There is no gold-standard test to confirm the presence or absence of TB infection. In lieu of a gold standard, surrogate populations are used to estimate the sensitivity and specificity of TB infection diagnostic tests. Typically, sensitivity is estimated among persons who have TB disease. There are limitations to this reference standard, as persons with TB disease may experience temporary anergy, causing a negative TST or IGRA. Specificity is estimated among persons who are at very low risk of exposure to M. tuberculosis and NTM. This too has limitations, as it is not possible to completely rule out exposure. However, in the absence of better reference standards, these surrogates have been utilized.19,22,27
3.3.1. Tuberculin skin test
The sensitivity of the TST among persons with TB disease has been estimated in systematic reviews and meta-analyses.11,27,33–35 One of the largest meta-analyses suggests that the TST at a threshold of ≥10 mm has a sensitivity of 77% (95% CI: 72 to 81%).27 Among children, TST sensitivity is similar.36
Among persons with immunocompromising conditions (such as HIV), sensitivity of the TST is significantly lower. In one meta-analysis, sensitivity of the TST at a threshold of ≥5 mm was estimated to be 60% (95% CI: 34 to 82%) among people living with HIV.37 For other populations with immunocompromising conditions, similar reductions in sensitivity are found, such as among persons receiving dialysis, where sensitivity is 50-55%.38–40
The specificity of the TST is primarily affected by the presence of NTM infection and/or previous BCG vaccination.20 Among persons without a history of BCG vaccination, TST specificity was estimated in a meta-analysis to be 97% (95% CI: 95 to 99%).27 Among BCG-vaccinated persons, TST specificity was estimated in the same meta-analysis to be 59% (95% CI: 46 to 73%).27 However, studies conducted in Canada and several other countries show that if BCG was received in infancy (the first year of life), only 1% had a TST result of ≥10 mm if tested >10 years later.20 Therefore, a history of BCG vaccination received in infancy can be ignored as the cause of a positive result in all persons aged 10 years and older when interpreting an initial TST reaction of 10 mm or greater.20,41–44
BCG vaccination should only be considered the likely cause of a positive TST if BCG vaccine was given after 12 months of age AND there has been no known exposure to TB disease or other risk factors for TB infection AND the person is either Canadian-born non-Indigenous45 OR an immigrant/visitor from a low-TB-incidence country (<50 cases per 100,000 persons per year).46 International TB incidence rates are available from the WHO TB data repository (https://www.who.int/teams/global-tuberculosis-programme/data).
In a prospective study in the USA of more than 20,000 persons, including both US-born persons and persons born abroad, TST and IGRA positivity varied.30 Among US-born persons, the proportion testing positive with a TST and IGRA did not vary; however, among persons born abroad, IGRA positivity was substantially lower than TST positivity, likely due to the prevalence of BCG vaccination in the cohort (64.5%). In this study, timing of BCG vaccination was not collected, and longitudinal incidence of TB disease was not reported. In practice, when there is uncertainty about the timing of BCG vaccination, it is recommended to consult the BCG vaccination policies in different countries, as summarized in the recently updated BCG World Atlas (http://www.bcgatlas.org/ – see Figure 1).47 However, if uncertainty remains regarding BCG vaccination and its timing, it is best to use an IGRA, if available, as the proportion of people testing false positive is expected to be lower.
3.3.2. Interferon-gamma release assay
A meta-analysis estimating the sensitivity and specificity of QFT-Plus suggests there is no significant difference in sensitivity (1.3% higher; 95% CI: 0.3% lower to 2.9% higher) and specificity (0.9% lower; 95% CI: 2.4% lower to 0.6% higher) compared to the previous generation QFT.48 A previous meta-analysis of older QFT generations suggested sensitivity is 78% (95% CI: 73 to 81%), while among 13 studies of T-SPOT.TB, sensitivity was estimated to be 90% (95% CI: 86 to 93%).27
Similar to the TST, IGRA sensitivity is reduced among people with immune-compromising conditions.37,49 IGRAs also have elevated rates of indeterminate results due to failure of positive controls in these populations. Sensitivity for T-SPOT.TB among people living with both HIV and TB disease was estimated to be 76% in one meta-analysis, while sensitivity for a previous generation QFT (QFT Gold) was estimated to be 69%.50 A prospective study among people living with both HIV and TB disease tested with QFT-Plus exhibited similar sensitivity.51
Both IGRAs are unaffected by BCG vaccination. For both QFT-Plus and T-SPOT.TB, specificity is high, around 98 and 93%, respectively.27
There is evidence for previous QFT generations that the strength in response (higher IU/ml) may be associated with increased risk of developing TB disease in a dose-dependent manner (like magnitude of TST induration size).52 Similar findings for T-SPOT.TB were found in a large prospective study in the United Kingdom.53 A comparable analysis for the current generation of QFT (QFT-Plus) has not been performed.
We conditionally recommend that an interferon-gamma release assay is preferred over a tuberculin skin test in the following situations: (1) When children over 2 years of age and less than 10 years of age previously received a Bacille Calmette-Guérin vaccine (BCG); (2) when persons at least 10 years of age received a BCG vaccine after infancy (older than 1 year of age), received a BCG vaccine more than once and/or are uncertain about when they received a BCG; (3) when adequate training and quality assessment and control are NOT available for tuberculin skin test administration and/or reading, but personnel and facilities to perform interferon-gamma release assays are available; (4) when a person is unable or unlikely to return to have their tuberculin skin test read; and (5) when the tuberculin skin test is contraindicated (poor evidence).
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