Research Article: Serial Testing for Tuberculosis: Can We Make Sense of T Cell Assay Conversions and Reversions?

Date Published: June 12, 2007

Publisher: Public Library of Science

Author(s): Madhukar Pai, Richard O’Brien

Abstract: The authors discuss a new study, which they say is a valuable addition to the existing literature on the performance of interferon gamma release assays in serial testing for TB infection.

Partial Text: In many high-income countries with low rates of tuberculosis (TB), serial testing for latent TB infection (LTBI) is recommended for persons at increased risk of TB exposure. For example, periodic screening of health care workers for LTBI is an important component of nosocomial TB infection control programs. Serial testing is also performed during household contact investigations. However, the conventional tuberculin skin test (TST) has known limitations in accuracy and reliability [1,2]. Furthermore, the interpretation of serial TST results is particularly complicated because of non-specific variations in test results, boosting, conversions, and reversions (see Glossary for definitions) [3]. In this context, the development of more specific, in vitro assays for LTBI—interferon gamma (IFNγ) release assays (IGRAs)—is a welcome development. These assays are highly specific, especially in bacillus Calmette Guérin (BCG)-vaccinated populations [4,5].

In theory, IGRAs have features that make them ideal for serial testing. They are more specific than TST, can be repeated any number of times without sensitization and boosting, the testing protocol requires only one visit, and unlike the TST, there is no need for a baseline two-step testing protocol to avoid misclassifying TST increases due to boosting as true conversions due to new infection. Furthermore, there is some evidence, although not consistent, that IGRAs may be better at detecting recent rather than remote infection [6].

An interesting finding in the Gambian study is the high rate of reversions among household contacts, even within a time span of three months and despite the newness of exposure [7]. Previous studies have also found high reversion rates with IGRAs [8,9,11]. In general, reversions are least likely when baseline IFNγ responses are strong and concordantly positive (i.e., positive by both TST and IGRA). Concordantly positive individuals are likely to have very strong IFNγ responses. Consequently, unless their responses drop dramatically, reversions are not likely. In contrast, IGRA reversions are more likely when the baseline test results are discordant (i.e., positive by IGRA but negative by TST) [7–9,11]. Discordant results are often weakly positive, and weakly positive IFNγ levels are likely to be just above the diagnostic threshold. Therefore, even minor nonspecific variations around the threshold can lead to apparent reversions.

Although a fairly high rate of IGRA conversions has been documented in high-risk populations in highly endemic settings [8,11], there is no consensus on how to define and interpret conversions. Data are lacking on key questions, such as: How much increase in IFNγ indicates a true new infection, and how much is merely test or biological variability? Should the same threshold be used for diagnosis of LTBI as well as conversions (see Box 1)? If not, what is the ideal data-driven approach to deriving cut-offs for conversions?

With the TST, the risk of development of active TB has been established in several cohort studies (reviewed in [1]). Also, from controlled clinical trials, we know that treatment of TST-positive persons reduces the risk of active disease [14]. This knowledge has resulted in guidelines for targeted TST testing and treatment for LTBI [14]. Unfortunately, there are no equivalent data for IGRAs. Although the data are limited to one small study [15], of an association between strong IFNγ response to ESAT-6 and subsequent progression to active TB among household contacts of index cases, the prognosis of a positive IGRA result has yet to be determined (Box 1).



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