Positivity rate of QuantiFERON-TB Gold Plus ® test among candidates for biotherapy and factors influencing results

Abstract

Background:

Latent tuberculosis infection, an infection caused by Mycobacterium tuberculosis, affects one-quarter of the world’s population. The World Health Organization recommends screening for latent tuberculosis infection in at-risk populations to reduce morbidity and mortality risks associated with tuberculosis using the tuberculin skin test and interferon-gamma release assays, including the QuantiFERON-TB Gold Plus^® test (QTF-Plus^® test).

Objectives:

This study aimed to assess the place of QTF-Plus test in latent tuberculosis infection screening among a high-risk population.

Methods:

A total of 969 biotherapy candidates were included in the study (52.63% female and 47.36% male; sex ratio = 0.9).

Results:

The mean age was 38.29 ± 15.83 years. The frequency of latent tuberculosis infection, according to QTF-Plus test results, was 20.22%. Factors such as age and history of tuberculosis were significantly associated with QTF-Plus test results (p = 0.002 and p < 0.0001, respectively). QTF-Plus test and tuberculin skin test were performed simultaneously on 632 patients. A weak agreement between these tests was found (77.50%, Cohen’s kappa coefficient of 0.13). However, a good correlation between TB antigen tube 1 and TB antigen tube 2 (r = 0.72, p < 0.0001; 95% CI: 0.68–0.74) was observed.

Conclusion:

Our findings demonstrate that the QTF-Plus test is useful for latent tuberculosis infection screening in a highly vaccinated population with an intermediate prevalence of tuberculosis

Keywords

Latent tuberculosis infection IGRA Algeria

Introduction

Tuberculosis is a major global health problem caused by the intracellular pathogen Mycobacterium tuberculosis. It is currently the leading cause of death attributable to a single infectious agent, surpassing even human immunodeficiency virus (HIV) until the emergence of the COVID-19 pandemic. According to the 2023 report by the World Health Organization (WHO), an estimated 10.8 million people contracted tuberculosis worldwide in 2021.¹ Algeria is considered a country with an intermediate prevalence of the disease, with an incidence rate of 41.10 cases per 100,000 persons (5635 pulmonary tuberculosis (TB) cases, 13249 extrapulmonary TB cases).²

Diagnosis and treatment of active tuberculosis alone are not sufficient to restrain its global incidence. For this reason, the WHO recommends screening and treating latent tuberculosis infection (LTBI) in at-risk populations as part of its “THE END-TB STRATEGY,” which aims to reduce global TB incidence by 90% and TB-related deaths by 95% by the year 2035.³

LTBI is defined as the presence of M. tuberculosis with the absence of any clinical or radiological proof of active tuberculosis. It represents a state of dynamic equilibrium between the host and the pathogen, characterized by a specific immune response that controls the TB multiplication but is unable to eliminate it.⁴ The risk of developing active tuberculosis due to LTBI reactivation could increase considerably in high-risk populations, particularly in patients candidates for biological therapies, notably anti–tumor necrosis factor alpha, renal transplant recipients, and HIV patients.¹

For several reasons, the diagnosis of LTBI is challenging. First, no diagnostic gold standard exists for this condition. Second, all available methods rely on the detection of cell-mediated immune (CMI) response to M. tuberculosis, which explains why performance is reduced in immunosuppressed individuals, who are also at increased risk of progression to active disease. Finally, current tests cannot distinguish between true latent infection, persistence of contained viable bacteria, cleared TB infection, and active disease.

Several tests have been used to help diagnose LTBI infection by tuberculin skin test (TST) and interferon-gamma release assays (IGRA),⁵ such as QuantiFERON-TB Gold Plus^® (QTF-Plus^® test) (ELISA) and T-SPOT-TB^® (ELISpot). The QTF-Plus test is a test for CMI responses to peptide antigens that stimulate mycobacterial proteins. These proteins, early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10), are absent from all Bacille Calmette–Guérin (BCG) strains and from most non-tuberculous mycobacteria except Mycobacterium kansasii, Mycobacterium szulgai, and Mycobacterium marinum. Individuals infected with M. tuberculosis complex (MTB-complex) organisms usually have lymphocytes (CD4⁺ T lymphocytes and CD8⁺ T lymphocytes) in their blood that recognize these and other mycobacterial antigens. This recognition process involves the generation and secretion of the cytokine IFN-γ. The detection and subsequent quantification of IFN-γ forms the basis of this test.

This study aimed to assess the test’s contribution to LTBI screening in high-risk populations, taking into account factors that could influence the results, as well as the agreement between the TST and QTF-Plus test in a country that is largely vaccinated with BCG and has an intermediate prevalence of tuberculosis.

Patients and methods

Patients

In this retrospective cross-sectional study, a total of 969 patients candidates for biotherapy were included from various departments: 385 from the Gastroenterology Department, 87 from the Dermatology Department, 71 from the Internal Medicine Department, and 385 outpatients (from public and private institutions), most of whom were recruited from the Rheumatology Department. This study was approved by the Ethics Committee of Mustapha Bacha Teaching Hospital, Algiers, Algeria. Demographic and clinical data, bacteriological status, chest X-ray, and BCG vaccination were collected from patient records. In addition, the results of 632 patients’ TST, performed 3 days prior to blood sampling, were recorded, along with data related to a blood count formula.

Inclusion criteria were patients of all ages with autoimmune diseases, or inflammatory bowel diseases (IBD), who were candidates for biological therapies and who underwent QFT-Plus testing as part of the pre-treatment screening for LTBI, prior to therapy initiation. Patients with suspected pulmonary or extrapulmonary tuberculosis were excluded from the study.

Methods

The study period extended from January 2023 to April 2025. All patients included underwent the QTF-Plus test. During the pre-analytical phase of the test, whole blood was divided into specialized tubes and incubated at 37°C. Plasma was collected after 16–24 h. The analytical phase involves quantifying INF-γ in plasma by the enzyme-linked immunosorbent assay (ELISA) technique.

The antigens used in the QTF-Plus test are a peptide cocktail simulating the proteins ESAT-6 and CFP-10. QTF-Plus test has two distinct TB antigen tubes: TB antigen tube 1 (TB1) and TB antigen tube 2 (TB2). Both tubes contain peptide antigens from the MTB–complex–associated antigens, ESAT-6 and CFP-10. Whereas the TB1 tube contains peptides from ESAT-6 and CFP-10 that are designed to elicit CMI responses from CD4⁺ T-helper lymphocytes, the TB2 tube contains an additional set of peptides targeted to the induction of CMI responses from CD8⁺ cytotoxic T lymphocytes.

The test was positive when the Ag-tube nil value is ⩾0.35 IU/ml and ⩾25% of the null value; negative when the Ag-tube nil value <0.35 IU/ml or <25% of the null value. Indeterminate when the response to negative control is positive (⩾8 IU/ml) or the response to mitogen is negative (⩽0.5 IU/ml).

Regarding the TST, it was performed using the Mantoux method and read after 72 h by trained healthcare personnel. Induration was measured in millimeters, and the TST was considered positive when the induration was ⩾10 mm.

Ethical considerations

The study was approved by the Institutional Review Board. In Algeria, ethics committees generally do not provide a formal approval number. The Institutional Review Board waived the requirement for written informed consent due to the retrospective nature of the study.

Statistical analysis

Associations between the variables studied and the QTF-Plus test were analyzed using the Student’s t-test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. The results were presented as odds ratios with their 95% confidence intervals. Concordance was evaluated using Cohen’s kappa coefficient, interpreted according to the Landis and Koch classification (κ < 0.4, low; 0.4 ⩽ κ < 0.75, moderate to good; κ ⩾ 0.75, excellent). Correlation between TB1 and TB2 was analyzed using Spearman’s correlation test (non-parametric test). A significant difference was observed between the two variables for any p-value less than or equal to 0.05.

Results

Socio-demographic and clinical data

Of the 969 patients included in this study, 52.63% were women and 47.36% were men, with a sex ratio of 0.9. The mean age was 38.29 ± 15.83 years.

Patient demographics and clinical characteristics are summarized in Table 1.

Table 1.

Socio-demographic and clinical data of the study participants.

Variable	Total (n = 969)
Age (years), mean ± SD	38.29 ± 15.83
Gender, n (%)
Male	459 (47.36)
Female	510 (52.63)
BCG vaccination, n (%)
Yes	818 (84.41)
No	30 (3.09)
Unknown	121 (12.48)
History of TB, n (%)	28 (2.88)
TST, n (%)	632 (65.22)
Positive	54 (35.57)
Negative	566 (58.41)
Diagnosis, n (%)
Crohn’s disease	453 (46.74)
Ulcerative colitis	58 (5.98)
Spondyloarthritis	138 (14.24)
Rheumatoidarthritis	99 (10.21)
Autoimmune diseases: systemic lupus erthematosus, autoimmune bullous disease, ANCA (Anti-Neutrophil Cytoplasmic Antibodies) associated vascularitis	148 (15.27)

SD: standard deviation; TST: tuberculin skin test; BCG: Bacille Calmette–Guérin; TB: tuberculosis.

QTF-Plus test result

Of the 969 patients included in the study, 196 (20.22%) were positive for the QTF-Plus test. Of these, 17 had a history of tuberculosis. Twenty-five patients (2.57) had indeterminate results.

Factors influencing the result of the QTF-Plus test

A significant association was found between age over 60 years and a negative result on the QTF-Plus test (p = 0.002; OR = 0.48; 95% CI: 0.30–0.77) and the presence of a history of tuberculosis (p < 0.0001; OR = .009; 95% CI: 2.81–12.85). On the other hand, no association was found between BCG vaccination and gender and QTF-Plus test (p = 0.81; OR = 1.29; 95% CI: 0.48–3.43, p = 0.1327; OR = 0.78; 95% CI: 0.57–1.07; respectively). QTF-Plus test results, according to the influencing factors, are summarized in Table 2.

Table 2.

Factors influencing results of the QTF-Plus^® test.

Factors	QTF-Plus test
Factors	Positive (n = 196)	Negative (n = 751)	Indeterminate (n = 22)	OR (95% CI)	p-value
Age (years) >60	173	664	3	0.48 (0.42–0.80)	0.002
Age (years) <15	23	87	19	0.39 (0.21–0.75)	<0.0001
Gender, n (%)
Male	103 (10.62)	351 (35.91)	6 (0.61)	0.78 (0.57–1.07)	ns
Female	93 (9.59)	400 (41.27)	16 (1.65)	0.78 (0.57–1.07)	ns
BCG, vaccination n (%)
Yes	163 (16.82)	630 (65.01)	20 (2.06)	1.29 (0.48–3.43)	ns
No	5 (0.51)	25 (2.57)	2 (0.20)	1.29 (0.48–3.43)	ns
History of TB, n (%)
Yes	17 (1.75)	12 (1.23)	0	6.009 (2.8–12.58)	<0.0001
No	153 (15.78)	649 (66.97)	22 (2.27)	6.009 (2.8–12.58)	<0.0001

BCG: Bacille Calmette–Guérin, QTF-Plus test: QuantiFERON-TB Gold Plus^® test, OR: odds ratio, ns: not significant, n: number of participants, 95% CI: 95% confidence interval, TB: tuberculosis.

A total of 25 indeterminate QTF-Plus test results (2.57%) were recorded. After excluding repeated indeterminate results in the same individuals, 22 unique patients were identified (88%). Among these 22 patients, 7 patients (31.81%) had moderate lymphopenia (1500–4000 lymphocytes/mm³) with a significant association (p = 0.012). In three other cases (13.63%), indeterminate results were due to positivity of the negative control, reflecting high background IFN-γ levels. A significant association (p < 0.0001) was also found between age below 15 and the indeterminate results of the QTF-Plus test.

Concordance of QTF-Plus test and TST test results

The agreement between TST and QTF-Plus test was low, 77.50%, with a Cohen kappa coefficient of 0.13, indicating a low concordance. Of the 124 patients with a discrepancy between the two tests in the majority, 89 patients had QTF-Plus test positive and TST negative, while 35 patients had QTF-Plus negative and TST positive. The agreement was better when the TST threshold was set at 5 mm compared to the 10 mm (k = 0.17) threshold (Table 3). QTF-Plus test results and the induration diameter of the TST reveal a significant association (p < 0.0001; Figure 1).

Table 3.

Concordance between the QTF-Plus^® test and the TST.

Total (n = 610)	TST⁻	TST⁺	Total	Kappa
QTF-Plus test: Positive	89	19	108	0.13
QTF-Plus test: Negative	467	35	502
Total	556	54	610

Undetermined results were excluded. TST: tuberculin skin test.

Figure 1.

Association between induration diameter and QTF-Plus^® test results.

None of the factors studied (age, gender, BCG vaccination, TB history, lymphopenia) was associated with a discrepancy in our series (Table 4).

Table 4.

Patient characteristics according to the TST and the QTF-Plus^® test type of discordance.

Characteristics	TST⁺/QTF⁻ (n = 35)	TST⁻/QTF⁺ (n = 89)	p-value
Age (years), mean ± SD	38.35 ± 15.71	38.29 ± 15.58	ns
Gender, n (%)			ns
Male	23	48
Female	12	41
BCG vaccination, n (%)			ns
Yes	33	76
No	0	1
History of TB, n (%)	1	7	ns
Lymphopenia, n	0	8	ns

BCG: Bacille Calmette–Guérin, QTF-Plus test: QuantiFERON-TB Gold Plus^® test, TB: tuberculosis, ns: not significant, n: number of participants, TST: tuberculin skin test; SD: standard deviation.

Evaluation of the TB1 versus TB2 response

To evaluate the responses to peptides in TB1 and TB2, a comparative analysis was performed between TB1 and TB2, and IFN-γ levels in TB1 and TB2 were also analyzed relative to the induration diameter of TST test. The results of the QTF-Plus test were stratified according to the ability of subjects to respond to both TB1 and TB2, only TB1, or only TB2. We observed that 159 patients were positive for both TB1 and TB2 tubes, while 7 patients were positive only for TB1 and 27 for TB2. The correlation coefficient between the two tube responses were r = 0.72 (p < 0.0001; Figure 2). Analysis of IFN-γ levels showed a significant association between TST diameter and TB1 or TB2 IFN-γ levels (p < 0.0001 and p < 0.0001, respectively; Figure 3).

Figure 2.

Correlation between IFN-γ levels in TB1 and TB2.

Figure 3.

Association between the IFN-γ levels in TB1 and TB2 with the induration diameter.

Discussion

Screening for latent TB infection is strongly recommended to reduce the risk of progression to active TB. This progression risk is estimated at 5%–10% in subjects at risk and can be detected using the IGRA tests more than the TST.¹

In this study, a total of 969 patients candidates for biotherapy were enrolled in a country (Algeria) with intermediate prevalence of tuberculosis, where BCG vaccination is mandatory.

The frequency of LTBI, based on the results of the QTF-Plus test, was 20.22%. This is consistent with the results of studies in countries with intermediate prevalence of TB using the same test, as evidenced by studies conducted in Tunisia in patients with chronic IBD (21.9%),⁵ in Spain involving 2999 immunosuppressed patients and/or candidates for biologics therapy with a rate of 18.71%⁶ and in South Korea with immunocompromised patients a rate of 18.8%.⁷

It is important to note that our findings do not reflect the true prevalence of LTBI among the general Algerian population. In fact, our study was conducted on a pre-selected population, consisting of candidates for biotherapy.

Several factors that may influence the results of the QTF-Plus test, such as age, gender, tuberculosis history, and BCG vaccination, have been well described and documented in the literature.

In our study, a significant association was observed between age over 60 years and a negative result on the QTF-Plus test. This finding may be explained by immunosenescence, as a decline in immune function in older individuals may reduce the sensitivity of assays used to detect LTBI in this population. This limitation is observed for the TST, with a higher proportion of false negatives attributed to compromised skin immunity in older people. A lower sensitivity has also been reported for the QTF-Plus test in older people, although less marked than with the TST.⁸ However, we did not have a gold standard for LTBI, and hence, we cannot rule out a lower sensitivity of the QTF-Plus test in the oldest participants (⩾60 years).

Nevertheless, evidence in the literature remains inconsistent. Two studies conducted on similar populations: Sellami et al. study, which included 105 patients with IBD,⁵ and the Igari et al. study, which involved 135 renal transplant recipients, aged 60 years or higher, were related to the higher positivity rate.⁹ A study by Scordo et al. in community controls with no reported exposure or a remote history of exposure to a TB case also came to a similar conclusion.¹⁰ This association may be explained by the fact that older individuals have an increased risk of being exposed to TB in their lifetime. In addition, with age, immune response capabilities tend to decrease gradually. This decrease may promote endogenous reactivation of tuberculosis.^11,12

In patients under 15 years of age, we observed an association between indeterminate results of the QTF-Plus test. This finding is in line with the results of other studies, notably that conducted by Zheng et al., which involved 33,662 children¹³ and that of Soler-Garcia et al.¹⁴ In addition, we found that of the eight indeterminate results in children, seven were due to insufficient production of IFN-γ in response to phytohemagglutinin (PHA) stimulation, indicating insufficient mitogen responses. This observation is consistent with other studies’ results.¹⁵

These findings may be explained by the influence of age on cytokine release and the decrease in this release in children.^16,17 Age seems to influence the amplitude of PHA-induced IFN-γ. The use of age-specific thresholds for positive controls or the incorporation of another stimulant could help reduce the rate of indeterminate results.¹⁵ These indeterminate results pose a considerable challenge to clinicians, as they do not provide any information about the patient’s TB infection status.

Although previous studies have reported a higher prevalence of indeterminate results in immunocompromised patients, patients undergoing immunosuppressive therapy, or patients with lymphopenia,¹⁸ our findings showed a statistically significant association between indeterminate results and the presence of lymphopenia.

Consistent with other studies, we also observed a significant association between the positive QTF-Plus test and a history of tuberculosis. Matilus et al. found that the performance of the QTF test was related to the presence of risk factors for LTBI, such as a history of tuberculosis or close contact with a sick person.¹⁹ This association has also been supported by additional studies.^20,21

A low agreement was found between the QTF-Plus test results and TST, similar to what has been observed in other studies. Sellami et al. studied IBD patients⁵ and Rendón et al. studied healthy subjects.²² These studies were conducted in countries with intermediate TB prevalence where BCG vaccination is mandatory. In addition, some studies have revealed a low agreement between the two tests in people born in countries where the prevalence of tuberculosis is high; this phenomenon would be attributed to BCG vaccination, which could lead to false-positive results with the TST test.^23,24

Conversely, studies in countries with low or moderate TB prevalence such as Belgium and Venezuela, where BCG vaccination is less common and with low TB prevalence, reported a better agreement between the two tests 0.59²⁵ and 0.76.²⁶

This makes the choice of LTBI screening difficult, as it will depend on the prevalence of tuberculosis and the rate of BCG vaccination.

Studies that evaluated factors associated with discordance have attributed an association between QTF⁺/TST⁻ discordance and immunosuppressive therapy or corticosteroid treatment that affects TST, leading to false negatives.^5,27 This explanation is highly relevant to our cohort, which predominantly consisted of immunocompromised patients receiving corticosteroids and/or other immunosuppressive treatments. This effect has not been confirmed by all authors. However, it does not influence the QTF-Plus test.⁵ This is also because the QTF-Plus test only detects IFN-γ in vitro, whereas the TST is an in vivo test that requires various cytokines, including IFN-γ. All these cytokines are easily inhibited by immunosuppressive drugs.²⁸

The QTF-Plus test is the fourth generation of IGRA tests introduced in 2016, replacing the latest QuantiFERON Gold-In-Tube^®. A major difference of this last generation is the inclusion of two tubes containing specific antigens of M. tuberculosis namely TB1 and TB2. This particular feature of the TB2 is capable of activating CD8⁺ T cells, which was supposed to improve the test’s sensitivity.²⁹ This benefit of TB2 was particularly noted in immunocompromised subjects with a collapse of the CD4⁺ T-cell count (such as HIV patients). Other studies have shown that a high level of Mycobacterium-specific CD8⁺ T cells was present in patients with tuberculosis disease, but not in those with LTBI. Furthermore, according to Barcellini et al., a difference between TB2 and TB1 responses greater than 0.6 IU/ml could predict the development of LTBI toward disease.³⁰

In contrast to the CD4-dominant TB1 tube, which primarily stimulates helper T cells, the TB2 tube was specifically engineered to improve diagnostic sensitivity by stimulating CD8⁺ T cells. This design is theoretically advantageous in immunocompromised environments; however, our data indicate that it provides minimal additional value in routine screening. In our study, a strong correlation was found between TB1 and TB2 responses, which is consistent with other studies such as Tsuyuzaki et al.,³¹ Gupta et al.,³² and Djibougou et al.²⁴ However, our study could not show a significant advantage of TB2, which distinguishes the QTF-Plus test from previous generations. In other words, responses to TB2 did not differ significantly from responses to TB1, suggesting that the new tube makes only a limited contribution to the diagnosis of LTBI. Further studies on patients with tuberculosis disease could more accurately assess the usefulness of TB2.

However, it is important to note that the CD8⁺ T-cell response is more associated with tuberculosis disease than with LTBI. Therefore, further studies on patients with confirmed tuberculosis are necessary to fully assess its usefulness.

Our study highlights the challenges of establishing a diagnosis of LTBI in the absence of an undisputed diagnostic reference. The evaluation of the performance of the QTF-Plus test in LTBI screening is complex due to the lack of a diagnostic reference. Various approaches have been suggested to estimate the sensitivity and specificity of this test, although these estimates are less reliable. These approaches include the use of partial reference tests, such as chest CT scan,⁵ specificity assessment in subjects with a very low risk of tuberculosis (such as those living in countries with low incidence) and sensitivity in culture-confirmed patients with active tuberculosis,³³ or assuming that all patients with at least one positive test (QTF and/or TST) have an LTBI.¹²

Our study has some limitations. First, the study was conducted at a single referral center where BCG vaccination is mandatory, and the TB burden is intermediate. Therefore, the results of this study may not be applicable to regions where the TB burden is low or high. Second, we collected data on patients candidates for biologic therapy; complete information on underlying diseases and previous or concurrent medications was not available for all participants. This limited our ability to fully analyze the potential influence of these factors on QFT-Plus results. Third, the study population consisted mainly of patients with immune-mediated inflammatory diseases who were already receiving conventional immunosuppressive therapy, which may limit the generalizability of our findings to other populations. Finally, the absence of a priori sample size calculation, since all eligible participants during the study period were included.

Conclusion

In summary, the QTF-Plus test remains a valuable tool for screening LTBI, particularly in populations with widespread BCG vaccination, such as Algeria. The performance of the QTF-Plus test is influenced by factors such as age and a history of tuberculosis.

To better assess its utility, it would be beneficial to evaluate each risk group separately and to follow patients longitudinally, to estimate the test’s prognostic value and the risk of progression to active tuberculosis in at-risk individuals.

Footnotes

Acknowledgements

The authors would like to express their sincere gratitude to the residents Dr. Khelfaoui, Dr. Bradai, Dr. Aberkane, and Dr. Oukrif for their valuable assistance in the practical laboratory work, particularly in performing the QuantiFERON-TB Gold Plus assays. We also extend our heartfelt thanks to Professor Meddour for his insightful comments and constructive revisions that significantly improved the quality of the manuscript.

The authors also acknowledge all collaborating clinical departments for their cooperation and support throughout the study, which contributed to the successful completion of this work. Special thanks to Qiagen for their technical support.

ORCID iD

Hanane Mezenner

Author contributions

Mezenner Hanane: contributed to investigation and data collection, laboratory analysis, formal statistical analysis, and wrote the original draft of the manuscript.

Hiba Ait Hamoudi: contributed to conceptualization and methodology, and participated in manuscript writing, review and editing.

Soumia Naamoune, Meriem Abbadi: reviewed and approved the final manuscript.

Meriem Khedimallah: contributed to data collection.

Kafia Belhocine, Samira Zobiri, Samia Taright: contributed by providing access to eligible patients and clinical records.

Yanis Meddour: contributed to manuscript writing, review and editing, and approved the final version.

Sofiane Samir Salah: contributed to conceptualization, methodology, supervision, and project administration, and critically reviewed and edited the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The Study was funded by QIAGEN.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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