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

Abstract

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.

Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis

“…While the quality of study participation, analytical procedure, outcome measurement and analysis were mostly good to evaluate among studies, that of the participation rate and the confounding measurement and account were relatively poor. Only 7 14,17,18,20,21,23,25 of 17 studies had a sufficient participation rate, and the rates in the others were under 50%. For confounding measurement and accounting, eight studies did not assess adequately.…”

“…Advanced age. Pooled odds ratio (pooled OR: 2.06, 95% CI 1.68-2.52) of advanced age calculated with raw data available in 5 of the 14 included studies 6,8,15,20,22 showed a significant relationship between advanced age and false negative results with very low heterogeneity (Fig. 2).…”

“…We finally included 17 studies in this systematic review: 14 6,7,13-24 and 3 studies 8,25,26 were retrospective and prospective observational studies, respectively. These published studies, 4 from low-incidence countries: United States of America (n = 2) 6,22 , Denmark (n = 1) 13 and the EU (n = 1) 14 ; 11 from middle-incidence countries: South Korea (n = 6) 14, [16][17][18]20,26 and China (n = 4) 8,13,15,21 and Japan (n = 1) 7 ; and 3 from high-incidence countries: Viet Nam (n = 1) 25 , Tanzania (n = 1) 13 and Zambia (n = 1) 23 . The results from Denmark and Tanzania were reported collectively in one study 13 .…”

“…The results from Denmark and Tanzania were reported collectively in one study 13 . Six studies evaluated risk factors for false negative results of IGRAs in a non-HIV population 7,8,16,18,20,24 (Table 1). How many times the IGRA was performed per sample was not mentioned in any study included in this review.…”

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

“…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.…”