Original articleDiagnosis of tuberculosis infection in patients awaiting liver transplantation
Introduction
Immunocompromised individuals, such as recipients of solid organs, recipients of peripheral blood stem cells, or children less than 2 years old and receiving chemotherapy, bear a high risk of infectious complications [1], [2], [3], [4], [5]. For example, the incidence of active tuberculosis (TB) among transplant recipients is 20–74 times higher than that for the general population, with a mortality rate of 21–33% [2], [3], [4], [5]. Active TB is usually caused by the reactivation of latent TB. Latent TB infection is defined by the presence of quiescent Mycobacterium tuberculosis [6], [7]. In other words, latent TB infection occurs when a person has been exposed to enough TB bacilli to elicit an immune response, as evidenced by delayed-type hypersensitivity reaction when purified protein derivative (PPD, synonymous to tuberculin) is injected intradermally. A positive PPD test result in the absence of symptoms or chest radiograph evidence of disease constitutes latent TB infection. However, the delayed-type hypersensitivity reaction toward tuberculin (tuberculin skin test, TST), the standard diagnostic test for latent TB, is frequently false negative (anergic) in immunosuppressed patients, especially transplant recipients [2], [8]. Furthermore, a false-positive TST reaction can be caused by prior Bacille Calmette–Guérin (BCG) vaccination or by environmental mycobacteria [9], [10]. Thus, the sensitivity and specificity of the TST in this population are low [2], [9], [11], [12]. Nonetheless, accurate diagnosis of individuals infected with TB is essential because active TB causes severe complications in liver transplant recipients and resulting from the hepatotoxicity of any treatment for either active or latent TB. It would be desirable to diagnose TB as early as possible, ideally prior to transplantation. Given the acknowledged deficiencies of the TST in this population, it is important to study whether the two newly introduced interferon-γ release assays (IGRAs) might perform better in these populations. Currently only one report exists on the use of one of these IGRAs, the QuantiFERON-TB Gold test, in liver transplant patients [13]. However, because of concerns over the test's performance in this group, we decided to use the alternative enzyme-linked immunospot (ELISpot) method (T-SPOT.TB, Oxford Immunotec, Abingdon, UK) to examine its ability to identify latent TB in 48 patients prior to liver transplantation. This assay has previously been described as highly sensitive and specific in AIDS patients and in patients with hematological disease, two other cohorts with severe immunosuppression [14], [15], [16], [17], suggesting it may also be useful in this immunosuppressed population. The ELISpot assay quantifies T cells with specific interferon (IFN)-γ response toward the early secretory antigenic target-6 and the culture filtrate protein-10, two antigens specific for the Mycobacterium tuberculosis complex. To our knowledge, this is the first study reporting results from this ELISpot test in patients prior to and following liver transplantation.
Section snippets
Patients
Forty-eight patients from our liver transplant waiting list (Table 1), recruited between July 2004 and January 2007, were tested using the TST, T-SPOT.TB, and the lymphocyte transformation test (LTT). In contrast to the T-SPOT.TB, the TST and the LTT used a broad antigen mixture (PPD) as a stimulus. These cellular tests were combined with a questionnaire to gain information on prior TB exposure. There were no exclusion criteria. After 10 ml of heparinized blood was sampled for the in vitro
Results
Overall, 4 of 48 patients from our liver transplant waiting list (8%) were defined as positive by T-SPOT.TB, 6 of 47 (13%) by TST, and 28 of 48 (58%) by LTT. The 4 patients with positive results to T-SPOT.TB were also positive in the TST and the LTT (Fig. 1). We considered them to have latent TB infection because they were repeatedly (two or three times) positive to the T-SPOT.TB test (Fig. 2) and because they reported previous exposure to a TB patient or birthplace in countries with a TB
Discussion
This study analyzed cellular TB immune responses in patients from our liver transplant waiting list and followed-up patients with positive reactions to T-SPOT.TB (4/48). Because ELISpot results were repeatedly positive in these patients and because the data were consistent with TST, LTT, and anamnestic data, we assume that all reactions were truly positive. Applying the same diagnostic methods in health care workers from the Ruhr area, only 1 of 95 could be classified as latently TB infected
Acknowledgments
This article is a partial fulfilment of requirements for the doctor's degree at the Medical Faculty, University of Duisburg-Essen, for Mr. Y. Dioury. We thank M. Huben and S. Wortmann for their excellent technical assistance and Anke Hörster for her help in organizing the study. The T-SPOT.TB kits were kindly provided by Oxford Immunotec (Abingdon, UK).
References (31)
- et al.
[Evaluation of a screening strategy after occurrence of two simultaneous contaminating tuberculosis cases in a pediatric oncology department]
Arch Pediatr
(2008) - et al.
Tuberculosis
Lancet
(2007) - et al.
Comparison of Quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation
Am J Transplant
(2007) - et al.
Prevalence of latent tuberculosis infection in German radiologists
J Hosp Infect
(2008) - et al.
ELISpot assay as a sensitive tool to detect cellular immunity following influenza vaccination in kidney transplant recipients
Clin Immunol
(2006) - et al.
Mycobacterium tuberculosis infection in recipients of solid organ transplants
Clin Infect Dis
(2005) - et al.
Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management
Clin Infect Dis
(1998) - et al.
Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in SpainSpanish Transplantation Infection Study Group, GESITRA
Transplantation
(1997) - et al.
Mycobacterium tuberculosis infection in pediatric liver transplant recipients
Pediatr Infect Dis J
(2000) Tuberculosis in the cytokine era: what rheumatologists need to know
Arthritis Rheum
(2003)
Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents
Ann Rheum Dis
Diagnosis and treatment of latent tuberculosis infection in liver transplant recipients in an endemic area
Transplantation
The tuberculin skin test
Clin Infect Dis
Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi
J Infect Dis
The negative tuberculin testTuberculin, HIV, and anergy panels
Am J Respir Crit Care Med
Cited by (23)
Prevalence of latent tuberculosis infection in transplant candidates: A systematic review and meta-analysis
2018, Microbial PathogenesisCitation Excerpt :To our knowledge, our systematic review/meta-analysis is the first to examine the prevalence of the TST and IGRAs (QFT and T-SPOT) in different transplant candidates. The mean/median age of transplant candidates was lower in Asian countries [17–19,22,26,27,29,35,38,39,45,48,49] compared with the USA and European countries [1,15,20,21,24,25,32,37,41,42]; this matter might be due to lower life expectancy in patients these regions compared with developed countries or may be explained by the different etiologies for transplantation in different countries. No difference in the prevalence of LTBI was observed when the TST cutoff was considered ≥5 mm or ≥10 mm induration.
Interferon gamma release assay tests for the diagnosis of latent and active tuberculosis in hemodialysis patients or solid organ transplant recipients
2018, Revue des Maladies RespiratoiresInfections transmitted by transplantation
2010, Infectious Disease Clinics of North AmericaCitation Excerpt :A recent widely publicized case of donor-derived tuberculosis (TB) that resulted in the infection of 2 of the 3 transplant recipients and resulted in 1 death,12 combined with the availability of new blood tests to measure for previous exposure to the TB bacillus, have led to discussions regarding donor TB screening in the organ procurement community.63 Until such testing has been validated in other settings, including the organ recipient population,64,65 OPOs will continue to rely on historical information and donor physical examination to guide TB risk assessment. Hyperinfection strongyloidiasis is a life-threatening infection that can present a diagnostic challenge after transplant.
Diagnosis of latent tuberculosis in liver transplant candidates, a single center experience
2021, Clinical Laboratory