Tuberculosis screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]; Mashal Awais, M.D.[3]; Alejandro Lemor, M.D. [4]; Marjan Khan M.B.B.S.[5]

Tuberculosis (TB) screening is the risk-based identification of asymptomatic persons who may have Mycobacterium tuberculosis infection and who would benefit from further evaluation and treatment of latent tuberculosis infection (LTBI). Screening is performed using either the Mantoux tuberculin skin test (TST) or an interferon-gamma release assay (IGRA). Neither TST nor IGRA distinguishes LTBI from active TB disease, and neither test should be used to monitor response to treatment.^[1][2]

Screening should be targeted to persons at increased risk for TB infection or increased risk of progression from LTBI to active disease. Universal testing of low-risk populations is not recommended because the positive predictive value is poor when pretest probability is low, and false-positive results may lead to unnecessary radiography, follow-up testing, and treatment.^[3][1]

The United States Preventive Services Task Force recommends screening for LTBI in asymptomatic adults aged 18 years or older who are at increased risk for TB infection.^[3] The CDC and specialty guidelines also recommend testing selected children, contacts, healthcare personnel, and immunocompromised persons based on exposure risk and risk of progression.^[1][4]

Conditions such as diabetes mellitus, chronic kidney disease, low body weight, smoking, gastrectomy, and head or neck cancer increase risk of progression once infection is present, but they are not usually independent indications for LTBI testing without epidemiologic exposure risk.^[2]

Two test categories are used for LTBI screening: the TST and IGRAs. Both detect immune sensitization to M. tuberculosis antigens. Neither test can determine whether infection is latent or active.^[1][2]

The Mantoux tuberculin skin test is performed by intradermal injection of 0.1 mL of purified protein derivative (PPD; 5 tuberculin units) into the volar surface of the forearm. A properly placed test produces a 6-10 mm wheal. The result is read 48-72 hours later by measuring the transverse diameter of induration, not erythema, in millimeters.^[1][7]

The only absolute contraindication to TST is a prior severe reaction, such as necrosis, blistering, ulceration, or anaphylaxis, after a previous TST. TST is not contraindicated in pregnancy, infants, children, persons with HIV infection, or persons who received BCG vaccine.^[7]

• 
  Mantoux tuberculin skin test placement. Image from the CDC Public Health Image Library.
• 
  Tuberculin skin test reading. Image from the CDC Public Health Image Library.
• 
  Tuberculin skin test reaction. Image from the CDC Public Health Image Library.

TST interpretation depends on both the measured induration and the patient's risk of TB infection or progression to active disease.^[1][7]

Interferon-gamma release assays measure interferon-gamma release by T cells after stimulation with M. tuberculosis-specific antigens, including ESAT-6 and CFP-10. These antigens are absent from BCG strains and most nontuberculous mycobacteria, giving IGRAs higher specificity than TST in BCG-vaccinated persons.^[1][2]

Two FDA-approved IGRAs are used in the United States:

The 2023 USPSTF evidence review reported sensitivity of 89% for QuantiFERON-TB Gold Plus (95% CI, 84%-94%) and 90% for T-SPOT.TB (95% CI, 87%-92%). Reported specificity was 98% for QuantiFERON-TB Gold Plus (95% CI, 95%-99%) based on one study, and approximately 95%-97% for T-SPOT.TB based on two studies.^[9] Indeterminate or invalid IGRA results occur in a minority of tests and should prompt repeat testing or use of an alternate test, depending on clinical context.^[1]

The choice between TST and IGRA depends on age, BCG vaccination history, likelihood of return for TST reading, immune status, test availability, and local practice.^[1]

Two-step TST is used to establish a baseline in persons who will undergo serial TST testing and who have not had a TST within the previous 1-2 years. Remote TB infection, prior BCG vaccination, or nontuberculous mycobacterial exposure may produce waning immune reactivity, so the first TST may boost the immune response and make a later TST appear falsely converted.^[1][11]

If the first TST is negative, a second TST is placed 1-3 weeks later. If the second test is negative, the person is considered uninfected at baseline. If the second test is positive, this is interpreted as boosting rather than new infection.^[11]

Two-step testing is recommended when TST is used for baseline testing in healthcare personnel, selected residents of congregate facilities, and travelers who will undergo serial TST testing. Two-step testing is unnecessary when using an IGRA.^[5][11]

Borderline or low-positive IGRA results may have limited reproducibility, especially in low-risk populations. When testing is performed despite low pretest probability, confirmatory testing is recommended after an initial positive result.^[1]

All persons with HIV infection should be evaluated for LTBI at the time of HIV diagnosis, regardless of epidemiologic risk.^[6] Either TST or IGRA may be used; IGRA is preferred in BCG-vaccinated persons. TST is positive at ≥5 mm in persons with HIV.^[6]

Progressive immunodeficiency reduces the sensitivity of both TST and IGRA. Persons with HIV who initially test negative during advanced immunosuppression should be retested after immune reconstitution on antiretroviral therapy if they remain at risk.^[6] Annual retesting is recommended for persons with ongoing exposure risk.^[6]

In a U.S. prospective study of persons with HIV, T-SPOT.TB had the highest specificity and positive predictive value, whereas QFT-GIT had higher sensitivity than TST. These data support guideline statements that test performance varies with immune status and that no single test is clearly preferred for all persons with HIV.^[6]

Children should be tested only when they have risk factors for TB infection or progression. Testing should not be performed routinely in low-risk children.^[10]

The ATS/IDSA/CDC guideline suggests TST rather than IGRA in healthy children younger than 5 years, whereas the American Academy of Pediatrics supports IGRAs in children aged 2 years or older, especially if BCG-vaccinated.^[1][10] This creates a practical pediatric cutoff discrepancy: CDC TST interpretation tables use children younger than 4 years in the ≥10 mm threshold group, while AAP guidance often uses younger than 5 years when discussing high-risk pediatric testing considerations.^[7][10] In exposed young children, a negative initial test does not exclude recent infection; repeat testing 8-10 weeks after last exposure is required.^[10]

TST is not contraindicated during pregnancy. Either TST or IGRA may be used when risk factors for TB infection or progression are present.^[7] Screening should not be delayed when the pregnant patient has recent exposure, HIV infection, or other major risk factors for progression.

The 2019 National Tuberculosis Controllers Association and CDC recommendations changed the approach to healthcare personnel screening. Baseline screening is still recommended, but routine serial testing is no longer recommended in the absence of known exposure or ongoing transmission.^[5]

If baseline testing is positive in a healthcare worker who is asymptomatic and low risk, a second confirmatory test should be performed before chest radiography and LTBI diagnosis.^[5] Healthcare personnel with untreated LTBI should receive annual symptom screening.^[5]

HIV testing is recommended for all patients with suspected or confirmed TB disease and for persons diagnosed with LTBI or identified as TB contacts. Testing should be offered using an opt-out approach, meaning that testing is performed after the patient is informed unless the patient declines.^[12]

Separate written consent and prevention counseling are not required for HIV screening in healthcare settings unless required by local law.^[12]

In low-incidence settings such as the United States, chest radiography is used primarily after a positive TST or IGRA to exclude active pulmonary TB before diagnosing LTBI.^[1] A normal chest radiograph and absence of symptoms support LTBI rather than active pulmonary TB; abnormal radiography or TB symptoms require sputum testing for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing.^[1]

In high-burden settings, chest radiography is also used for systematic screening for active pulmonary TB. Computer-aided detection (CAD) software can interpret digital chest radiographs for TB-suggestive abnormalities and has been conditionally recommended by WHO as an alternative to human readers in screening programs, although all positive screens require bacteriologic confirmation.^[13]

Recent prospective studies suggest that CAD-based chest radiography may improve screening throughput in high-burden settings, but thresholds, local prevalence, confirmatory testing capacity, and cost-effectiveness must be considered before implementation.^[14][15]

A positive TST or IGRA result requires clinical evaluation to exclude active TB disease before LTBI is diagnosed and treated.^[1][2]

• Screening low-risk persons, which increases false-positive results.
• Measuring erythema rather than induration when reading the TST.
• Using a single TST cutoff for all patients rather than risk-stratified thresholds.
• Using TST or IGRA to rule out active TB disease.
• Failing to perform chest radiography after a positive TST or IGRA.
• Treating a positive test as LTBI before excluding active TB disease.
• Ordering routine annual TB testing for all healthcare personnel despite the 2019 NTCA/CDC update.
• Using older QuantiFERON-TB Gold In-Tube language when QuantiFERON-TB Gold Plus is the current-generation assay.
• Using TST or IGRA to monitor response to anti-tuberculosis therapy.

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