ABSTRACT
Quantiferon-TB Gold Plus (QFT-Plus) is an interferon gamma release assay used to diagnose latent tuberculosis (LTB). A borderline range (0.20 to 0.99 IU/ml) around the cutoff (0.35 IU/ml) has been suggested for the earlier QFT version. Our aims were to evaluate the borderline range for QFT-Plus and the contribution of the new TB2 antigen tube. QFT-Plus results were collected from clinical laboratories in Sweden and linked to incident active TB within 3 to 24 months using the national TB registry. Among QFT-Plus results from 58,539 patients, 83% were negative (<0.20 IU/ml), 2.4% were borderline negative (0.20 to 0.34 IU/ml), 3.4% were borderline positive (0.35 to 0.99 IU/ml), 9.6% were positive (≥1.0 IU/ml), and 1.6% were indeterminate. Follow-up tests after initial borderline results were negative (<0.20 IU/ml) in 38.3%, without any cases of incident active TB within 2 years. Applying the 0.35-IU/ml cutoff, 1.5% of TB1 and TB2 results were discrepant, of which 52% were within the borderline range. A TB2 result of ≥0.35 IU/ml with a TB1 result of <0.20 IU/ml was found in 0.4% (231/58,539) of all included baseline QFT-Plus test results, including 1.8% (1/55) of incident TB cases. A borderline range for QFT-Plus is clinically useful as more than one-third of those with borderline results are convincingly negative upon retesting, without developing incident active TB. The TB2 tube contribution to LTB diagnosis appears limited.
KEYWORDS: latent tuberculosis, interferon gamma release assay, active tuberculosis, borderline-range results, Quantiferon Plus
INTRODUCTION
To reach the WHO’s target for tuberculosis (TB) elimination, improved eradication strategies for latent TB (LTB) are required (1, 2). LTB is defined as a persistent immune response to Mycobacterium tuberculosis antigens without clinical signs of active TB (2), and LTB preventive treatment has been shown to reduce the risk of progression to active TB by 60 to 90% (3). In low-endemicity countries, the interferon gamma (IFN-γ) release assays (IGRAs) Quantiferon (QFT) and T-spot.TB are commonly used to identify LTB. The Quantiferon-TB Gold Plus (QFT-Plus) assay has recently replaced the QFT-TB Gold in-tube (QFT-GIT) assay and includes an additional tube (TB2) containing TB antigens promoting a combined CD4+ and CD8+ T-cell reaction claimed to increase sensitivity for the detection of active TB and recent exposure (4).
Recent studies suggest a QFT-Plus and QFT-GIT concordance rate of 89 to 94% (5, 6), where discrepant results were mainly within a borderline range of 0.20 to 0.99 IU/ml (5, 6). Since 2017, a borderline range (0.20 to 0.99 IU/ml) has been recommended by the Swedish Public Health Authority, where follow-up testing is suggested to avoid false-positive or false-negative results near the current cutoff at 0.35 IU/ml (7). Several authors showed that QFT-GIT results within the borderline range should be interpreted with caution and are often due to test variability rather than true immunological responses (8–11). Possible reasons are preanalytical factors such as variations in transportation temperature or tube shaking intensity or variability in the enzyme-linked immunosorbent assays (ELISAs) for quantification of IFN-γ (8–10). Borderline ranges have been applied ranging from 0.20 to 0.70 to 1.0 IU/ml (9, 12–14). Our previous study showed that 42.5% of QFT-GIT results in the borderline positive range (0.35 to 0.99 IU/ml) were negative (<0.05 IU/ml) in follow-up testing, indicating potentially false-positive results in the first samples (13). So far, evaluations of the borderline range for QFT-Plus as well as the clinical value of the TB2 tube under routine clinical conditions are scarce. Thus, our aims were to evaluate the introduction of a borderline range for QFT-Plus and the contribution of the TB2 tube for diagnosing LTB.
MATERIALS AND METHODS
QFT-Plus results were collected from 2017 to 2018 from clinical microbiological laboratories covering approximately 75% of the Swedish population. Data on individual test indications, the presence of immunosuppressive conditions, previous LTB treatment, or screening for active TB at the time of the QFT-Plus test confirmed by individual patient records were not available. In Sweden, LTB screening by QFT-Plus is routinely used for screening of asylum seekers and pregnant women from high-TB-incidence countries, prior to immunosuppressive treatment (such as organ transplantation and tumor necrosis factor alpha [TNF-α]-blocking medication) or immunosuppressive disease (such as HIV or hemodialysis), and in contact investigations (15). According to Swedish guidelines, a questionnaire considering symptoms and signs of active TB is completed by subjects screened for LTB. Anyone with symptoms and/or a positive QFT-Plus result is referred for chest X ray and medical evaluation (15). Follow-up retesting of borderline results (0.20 to 0.99 IU/ml) was recommended through laboratory reports. For data analysis, duplicates and samples where either TB1 or TB2 values were missing were excluded.
The dichotomous cutoff set by the manufacturer is an interferon gamma level of 0.35 IU/ml (4). According to national guidelines, borderline-range data were categorized as negative (<0.20 IU/ml), borderline negative (0.20 to 0.34 IU/ml), borderline positive (0.35 to 0.99 IU/ml), and positive (≥1.0 IU/ml) based on the interferon gamma level (15). The definition of indeterminate was according to the manufacturer. The incidence of active TB during follow-up among individuals with borderline QFT-Plus results was evaluated using the Swedish national tuberculosis register from 1 January 2017 to 9 March 2020. All TB patients were examined by smear microscopy, PCR for the M. tuberculosis complex, and culture in Bactec 960 MGIT. Incident TB was defined as an active TB diagnosis between 3 months and up to 2 years after QFT-Plus sampling (13). QFT-Plus analyses were performed according to the manufacturer’s instructions by accredited laboratories (4) by a manual ELISA (n = 2) or with an ELISA robot (n = 6). Parametric data are presented as medians with interquartile ranges (IQR). Agreement between TB1 and TB2 tubes was assessed through kappa analysis. The project was approved by the Swedish Ethical Review Authority (registration number 2019-00195).
RESULTS
Distribution of QFT-Plus results in relation to the borderline range.
Among QFT-Plus results from 58,539 patients after removing duplicates and incomplete reports (Fig. 1), 83% were negative (<0.20 IU/ml), 2.4% were borderline negative (0.20 to 0.34 IU/ml), 3.4% were borderline positive (0.35 to 0.99 IU/ml), 9.6% were positive (≥1.0 IU/ml), and 1.6% were indeterminate (Table 1). In total, 5.8% (n = 3,426) were within the borderline range. Overall, 36.6% (n = 1,254) of individuals with a borderline-range QFT-Plus result were retested within a median of 36 days (IQR, 20 to 65 days). Follow-up tests after borderline results were negative (<0.20 IU/ml; median, 0.02 IU/ml) upon retesting (Table 1) in 38.3% (480/1,254). Applying the manufacturer’s cutoff of 0.35 IU/ml for initial samples, 85.4% (n = 50,007) were negative, 13.0% (n = 7,605) were positive, and 1.6% (n = 927) were indeterminate (Table 1).
FIG 1.
Flowchart of inclusion of individuals and Quantiferon Plus test results.
TABLE 1.
Incident active TB cases in relation to follow-up QFT-Plus results
| Initial QFT-Plus result | % (no.) of patients with result | % (no.) of incident active TB cases | % (no.) of cases retested per baseline category | Follow-up QFT-Plus test result | % (no.) of cases with follow-up QFT-Plus test result | % (no.) of cases with incident active TB per follow-up QFT-Plus result category |
|---|---|---|---|---|---|---|
| Negative (<0.2 IU/ml) | 83.0 (48,573) | 0.01 (7) | 4.3 (2,118) | Negative | 94.7 (2,005) | 0.1 (2/2,005) |
| Borderline negative | 1.6 (33) | 0 | ||||
| Borderline positive | 0.9 (20) | 0 | ||||
| Positive | 1.5 (32) | 0 | ||||
| Indeterminate | 0.8 (18) | 0 | ||||
| Borderline negative (0.2–0.34 IU/ml) | 2.4 (1,434) | 0.2 (3) | 27.0 (387) | Negative | 59.2 (229) | 0 |
| Borderline negative | 15.8 (61) | 0 | ||||
| Borderline positive | 18.3 (71) | 0 | ||||
| Positive | 6.2 (24) | 8.3 (2/24) | ||||
| Indeterminate | 0.5 (2) | 0 | ||||
| Borderline positive (0.35–0.99 IU/ml) | 3.4 (1,992) | 0.3 (5) | 43.5 (867) | Negative | 29.0 (251) | 0 |
| Borderline negative | 13.4 (116) | 0 | ||||
| Borderline positive | 36.0 (312) | 0 | ||||
| Positive | 21.0 (182) | 1.1 (2/182) | ||||
| Indeterminate | 0.7 (6) | 0 | ||||
| Positive (≥1.00 IU/ml) | 9.6 (5,613) | 0.7 (38) | 3.9 (221) | Negative | 10.9 (24) | 0 |
| Borderline negative | 4.1 (9) | 0 | ||||
| Borderline positive | 13.1 (29) | 0 | ||||
| Positive | 70.1 (155) | 0 | ||||
| Indeterminate | 0.9 (2) | 0 | ||||
| Indeterminate | 1.6 (927) | 0.2 (2) | 43.3 (401) | Negative | 56.9 (228) | 0 |
| Borderline negative | 1.0 (4) | 0 | ||||
| Borderline positive | 1.2 (5) | 0 | ||||
| Positive | 7.0 (28) | 0 | ||||
| Indeterminate | 33.9 (136) | 0.7 (1/136) | ||||
| Total | 58,539 | 0.09 (55/58,539) | 6.8 (3,994/58,539) | 0.2 (7/3,994)a | ||
Incident TB among those retested.
Development of incident active TB.
In total, 55 patients developed incident active TB 3 to 24 months after the baseline QFT-Plus was analyzed, of whom 12.7% (n = 7) were negative, 5.5% (n = 3) were borderline negative, 9.1% (n = 5) were borderline positive, 69.1% (n = 38) were positive, and 3.6% (n = 2) were indeterminate (Table 1). A majority (87.2%; 48/55) of incident active TB cases were detected among individuals tested only once. Out of the incident active TB cases tested once, most individuals were positive at ≥1.00 IU/ml (38/48; 79.2%), whereas three additional incident active TB cases were initially borderline positive (0.35 to 0.99 IU/ml) (Table 1). Further characteristics of the subgroup that developed incident active TB are shown in Table 2.
TABLE 2.
Characteristics of patients with incident active TB
| Characteristic | Value for patients with incident active TB (n = 55) |
|---|---|
| Median age (yrs) (range) | 26 (2–86) |
| No. of patients of sex (M/F) | 19/36 |
| No. (%) of patients of origin | |
| Sub-Saharan Africa | 55 (30) |
| Asia | 18 (10) |
| Eastern Europe | 7 (4) |
| Northern Africa and the Middle East | 9 (5) |
| Sweden | 11 (6) |
| No. (%) of patients with reason for initial QFT-Plus test | |
| Screening of migrants | 29 (16) |
| Screening in pregnancy (high-endemicity area) | 16 (9) |
| Screening before planned immunosuppression | 7 (4) |
| Contact tracing | 13 (7) |
| Unknown or symptoms of suspected TB | 35 (19) |
| No. (%) of patients with site of tuberculosis disease | |
| Pulmonary | 45 (25) |
| Extrapulmonary | 55 (30) |
| No. (%) of patients with culture- and/or PCR-positive TB | 85 (47) |
| No. (%) of patients with initial QFT-Plus result | |
| Indeterminate | 4 (2) |
| Negative (<0.20 IU/ml) | 13 (7) |
| Borderline negative | 5 (3) |
| Borderline positive | 9 (5) |
| Positive (≥1.00 IU/ml) | 69 (38) |
Among 7,605 patients with a positive baseline QFT-Plus result above the cutoff recommended by the manufacturer (≥0.35 IU/ml), 0.6% (43/7,605) developed incident active TB within 3 to 24 months. Among the 1,254 individuals with an initial borderline QFT-Plus result who were retested, 38.3% (480/1,254) reverted to negative at <0.20 IU/ml in the follow-up test. In this group, no case of incident active TB was reported within 2 years of follow-up (Table 1). There was a small subgroup of seven TB patients where both initial and follow-up samples were available. In this subgroup, the initial test was borderline positive (0.35 to 0.99 IU/ml) or borderline negative (0.20 to 0.34 IU/ml) in two cases each, which turned positive in all four cases (>1.0 IU/ml), whereas two were negative both initially and upon retesting (<0.20 IU/ml) and one case showed indeterminate results repeatedly (Table 1). Data regarding the reasons for retesting those not initially within the borderline range were not available.
Agreement between TB1 and TB2 tube QFT-Plus results.
Applying the 0.35-IU/ml cutoff, 1.5% (872/58,539) (Table 3) of TB1 and TB2 results were discrepant, of which 52% (452/872) were within the borderline range of 0.20 to 0.99 IU/ml. Among patients developing active incident TB, 72% (40/55) had a TB1 and a TB2 result of ≥0.35 IU/ml.
TABLE 3.
Agreement between TB1 and TB2 results
| TB2 result | No. of patients with TB1 result |
|||||
|---|---|---|---|---|---|---|
| Negative (<0.2 IU/ml) | Borderline negative (0.2–0.34 IU/ml) | Borderline positive (0.35–0.99 IU/ml) | Positive (≥1.00 IU/ml) | Indeterminate | Total | |
| Negative (<0.2 IU/ml) | 48,527 | 439 | 145 | 28 | 75 | 49,214 |
| Borderline negative (0.2–0.34 IU/ml) | 549 | 444 | 211 | 4 | 4 | 1,212 |
| Borderline positive (0.35–0.99 IU/ml) | 188 | 241 | 1,205 | 190 | 5 | 1,829 |
| Positive (≥1.00 IU/ml) | 43 | 12 | 203 | 5,143 | 4 | 5,405 |
| Indeterminate | 35 | 2 | 2 | 6 | 834 | 879 |
| Total | 49,342 | 1,138 | 1,766 | 5,371 | 922 | 58,539 |
A uniquely positive TB2 result of ≥0.35 IU/ml with a TB1 result of <0.20 IU/ml was found in 0.4% (231/58,539) of all QFT-Plus cases (Table 3), including 1.8% (1/55) of incident TB cases. This group (TB2 result of ≥0.35 IU/ml and TB1 result of <0.20 IU/ml) would not have been detected by the previous QFT-GIT test even if a borderline range from 0.20 IU/ml had been introduced. No incident TB case was present among subjects who were uniquely QFT-Plus positive (≥0.35 IU/ml) by TB1 (Table 4).
TABLE 4.
Incident active TB in relation to initial TB1 and TB2 results
| TB2 result for cases of incident active TB (n = 55) | No. of patients with TB1 result |
|||||
|---|---|---|---|---|---|---|
| Negative (<0.2 IU/ml) | Borderline negative (0.2–0.34 IU/ml) | Borderline positive (0.35–0.99 IU/ml) | Positive (≥1.00 IU/ml) | Indeterminate | Total | |
| Negative (<0.2 IU/ml) | 7 | 1 | 8 | |||
| Borderline negative (0.2–0.34 IU/ml) | 1 | 1 | 2 | |||
| Borderline positive (0.35–0.99 IU/ml) | 2 | 3 | 5 | |||
| Positive (≥1.00 IU/ml) | 1 | 2 | 35 | 38 | ||
| Indeterminate | 2 | 2 | ||||
| Total | 9 | 4 | 5 | 35 | 2 | 55 |
Without considering borderline results, TB2 was uniquely positive (≥0.35 IU/ml) leading to a QFT-Plus result above 0.35 IU/ml (i.e., with a TB1 result of <0.35 IU/ml) in 5% (3/55) of incident TB cases (Table 4). Moreover, a TB2-TB1 result of >0.60 IU/ml, which has been suggested as a marker of recent infection (16, 17), was found in 11.6% (875/7,605) of QFT-Plus-positive (≥0.35 IU/ml) subjects, and among patients with incident active TB, 11% (6/55) had a TB2-TB1 result of >0.60 IU/ml.
Overall, the agreement between the TB1 and TB2 tubes was excellent (>95%), with a kappa value of 0.86. The TB1 tube solely provided a QFT-Plus result above 0.35 IU/ml in 5.1% of cases (388/7,605), whereas the TB2 result uniquely provided a QFT-Plus result of ≥0.35 IU/ml in 6.3% (484/7,605).
DISCUSSION
In the first evaluation of borderline-reactive QFT-Plus results obtained under routine clinical conditions in a low-endemicity country from a total of 58,539 subjects, we found that among subjects with an initial borderline-range result who were retested, 38% were convincingly negative (<0.20 IU/ml; median, 0.02 IU/ml), without any case of incident TB within 2 years. Additionally, a TB2 result of ≥0.35 IU/ml along with a TB1 result of <0.20 IU/ml was detected in 0.4% (231/58,539) of all QFT-Plus-positive results, and in this group, only 1.8% (1/55) of incident TB cases were found. This supports previous data indicating the limited clinical value of the TB2 tube (5, 18, 19) as this subgroup is representative of reactivity (TB2 result of ≥0.35 IU/ml and TB1 result of <0.20 IU/ml) that would not have been detected by the previous QFT-GIT version even if a borderline range would have been applied.
In our evaluation of the previous QFT version (QFT-GIT), we found a slightly higher fraction (55%) converting to a negative result (<0.20 IU/ml) upon retesting of the borderline group (13). We speculate that one reason for this difference may be that preanalytical practices have been improved, especially the tube shaking and transportation logistics (10, 20). This is partly supported by the observation that the initially borderline-reactive samples decreased over time between our studies (9% to 6%) (13). Our results, as well as those from others (8–10, 21, 22), strongly indicate that borderline-reactive samples may represent a false increase in QFT levels if not confirmed by retesting. It is highly unlikely that borderline QFT results that are convincingly reverting to negative close to 0 IU/ml within 4 weeks are a result of an initial specific immune response to TB antigens. This is also supported by the fact that no patient with incident active TB was identified during a 2-year follow-up in this group; i.e., no reactivation as a sign of LTB infection was found. Additionally, experimental data support that transportation temperature, vigorous shaking, choice of ELISA platform, errors in incubation conditions, and several other factors may contribute to false-positive QFT results (10, 20, 23). We acknowledge that in many, but far from all, cases, borderline IGRA reactivity may well be based on “true” antigen reactivity if it is repeatable and linked to clinically relevant outcome data (24). However, without considering preanalytical variability that is present in all laboratory methods and relying on a confirmation of IGRA antigen reactivity based on even further unspecific methods such as the tuberculin skin test (TST) or epidemiological data at a group level without retesting and confirmation of IGRA results, we find it difficult to prove that all IGRA reactivity around a questioned cutoff is clinically relevant and represents a specific antigen response (24).
The contribution of the additional tube (TB2) to QFT-Plus has been widely discussed; it has been suggested to increase sensitivity due to the CD8+ T-cell response (4–6, 25). Several studies have shown that the median level of IFN-γ release is slightly higher in the TB2 tube but that the clinical importance of this finding and the contribution of the TB2 tube to the diagnosis of active TB or LTB appear limited and similar to that of QFT-GIT (5, 6, 25). Our data support those results as uniquely TB2-positive subjects (TB2 result of ≥0.35 IU/ml and TB1 result of <0.20 IU/ml) were found in 0.4% (231/58,539) of all QFT-Plus-positive cases, including 1.8% (1/55) of incident TB cases. In relation to previous results showing an association with a TB2-TB1 result of >0.60 IU/ml and recent exposure (16, 17), we found that this subgroup to some extent was present among active incident TB cases (11%; 6/55). However, our study is based in a very low-endemicity setting for active TB, and further studies from high-endemicity areas are needed before firm conclusions can be drawn about the contribution of the TB2 tube.
Our study has several limitations. First, a major and important limitation is that information on the indication for testing at the individual level was lacking, which makes data prone to bias when evaluating the risk for developing incident active TB and the contribution of the TB2 tube. Factors such as HIV, malnutrition, and immunosuppression may have affected test performance. However, the majority of subjects screened for LTB are among migrants, who also constitute about 85% of the active TB cases in Sweden (26, 27). Second, treatment of LTB may have underestimated the development of incident active TB although not in the group of borderline-reactive samples where LTB treatment is very rarely provided before retesting. Third, the analytical reason for the borderline-positive result reverting to negative was not addressed, including at which time of the day the sample was collected, which may affect T-cell responses. Fourth, our results are mainly valid for similar low-endemicity settings using QFT-Plus for similar clinical indications. Finally, the number of incident active TB cases is limited.
In conclusion, a borderline range is also valid for the QFT-Plus test and leads to a convincingly negative result upon retesting in about one-third of subjects during screening for LTB in a low-endemicity area. The contribution of the TB2 tube to the diagnosis of LTB and active TB needs to be further evaluated.
Contributor Information
T. Schön, Email: tschon@hotmail.com.
Christine Y. Turenne, University of Manitoba
REFERENCES
- 1.Cohen A, Mathiasen VD, Schön T, Wejse C. 2019. The global prevalence of latent tuberculosis: a systematic review and meta-analysis. Eur Respir J 54:1900655. doi: 10.1183/13993003.00655-2019. [DOI] [PubMed] [Google Scholar]
- 2.World Health Organization. 2015. The End TB Strategy. World Health Organization, Geneva, Switzerland. [Google Scholar]
- 3.Kim HW, Kim JS. 2018. Treatment of latent tuberculosis infection and its clinical efficacy. Tuberc Respir Dis (Seoul) 81:6–12. doi: 10.4046/trd.2017.0052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Qiagen. 2016. QuantiFERON-TB Gold Plus (QFT-Plus) ELISA package insert—the whole blood IFN-γ test measuring responses to ESAT-6 and CFP-10 peptide antigens. 1083163 Rev. 04. Qiagen, Valencia, CA. [Google Scholar]
- 5.Venkatappa TK, Punnoose R, Katz DJ, Higgins MP, Banaei N, Graviss EA, Belknap RW, Ho CS. 2019. Comparing QuantiFERON-TB Gold Plus with other tests to diagnose Mycobacterium tuberculosis infection. J Clin Microbiol 57:e00985-19. doi: 10.1128/JCM.00985-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lee M-R, Chang C-H, Chang L-Y, Chuang Y-C, Sun H-Y, Wang J-T, Wang J-Y. 2019. CD8 response measured by QuantiFERON-TB Gold Plus and tuberculosis disease status. J Infect 78:299–304. doi: 10.1016/j.jinf.2019.01.007. [DOI] [PubMed] [Google Scholar]
- 7.Swedish Public Health Authority. 2017. Recommendations for preventive measures against tuberculosis. 00497-2017: revised 2020. Swedish Public Health Authority, Stockholm, Sweden. [Google Scholar]
- 8.Dorman SE, Belknap R, Graviss EA, Reves R, Schluger N, Weinfurter P, Wang Y, Cronin W, Hirsch-Moverman Y, Teeter LD, Parker M, Garrett DO, Daley CL, Tuberculosis Epidemiologic Studies Consortium . 2014. Interferon-γ release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States. Am J Respir Crit Care Med 189:77–87. doi: 10.1164/rccm.201302-0365OC. [DOI] [PubMed] [Google Scholar]
- 9.Tagmouti S, Slater M, Benedetti A, Kik SV, Banaei N, Cattamanchi A, Metcalfe J, Dowdy D, van Zyl Smit R, Dendukuri N, Pai M, Denkinger C. 2014. Reproducibility of interferon gamma (IFN-γ) release assays. A systematic review. Ann Am Thorac Soc 11:1267–1276. doi: 10.1513/AnnalsATS.201405-188OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Nemes E, Rozot V, Geldenhuys H, Bilek N, Mabwe S, Abrahams D, Makhethe L, Erasmus M, Keyser A, Toefy A, Cloete Y, Ratangee F, Blauenfeldt T, Ruhwald M, Walzl G, Smith B, Loxton AG, Hanekom WA, Andrews JR, Lempicki MD, Ellis R, Ginsberg AM, Hatherill M, Scriba TJ, C-040-404 Study Team, Adolescent Cohort Study Team . 2017. Optimization and interpretation of serial QuantiFERON testing to measure acquisition of Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 196:638–648. doi: 10.1164/rccm.201704-0817OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Folkvardsen DB, Holicka Y, Ködmön C, van der Werf MJ, Lillebaek T, Nikolayevskyy V, Participants from the ERLTB-Net-2 Network . 2021. Reporting of interferon-gamma release assay results close to cut-off values. Int J Tuberc Lung Dis 25:66–68. doi: 10.5588/ijtld.20.0585. [DOI] [PubMed] [Google Scholar]
- 12.Metcalfe JZ, Cattamanchi A, McCulloch CE, Lew JD, Ha NP, Graviss EA. 2013. Test variability of the QuantiFERON-TB Gold in-tube assay in clinical practice. Am J Respir Crit Care Med 187:206–211. doi: 10.1164/rccm.201203-0430OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jonsson J, Westman A, Bruchfeld J, Sturegård E, Gaines H, Schön T. 2017. A borderline range for Quantiferon Gold in-tube results. PLoS One 12:e0187313. doi: 10.1371/journal.pone.0187313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Schablon A, Nienhaus A, Ringshausen FC, Preisser AM, Peters C. 2014. Occupational screening for tuberculosis and the use of a borderline zone for interpretation of the IGRA in German healthcare workers. PLoS One 9:e115322. doi: 10.1371/journal.pone.0115322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Swedish Public Health Agency. 2020. Recommendations for preventive measures against tuberculosis. Swedish Public Health Agency, Stockholm, Sweden. [Google Scholar]
- 16.Petruccioli E, Chiacchio T, Pepponi I, Vanini V, Urso R, Cuzzi G, Barcellini L, Cirillo DM, Palmieri F, Ippolito G, Goletti D. 2016. First characterization of the CD4 and CD8 T-cell responses to QuantiFERON-TB Plus. J Infect 73:588–597. doi: 10.1016/j.jinf.2016.09.008. [DOI] [PubMed] [Google Scholar]
- 17.Barcellini L, Borroni E, Brown J, Brunetti E, Campisi D, Castellotti PF, Codecasa LR, Cugnata F, Di Serio C, Ferrarese M, Goletti D, Lipman M, Rancoita PMV, Russo G, Tadolini M, Vanino E, Cirillo DM. 2016. First evaluation of QuantiFERON-TB Gold Plus performance in contact screening. Eur Respir J 48:1411–1419. doi: 10.1183/13993003.00510-2016. [DOI] [PubMed] [Google Scholar]
- 18.Shafeque A, Bigio J, Hogan CA, Pai M, Banaei N. 2020. Fourth-generation QuantiFERON-TB Gold Plus: what is the evidence? J Clin Microbiol 58:e01950-19. doi: 10.1128/JCM.01950-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Takasaki J, Manabe T, Morino E, Muto Y, Hashimoto M, Iikura M, Izumi S, Sugiyama H, Kudo K. 2018. Sensitivity and specificity of QuantiFERON-TB Gold Plus compared with QuantiFERON-TB Gold in-tube and T-SPOT.TB on active tuberculosis in Japan. J Infect Chemother 24:188–192. doi: 10.1016/j.jiac.2017.10.009. [DOI] [PubMed] [Google Scholar]
- 20.Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, Metcalfe JZ, Cattamanchi A, Dowdy DW, Dheda K, Banaei N. 2014. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 27:3–20. doi: 10.1128/CMR.00034-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Knierer J, Gallegos Morales EN, Schablon A, Nienhaus A, Kersten JF. 2017. QFT-Plus: a plus in variability? Evaluation of new generation IGRA in serial testing of students with a migration background in Germany. J Occup Med Toxicol 12:1. doi: 10.1186/s12995-016-0148-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Fernández-Huerta M, Moreto C, Vila-Olmo N, García de Cara E-I, Basaez M-C, Santín M, Alcaide F. 2021. Evaluation of the fully automated chemiluminescence analyzer Liaison XL for the performance of the QuantiFERON-TB Gold Plus assay in an area with a low incidence of tuberculosis. J Clin Microbiol 59:e00603-21. doi: 10.1128/JCM.00603-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Banaei N, Gaur RL, Pai M. 2016. Interferon gamma release assays for latent tuberculosis: what are the sources of variability? J Clin Microbiol 54:845–850. doi: 10.1128/JCM.02803-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Uzorka JW, Kroft LJM, Bakker JA, Van Zwet EW, Huisman E, Knetsch-Prins C, van der Zwan CJ, Ottenhoff THM, Arend SM. 2017. Proof of concept that most borderline Quantiferon results are true antigen-specific responses. Eur Respir J 50:1701630. doi: 10.1183/13993003.01630-2017. [DOI] [PubMed] [Google Scholar]
- 25.Hogan CA, Tien S, Pai M, Banaei N. 2019. Higher positivity rate with fourth-generation QuantiFERON-TB Gold Plus assay in low-risk U.S. health care workers. J Clin Microbiol 57:e01688-18. doi: 10.1128/JCM.01688-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Shedrawy J, Deogan C, Öhd JN, Hergens M-P, Bruchfeld J, Jonsson J, Siroka A, Lönnroth K. 2021. Cost-effectiveness of the latent tuberculosis screening program for migrants in Stockholm region. Eur J Health Econ 22:445–454. doi: 10.1007/s10198-021-01265-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Swedish Public Health Authority. 2021. Annual tuberculosis report 2020. (In Swedish.) Swedish Public Health Authority, Stockholm, Sweden. https://www.folkhalsomyndigheten.se/folkhalsorapportering-statistik/statistik-a-o/sjukdomsstatistik/tuberkulos/. Accessed 5 September 2021. [Google Scholar]