Korean J Transplant 2020; 34(1): 8-14
Published online March 31, 2020
© The Korean Society for Transplantation
Sun Joo Yoon1, Won Kyung Kwon1, Mi Jeong Jeong1, Jinyoung Lee1, Ha Young Oh2, Wooseong Huh2, Hye Ryoun Jang2, Jae-Won Joh3, Jong Man Kim3, Gyu-Seong Choi3, Sung Joo Kim3, Jae Berm Park3, Kyo Won Lee3, Dong Hyun Sinn4, Jin-Oh Choi5, Eun-Suk Kang1
1Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Department of Transplantation Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
5Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence to: Eun-Suk Kang
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: The diagnosis of latent tuberculosis infection (LTBI) in solid organ transplantation (SOT) patients under lifelong immunosuppression has profound effects on preoperative and postoperative management. Interferon-gamma release assay (IGRA) is widely used to screen LTBI before or after transplantation.
Methods: We evaluated the effect of posttransplantation immunosuppression on IGRA and influencing factors by measuring interval change of QuantiFERON-TB Gold Plus (QFT-Plus) between pretransplantation (pre-QFT-Plus) and posttransplantation (post-QFT-Plus) state in 20 patients who previously had reactive IGRA but not taken LTBI treatment.
Results: Eleven (55%) out of 20 pre-QFT-Plus reactive patients became nonreactive state in repeated QFT-Plus (post-QFT-Plus) at 194–413 days (median, 257 days) after transplantation (discordant group). Even in persistently reactive group (concordant group), interferon-gamma (IFN-γ) levels after transplantation were decreased about 34% and 36% of their pretransplantation levels for TB1 and TB2, respectively. The only significant factors that affect interval change of QFT-Plus between pre- and post-SOT status were the concentrations of IFN-γ in pre-QFT-Plus (6.93 vs. 0.44 IU/mL in TB1 and 7.33 vs. 0.71 IU/mL in TB2).
Conclusions: The reactivity of QFT-Plus is significantly compromised by immunosuppressive therapy, which increase the risk of false negative, particularly in patients with low level of IGRA reactivity. Therefore, interpretation of IGRA under immunosuppressive treatment require a caution and eventually, more sensitive tuberculosis-specific cytokine markers might be needed.
Keywords: Organ transplantation, Interferon-gamma releasing assay, Immunosuppression
Latent tuberculosis infection (LTBI) is an infection of
The study protocol was approved by Samsung Medical Center Ethics Review Committee (No. 2016-04-076). Written informed consent was obtained from each patient.
We prospectively included 169 patients with primary organ failure and awaiting SOT from February to August 2017 at Samsung Medical Center (Seoul, Korea). Diagnosis of LTBI was made primarily by IGRA using QFT-Plus. Among 169 patients, 20 patients diagnosed with LTBI were included consecutively in this study for evaluating quantitative interval change of QFT-Plus. Based on clinician's discretion, these 20 patients did not receive LTBI treatment before transplantation. Patients' medical records including previous tuberculosis history, microbiological studies, and concomitant immunosuppression were reviewed. QFT-Plus assays (Qiagen, Hilden, Germany) were performed according to the manufacturer's instructions. Within 4 hours of whole blood collection in lithium heparin tubes, each milliliters of whole blood was transferred to
Among a total of 169 patients who were awaiting SOT, 63 patients (37.3%) were diagnosed LTBI based on reactivity in QFT-Plus performed before transplantation (pre-QFT-Plus). Initial characteristics of SOT candidates are described in Table 1. Median concentrations of IFN-γ in reactive group were 1.49 UI/mL (range, 0.01–10.0 UI/mL) and 2.22 UI/mL (range, 0.05–10.0 UI/mL) for TB1 tube and TB2 tube, respectively. Of 63 patients who had diagnosed with LTBI before transplantation, 20 patients had not received TB prophylaxis were subjected to second QFT-Plus after transplantation (post-QFT-Plus) at a median of 257 days (range, 194–413 days). Of 20 patients, 14 patients had kidney transplantation and six patients had liver transplantation (Table 2).
Among 20 recipients, 11 cases (55%) became nonreactive in post-QFT-Plus, which is discordant reactivity with pre-QFT-Plus (discordant group). Although the qualitative results had not changed in nine patients (concordant group), reduction rate of IFN-γ concentrations after transplantation were 34% and 36% for TB1 and TB2, respectively. Pretransplantation IFN-γ concentrations of TB1 and TB2 tubes were 0.44 IU/mL (median, 0.01–4.58 IU/mL) and 0.71 IU/mL (median, 0.4–4.62 IU/mL), respectively, in the discordant group. On the other hand, IFN-γ concentrations of TB1 and TB2 tubes were 6.93 IU/mL (median, 1.03–10.0 IU/mL) and 7.33 IU/mL (median, 0.84–10.0 IU/mL), respectively, in the concordant group (Table 2, Fig. 1).
Factors that might affect reversion of QFT-Plus reactivity were analyzed (Table 3). Patient demography, type of transplantation organ and time to perform post-QFT-Plus were not different between concordant and discordant groups. Well known factors affecting IGRA results such as lymphocyte count, CD4 count, albumin level and immunosuppressive treatment were not related to the reversion of QFT-Plus reactivity. The only significant factors that affect interval change of QFT-Plus between pre- and post-SOT status in concordant and discordant groups were the concentrations of IFN-γ in pre-QFT-Plus (6.93 vs. 0.44 IU/mL in TB1 and 7.33 vs. 0.71 IU/mL in TB2, respectively).
Introduction of immunosuppressant in SOT made it possible to prevent acute graft rejection and to help achieving high survival rate without devastating immune reaction [9,10]. On the other hand, instead of permitting immune tolerance, immunosuppressant also arouses many kinds of complication such as neurotoxicity, nephrotoxicity, and other metabolic side effects . Most of all, immunosuppression can stir up the immune system and make a patient susceptible to infection [10,11]. Therefore, SOT patients taking IST are still at risk of active or latent TB infection by exposure [2-4]. IGRA becomes useful tool to monitor and to diagnose LTBI not only in immunocompetent individuals but also in SOT patients. Diagnosis and treatment guidelines for latent tuberculosis have been revised to insist the role of IGRA in many countries including Korea [4,12]. Because negative TST or IGRA cannot exclude the potential LTBI, it is recommended to use both diagnostic tools complementarily and to combine the radiological findings and previous treatment history, particularly in immunocompromised subjects. LTBI treatment is indicated in SOT patients who are taking immunosuppressant or being planned to take immunosuppressant. Previous reports have shown the reduced reactivity in immunosuppressed patients including SOT recipients , however, sequential studies of pre-SOT and post-SOT IGRA in same individuals are rarely reported. For this, we've studied 20 patients who did not receive LTBI treatment before transplantation base on clinician's decision. While TB prophylaxis is recommended to patients who are diagnosed LTBI and awaiting organ transplantation according to 2017 revised Korean guideline which published at the beginning of 2018 “Diagnosis and Treatment of Latent Tuberculosis Infection: The Updated 2017 Korean Guidelines ,” the study designed and prospectively recruit the patients with primary organ failure from February to August 2017 and TB prophylaxis was determined according to past history, imaging of the chest with computerized tomography scan or X-ray.
Herein, we compared results between pre-SOT status and post-SOT status with QFT-Plus. In this sequential test, eleven (55%) out of 20 patients had nonreactivity after transplantation. Discrepant result between pre-SOT status and post-SOT status with QFT-Plus and about 34% of reduction rate between pre- and posttransplantation status in the same reactivity group may indicate that the risk of false-negative could expressively increase after IST and this study would be a good example of IST effect on IGRA. Although effects on QFT-Plus induced by types of donor, combination of IST regimen, leukopenia and hypoalbuminemia were uncertain in this report, significant differences between concordant and discordant groups were observed in distributed levels of IFN-γ. Patients who had low IFN-γ levels in pretransplantation work-up (less than 1.07 IU/mL for TB1 and less than 3.02 IU/mL for TB2) became nonreactive during posttransplantation period (which were considered false negative results). Thus, clinicians need to interpret results of posttransplantation IGRA carefully by combining clinical findings with other laboratory results such as TST and chest radiology.
By presenting significant interval changes of IFN-γ between pre- and posttransplantation work-up in this report, we emphasize not only the importance of LTBI work-up before transplantation, but also the necessity of more sensitive test to detect MTB-specific immune response. QFT-Plus has two
No potential conflict of interest relevant to this article was reported.
Conceptualization: HYO, WH, HRJ, JWJ, JMK, GSC, SJK, JBP, KWL, DHS, JOC. Data curation: MJJ. Formal analysis: SJY, WKK. Methodology: JL. Project administration: ESK. Visualization: SJY. Writing-oritianl draft: SJY. Writing- review & editing: ESK.
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