Tuberculin skin test and QuantiFERON performance, and testing of populations at low risk for tuberculosis infection.

TO THE EDITOR—In university-entering students with low to no risk for past tuberculosis exposure, McMullen et al [1] somewhat unexpectedly report that specificity may be lower with interferon-γ release assays (IGRAs) than with the tuberculin skin test (TST). Although their findings add to our understanding of IGRA’s potential limitations in various contexts, they should be contrasted with other groups’ published data and our own experience in the San Francisco tuberculosis control program. Also, the study’s general distribution of participants’ testing and outcomes available for analysis are noteworthy. From Figure 1 [1], 23% (3667/15 936) of tests were excluded for being noninitial tests on the same subject; this is a substantial proportion and is not elaborated upon. If, for example, these were students from higher-incidence countries, who underwent multiple TSTs as part of 2-step-testing or due to travel to their home countries during the study period, and a significant percentage of their later tests were positives, TST-positive results could be higher, and specificity lower. From the available information, an overall 43% of TST results were excluded from analysis. Also, rates of inconclusive results impact consideration of test performance, as well as cost analyses, and failed return for TST interpretation is a common issue for tuberculosis programs; in this study, 6% of TSTs (872/1468) were unread, whereas <1% of the QuantiFERON-TB Gold In-Tube (QFT ) tests were indeterminate. Several prior reports support the converse of McMullen’s findings, that IGRAs have lower overall positive rates and offer improved specificity than the TST. In an early, direct comparison of QFT with TST in close contacts of active tuberculosis cases in Germany, half of whom were BCG vaccinated, QFTpositive rates were a quarter of that of the skin test (10% vs 44%). [2] In a prior analysis by our San Francisco tuberculosis control program, where an equal number of tuberculosis contacts were evaluated by the QFT as the TST, positive rates were 20% and 25%, respectively [3] Numerous studies demonstrate that TSTpositive individuals at relatively lower risk for tuberculosis infection frequently test negative with IGRAs, raising concern for high false-positive rates with TST [4–8]. In teenage students, this discordance can be dramatic: Only 9% of TST-positive ninth graders were QFT positive in routine screening in Norway [9]; in a Japanese school contact investigation, 84 of 88 TSTpositive students were QFT negative [10]. We have recently performed a comprehensive review of the San Francisco tuberculosis control program from 2005 to 2008 (Table 1). In the population that most resembles that of the McMullen et al study [1]—16to 29-year-olds without known tuberculosis history, evaluated in the community for immigration or school requirements—only 5% of QFTs were positive. In a pediatric-focused analysis of those who underwent dual testing, TST-positive/QFT-negative discordant rates were 71% overall, and 91% in 58 BCG-vaccinated children aged <5 years. False-positive IGRA results may occur when testing individuals at low risk for tuberculosis infection; that tuberculosis tests positivity rates were essentially equivalent for those with—as for those without—most traditionally emphasized risk factors is perhaps the most important finding by McMullen et al. These results argue for a reconsideration of current screening policy and more selective tuberculosis testing, in university students and all other contexts where risks for tuberculosis infection and progression to disease are generally low.