Elsevier

Human Immunology

Volume 70, Issue 1, January 2009, Pages 24-28
Human Immunology

Original article
Diagnosis of tuberculosis infection in patients awaiting liver transplantation

https://doi.org/10.1016/j.humimm.2008.10.005Get rights and content

Abstract

This study examined the performance of a tuberculosis (TB)-specific enzyme-linked immunospot assay in 48 patients awaiting liver transplantation. They were tested with T-SPOT.TB, tuberculin skin test (TST), and lymphocyte transformation test (LTT) using tuberculin as a stimulus. A questionnaire was used to gain information on TB exposure. Four patients were defined as positive by T-SPOT.TB, 6 by TST, and 28 by LTT. The patients displaying positive results to T-SPOT.TB were also positive in the TST and LTT. We considered them to have latent TB because they were repeatedly (two or three times) positive to the T-SPOT.TB and reported TB exposure. Active TB was excluded by negative multislice computed tomography, negative culture, and absence of symptoms. In 1 patient, T-cell reactivity toward TB peptides was lost 1 and 2 months posttransplantation. Another patient, however, tested 8 and 13 months posttransplantation, displayed measurable cellular TB immune responses. This finding suggests that the measurement of cellular TB immune responses shortly after transplantation may fail. If possible, patients with end-stage liver disease should be screened for TB prior to transplantation. Our data are the first evidence that T-SPOT.TB may be useful to diagnose latent TB 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)

  • D.E. Furst et al.

    Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents

    Ann Rheum Dis

    (2002)
  • N. Benito et al.

    Diagnosis and treatment of latent tuberculosis infection in liver transplant recipients in an endemic area

    Transplantation

    (2002)
  • R.E. Huebner et al.

    The tuberculin skin test

    Clin Infect Dis

    (1993)
  • G.F. Black et al.

    Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi

    J Infect Dis

    (2001)
  • E.L. Pesanti

    The negative tuberculin testTuberculin, HIV, and anergy panels

    Am J Respir Crit Care Med

    (1994)
  • Cited by (23)

    • Prevalence of latent tuberculosis infection in transplant candidates: A systematic review and meta-analysis

      2018, Microbial Pathogenesis
      Citation 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.

    • Infections transmitted by transplantation

      2010, Infectious Disease Clinics of North America
      Citation 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.

    View all citing articles on Scopus
    View full text