chronic disease, such as diabetes mellitus
  • Injection drug users
How the laboratory can help

Quest Diagnostics offers blood tests for the detection of TB infection, as well as tests for the diagnosis and management of TB and other infectious diseases. Additional information on tests for TB and other infectious diseases is available through the links below:

Please complete the form below to recieve the latest updates.

References
  1. Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. Centers for Disease Control and Prevention; 2020. Accessed May 16, 2022. https://www.cdc.gov/tb/publications/ltbi/pdf/LTBIbooklet508.pdf
  2. Tuberculosis: key facts. World Health Organization. Published October 14, 2021. Accessed May 13, 2022. https://www.who.int/news-room/fact-sheets/detail/tuberculosis
  3. WHO consolidated guidelines on tuberculosis: module 2: screening – systematic screening for tuberculosis disease. World Health Organization. Published March 22, 2021. Accessed May 13, 2022. https://apps.who.int/iris/bitstream/handle/10665/340255/9789240022676-eng.pdf
  4. Lewinsohn DM, Leonard MK, LoBue PA, 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. Clin Infect Dis. 2017;64(2):111-115. doi:10.1093/cid/ciw778
  5. US Preventive Services Task Force. Screening for latent tuberculosis infection in adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316(9):962-969. doi:10.1001/jama.2016.11046
  6. Data and statistics. Centers for Disease Control and Prevention. Reviewed March 24, 2022. Accessed May 23, 2022. https://www.cdc.gov/tb/statistics/default.htm
  7. Latent tuberculosis infection in adults: screening. US Preventive Services Task Force. Published June 10, 2021. Accessed May 13, 2022. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-research-plan/latent-tuberculosis-infection-adults
  8. Nolt D, Starke JR. Tuberculosis infection in children and adolescents: testing and treatment. Pediatrics. 2021;148(6):e2021054663. doi:10.1542/peds.2021-054663
  9. Tuberculosis technical instructions for civil surgeons. Centers for Disease Control and Prevention. Reviewed March 15, 2021. Accessed May 23, 2022. https://www.cdc.gov/immigrantrefugeehealth/civil-surgeons/tuberculosis.html
  10. Use of alternative interferon-gamma release assays for the diagnosis of TB infection: WHO policy statement. World Health Organization. 2022. Accessed May 19, 2022. https://apps.who.int/iris/rest/bitstreams/1406898/retrieve
  11. QuantiFERON®-TB Gold Plus (QFT®-Plus). Package insert. Qiagen; 2021.
  12. T-SPOT®.TB. Package insert. Oxford Immunotec; 2019.
  13. Mayanja-Kizza H, Katamba A. Interferon-γ release assays or tuberculin skin test for latent tuberculosis infection? Lancet Infect Dis. 2020;20(12):1359-1360. doi:10.1016/S1473-3099(20)30363-7
  14. Leyten EMS, Prins C, Bossink AWJ, et al. Effect of tuberculin skin testing on a Mycobacterium tuberculosis-specific interferon-g assay. Eur Respir J. 2007;29(6):1212-1216. doi:10.1183/09031936.00117506
Content reviewed 7/2022

Models used for illustrative purposes.
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