While cases of active tuberculosis are relatively rare in the United States, TB is a major cause of morbidity and mortality worldwide. In the United States, there are an estimated 11 million individuals who have latent TB infection (LTBI). Without prophylactic treatment, somewhere between 4%-6% of individuals with LTBI will develop active disease during their lifetimes; roughly half of these cases will occur within a few years of the initial infection. Treatment of LTBI reduces – but does not eliminate – the risk for active disease, decreasing the consequences of active disease for the patient and the risk of transmitting infection to others.
Dr. Neil Skolnik and Dr. Mathew Clark
Diagnostic tests for LTBI
The tuberculin skin test (TST) has been the standard method of diagnosing LTBI. It involves measuring induration caused by a delayed-type hypersensitivity reaction to Mycobacterium tuberculosis (Mtb) 2 or 3 days after injecting the reagent into the skin. The TST can result in false positives when detecting antibodies to BCG and nontuberculous mycobacteria, and false negatives when the patient does not demonstrate a robust immune response. A newer testing method is the Interferon Gamma Release Assay (IGRA), which involves phlebotomy, followed by a series of laboratory procedures that measure IFN-gamma release by T cells that have been sensitized to Mtb. The sensitivity of IGRA is similar to the TST, but it has better specificity; it is much less likely to react to antigens from BCG or nontuberculous mycobacteria. As detailed below, this guideline suggests a significantly more prominent role for IGRA, compared with previous recommendations.
Recommendation 1. Perform an IGRA, rather than a TST, in individuals 5 years or older who meet the following criteria: 1) are likely to be infected with Mtb; 2) have a low or intermediate risk of disease progression; 3) in whom it has been decided that testing for LTBI is warranted. A TST is an acceptable alternative, particularly if an IGRA is not available, is too costly, or is too burdensome. If an individual either has a history of BCG vaccination or is unlikely to return to have their TST read, then it is strongly recommended to use the IGRA as the test of choice.
Recommendation 2. There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are likely to be infected with Mtb, who have a high risk of progression to active disease, and in whom it has been determined that diagnostic testing for LTBI infection is warranted; either test would be acceptable. In very high-risk patients, consider dual testing, with a positive result from either test (TST or IGRA) being considered positive.
Recommendation 3. Guidelines do not recommend testing for persons at low risk for Mtb infection. However, the authors recognize that testing in such persons may nevertheless be mandated in certain situations (for example in some school or child care settings). In these cases, the authors recommend performing an IGRA instead of a TST, to minimize the chance of a false-positive result, although a TST is an acceptable alternative. Furthermore, if the initial test is positive, they suggest performing a confirmatory test (either an IGRA or TST) and considering the person infected only if both tests are positive.
Recommendation 4. The authors suggest performing a TST rather than an IGRA in healthy children less than 5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted. This recommendation reflects the limited body of evidence regarding IGRA testing in young children and the apparent decreased sensitivity (i.e. more false negatives) in this population, compared with TST use.
In the area of serial testing for TB infection, often done in health care and institutional settings, the guideline points out areas of uncertainty with IGRA testing. Specifically, the IGRA test is subject to variability in readings and boosting with antigen exposure that can complicate interpretation of apparent conversion on repeat testing. One longitudinal study showed conversion rates with IGRA to be six to nine times higher than that seen for the TST, and those conversions were thought to represent false positive tests. The guideline concludes that, “There is insufficient information available to guide the establishment of definitive criteria for the conversion.” The committee thought that a positive test in a low-risk individual was likely to be a false-positive result and recommended repeat testing. Because of the possibility of boosting with antigen exposure in situations where dual testing is anticipated, it may be preferable to obtain a specimen for IGRA prior to, or concurrently with TST placement.