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Clinical and Translational Research

Contribution of Interferon-γ Release Assays (IGRAs) to the Diagnosis of Latent Tuberculosis Infection After Renal Transplantation

Hadaya, Karine1,2,5; Bridevaux, Pierre-Olivier3; Roux-Lombard, Pascale4; Delort, Armelle1; Saudan, Patrick1; Martin, Pierre-Yves1; Janssens, Jean-Paul3

Author Information

1 Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland.

2 Division of Transplantation, Geneva University Hospitals, Geneva, Switzerland.

3 Division of Pulmonary Diseases, Geneva University Hospitals, Geneva, Switzerland.

4 Division of Immunology and Allergology, Geneva University Hospitals, Geneva, Switzerland.

5 Address correspondence to: Karine Hadaya, M.D., Divisions of Nephrology and Transplantation, Geneva University Hospitals, 1211 Geneva 14, Switzerland.

The study protocol was approved by the Geneva University Hospital Ethics Committee and registered at www.clinicaltrials.gov (N°NCT01608685).

The authors declare no funding or conflicts of interest.

E-mail: [email protected]

K.H., P.-O.B., P.R.-L., and J.-P.J. participated in the conception, design, analysis, and interpretation of data. K.H., P.-O.B., P.R.-L., A.D., P.S., P.-Y.M., and J.-P.J. participated in the drafting and revision of the article, provided intellectual content of the critical importance to the work described, and participated in the final approval of the version to be published.

Received 2 January 2013. Revision requested 21 January 2013.

Accepted 4 May 2013.

doi: 10.1097/TP.0b013e3182907073
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Abstract

Prevalence of latent tuberculosis infection (LTBI) is high in patients under chronic hemodialysis (1–8), although this may, to some extent, be related to the incidence of TB in the countries in which these studies were performed. End-stage renal disease (ESRD) is per se a risk factor for progression from LTBI to active TB (9). Risk of progression to active TB in this population is estimated to be 10 to 15 times greater than that of the general population (10–14). Furthermore, a substantial number of pathologies leading to ESRD, including diabetes or autoimmune diseases, increase the risk of progression of LTBI to active TB (15).

For many patients with ESRD, renal transplantation is the only therapeutic option. Renal transplantation requires chronic immunosuppression, which increases the risk of TB reactivation. It is therefore of major importance to identify transplant candidates with LTBI (16) and, whenever possible, to treat LTBI before transplantation (17, 18). It is also necessary to be able to identify newly acquired LTBI after renal transplantation, either through exposure to an index case or because of transmission by the donor (19). Indeed, published incidence of active TB in patients who underwent solid organ transplantation and, more specifically, renal transplantation, is quite high, although many publications are from medium or high incidence areas (18, 20–26). As in other groups of immunosuppressed individuals, atypical clinical presentation of TB may delay diagnosis, leading to higher mortality rates (20, 26).

Until the last decade, the tuberculin skin test (TST) was the only diagnostic test available for detecting LTBI and deciding whether or not to propose a specific treatment, as recommended by the American Thoracic Society/Centers for Disease Control/Infectious Diseases Society of America guidelines (27–29). Over the past 10 years, the diagnostic tools for LTBI have evolved: interferon-γ release assays (IGRAs) are now widely used either sequentially, after screening with the TST, or as first-line diagnostic tests (27–30). Both commercially available IGRAs test in vitro T-cell responsiveness to antigens that are specific of the Mycobacterium tuberculosis complex (ESAT-6; CFP-10; for the QuantiFERON Gold In-Tube [QGIT], Cellestis, Australia: TB7.7). There is a considerable body of literature concerning the use of IGRAs in immunocompetent individuals, showing both an increase in sensitivity and specificity when compared with the TST (28, 29). Because there is no gold standard available for confirming LTBI, clinical studies either compare performances of IGRAs and TST in cases of active TB or use surrogate markers of probability of LTBI (scores of exposure for instance). In patients with ESRD, it is now well documented that IGRAs are better correlated with the risk of TB infection than the TST (1, 3, 5–8, 30–36). Results of TST can be affected by prior Bacillus Calmette-Guérin (BCG) and infection by nontuberculous mycobacteria and thus lose specificity when compared with IGRAs (1, 7, 8). There is, however, to our knowledge no published evidence concerning the performance of IGRAs after renal transplantation.

This study aims to compare the diagnostic performance of the TST and the two presently commercialized and Food and Drug Administration–approved IGRAs (T-SPOT.TB, Oxford Immunotec, Oxford, UK, and QuantiFERON Gold In-Tube [QGIT], Cellestis, Australia) in renal transplant recipients (RTRs) under stable immunosuppression.

RESULTS

Two hundred five RTRs were enrolled in the present study. Five RTRs had indeterminate IGRAs according to the manufacturer’s definition: 2 (1%) for the T-SPOT.TB and 3 (1.5%) for the QGIT. RTRs with indeterminate IGRAs were middle aged, had been under immunosuppression for 7.3 years, and had normal CD4 lymphocyte counts. After exclusion of indeterminate results, 200 RTRs were included (57.6% male, aged 59±13.2 years; range, 22–85). Average time since renal transplantation was 10.4±7.1 years (range, 2–40 years). Details of immunosuppressive therapy, serum creatinine, CD3 and CD4 lymphocyte counts, results of chest radiographs, and exposure or prior treatment for LTBI/active TB are summarized in Table 1. Most patients were on 2 (65.0%) or 3 (31.9%) immunosuppressive medications. Average serum levels (mean [SD]) were 7.5 (2.7) ng/mL for tacrolimus, 103 (41) ng/mL for cyclosporine A, and 5.8 (3.3) ng/mL for sirolimus. Prevalence of a positive TST (>5 mm induration) was very low (4.5%) when compared with either IGRAs (T-SPOT.TB [20.5%] and QGIT [23.5%]). Nine (4.5%) patients had a history of TB (Composite outcome 1) and 42 (21.0%) patients had a risk factor for LTBI (Composite outcome 2). Close contact with TB patients was reported by 41 patients.

T1-10
TABLE 1:
Patient characteristics

Table 2 shows the positivity rate of TST and IGRAs according to age and other risk factors for tuberculous infection. Older age was associated with a higher rate of positive QGIT (P=0.004) but a lower rate of TST (P=0.039). Between both IGRAs, only T-SPOT.TB was significantly related to variables suggestive of prior TB infection (Composite outcomes 1 and 2, history of prior contact with TB, history of prior active TB and/or TB therapy, and history of prior treatment for LTBI). In contrast, we found no association between TST and TB-related variables. Notably, among nine patients with a history of active TB and/or treatment for active TB, one had a positive TST, five had a positive QGIT, and five had a positive T-SPOT.TB. Among 12 patients with a history of prior treatment for LTBI, none had a positive TST, 4 had a positive QGIT, and 5 had a positive T-SPOT.TB. Also, we found no association between granulomas found on chest X-rays and results of either IGRAs or TST. Higher lymphocyte counts were weakly associated with positive IGRA results (P=0.01). However, no lymphocyte count threshold could be identified.

T2-10
TABLE 2:
Results of IGRAs and TST

Table 3 summarizes the sensitivity, specificity, and negative predictive values of TST, either IGRA, and both IGRAs combined for detecting either patients with a definite history of prior TB or those with a high risk of latent TB (Composite outcomes 1 and 2). For these outcomes, the sensitivity of the TST is extremely low. Combining IGRAs slightly improved sensitivity at the cost of a lower specificity. Given the low prevalence of prior TB in our study population, negative predictive values for having a history of active TB were high (95%) when using both IGRAs. This contrasts with the much lower negative predictive values found for detecting risk factors for latent TB (82%). False-negative rate of combined IGRAs was 44.4% (95% confidence interval [95% CI], 13.7%–78.8%) for detecting history of active TB and 61.9% (95% CI, 45.6%–76.4%) for detecting probable latent TB. False-negative rate for TST was 100% (95% CI, 66.4%–100%) for history of active TB and 92.9% (95% CI, 81.0%–98.5%) for detecting probable latent TB.

T3-10
TABLE 3:
Results of IGRAs and TST

Table 4 summarizes agreement between tests: κ values showed a good agreement between both IGRAs (37).

T4-10
TABLE 4:
Agreement between tests (κ values; P value)

After 24±4 months of follow-up, no case of active TB occurred among RTRs tested.

DISCUSSION

This is, to our knowledge, the first report comparing IGRAs and TST in patients with long-lasting immunosuppressive therapy having received a renal transplant at least 1 year earlier. In this study, IGRAs and TST both yielded a high rate of false-negative results for the detection of risk factors for LTBI. Positivity rate for TST (4.8%) was much lower than what had been recently documented in patients under hemodialysis for ESRD in our area (8). Furthermore, the TST did not identify subjects with a prior diagnosis of either TB or LTBI. Conversely, IGRAs suggested a rate of prior TB infection of 20% (T-SPOT.TB)–23.4% (QGIT). These rates were similar to those previously reported in our area for patients under hemodialysis (8). Cumulative rate of LTBI or history of TB rate was evaluated at 25%. Agreement between IGRAs was good (Table 4). As expected, neither IGRA was significantly related to history of BCG. In this population, between both IGRAs, only T-SPOT.TB was significantly related to variables suggestive of prior TB infection (Composite outcomes 1 and 2, history of prior contact with TB, history of prior active TB and/or TB therapy, and history of prior treatment for LTBI). All tests had a very low sensitivity for identifying subjects with prior TB or LTBI.

Based on these findings, and numerous earlier studies in patients with ESRD (1, 3, 5–8, 30–36), it would seem reasonable to abandon the use of the TST in this setting. As opposed to strategies used in immunocompetent individuals (“two-step” approach: sequential use of TST then an IGRAs) (37, 38), the very low sensitivity of the TST in this setting renders it unreliable as an initial screening test in a “two-step” approach. Indeed, in an extensive review of the risk of TB in transplant candidates and recipients, a TB-NET consensus review suggested that, in a low prevalence setting, IGRAs should be used instead of the TST and also that the decision of treating a possible infection should depend not only on results of IGRAs but also, in the case of negative IGRA results, on the local prevalence and incidence of TB (19). Although much more sensitive for detecting subjects with prior documented TB exposure or treatment, both IGRAs (individually or combined) clearly have a too low sensitivity to exclude LTBI (Table 3). Combining both tests (Table 3) slightly increases sensitivity without reaching a clinically useful value. Negative predictive values are also too low in our view to rule out latent TB if this diagnosis is considered once patients are already treated with immunosuppressive medication. Because of the high risk for RTRs of evolving from LTBI toward active TB, these results emphasize the importance of detecting LTBI before starting immunosuppressive therapy. Furthermore, clinicians must bear in mind the possibility of active TB even in the presence of negative IGRAs either before or after transplantation.

In this study, results of the T-SPOT.TB were significantly correlated to exposure to TB but not those of the QGIT. In a prior study of our group, while performing the tests in the same conditions and in the same experienced laboratory, the QGIT was shown to be correlated to exposure in patients under hemodialysis, whereas the T-SPOT.TB was not (8). Reasons for these differences between tests are unclear. Both tests performed similarly in terms of indeterminate results. Larger studies will be necessary to determine if, in specific groups, one IGRA is superior to another or if the answer in terms of optimizing performances would be a systematic combination of both tests.

Quantifying the specific impact of immunosuppression on the results of the TST and IGRAs would require a prospective comparison of pretransplantation and posttransplantation data. These results were unfortunately not available in this study, for two reasons: (1) pretransplantation evaluation and posttransplantation follow-up was multicentric (Geneva, Neuchâtel, and Wallis); thus, many results were not available; and (2) the use of IGRAs on a routine basis is rather recent (6 years), and only 63 (30%) RTRs were transplanted within the last 6 years. Comparison of data obtained in our RTRs with results obtained from hemodialysis patients followed in our center does, however, give a few clues (8). Although our RTR population was slightly younger (59±13 years) than hemodialysis patients studied (66±13 years), the percentage of cases with risk factors for LTBI was identical in both groups. TST positivity rate was markedly lower in RTRs. T-SPOT.TB rates were also lower in RTRs (29% vs. 20.2%). Conversely, QGIT positivity rates were slightly higher in RTRs (23.8% vs. 21%). As in RTR, agreement between TST and either IGRA was very low. Comparison between these two studies suggests that (1) the use of TST is inappropriate in RTR because of a very low sensitivity, and (2) although their sensitivity is certainly decreased, IGRA may still identify immunosuppressed RTR patients with probable LTBI. Reasons for differences in IGRA performance in hemodialysis versus RTR are unclear.

Our study has a few limitations. First, as prior studies dealing with the contribution of IGRAs, our results suffer from the absence of a reliable definite marker of LTBI: our approach is thus probabilistic, as most of the literature on IGRAs (8, 39–42). We chose two composite variables as surrogate markers of LTBI. Second, prior treatment for TB or LTBI may have affected absolute values of either interferon-γ (QGIT) or spots (T-SPOT.TB), which, combined to the impact of immunosuppression, may lead to false-negative results. Indeed, a decrease in interferon-γ levels or spots has been reported in subjects treated for active TB (43–47). Spontaneous reversion of IGRAs over time has also been reported and may also have affected our results (48). Third, no booster testing was performed for TST: this was mainly for logistic reasons; many patients, although followed by our center, lived in other parts of Switzerland, and performing booster TST is very unpractical. The performances of the TST may be underevaluated for this reason (49). Also, we chose a very low cutoff value for scoring TST as positive (≥5 mm) according to national guidelines, to maximize TST sensitivity, at the cost of specificity. Fourth, because the immunosuppression regimen was rather standardized in our patients, and immunosuppressive drugs were combined, it was not possible to measure the specific impact of the drugs prescribed on IGRA results. Finally, the search for LTBI among immunosuppressed patients aims at detecting not only patients who have LTBI but also among those who presumably have LTBI—those who are at risk of further progression to active TB. In this study, we could not determine the positive predictive value or negative predictive value of results of IGRAs because no cases of active TB occurred during follow-up (24±4 months). The very low incidence rate of TB in our center when compared with the literature is probably explained by the low incidence of TB in Switzerland and by systematic treatment of IGRA-positive subjects in renal transplant candidates over the past 6 years. The surrogate markers of LTBI in our study may also have overestimated the true infection rate.

In conclusion, neither the TST nor the IGRAs are sensitive enough in RTRs to exclude a diagnosis of TB or LTBI. Using a composite variable to estimate the probability of LTBI (≈22% in this study), sensitivity of both IGRAs was approximately 33%. In our study, combining results of both IGRAs did not significantly increase test performance. These results emphasize the limitations of IGRAs in the setting of chronic immunosuppressive therapy. Large prospective studies are needed to determine the true incidence of TB in RTRs with negative IGRAs but high probability of LTBI. As a provisory measure, we think that LTBI should be considered and treated despite negative IGRAs if risk factors for LTBI, such as close contact with an active TB case, are found.

PATIENTS AND METHODS

The study was performed among RTRs followed by the Division of Nephrology at Geneva University Hospital. The division covers the Geneva area (i.e., ∼450,000 inhabitants), with an incidence of TB of 20/105 per year; cases are also referred from the neighboring cantons (Valais, Neuchâtel). The study protocol was approved by the Geneva University Hospital Ethics Committee and registered at www.clinicaltrials.gov (N°NCT01608685). Subjects were prospectively included between November 2009 and December 2011. Inclusion criteria were being aged more than 18 years, being able to provide informed consent, having had a renal transplant at least 12 months before inclusion, and having a stable immunosuppression. Exclusion criteria were treatment for acute rejection within the preceding 3 months and signs or symptoms of acute infection.

Patients were included during their regular elective follow-up visits. Blood sampling was performed for red and white blood cell counts, including total lymphocyte, CD3 and CD4 counts, serum blood urea nitrogen, creatinine, and albumin, as well as IGRA testing (see below).

Variables and Items Recorded

The following variables were included in a computerized database (Filemaker Pro 7 for Windows, 2004, Santa Clara, CA): details of immunosuppressive medication, dosage and serum levels, and results of blood samplings (see above), including IGRA tests. The following variables were also recorded: history of BCG, presence of a scar suggestive of prior BCG, history of prior exposure to TB, origin and incidence of TB in country of origin, prolonged stay in high incidence country for TB, and prior treatment for LTBI or active TB.

A chest radiography was performed either during the elective visit or, for patients living in other cantons of Switzerland, before the routine checkup at Geneva University Hospital. All chest radiographs were read independently by two experienced pulmonologists and scored for the presence of signs suggestive of prior tuberculous infection (calcified granulomas, calcified hilar or mediastinal lymph nodes, and pleuro-parenchymal sequelae in upper lobes).

Tests Performed (TST and IGRAs)

A TST was performed intradermally, according to the Mantoux technique, using two units of purified protein derivative (RT-23; Statens Serum Institute, Copenhagen, Denmark), which is the biological equivalent of five units of US purified protein derivative. Results of TST were considered positive if the transverse diameter, measured 48 to 72 hr after injection, was ≥5 mm.

Blood samplings for determination of M. tuberculosis–specific interferon-γ-secreting T cells (T-SPOT.TB (Oxford Immunotec) and QGIT (Cellestis) were performed simultaneously, processed, and scored according to the manufacturer’s recommendations, as reported previously (8). Peripheral venous blood samples were processed by our laboratory within 3 hr.

Statistical Methods

Two composite variables were defined as main outcomes of interest:

  • Composite outcome 1: “History of active TB or prior therapy for active TB” was defined by report of prior diagnosis or treatment for TB
  • Composite outcome 2: “Risk factors for LTBI” was defined by chest radiography suggestive of prior infection (calcified granuloma or adenopathy, suggestive fibrotic scars) and/or established “at risk” contact with a patient with contagious TB.

Both composite variables were mutually exclusive.

Analyses were run separately for T-SPOT.TB, QGIT, and TST. Sensitivity, specificity, negative predictive value, and false-negative rate of T-SPOT.TB, QGIT, and TST were calculated for the two composite outcomes with the exact method by Clopper and Pearson for CIs. To compare factors associated with IGRA positivity, we used chi-square tests for categorical values (or Fisher’s test when appropriate) and parametric or nonparametric methods for continuous variables.

Agreement between tests was quantified using κ statistics (50). κ statistics was interpreted according to Landis and Koch: (κ>0.75: excellent agreement, κ=0.40–0.75: fair to good agreement, and κ<0.40: poor agreement).

All statistical analyses were performed with STATA version 11 (Stata, College Station, TX).

ACKNOWLEDGMENTS

The authors thank the “Ligue Pulmonaire Genevoise” (www.lpge.ch), a nonprofit organization that supports research in the field of pulmonary disorders, for its financial support and Carmelina de Luca for her skilful technical assistance.

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Keywords:

Interferon-γ release assays; Latent tuberculosis infection; Renal transplantation

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