Latent tuberculosis (TB) infection among TB contacts is diagnosed using plain chest radiography and interferon-gamma release assays (IGRAs). However, plain chest radiographs often miss active TB, and the results of IGRA could fluctuate over time. The purpose of this study was to elucidate changes in the results of the serial IGRAs and in the findings of the serial submillisievert chest computed tomography (CT) scans among the close contacts of active pulmonary TB patients.
Patients age 20 or older with active pulmonary TB and their close contacts were invited to participate in this study. Two types of IGRA (QuantiFERON-TB Gold In-Tube assay [QFT-GIT] and the T-SPOT.
In total, 19 close contacts participated in this study. One was diagnosed with active pulmonary TB and was excluded from further analysis. At baseline, four of 18 contacts (22.2%) showed positive results for QFT-GIT and T-SPOT; there were no discordant results. During the follow-up, transient and permanent positive or negative conversions and discordant results between the two types of IGRAs were observed in some patients. Among the 17 contacts who underwent submillisievert chest CT scanning, calcified nodules were identified in seven (41.2%), noncalcified nodules in 14 (82.4%), and bronchiectasis in four (23.5%). Some nodules disappeared over time.
The results of the QFT-GIT and T-SPOT assays and the CT images may change during 1 year of observation of close contacts of the active TB patients.
Tuberculosis (TB) has a great impact on human health. Globally, an estimated 10.0 million (range, 9.0–11.1 million) people fell ill with TB in 2018, a number that has been relatively stable in recent years. In 2018, there were an estimated 1.2 million TB deaths among human immunodeficiency virus (HIV)–negative people and an additional 251,000 deaths among HIV-positive people [
To eradicate TB, the diagnosis of latent TB infection and the prevention of active TB through treatment is crucial. The recent contacts of patients with active pulmonary TB constitute a high-risk group for progression to active TB [
However, plain chest radiographs often miss active TB. According to a previous study, 18 of 87 close TB contacts were diagnosed as having active pulmonary TB. Nine of the 18 had normal chest radiograph images, but had lesions that were suggestive of active TB on chest computed tomography (CT) scans [
The aim of this study was to elucidate changes in the serial results of two types of IGRAs and in the findings of serial submillisievert chest CT scans among close contacts of active pulmonary TB patients.
Patients aged 20 years or more with active pulmonary TB who were diagnosed at Seoul National University Hospital between October 1, 2017, and November 30, 2018, and their close contacts were invited to participate in this study. A diagnosis of active pulmonary TB was made if (1) a culture of
At the time of enrollment, we interviewed and examined the participants. We performed two types of IGRA tests (QuantiFERON-TB Gold In-Tube assay [QFT-GIT, Qiagen, Hilden, Germany] and the T-SPOT.
The QFT-GIT assay was performed in two stages, according to the instructions of the manufacturer [
All chest CT scans were obtained using a dual-source, 192-channel, multidetector CT scanner (Somatom Force; Siemens Healthineers, Forchheim, Germany) without intravenous administration of contrast medium. The CT parameters were as follows: a peak kilo-voltage of 100 kV with spectral shaping by tin (Sn) filtration, a reference tube current of 40 mA·sec, a tube rotation time of 0.25 milliseconds, a detector collimation of 0.6×1.92 mm, and a reconstruction kernel of Br59-3. Patients were scanned in the supine position at full inspiration in the craniocaudal direction from the lung apex to the lung base. CT images were reconstructed by 3-mm and 1-mm slice thicknesses in the transverse plane and 3-mm slice thickness in the coronal plane. The mean dose–length product and effective dose per CT scan were 8.9±2.7 mGy·cm and 0.13±0.03 mSv, respectively [
Categorical variables were summarized as numbers with percentages, and continuous variables are presented as the median and the interquartile range (IQR). All statistical analyses were performed using Stata, version 13.0 (Stata Corp., College Station, TX, USA).
In total, 19 patients with active pulmonary TB participated in this study (15 [78.9%] were men; median age, 70 years [IQR, 61–80]). One patient (5.3%) was a current smoker and 10 (52.6%) were ex-smokers. Two (10.5%) had a history of TB, five (26.3%) had diabetes, and two (10.5%) were taking immune suppressants. The most common symptoms were cough (9 patients, 47.4%) and sputum (9 patients, 47.4%). Of the 19 patients, 18 (94.7%) were diagnosed based on
In total, 19 close contacts participated in this study. One was diagnosed as having active pulmonary TB and was excluded from further analysis. The median age of the remaining 18 close contacts was 64 years (IQR, 52–72), and four (22.2%) were male. The median BMI of the 18 close contacts was 24.1 kg/m2 (IQR, 22.8–26.4). None of the close contacts had a history of TB, but four (22.2%) had diabetes. Among the close contacts, 17 (94.4%) were family members of index patients and one was a full-time care giver (
At baseline, QFT-GIT and T-SPOT assays were performed in 18 close contacts. Four (22.2%) showed positive results for both QFT-GIT and T-SPOT, and there were no discordant results. At 3 months, both tests were repeated in 15 close contacts. Only one (6.7%) showed positive results in both tests, five (33.3%) showed positive QFT-GIT/negative T-SPOT results, and one (6.7%) showed negative QFT-GIT/positive T-SPOT results. At 12 months, both tests were performed in 15 close contacts. Two (13.3%) showed positive results in both tests and another two (13.3%) showed positive QFT-GIT/negative T-SPOT results, but none showed negative QFT-GIT but positive T-SPOT results (
One contact (participant 7) showed positive conversion in QFT-GIT assay results at 3 months and at 12 months from negative results at baseline. The levels of interferon-γ (TB antigen-minus null) at baseline, 3 months, and 12 months were 0.18, 1.12, and 1.23 IU/mL, respectively. However, the T-SPOT was consistently negative. Another contact (participant 10) showed positive conversion at 3 months in the QFT-GIT result but had reconverted to negative at 12 months. In this contact, the levels of interferon-γ at baseline, 3 months, and 12 months were 0.00, 0.37, and 0.17 IU/mL, respectively. Others showed consistent QFT-GIT results through the serial tests (
At baseline, submillisievert chest CT scanning was performed in 17 close contacts. Calcified nodules were identified in seven (41.2%), noncalcified nodules in 14 (82.4%), and bronchiectasis in four (23.5%). Two of seven contacts with calcified nodule(s) had positive IGRA results at baseline. In addition, two of 14 contacts with noncalcified nodules had positive IGRA results at baseline. Changes in serial CT findings were detected in two close contacts (participants 2 and 9) in whom some of the noncalcified nodules disappeared (
We investigated the consistency over time of the results of two IGRAs (the QFT-GIT and T-SPOT assays) and the findings of submillisievert chest CT scans performed serially for 1 year among the close contacts of patients with active pulmonary TB. We observed persistent or transient conversions of IGRAs among the contacts. Furthermore, we showed that most of the close contacts had nodules (mainly noncalcified) on submillisievert chest CT, and some of these nodules regressed over time.
At baseline, four of the 18 close contacts showed positive results for both QFT-GIT and T-SPOT, and there were no discordant results. However, the evolution of the results over time was diverse. Participants 7 showed negative results of both QFT-GIT and T-SPOT at enrollment. However, at 3 and 12 months, QFT-GIT had converted to positive, but the T-SPOT results remained negative throughout the 1-year observation period. These mismatches could be explained by possible false-positive QFT-GIT results or false-negative T-SPOT results. It is noteworthy that discordant results between QFT-GIT and T-SPOT assays have been reported [
In participant 4, the T-SPOT result converted positive at 3 months but returned to negative at 12 months. Given that QFT-GIT was consistently negative in that contact, this transient conversion of T-SPOT could be understood as the intrinsic poor reproducibility of IGRAs in serial testing [
The importance of chest CT in the diagnosis of latent TB infection has been noted. Previously, our group reported that 9 of 18 patients who were diagnosed with active pulmonary TB in the investigation of an outbreak had normal chest radiographs but had lesions suggesting active pulmonary TB on chest CT scans [
To correctly interpret the results of our study, its limitations should be recognized. First, the number of participants was small. Because of this limitation, we could not provide fully generalizable information. However, our study provides some pointers as a preliminary investigation of this topic. Second, the participants were relatively old, with a median age of 64 years. Consequently, we could not be sure that the lung parenchymal abnormalities identified on submillisievert chest CT developed from the current episode of exposure. Studies involving larger numbers of close contacts with a wider range of ages could confirm and explain the meaning of the findings of the current study.
In conclusion, the results of QFT-GIT and T-SPOT assays and the extent of CT lesions may change during 1 year’s observation of the close contacts of active TB patients. The clinical meaning of these findings should be elucidated in large-scale studies in the future.
Conceptualization: Yim JJ. Methodology: Yoon S, Mihn DC. Formal analysis: Yoon S, Mihn DC, Yim JJ. Data curation: Song JW, Kim SA, Yim JJ. Writing - original draft preparation: Yim JJ. Writing - review and editing: Song JW, Yoon S, Mihn DC. Approval of final manuscript: all authors.
No potential conflict of interest relevant to this article was reported.
This work was supported by the Seoul National University College of Medicine Research Fund (grant 03-2017-0010).
Supplementary material can be found in the journal homepage (
Serial values of QuantiFERON-TB Gold In-Tube assay in 18 close contacts.
Serial values of QuantiFERON-TB Gold In-Tube ass T-SPOT.
Clinical characteristics of 19 index patients with active pulmonary TB
Characteristic | Value |
---|---|
Total | 19 (100) |
Male sex | 15 (78.9) |
Age, yr | 70 (61–80) |
Smoking | |
Current | 1 (5.3) |
Ex-smoker | 10 (52.6) |
History of TB | 2 (10.5) |
Diabetes | 5 (26.3) |
Immune suppressant use | 2 (10.5) |
Symptoms | |
Cough | 9 (47.4) |
Sputum | 9 (47.4) |
Weight loss | 4 (21.1) |
Hemoptysis | 2 (10.5) |
Diagnosis | |
Sputum AFB smear positive | 12 (63.2) |
Sputum mycobacterial culture positive | 18 (94.7) |
Sputum MTB-PCR positive | 13 (68.4) |
Sputum Xpert assay positive | 13 (68.4) |
Bronchial washing AFB smear positive |
3 (15.8) |
Bronchial washing mycobacterial culture positive |
5 (26.3) |
Bronchial washing Xpert assay positive |
6 (31.6) |
Drug resistance | |
MDR | 2 (10.5) |
Resistance, but not MDR | 0 (0) |
Radiography | |
Cavity | 5 (26.3) |
Bilateral involvement | 13 (68.4) |
Values are presented as number (%) or median (interquartile range).
Bronchial washing was performed in six patients.
TB: tuberculosis; AFB: acid-fast baclli; MTB-PCR:
Baseline characteristics of 18 close contacts
Characteristic | Value |
---|---|
Total | 18 (100) |
Male sex | 4 (22.2) |
Age, yr | 64 (52–72) |
BMI (kg/m2) | 24.1 (22.8–26.4) |
History of TB | 0 (0) |
Diabetes | 4 (22.2) |
Immune suppressant use | 1 (5.6) |
Type of contacts | |
Family | 17 (94.4) |
Care giver | 1 (5.6) |
Submillisievert chest CT (n=17) | |
No abnormality | 1 (5.9) |
Presence of bronchiectasis | 4 (23.5) |
Presence of nodules | 16 (94.1) |
Micronodule only | 3 (17.6) |
With calcified nodules | 7 (41.2) |
Decrease in the number of nodules over time | 2 (11.8) |
Values are presented as number (%) or median (interquartile range).
BMI: body mass index; TB: tuberculosis; CT: computed tomography.
Serial changes of QFT and T-SPOT results in 18 close contacts
Participant No. | Index patient |
Baseline |
3 Months |
12 Months |
||||
---|---|---|---|---|---|---|---|---|
AFB smear positive | Presence of cavity | QFT | T-SPOT | QFT | T-SPOT | QFT | T-SPOT | |
1 | Yes | Yes | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
2 | Yes | Yes | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
3 | Yes | No | Pos. | Pos. | Pos. |
Neg. |
Pos. | Pos. |
4 | Yes | Yes | Neg. | Neg. | Neg. |
Pos. |
Neg. | Neg. |
5 | Yes | No | Neg. | Neg. | ||||
6 | Yes | No | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
7 | Yes | No | Neg. | Neg. | Pos. |
Neg. |
Pos. |
Neg. |
8 | Yes | No | Pos. | Pos. | Pos. | Pos. | Pos. | Pos. |
9 | Yes | No | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
10 | No | No | Neg. | Neg. | Pos. |
Neg. |
Neg. | Neg. |
11 | Yes | Yes | Pos. | Pos. | Pos. |
Neg. |
Pos. |
Neg. |
12 | No | Yes | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
13 | No | No | Neg. | Neg. | Neg. | Neg. | ||
14 | No | No | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
15 | No | No | Pos. | Pos. | Pos. |
Neg. |
||
16 | Yes | No | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
17 | No | No | Neg. | Neg. | ||||
18 | No | No | Neg. | Neg. | Neg. | Neg. | Neg. | Neg. |
Indicates discordant results between QFT and T-SPOT.
QFT: QuantiFERON-TB Gold In-Tube assay; T-SPOT: T-SPOT.
Radiographic lesions and their changes on submillisievert chest CT scans in 18 close contacts
Participant No. | Calcified nodule | Noncalcified nodule | Bronchiectasis | Temporal change |
---|---|---|---|---|
1 | No | Yes | Yes | No |
2 | No | Yes | No | Yes |
3 | Yes | No | No | No |
4 | No | Yes | No | No |
5 | Yes | Yes | Yes | No |
6 | Yes | No | No | No |
7 | No | Yes | No | No |
8 | No | No | No | No |
9 | No | Yes | No | Yes |
10 | Yes | Yes | No | No |
11 | No | Yes | No | No |
12 | No | Yes | No | No |
13 | Yes | Yes | No | No |
14 | Yes | Yes | Yes | No |
15 | Yes | Yes | No | No |
16 | No | Yes | Yes | No |
17 | Not performed | |||
18 | No | Yes | No | No |
CT: computed tomography.