Table 2.

Ten common misconceptions about IGRAs

	Misconception	Evidence
1	“IGRAs are tests for the diagnosis of active TB.”	The pooled sensitivities and specificities for the diagnosis of active TB of the Quantiferon-Gold-in tube test and the T-Spot-TB test were 80% (95% CI 75– 84%)/ 79% (95% CI 75–82%) and 81% (95% CI 78–84%)/59% (95% CI 56–62%) In a recent systematic-review and meta-analysis [33]. The diagnostic accuracy is higher, when IGRAs are performed on extrasanguinous fluids, e.g. CSF, ascites, BAL [33, 34]. Standard IGRAs performed with cells from the peripheral blood should not be used for the diagnosis of active TB.
2	“A negative IGRA test result excludes active TB.”	In active TB approximately 20 % of patients have a negative IGRA test result [35].
3	“IGRAs can safely exclude the progression to active TB because of a very high negative predictive value.”	While the negative predictive value of IGRAs is very high when healthy contacts are evaluated, the negative predictive value is low in HIV-infected hosts. More than 50 % of HIV-infected individuals who later developed active TB in low incidence countries of TB had a negative test results in both IGRAs at the time of screening [8].
4	“IGRAs are better than the TST to predict progression to active TB in immunocompromised patients.”	In the largest prospective multicenter observational cohort study that evaluated the role of IGRAs and the TST as predictors for progression to active TB in immunocompromised hosts, prediction of disease progression by IGRA was not superior to the TST [8].
5	“The higher the concentration of IFN-γ in the QFT-G-IT test or the number of spot-forming cells in the T-SPOT.TB test, the greater the risk for the progression to active TB.”	The cut-offs for test-positivity provided by the manufacturers of the QFT-GIT and the T-SPOT.TB test have been validated in at least one prospective study including more than 5000 close contacts of patients with active TB. In contrast to previous smaller studies, in this multinational study in Europe, there was no correlation between the magnitude of a positive test and the risk for progression to tuberculosis [36].
6	“After treatment initiation for active TB presence and magnitude of IGRA responses reflect the response to anti-TB therapy, thus IGRAs can be used for treatment monitoring.”	In those studies that evaluated possible relationships between IGRA responses and treatment-monitoring parameters no clear correlation could be found [37–40].
7	“Positive IGRA responses that develop after anti-TB vaccination are an indicator for protective immunity against TB.”	In a large placebo controlled prospective randomized trial evaluating a novel MVA-Ag85 vaccine, M. tuberculosis specific immune responses could be detected by IGRA in the group of MVA-Ag85 vaccinated children, but not in the placebo group. During follow-up, the TB incidence was similar on the MVA-Ag85 vaccine and in the placebo arm, suggesting that IGRAs are not correlate markers of protective immunity against TB [41].
8	“Health-care workers in low-incidence countries of TB should undergo regular IGRA screening.”	In 3 recent studies where health-care workers were tested by IGRAs in low-incidence countries of TB and followed for > 2 years not a single case of TB occurred among > 1500 IGRA positive healthcare workers in the absence of preventive chemotherapy [42–44]. The risk of healthcare workers for the development of TB is low, unless a specific intensive contact to a TB patients occurred. Regular screening is not justified.
9	“A positive IGRA result carries the same risk for the development of tuberculosis in different groups of patients or healthy individuals.”	The positive predictive values of IGRAs and the number needed to treat to prevent one case of tuberculosis based on IGRA results show substantial differences among different groups of individuals. In persons with HIV infection and ongoing viral replication [45] or in small children who are household contacts [36], the number needed to treat to prevent one case of TB is approximately 10, thus IGRA screening followed by preventive chemotherapy is highly effective. In persons from low-incidence countries of TB with chronic renal failure 1/ 4 persons has a positive IGRA test result but the risk for TB is very low [8], Regular screening and preventive chemotherapy is not indicated in this group.
10	“Indeterminate test results are always caused by immunodeficiency.”	While failure of the positive control is the most common cause of an indeterminate IGRA test result, failure of the negative control may also be a cause of an indeterminate test result [8], most commonly in persons with autoimmune disorders (e.g. Systemic lupus erythematodes).