They concluded that IFNγ release assays should be preferred over the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection.
However, after extending the in-vitro incubation time of IFNγ release assays, almost all samples responded positively to tuberculosis-specific antigens in vitro, indicating that the standard IFNγ release assays gave false negatives.
The explanation is that IFNγ release assays use an incubation time of, at most, 24 h, which can be too short to detect memory immune responses. Second, IFNγ release assay results are formally classified as negative or positive, but the actual value has significance even below the formal cutoff. In a previous study, we showed that borderline results (in our definition, results just below the formal cutoff) are actually a reflection of latent tuberculosis infection in two-thirds of cases.
Third, in a follow-up study among supermarket customers in a large outbreak of tuberculosis who had not been BCG vaccinated that used the same tests as used in the study by Ho and colleagues, results of IFNγ release assays could revert to negative if repeated in the future.
Taken together, discordant TST-positive and IFNγ release assay-negative results could indeed reflect false-positive TSTs related to BCG vaccination, but could also be indicative of false-negative IFNγ release assays, because IFNγ release assays are less sensitive to the detection of past infection.
To treat latent tuberculosis infection only if the patient has a positive IFNγ release assay is a safe approach, but only as long as the individual is immunocompetent. The situation is different in individuals who are immunocompromised, because the risk of reactivation is much increased in this population, and a positive TST or borderline IFNγ release assay result should be taken seriously in that setting.
We declare no competing interests.
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