False-negative interferon-γ release assay results in active tuberculosis: a TBNET study

Visser, Veerle De; Sotgiu, Giovanni; Lange, Christoph; Aabye, Martine G.; Bakker, Marleen; Bartalesi, Filippo; Brat, Kristián; Chee, C. B. E.; Dheda, Keertan; Domínguez, José; Eyüboğlu, Füsun Öner; Ghanem, Maha; Goletti, Delia; Dilektaşlı, Aslı Görek; Guglielmetti, Lorenzo; Koh, Won‐Jung; Latorre, Irene; Losi, Monica; Polanova, Monica; Ravn, Pernille; Ringshausen, Felix C.; Rumetshofer, Rudolf; Souza-Galvão, Maria Luiza de; Thijsen, Steven; Bothamley, Graham; Bossink, Aik

doi:10.1183/09031936.00120214

Cited by 36 publications

(34 citation statements)

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“…Previous studies reported that negative bacteria in sputum [3-5], hypoproteinemia [6-8], combined HIV infection [4, 7, 9], anti-TB treatment [10, 11], medical history [8, 12], anemia [6, 13], diabetes [14], parasitic infections [13], noncavitary lesions in the lung [5], fall and winter seasons [15], increased human leukocyte antigen DRB1-0701 allele [16] and non-Hispanic white or Asian ethnicity [6, 9] are risk factors for false negative IGRA. The association between IGRA and age [3, 7-9, 12, 13, 15-18], body mass index [12, 16] and reduced lymphocyte levels [3, 5, 7, 8, 17, 19, 20] is inconsistent among previous studies. Some of these studies were qualitative studies with small samples and did not consider the possibility that different antigen risk factors might have confounded or biased the results.…”

Section: Introductionmentioning

confidence: 99%

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Yang

Jiang

et al. 2019

Preprint

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23Background 24 Previous qualitative studies suggested that the false negative rate of T cell spot test 25 for tuberculosis infection (T-SPOT.TB) is associated with many risk factors in 26 tuberculosis patients; However, more precise quantitative studies are not well known. 27 Objective 28 To investigate the factors affecting quantified T-SPOT.TB in patients with active 29 tuberculosis.30Methods 31 We retrospectively analyzed the data of 360 patients who met the inclusion criteria. 32 Using the levels of early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate 33 protein 10 kDa (CFP-10) as dependent variables, variables with statistical 34 significance in the univariate analysis were subjected to optimal scaling regression 35 analysis. 36 Results 37The results showed that the ESAT-6 regression model had statistical significance 38 (P-trend < 0.001) and that previously treated cases, CD4+ and platelet count were its 39 independent risk factors (all P-trend < 0.05); their importance levels were 0.095, 40 0.596 and 0.100, respectively, with a total of 0.791. The CFP-10 regression model 41 also had statistical significance (P-trend < 0.001); platelet distribution width and 42 alpha-2 globulin were its independent risk factors (all P-trend < 0.05), their 43 importance levels were 0.287 and 0.247, respectively, with a total of 0.534. The 44 quantification graph showed that quantified T-SPOT.TB levels had a linear correlation 45 3 with risk factors. 46 Conclusion 47 The test results of T-SPOT.TB should be given more precise explanations, especially 48 in patients with low levels of CD4+, platelet, alpha-2 globulin and high platelet 49 distribution width. 50 51 Introduction 52 The interferon-gamma release assay (IGRA) represents one of the most important 53 advances in the immunodiagnosis of Mycobacterium tuberculosis (MTB) infection in 54 the past two decades. As a new adjuvant method for the diagnosis of MTB infection, 55 IGRA has been widely applied and accepted clinically. In principle, IGRA determines 56 whether the subject is infected with MTB by examination of the levels of released 57 γ -interferon (IFN-γ) after stimulation of whole blood or peripheral blood mononuclear 58 cells (PBMCs) with MTB-specific antigen. This test is not affected by Bacillus 59 Calmette-Guerin (BCG) vaccination [1], a feature that is very beneficial in countries 60 such as China in which general BCG vaccination is practiced. Currently, the T cell 61 spot test for tuberculosis infection (T-SPOT.TB) is the main IGRA test method; it 62 provides intuitive and reproducible results and quantitatively reflects the number of 63 IFN-γ secreting cells in preparations of PBMCs [2]. 64 IGRA still has a certain false negative rate among patients with tuberculosis (TB). 65 Previous studies reported that negative bacteria in sputum [3-5], hypoproteinemia 66 [6-8], combined HIV infection [4, 7, 9], anti-TB treatment [10, 11], medical history [8, 67 4 12], anemia [6, 13], diabetes [14], parasitic infections [13], noncavitary lesion...

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Section: Introductionmentioning

confidence: 99%

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Yang

Jiang

et al. 2019

Preprint

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“…In recent meta-analyses, pooled QFT-GIT sensitivity among persons with confirmed TB ranged from 65 to 84% with the lowest sensitivity among those with human immunodeficiency virus (HIV) infection [7, 8, 11]. As a result of inadequate sensitivity, IGRAs are considered insufficient to rule out active TB [12–22]. Identification of the host factors associated with false-negative and indeterminate QFT-GITs may improve their utility as diagnostic aids.…”

Section: Introductionmentioning

confidence: 99%

Factors that Predict Negative Results of QuantiFERON-TB Gold In-Tube Test in Patients with Culture-Confirmed Tuberculosis: A Multicenter Retrospective Cohort Study

et al. 2015

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BackgroundInterferon-γ release assays such as the QuantiFERON-TB Gold In-Tube Test (QFT-GIT) are designed to detect Mycobacterium tuberculosis infections, whether latent or manifesting as disease. However, a substantial number of persons with culture-confirmed tuberculosis (TB) have negative QFT-GITs. Information on host factors contributing to false-negative and indeterminate results are limited.MethodsA multicenter retrospective cohort study was performed with 1,264 culture-confirmed TB patients older than 18 years who were subjected to the QFT-GIT at one of the six hospitals between May 2007 and February 2014. Patients with human immunodeficiency virus infection were excluded. Clinical and laboratory data were collected in South Korea.ResultsOf all patients, 87.6% (1,107/1,264) were diagnosed with pulmonary TB and 12.4% (157/1,264) with extrapulmonary TB. The rate of negative results was 14.4% (182/1,264). The following factors were highly correlated with false-negative results in the QFT-GIT: advanced age (age ≥ 65 years, odds ratio [OR] 1.57, 95% confidence interval [CI] 1.03–2.39), bilateral disease as determined by chest radiography (OR 1.75, 95% CI 1.13–2.72), malignancy (OR 2.42, 95% CI 1.30–4.49), and lymphocytopenia (total lymphocyte count < 1.0 × 109/L, OR 1.86, 95% CI 1.21–2.87).ConclusionsConsequently, QFT-GIT results need to be interpreted with caution in patients with these host risk factors such as the elderly, bilateral disease on chest radiography, or malignancy, or lymphocytopenia.

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“…By contrast, based on positive control results (PBMCs stimulated with phytohemagglutinin) as an indicator of a patient's immune response, we did not identify immunosuppression as a risk factor for false-negative results obtained for active cases. Nevertheless, a potential explanation for negative IGRA results may relate to the spatial compartmentalization of T cells in the body during infection [18]. Considering that peripheral blood T cells are isolated from blood in order to measure IFN-γ levels via in vitro IGRA assays, such assays may miss TB antigen-speci c T cells previously recruited to infection sites from the blood during the initial course of TB disease; this loss of blood antigen-speci c T cells may thus explain the negative IGRA results we obtained for early TB cases.…”

Section: Discussionmentioning

confidence: 99%

Combined IFN-γ and IL-2 Release Assay for Detect Active Pulmonary Tuberculosis: A Prospective Multicentre Diagnostic Study in China

Yaoju

Tan

et al. 2020

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Background: We performed a prospective multicenter diagnostic study to evaluate combined interferon-γ (IFN-γ) and interleukin-2 (IL-2) release assays for detecting active pulmonary tuberculosis (TB) in China. Methods: Adult patients presenting with symptoms suggestive of pulmonary TB were consecutively enrolled in three TB-specialized hospitals. Sputum specimens and blood samples were collected from each participant at enrollment. In vitro measurements of IFN-γ and IL-2 release from Mycobacterium tuberculosis (MTB)-specific antigen-stimulated patient peripheral blood mononuclear cells were conducted using enzyme-linked immunosorbent assays (ELISAs).Results: Between July 2017 and December 2018, a total of 3,245 patients with symptoms suggestive of pulmonary TB were included in the final analysis. Of these patients, 2,536 were diagnosed with active TB, including 1,092 definite and 1,444 clinically diagnosed cases. Overall sensitivity and specificity rates of the IFN-γ release assay were 83.8% and 81.5%, respectively, as compared to IL-2 assay rates yielding greater specificity (94.3%) but lower sensitivity (72.6%). Notably, a parallel-type combination test for IFN-γ/IL-2 provided greatest overall sensitivity (87.9%) but relatively low specificity (79.8%). Meanwhile, a series-type combination test had an overall sensitivity rate of 68.5% that, when stratified by case subgroup, yielded sensitivity rates of 72.1% and 65.8% for definite and clinically diagnosed TB cases, respectively.Conclusion: We developed a new immunological method to differentiate between active TB and other pulmonary diseases. Our data demonstrated that both series-type and parallel-type IFN-γ/IL-2 combination tests may improve diagnosis of active TB cases in different settings. Additionally, the diagnostic accuracy of the series-type combination assay correlated with disease severity in our patient cohort.

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False-negative interferon-γ release assay results in active tuberculosis: a TBNET study

Cited by 36 publications

References 14 publications

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Factors that Predict Negative Results of QuantiFERON-TB Gold In-Tube Test in Patients with Culture-Confirmed Tuberculosis: A Multicenter Retrospective Cohort Study

Combined IFN-γ and IL-2 Release Assay for Detect Active Pulmonary Tuberculosis: A Prospective Multicentre Diagnostic Study in China

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