What are the guidelines-regulated indications for using Interferon-Gamma Release Assay (IGRA) as a confirmatory test for false-positive Tuberculin (Mantoux) test results, and what criteria define high-risk individuals who may be considered to have a positive Tuberculin test result despite a negative IGRA result?

From the Guidelines

Interferon-Gamma Release Assays (IGRAs) are recommended as confirmatory tests for false positive tuberculin skin tests (TSTs) in individuals with low risk for tuberculosis infection or disease, as stated in the guidelines from the MMWR Recommendations and Reports 1.

Guidelines for Using IGRAs

The guidelines recommend using IGRAs as aids in diagnosing infection with M. tuberculosis, and they should be used in compliance with Clinical Laboratory Improvement Amendment (CLIA) standards 1.

• IGRAs should be performed and interpreted according to established protocols using FDA-approved test formats.
• Both the standard qualitative test interpretation and the quantitative assay measurements should be reported together with the criteria used for test interpretation.

High-Risk Individuals

However, certain high-risk individuals should be considered to have true positive tuberculin tests regardless of negative IGRA results, as suggested by the guidelines from the Clinical Infectious Diseases journal 1.

• These high-risk groups include:
  • Individuals with recent close contact with active TB cases
  • Persons with chest X-ray findings consistent with previous TB
  • Immunocompromised individuals (including HIV-positive patients, transplant recipients, and those on immunosuppressive medications like TNF-alpha inhibitors)
  • Children under 5 years of age with TB exposure
  • Individuals from high TB-prevalence countries who have been recently exposed

Rationale for Consideration

The rationale for considering these individuals as having latent TB infection despite negative IGRA results is that both TST and IGRA have imperfect sensitivity, especially in immunocompromised hosts where false negatives can occur 1.

• In these high-risk scenarios, the potential consequences of missing latent TB infection outweigh the risk of unnecessary treatment, so preventive therapy should be strongly considered based on the positive TST alone, particularly when the risk of progression to active disease is substantial.

Testing Recommendations

All HIV-infected patients should be tested for M. tuberculosis infection by TST or IGRA upon initiation of care, as recommended by the HIV Medicine Association of the Infectious Diseases Society of America 1.

• Annual testing should be considered for those who have negative results by TST but are at ongoing risk for exposure.
• A TST or IGRA should be performed any time there is concern of a recent exposure or after increase of CD4 cell count to >200 cells/µL following initiation of ART.

From the Research

Guidelines for Interferon-Gamma Release Assay (IGRA) as a Confirmatory Test

• The IGRA test is used to detect latent tuberculosis prior to biological treatments in the context of suspected inflammatory rheumatism 2.
• The test is also used to confirm false-positive Tuberculin (Mantoux) test results, especially in high-risk individuals 3, 4.
• However, the IGRA test has limitations, including variable performance for active TB diagnosis and the potential for false-negative results, particularly in individuals with immunomodulator therapy 2, 5.

High-Risk Individuals for Latent Tuberculosis Infection

• High-risk individuals include those with a history of exposure to tuberculosis, close contacts of infectious tuberculosis cases, and people born in countries with high or moderate tuberculosis incidence 3, 4.
• Other risk factors for latent tuberculosis infection include HIV infection, end-stage renal disease, and diabetes 3.
• The presence of risk factors for latent tuberculosis infection is associated with positive results of TST and IGRA 5, 6.

Criteria for Positive Tuberculin Test Result Despite Negative IGRA Result

• A positive Tuberculin test result despite a negative IGRA result may be considered in individuals with high-risk factors for latent tuberculosis infection, such as a history of exposure to tuberculosis or close contacts of infectious tuberculosis cases 4, 6.
• Clinical risk factors, including a history of prior TB, close contacts, and suggestive chest x-ray lesions, should be taken into account when interpreting test results 6.
• The use of both TST and IGRA may maximize sensitivity in detecting latent tuberculosis infection, but may also reduce specificity, especially in patient populations with low rates of TB incidence and BCG vaccination 6.