European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-019-03768-9

REVIEW

Clinical application of QuantiFERON-TB Gold in-tube in the diagnosis

and treatment of tuberculosis
Guangming Chen 1 & Huabin Wang 2 & Yanhong Wang 3

Received: 3 October 2019 / Accepted: 11 November 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
At present, although it has made great progress in the diagnosis and treatment of tuberculosis, tuberculosis is still an important
cause of morbidity and mortality. There were approximately 8.6 million new cases of tuberculosis in 2012, and approximately 1.3
million people died from tuberculosis. Early diagnosis and timely treatment are essential for controlling the spread of tuberculosis
infection and reducing mortality. Conventional methods of Mycobacterium tuberculosis detection such as acid-fast staining
microscopy and tuberculin skin test are widely used, but with low sensitivity or specificity. In recent years, a newly developed
quantitative test, γ-interferon release test (IGRA), has been recognized and widely applied to the early diagnosis and monitoring
of tuberculosis. QuantiFERON-TB Gold in-tube (QFT-GIT) is one of the mature IGRA methods. This paper summarizes the
researches on QFT-GIT in recent years and introduces its principles, methodology, clinical application, and factors of uncertain
results for the diagnosis and treatment of tuberculosis.

Keywords Mycobacterium tuberculosis infection . QuantiFERON-TB Gold in-tube . Clinical application . False negative .
Uncertain results

Introduction for the detection of tuberculosis infection. However, there are

no optimum diagnostic criteria for active tuberculosis, and
According to World Health Organization report in 2016, the there are several shortcomings and disadvantages in the tradi-
global incidence of tuberculosis is about 142/100,000, and the tional detection methods.
mortality rate is about 19/100,000, which is 1 of the top 10 Firstly, sputum smear acid-fast staining microscopy and
causes of death in the world [1]. The number of tuberculosis Mycobacterium tuberculosis (MTB) culture positive are the
cases in China ranks second in the world. Therefore, tubercu- gold standards for the diagnosis of tuberculosis. Its advantage
losis is also one of the priority control chronic diseases in is a strong specificity, but the positive rate and sensitivity are
China. Although it has made great progress in the diagnosis low and time-consuming [3]. Secondly, tuberculin skin test
and treatment of tuberculosis, tuberculosis is still a major (TST)is also widely used to diagnose tuberculosis, but the
cause of morbidity and mortality [2]. Therefore, early diagno- purified protein derivative PPD crosses with non-tuberculous
sis and prevention of latent tuberculosis infections are impor- mycobacteria and BCG, and the results cannot distinguish
tant for epidemics control of tuberculosis and reducing tuber- between previous infections and current infections, which
culosis mortality. There are several commonly used methods may lead to false-positive results [4]; Thirdly, using imaging
technology to assist the diagnosis of tuberculosis, if it is ap-
plied alone, it may miss latent MTB infection easily due to the
* Huabin Wang low positive rate; it is also lack of specificity. On the other
whb798183844@126.com hand, molecular biology technology with high specificity and
high sensitivity develops rapidly in recent years; however, its
1
Department of General Practice, Jinhua Municipal Central Hospital, operation is complicated and requires high personnel, and the
Jinhua, People’s Republic of China lack of DNA extracted from the specimen (especially speci-
2
Central Laboratory, Jinhua Municipal Central Hospital, mens with negative sputum culture) will greatly reduce the
Jinhua, People’s Republic of China sensitivity [5, 6].Therefore, new sensitive and specific detec-
3
Department of Laboratory Medicine, Wenzhou Medical University, tion methods are urgently needed for the early diagnosis of
Wenzhou, People’s Republic of China MTB infection.
 Eur J Clin Microbiol Infect Dis

In recent years, a newly developed quantitative test, the γ- mitogen lutein is added to the positive control tube, and no
interferon release test (IGRA), has been recognized and wide- antigen stimulator is added to the negative control tube. These
ly applied to the early diagnosis and monitoring of tuberculo- three tubes must be transferred to 37 °C incubator within 16
sis, including QuantiFERON-TB Gold in-tube (QFT-GIT) test hours after collection. After 16 to 24 hours of incubation, the
and T-SPOT.TB test [7]. QFT-GIT assays γ-interferon secret- plasma was separated. Of note, violent vibration should be
ed by immune T lymphocytes under MTB infection using avoided to prevent the cell damage during the operation.
enzyme-linked immunosorbent assay can be used to diagnose Finally, ELISA was used to detect the concentration of γ-
the latent or early active tuberculosis [8]. This paper summa- interferon in plasma (IU/mL).
rizes the research on QFT-GIT in recent years and introduces
its principles, methodology, clinical application, and factors of The results interpretation of QFT-GIT test
uncertain results. It is expected to give clinicians some sug-
gestions for the choice of detection methods for the diagnosis According to the introduction, the following criteria can be
and treatment of tuberculosis. used to interpret the QFT-GIT test results (Table 1):

1) Positive: the γ-interferon of negative control tube ≤8.0

The principle and methodology of QFT-GIT IU/mL and γ-interferon of sample tube minuses the one
of negative control ≥ 0.35 and ≥ 25% of the negative
Test principle and operation process control value
2) Negative: γ-interferon in negative control tube ≤8.0 IU/
In 2007, QFT-GIT was approved by the US Food and Drug mL, positive control minuses negative control ≥0.5, and
Administration as the third generation of IGRA’s enzyme- γ-interferon of sample tube minuses the one of negative
linked immunosorbent assay (ELISA) for the diagnosis of control <0.35 or < 25% of the negative control value
MTB infection. It uses early secretory antigen target protein- 3) Uncertain result: γ-interferon of negative control tube
6 encoded by the region of difference-1 of Mycobacterium >8.0 IU/mL
tuberculosis, the culture filtrate protein-10, and the specific 4) Uncertain results: γ-interferon of negative control tube ≤
antigen TB7.7 (P4) encoded by the gene region of 8.0 IU/mL, positive control minuses negative control < 0.5
difference-13 to stimulate patient’s immune lymphocyte T IU/mL, and sample tube-negative control < 0.35 IU/mL
cells to produce γ-interferon; then the γ-interferon level is 5) Uncertain results: γ-interferon in the negative control
quantitatively measured by ELISA, and the results are per- tube ≤ 8.0 IU/mL, positive control minuses negative con-
formed according to the judgment standard [9, 10]. Since the trol < 0.5 IU/mL, sample tube minuses negative control ≥
specific antigens are not present in the BCG strain and most 0.35, and < 25% of negative control value
non-tuberculous mycobacteria, the specificity of QFT-GIT for
detecting MTB infection is superior to TST [3, 4]. According
to the manufacturer’s instructions, the specimens need to be
pretreated before the detection. The heparin anticoagulant
blood of patient is placed in three tubes (1 mL per tube), and Clinical application of QFT-GIT test
the three tubes are test sample tubes, positive control tubes,
and negative control tubes, respectively. A mixed polypeptide MTB can invade many organs of human body and cause tu-
of three specific antigens is added to the test sample tube; berculosis. According to the infection process of MTB, it can

Table 1 The interpretation of results of QFT-GIT test

γ-interferon in negative control γ-interferon in sample tube minuses γ-interferon in positive control minuses Results
(IU/mL) negative control (IU/mL) negative control (IU/mL)

≤ 8.0 < 0.35 ≥ 0.5 Negative

≥ 0.35 and < 25% of negative control value ≥ 0.5 Negative
≥ 0.35 and ≥ 25% of negative control value - Positive
< 0.35 < 0.5 Uncertain
≥ 0.35 and < 25% of negative control value < 0.5 Uncertain
> 8.0 - - Uncertain

Note: Negative results indicate that there is no or unlikely to be infected with MTB; positive results indicates suspected infection with MTB; uncertain
results indicate that tuberculosis antigen reactivity is uncertain, and further test is needed
Eur J Clin Microbiol Infect Dis

be divided into active tuberculosis and latent tuberculosis. tuberculosis; relatively, QFT-GIT was an effective method to
According to the specific infection site, it can be divided into predict the occurrence of tuberculosis. Similarly, Nijhawan
pulmonary tuberculosis and extrapulmonary tuberculosis. et al [14] also pointed out that QFT-GIT could screen out
Extrapulmonary tuberculosis is heterogeneous involving var- patients with latent MTB infection more accurately compared
ious organs. Lymph nodes, bone, central nervous system, gas- with TST, is higher than TST in positive rate, and can fully
trointestinal system and genitourinary system, and gastrointes- detect patients with latent MTB infection; furthermore, QFT-
tinal and skeletal systems are the most common sites of GIT was more efficient as an initial screening tool as the result
extrapulmonary tuberculosis, and the clinical manifestations of labor costs were reduced by four times.
of extrapulmonary tuberculosis are diverse [2]. QFT-GIT de- However, the use of QFT-GIT alone does not effectively
tection has important clinical application value for the diagno- distinguish between active tuberculosis and latent tuberculo-
sis and treatment of MTB infection. sis. In the retrospective study of Jeon et al. [15], 159 active
tuberculosis patients and 408 inactive tuberculosis patients
Auxiliary diagnosis of active tuberculosis and latent were recruited, and the results showed that the sensitivity of
tuberculosis QFT-GIT for the diagnosis of active tuberculosis was 90.6%
and the specificity was only 63.0%; the positive and negative
When latent infection converts into active tuberculosis, the predictive values were 48.8% and 94.5%, respectively. Jeon
number of MTB in the body increases, the response of specific et al. [15] indicated that the use of QFT-GIT alone could not
effector T cells to MTB will be upregulated, and as a result, the effectively distinguish between active tuberculosis and latent
concentration of γ-interferon in plasma will increase. tuberculosis without considering other cytokines.
Therefore, γ-interferon release test can be used as an auxiliary
tool for the diagnosis of tuberculosis. Lei et al. [11] recruited Application values of QFT-GIT in patients with AIDS
60 children and 212 adults suspected of tuberculosis in their combined with MTB infection
study and indicated that the sensitivity of QFT-GIT for the
diagnosis of active tuberculosis in children and adults was Human immunodeficiency virus (HIV) poses a serious threat
83.9% and 73.7%, respectively, and the specificity was to human health, and HIV infection increases the risk of MTB
88.5.% and 70.4%; Relatively, QFT-GIT has higher sensitivity infection [16]. It can affect the body’s immune response to
and specificity in children for detecting active tuberculosis. MTB, which results in interfering with the diagnosis of latent
The meta-analysis which included 20 studies showed that MTB infection [17]. Hence, accurate diagnosis of latent MTB
the comprehensive sensitivity of QFT-GIT for the diagnosis infection in AIDS patients is receiving increasing attention.
of latent MTB infection was 70% (CI: 63%–78%); the spec- Due to the interference of HIV infection, the efficacy of
ificity for the diagnosis of latent MTB infection among pa- QFT-GIT for diagnosing MTB infection was significantly re-
tients who were not vaccinated with BCG was 99% (CI: 98%– duced, with a sensitivity of approximately 57.89% [18].
100%), and the specificity among patients who received BCG However, the diagnostic efficiency of QFT-GIT is still obvi-
was 96% (CI: 94%–98%) [8]. Hence, Pai et al. [8] considered ously higher than the traditional method TST. The meta-
that QFT-GIT had the high specificity for diagnosing MTB analysis [16] which included 20 cross-sectional studies
infection, and it was not affected by BCG. In a prospective showed that the proportions of patients with negative TST
study [12] which compared the diagnostic efficiency of QFT- and positive QFT-GIT among HIV-infected patients were sig-
GIT for detecting active tuberculosis with that of T-SPOT.TB, nificantly higher than patients with positive TST and negative
185 (24.8%) patients were classified as confirmed tuberculo- QFT-GIT, indicating that the sensitivity of QFT-GIT for diag-
sis, 298 (39.9%) were suspected tuberculosis patients, and 263 nosing MTB infection is much higher than that of TST in
(35.2%) were non-tuberculosis patients. According to labora- AIDS patients. Christine et al. [19] investigated 975 adults
tory tests and follow-up visit, the sensitivity of QFT-GIT for with HIV infection and showed that the sensitivity, specificity,
detecting tuberculosis in the confirmed tuberculosis group and positive predictive value, and negative predictive value of
the suspected tuberculosis group were 88.4% (82.9%~92.3%) QFT-GIT for detecting active tuberculosis were 88.0%,
and 82.5% (77.6%~86.5%), respectively, and the difference 66.6%, 6.5%, and 99.5%, respectively. Negative QFT-GIT
was not significant (P > 0.05); the coincidence rate of QFT- could rule out active tuberculosis in HIV-infected patients
GIT and T-SPOT.TB was 92.3%, and there was a good diag- without severe immunosuppression, thereby avoiding repeat-
nostic consistency (kappa value = 0.82) between these two ed tuberculosis tests and accelerating diagnosis and treatment
methods. To compare the effectiveness of QFT-GIT and TST of other diseases. However, QIF-GIT had a high false-
in screening for latent tuberculosis infection, Abubakar et al.’s negative rate in HIV-infected patients with moderate or severe
study [13] which recruited 10,045 participants reported that immunosuppression, and further studies were needed to eval-
participants with positive TST showed a low prevalence of uate whether lowering the diagnostic threshold could improve
tuberculosis and TST was not a good predictor of active sensitivity [17].
 Eur J Clin Microbiol Infect Dis

Monitoring the treatment effect of active tuberculosis correlated with age. On the other hand, probably due to the
higher incidence of autoimmune diseases in female, the rate of
QFT-GIT may be a monitoring tool for the effectiveness of uncertain results of QFT-GIT test in female patients was sig-
active tuberculosis treatment. Chang et al. [20] researched the nificantly higher than that in male patients [24, 25].
diagnosis and treatment efficacy of active pulmonary tubercu- Glucocorticoid therapy, HIV-infected immunosuppression,
losis among 266 subjects and reported that 87.2% of patients or tumor necrosis factor antagonist therapy may result in false-
had a significant decrease in γ-interferon levels detected by negative or uncertain outcomes in QFT-GIT tests. Lei et al.
QFT-GIT (6.32 IU/mL vs 4.12 IU/mL) after 2 months of treat- [11] explored the effect of glucocorticoids and antituberculous
ment of active tuberculosis, indicating that QFT-GIT could be therapy on the diagnostic efficiency of QFT-GIT test and
used as a potential tool for diagnosing tuberculosis and mon- found that among the subjects with hormone-pretreated,
itoring the effectiveness of antituberculosis treatment. 25.0% of the children showed false-negative results and
Similarly, in the cohort study of Katiyar et al. [21], the finding 28.6% of the adults showed uncertain results; moreover,
showed that after 2 months of treatment of active tuberculosis, 44.4% of the subjects pretreated with antituberculosis drugs
77.6% of patients had significantly lower γ-interferon levels showed false-negative outcomes. Therefore, Lei et al. [11]
than basal levels; 22.4% of patients had persistent or increased indicated that glucocorticoid therapy had a negative effect
γ-interferon levels. The researchers [21] also pointed out that on the diagnostic efficiency of QFT-GIT test for detecting
compared with sputum culture results, QFT-GIT could inde- MTB infection in all age groups and antituberculosis treat-
pendently and significantly predict the possibility of positive ment could also reduce the sensitivity of QFT-GIT in the di-
sputum culture in active tuberculosis patients after 2 months agnosis of MTB infection. Telisinghe et al. [26] recruited 108
of treatment, so it could be a monitoring tool for detecting patients, 63% of whom were HIV-positive, and found that
anti-MTB infection treatment. although the integrated sensitivity of QFT-GIT test was not
However, QFT-GIT may not have the expected monitoring affected by HIV infection, the sensitivity of QFT-GIT detec-
efficacy for the treatment of latent MTB infection. Johnson tion was low in severe AIDS patients due to their severe im-
et al. [22] conducted a prospective study on the treatment of munosuppression. Similarly, studies by Kim et al. [27] had
latent MTB infection in patients with high risk of tuberculosis shown that significant decrease of lymphocyte count in pa-
and reported that there was no significant difference in the tients with miliary tuberculosis was an independent risk factor
proportion of γ-interferon level changes from positive to neg- for false-negative outcomes of QFT-GIT tests. Reduction in
ative between the isoniazid-treated group and the observation the total number of CD4 + cells also increased the risk of QFT-
group, indicating that during short-term follow-up visits, iso- GIT false negatives [26].
niazid therapy had no effect on the changes of γ-interferon Different extrapulmonary MTB infection sites resulted in
level among the adults with positive TST who had high risk of different rates of false-negative results of QFT-GIT tests. In
tuberculosis. Therefore, QFT-GIT may not be an effective the study of Youn et al. [2], 163 patients with extrapulmonary
biomarker for monitoring latent tuberculosis infection. tuberculosis were analyzed, and 28.8% of the participants
showed false-negative results of QFT-GIT test. Among the
proven extrapulmonary tuberculosis patients, 28.6% of pa-
Factors of uncertainty or false negative tients with pleural tuberculosis, 8.3% of patients with lym-
results of QFT-GIT phatic tuberculosis, 8.3% of patients with skeletal tuberculo-
sis, and 5.8% of patients with gastrointestinal tuberculosis
Uncertain outcomes of QFT-GIT detection of MTB infection showed false-negative results of QFT-GIT test; among the
may be related to age and gender. Seto et al. [23] analyzed probable extrapulmonary tuberculosis patients, false-
2420 subjects who had close contact with tuberculosis patients negative QFT-GIT results were found in 33.3% of pericardial
and found that the positive rate of QFT-GIT test increased tuberculosis, 46.2% of skeletal tuberculosis, and 30.8% of
with age; of note, the positive rate was still lower than the pleural tuberculosis, respectively. It can be seen that QFT-
predicted MTB infection rate, assuming that even in the elder- GIT test has a higher rates of false-negative results in patients
ly patients with a previous MTB infection, false-negative re- with pericardial tuberculosis, pleural tuberculosis, or skeletal
sults could also occur in QFT-GIT tests. Chen et al. [24] in- tuberculosis.
vestigated the rate of uncertain results of QFT-GIT test in In addition to age, gender, and immunosuppressive thera-
healthy population and found that the rate of uncertain results py, different sites of MTB infection have effects on false-
of QFT-GIT test varied with ages; especially among the par- negative or uncertain results of QFT-GIT test; other factors
ticipants over 46 years old, the rate was significantly higher such as smoking, diabetes, etc. may also cause interference.
than that among the subjects under 46 years old. This finding Aichelburg et al. [28] indicated that smoking had a slight
is not unique. Mo et al. [25] also indicated that the incidence of inhibitory effect on QFT-GIT test. The study of Choi et al.
uncertain results of QFT-GIT detection was significantly [29] pointed out that diabetes was an independent risk factor
Eur J Clin Microbiol Infect Dis

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