Abstract
Diagnosis of latent Mycobacterium tuberculosis infection (LTBI) by the tuberculin skin test (TST) is hampered due to anergy and impaired sensitivity in chronic renal failure (CRF) patients. We aimed to compare the diagnostic performance of the TST with that of interferon-gamma immunospot (T-SPOT.TB®) assay in diagnosing LTBI in CRF and immunocompetent (IC) patients. A total of 74 CRF and 75 IC patients prospectively underwent the TST and T-SPOT.TB. Latent M. tuberculosis infection estimated by TST and T-SPOT.TB was detected in 69% and 43 of CRF; 52 and 35% of IC patients, respectively. The sensitivity and specificity of the T-SPOT.TB were 73 and 74% in IC, whereas 50 and 55% in CRF patients. In conclusion, the prevalence of LTBI was noteworthy in both IC and CRF patients. T-SPOT.TB was less sensitive and specific than the IC group in CRF patients. Both T-SPOT.TB and TST were not associated with the TB exposure.
Introduction
Chronic renal failure (CRF) leads to a clinical state of immunodeficiency particularly characterized by impairment of cellular immunity that causes a 10- to 25-fold increased risk of developing active tuberculosis (TB) as compared with healthy individuals.Citation1–3 Furthermore, hemodialysis centers themselves were shown to be important units for spread of Mycobacterium tuberculosis infection.Citation4 Early detection of infectious TB cases and treatment of patients infected with M. tuberculosis is critical in prevention and control of TB. The tuberculin skin test (TST) is the widely used test to diagnose patients with latent tuberculosis infection (LTBI). Current guidelines recommend screening LTBI in immunocompromised patients to target appropriate LTBI treatment and prevent progression to active TB.Citation5,Citation6
On the other hand, TST has many well-known limitations, such as low sensitivity (influenced by immune status) and specificity (due to Bacille-Calmette-Guérin vaccination and environmental mycobacterial exposure).Citation7,Citation8 Screening CRF patients with TST is difficult due to impaired sensitivity caused by underlying immunosuppression and significant rates of cutaneous anergy.Citation9
The discovery of interferon-γ (IFN-γ) releasing assays (IGRAs) has appeared to be a promising alternative to the TST.Citation7 Both of the IGRAs [enzyme-linked immunosorbent assay (ELISA)-based IGRA and enzyme-linked immunospot assay (ELISPOT)-based IGRA] were shown to have increased sensitivity and specificity in immunocompetent (IC) subjects.Citation7,Citation10 Diagnostic performance of IGRAs in immunocompromised patients including CRF patients is a subject of interest in recent years. Most of the studies performed in order to assess the performance of IGRAs in CRF patients were performed by ELISA-based IGRAs. ELISA-IGRA was found to be more sensitive and specific than the TST in CRF patients and replacement of TST with ELISA-IGRA was recommended in a current systematic review. However, data regarding diagnostic and relative performance of ELISPOT-IGRA with the TST is still limited.Citation11 The present study aimed to evaluate the feasibility and performance of the interferon-gamma enzyme-linked immunospot assay (T-SPOT.TB™) with those of TST for diagnosing LTBI in CRF patients in a comparative manner with immunocompetent patients, and to analyze the concordance and discordance between the TST and T-SPOT.TB tests.
Materials and methods
Study sample
We prospectively enrolled 77 CRF patients undergoing renal replacement therapy for at least 6 months and 77 IC subjects admitted to Baskent University Hospital, and referred from Atatürk Training and Research Center for Chest Diseases and Thoracic Surgery in Ankara from a high BCG-coverage country, Turkey. The study protocol was approved by the Başkent University School of Medicine Ethics Committee and conformed to the standards defined in the Helsinki Declaration. All participants were asked to provide written, informed consent prior to their inclusion into the study. Five participants were excluded from the analysis due to unavailable TST results and missing clinical data. Finally, a total of 149 study participants older than 18 years old were classified into CRF and IC groups. Both groups included patients with active TB (who had received either no therapy or less than four weeks of therapy at the time of venipuncture), and non-TB patients (patients with known exposure to smear-positive pulmonary TB patients, and patients with no history of TB and exposure). Exclusion criteria for the IC group were the presence of immunosuppressive chronic disease, such as chronic liver disease, malignant disease, malnutrition and the use of immunosuppressive medication. CRF patients on renal replacement therapy for less than 6 months were not included in the study. All of the participants underwent the TST and T-SPOT.TB assay on the same day.
TST
Tuberculin skin testing was administered by the Mantoux method by injecting 0.1 mL of Purified Protein Derivative (5 TU PPD, PPD Tuberculin Tween 80, BB-NCLPD Ltd, Sofia, Bulgaria) intradermally on the volar side of the forearm. Induration was measured after 48 to 72 h. In Turkey, BCG vaccination is mandatory. Following BCG vaccination, a TST induration of 15 mm rather than 10 mm is recommended to diagnose LTBI.Citation12 A positive TST was defined as an induration of ≥10 mm for CRF patients and BCG-unvaccinated healthy individuals, and ≥15 mm for BCG-vaccinated, immunocompetent individuals.Citation12,Citation13 Cutaneous anergy was defined as the absence of induration <2 mm in diameter.Citation14
T-SPOT.TB
After obtaining informed consent, 8 mL of blood was drawn by venipuncture, and the T-SPOT.TB test was performed within 8 h in accordance with the manufacturer’s recommendations (Oxford Immunotec Ltd, Oxford, UK).Citation15 Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Hypaque density gradient centrifugation. PBMCs were resuspended and enumerated by a hemocytometer. PBMCs (2.5 × 105/well) were incubated overnight at 37°C, 5% CO2 with nil control, phytohemagglutinin (PHA), Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10) antigens separately in interferon-γ pre-coated ELISpot plates. T-SPOT.TB plates were scored manually by a magnifying glass, as well as by an automated ELISPOT counter (AID, Strassburg, Germany). Scoring was done according to the methods of the manufacturer. Results were interpreted by subtracting the spot count in the nil control well from the spot count in ESAT-6 and CFP-10 wells. Result was defined as negative in the presence of <4 spots in ESAT-6 and CFP-10 wells.Citation15 Positive test wells were defined as containing cells at least 10 spot-forming cells more than and at least twice as many as, negative control wells.Citation16 An indeterminate response (ITR) was recorded in the presence of less than 20 spot-forming cells (SFC) in the PHA well and the presence of a nil count greater than 10 SFCs.Citation17,Citation18
Statistical analyses
Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 17.0, SSPS Inc, Chicago, IL). All parameters were expressed as mean values ± standard derivation (SD) and median [min–max]. One-way analysis of variance, t-test and the Mann-Whitney U-test were used to compare the continuous variables between groups. Categorical variables were compared with the chi-square test and Fisher’s exact test. Concordance between the two tests was assessed using kappa (κ) statistics. Because there is no criterion standard for testing LTBI, sensitivity was estimated from patients with culture proven active TB, and specificity from healthy persons with a low likelihood of exposure according to their medical records and self-reports.Citation7 Multivariate logistic regression models were used to identify variables associated with positive TST and T-SPOT.TB results. Logistic regression analysis was performed to determine independent predictors of TST and T-SPOT.TB positivity. Hosmer-Lemeshow goodness-of-fit statistics were used to assess model fit. Two-tailed statistical significance levels were considered as 5%, and unadjusted p values were reported.
Results
Seventy-four CRF and 75 age-matched IC patients were recruited in the analysis. Characteristics of all patients are shown in . All patients were of Caucasian origin. In the CRF group, the underlying cause for chronic renal disease included diabetic nephropathy (n = 12), polycystic kidney (n = 13), nephrolithiasis (n = 10), chronic glomerulonephritis (n = 19), interstitial nephritis (n = 6), others (n = 5) and unknown etiology (n = 9). The median duration of renal replacement therapy for CRF patients were 7.0 years [0.5–26 years], and six patients were on continuous ambulatory peritoneal dialysis, while the rest were receiving regular hemodialysis. A total of 16 IC and 7 CRF patients were diagnosed as active TB. While all of the IC patients with active TB had pulmonary involvement, extrapulmonary involvement of TB was noted in four out of seven CRF patients. In both groups, the diagnosis of pulmonary TB was based on positive cultures of M. tuberculosis from sputum or bronchoalveolar lavage. Eleven of IC patients with active TB (62.5%) were smear positive while all had positive cultures of M. tuberculosis. Four (25%) of IC active TB patients had advanced disease (with one having military TB and three with cavitary disease).
Table 1. Characteristics of the study participants.
All of the four CRF patients with extrapulmonary TB had TB lymphadenitis diagnosed with clinical and pathological findings consistent with TB. The rest of the CRF patients with active TB (n = 3) were smear and culture-positive patients with two (26.8%) having advanced disease (one with miliary TB and one cavitary pulmonary disease). The frequency of active TB patients in advanced disease course were similar among IC and CRF groups (p = 0.68). One of the CRF patients with pulmonary TB had a previous diagnosis of TB, and one of the CRF patients with pulmonary TB was died due to disease progression.
The median TST induration in CRF and IC patients were 11 mm [0–25 mm] and 14 mm [0–30 mm], respectively (p = 0.0001). The TST was positive in 68.9% of the CRF group compared to 52% of IC patients (p = 0.04). The T-SPOT.TB test was positive in 43.2% of the CRF patients and 34.7% of IC patients (p = 0.33). The T-SPOT.TB positivity was significantly less prevalent than TST positivity in CRF patients (43.2 vs. 68.9%, p = 0.007, respectively). Among IC group, T-SPOT.TB and TST positivity rates were 34.7 and 52%, respectively (p = 0.81). The duration of renal replacement therapy was not an affecting factor for the T-SPOT.TB outcome (data not shown, p = 0.8). Median blood lymphocyte counts did not differ among CRF and IC patients [1252 cells/mL (512–2688) vs. 916 cells/mL (264–4174)], respectively (p = 0.07). TST and T-SPOT.TB results of the study groups are presented in .
Table 2. TST and T-SPOT.TB results in IC and CRF patients.
A cutaneous anergy with TST was determined in 2.7% of IC and 20.3% of CRF patients (p = 0.001, OR: 9.3, 95% CI: 2.0–42.2). In CRF group, anergy response with TST was significantly more prevalent in T-SPOT.TB negative yielded patients (anergy response rate 80% in T-SPOT.TB negative CRF patients and 20% in T-SPOT.TB positive CRF patients, p = 0.041). In vitro anergy was defined as less than 20 spot-forming cells/250.000 PBMC in the PHA-positive control wells.Citation17 Six tests (4.03%) yielded indeterminate (ITR) with T-SPOT.TB assay. Three of them owed to lack of response in positive control wells – also defined as in vitro anergy – and three were due to failure of negative control wells. Of these ITR tests, two were TST positive IC patients with one of them suffering from active TB, and four were TST positive CRF patients with one of them having active TB. ITR frequency did not differ among IC and CRF patients (2.7 vs. 5.4%, respectively; p = 0.38). Median blood lymphocyte count of patients with ITR T-SPOT.TB results did not show a significant difference when compared with valid T-SPOT.TB tests (840 cells/mL [412–2515] vs. 1170 cells/mL [264–4174], respectively, p = 0.34).
Sensitivity and specificity comparisons of TST and T-SPOT.TB were presented in . Among IC group, 68.8 (11/16) and 43.8% (7/16) of active TB cases were positive with T-SPOT.TB and TST, respectively (p = 0.002 for T-SPOT.TB among active TB vs. non-TB IC group and p = 0.57 for TST among active TB vs. non-TB immunocompetent patients). On the other hand, 42.9 (3/7) and 71.4% (5/7) of CRF patients with active TB yielded positive with T-SPOT.TB and TST, respectively (p = 0.042 for T-SPOT.TB among active TB vs. non-TB CRF patients and p = 1.0 for TST among active TB vs. non-TB CRF patients).
Table 3. Diagnostic performance of TST and T-SPOT.TB in study groups.
Concordance between TST and T-SPOT.TB was 61.4% (κ = 0.25, p = 0.021) in CRF, and 47.9% (κ = 0.03, p = 0.79) in IC group. Disconcordance between two tests was evident in 53.3 and 37.8% of the IC and CRF groups, respectively. Among discordant results 57.1% of them were TST+/T-SPOT.TB− and 32.1% were TST−/T-SPOT.TB+. The frequency of TST+/T-SPOT.TB− and TST−/T-SPOT.TB+ responders did not differ significantly among IC and CRF groups (data not shown). TST−/T-SPOT.TB+ type of disagreement was more frequent in active TB IC patients than the non-TB IC patients [OR: 6.9, 95% CI: 1.9–25.2, p = 0.005], while such type discordance frequency was similar in active TB and non-TB CRF patients [OR: 1.2, 95% CI: 0.1–11.6, p = 1.0]. On the other hand, TST+/T-SPOT.TB− type of disagreement was less frequent in active TB IC patients than the non-TB IC patients [OR: 0.1, 95% CI: 0.01–0.91, p = 0.016], while such type of discordance frequency was similar in active TB and non-TB CRF patients [OR: 0.58, 95% CI: 0.06–5.2, p = 1.0]. None of the other factors such as sex, BCG vaccination, having active TB, presence of diabetes mellitus and smoking were found to be associated with the discordant outcome. Disconcordant response frequency was higher in ICs rather than CRF patients (53.3 vs. 37.8%, p = 0.058). Among concordant results, TST+/T-SPOT.TB+ type of concordance was more prevalent in CRF patients when compared to IC group (32.4 vs. 16%, respectively; OR: 2.5, 95% CI: 1.15–5.5, p = 0.02), while TST−/T-SPOT.TB− type of concordance was similar in both groups (p = 0.21).
On multivariate analysis, presence of CRF and active TB were found as significant risk factors for T-SPOT.TB positivity (OR: 2.4, 95% CI: 1.1–5.3, p = 0.03 and OR: 5.4, 95% CI: 1.8–15.8, p = 0.002, respectively) while exposure to the index case and old TB history did not have an effect. Besides, presence of CRF, active TB, BCG vaccination, exposure to the index case and old TB history were not affecting factors for TST positivity. Risk factors effecting TST and T-SPOT.TB positivity in both study groups are presented in .
Table 4. Risk factors associated with TST and T-SPOT.TB positivity in study groups on multivariate analysis.
Discussion
In this prospective study, we report the comparative evaluation of the T-cell based assay – T-SPOT.TB- with that of TST in CRF and IC patients in an area with high BCG coverage, and an intermediate burden of active TB (an incidence rate for TB of 28.5/100000/year for 2007 in Turkey).Citation12 CRF patients have a higher risk of TB (6- to 52-fold) than the general population and TB usually present with extrapulmonary involvement.Citation14 Over half of active TB patients (57%) in the CRF group presented with extrapulmonary involvement in our study. We observed a remarkable prevalence of LTBI in both groups as 43–69% in CRF, and 35–52% in IC subjects based on T-SPOT.TB and TST, respectively. T-SPOT.TB was less sensitive and specific in CRF patients as compared with IC cases in the present study. We did not observe an association between TB exposure and both T-SPOT.TB and TST.
The prevalence of LTBI based on TST was more frequent in CRF patients rather than ICs (69 vs. 52%), while prevalence of LTBI based on T-SPOT.TB were similar in both groups (43 vs. 35%). When focused on the frequency of LTBI diagnosis, we saw that this figure is greater than most of the published reports from low-incidence settings, and similar with studies addressing Turkish population.Citation8,Citation19–21 Lee et al.Citation22,Citation23 hypothesized that the higher prevalence of LTBI in CRF patients can be explained by the increased risk of exposure to TB in healthcare setting and increased susceptibility of these patients to become latently infected more frequently than immunocompetent people. Passalent’s, Chung’s and Soysal’s studies have shown that T-SPOT.TB assay detected LTBI more frequent than TST.Citation24–26 Conversely, TST positivity rates were more frequent than the T-SPOT.TB positivity in both groups in our study. Since BCG coverage was high (87%) in our study population, BCG-vaccination may have caused false-positive TST results, whereas not influenced the T-SPOT.TB results. This finding is consistent with the fact that T-SPOT.TB assay is unaffected by the BCG-vaccination.Citation27
A gold standard test is lacking in diagnosis of LTBI. The risk of LTBI is closely related with proximity and duration of exposure to the index case. For that reason, investigators have used quantified TB exposure as a surrogate gold standard for LTBI.Citation28 Although previous studies reported a close correlation between ELISA-IGRAs and TB exposure, neither TST nor T-SPOT.TB associated with exposure in both study groups.Citation29,Citation30 Positive T-SPOT.TB was associated with the presence of active TB in IC subjects (OR: 5.9, CI 95%:1–33, p = 0.04).
The diagnostic agreement between two tests was fair in both groups (78.5%, κ = 0.29 vs. 47.9%, κ = 0.03, respectively). The most frequent disagreement between results was the TST+/T-SPOT.TB− type discordance. TST−/T-SPOT.TB+ type of disagreement was four times more frequent in active TB patients. TST positivity was associated with T-SPOT.TB positivity whereas T-SPOT.TB positivity was associated with not having BCG and TST positivity in CRF group on multivariate analysis. On the other hand, presence of active TB was a significant risk factor for T-SPOT.TB positivity in IC group in our study. Similarly, T-SPOT.TB was reported to be similar with TST regarding association with clinical risk factors.Citation11
Diagnostic performance of TST is diminished in BCG-vaccinated populations.Citation10 ELISA-based IGRAs were found to be more sensitive than TST for diagnosing LTBI.Citation25,Citation31 However, diagnostic performance of IGRAs was better in low TB endemic settings rather than Turkey.Citation10,Citation32 Data regarding the performance of T-SPOT.TB test in high-risk groups as CRF patients is limited. We found that T-SPOT.TB is less sensitive and specific in CRF patients as compared with IC cases. Sensitivity of immune-based tests – IGRAs and TST – is mainly confounded by the immune status of the patients.Citation7 Although, it was shown that intracellular IFN-gamma response to M. tuberculosis specific antigens was not adversely affected by moderate-extent of immunodeficiency, such as uremic patients, our results may indicate necessity of further research regarding performance of IGRAs – especially ELISPOT based IGRA – in CRF patients.Citation23 Another concern would be the effect of disease severity on diminished sensitivity of TST and T-SPOT.TB because immune system may display various responses in extensive active TB disease course and may be weaker, which may affect immune-based test results, such as TST and IGRAs.Citation33 However, the frequency of advanced TB cases were similar in both IC and CRF groups (25 vs. 28.6%, respectively), in our study. As there is no gold standard for testing LTBI, we estimated specificity from persons with a low likelihood of exposure – according to their medical records and self-reports – similar with other IGRA studies. For this reason, it was impossible to definitely rule-out M. tuberculosis exposure in these patients. As a result, we assumed that the lower specificity of T-SPOT.TB may be due to considerable rate of LTBI in our country and exposure to mycobacteria other than M. tuberculosis.
Specific cellular immune response in CRF patients is impaired by a defect of the antigen-presenting cells due to impaired expression and up-regulation of the co-stimulatory molecule, B7-2.Citation34 Previous studies reported a high rate of cutaneous anergy (40–58%) in CRF patients due to altered cellular immune response when compared with healthy subjects.Citation12,Citation20,Citation35,Citation36 In our study, CRF patients had an anergy response approximately 10 times higher than IC patients with TST. On the other hand, response to PHA mitogen is accepted as a surrogate marker for in vitro anergy and a determinant of the quality control of the IGRA assay.Citation18,Citation37 In the present study, 4% (n = 3) of CRF and none of the IC patients had in vitro anergy with T-SPOT.TB test. These findings support the hypothesis that the use of T-SPOT.TB test in CRF patients has the advantage of being less affected by anergy.
Previous studies reported that the frequency of ITR results among CRF patients ranged from 4.8 to 13%.Citation24,Citation25,Citation38 Our study showed no significant difference between the ITR result frequency among study groups (CRF vs. IC), and that 5.4% of CRF patients had an ITR result with T-SPOT.TB test, which is consistent with previous reports. Pre-determined risk factors, such as longer duration of renal replacement therapy, total lymphocyte number were not affecting T-SPOT.TB test yielding as ITR in our study.Citation39
Several studies have addressed the feasibility of IGRAs in CRF patients for diagnosing LTBI were mostly performed on settings including only hemodialysis patients. To our knowledge, one study performed by Lee et al.Citation21 allowed a head-to-head comparison of IGRAs in both CRF patients and immunocompetent participants. In this study, we also enrolled active TB patients from both immune status groups which enabled sensitivity analysis of the T-SPOT.TB assay and TST. Our study has several limitations. Firstly, the number of active TB patients recruited into the study was small, which restricts the clear evaluation of sensitivity performance of T-SPOT.TB test. Secondly, estimation of specificity from persons with a low likelihood of exposure to M. tuberculosis that it was impossible to definitely rule-out M. tuberculosis exposure may be the reason of reduced specificity measures of T-SPOT.TB. In addition, the relatively small number of participants included in this study limits the generalizability of these results to the chronic renal failure patients. Further studies including larger number of subjects are needed to explore these results.
In conclusion, the prevalence of LTBI was remarkable in CRF and IC groups based on both TST and T-SPOT.TB in an intermediate TB burden country. T-SPOT.TB seems to be less sensitive and specific in CRF patients as compared with IC cases. On the other hand, T-SPOT.TB has the advantage of being less affected by anergy in CRF patients. Further research regarding performance of interferon-gamma enzyme-linked immunospot assay in CRF patients is required.
Acknowledgements
The authors thank Elif Erdem, for technical assistance in performing T-SPOT.TB assays, Şeref Özkara, MD, Nilgün Kalaç, MD from Atatürk Training and Research Center for Chest Diseases and Thoracic Surgery; Nurhan Özdemir, MD from Baskent University School of Medicine, Department of Internal Medicine, Division of Nephrology; and medical staff of physicians in several TB dispensaries in Ankara, for contributing to the patient selection stage. All participants are also acknowledged. Additionally, we thank the laboratory technicians of Oxford Immunotec for scoring T-SPOT.TB plates by the automated ELISPOT reader.
Declaration of interest
This study was granted by The Scientific and Technological Research Council of Turkey 106S046 (SBAG-3324).
References
- Girndt M, Sester U, Sester M, Kaul H, Köhler H. Impaired cellular immune function in patients with end-stage renal failure. Nephrol Dial Transplant. 1999;14:2807–2810
- Kwan JT, Hart PD, Raftery MJ, Cunningham J, Marsh FP. Mycobacterial infection is an important infective complication in British Asian dialysis patients. J Hosp Infect. 1991;19(4):249
- Chia S, Karim S, Elwood RK, Fitzgerald JM. Risk of tuberculosis in dialysis patients: A population-based study. Int J Tuberc Lung Dis. 1998;2:989–991
- Tuberculosis transmission in a renal dialysis center – Nevada. MMWR Morb Mortal Wkly Report 2004;53:873–875. Joint Statement of the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:221–247
- Meije Y, Piersimoni C, Torre-Cisneros J, Dilektasli AG, Aguado JM; The ESCMID Study Group of Infections in Compromised Hosts (ESGICH). Mycobacterial infections in solid organ transplant recipients. Clin Microbiol Infect. 2014;20(Suppl 7):89–101
- Lalvani A. Diagnosing tuberculosis infection in the 21st century. Chest. 2007;131(6):1898–1906
- Pai M, Zwerling A, Menzies D. Systematic review: T-cell based assays for the diagnosis of latent tuberculosis. Ann Intern Med. 2008;149(3):177–184
- Wang L, Turner MO, Elwood RK, Schulzer M, FitzGerald JM. A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements. Thorax. 2002;57:804–809
- Woeltje KF, Mathew A, Rothstein M, Seiler S, Fraser VJ. Tuberculosis infection and anergy in hemodialysis patients. Am J Kidney Dis. 1998;31:848–852
- Dilektasli AG, Erdem E, Durukan E, Eyüboğlu FÖ. Is the T-cell based interferon-gamma releasing assay feasible for diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country? Jpn J Infect Dis. 2010;63:433–436
- Rogerson TE, Chen S, Kok J, et al. Tests for latent tuberculosis in people with ESRD: A systematic review. Am J Kidney Dis. 2013;61(1):33–43
- Gümüşlü F, Özkara Ş, Özkan S, et al. Childhood tuberculosis, Tuberculin Skin test (TST) and prevention from tuberculosis. In: Gümüşlü F, Özkara Ş, eds. Annual Report on the Tuberculosis Control in Turkey. Ankara: Rekmay; 2007:41–76
- The Official Statement of the American Thoracic Society and the Centers for Disease Control and Prevention. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376–1395
- Öner-Eyuboglu AF, Akcay MS, Arslan H, Demirhan B, Kalpaklioglu AF. Extrapulmonary involvement of Mycobacterial infections in dialysis patients. Transplant Proc. 1999;31:3199–3201
- Zhang L, Zhang Y, Shi X, et al. Utility of T-cell interferon-γ release assays for diagnosing tuberculosis serositis: A prospective study in Beijing, China. PLos One. 2014:9(1):e85030
- Lalvani A, Pathan AA, Durkan H, et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet. 2001;357:2017–2021
- Oni T, Patel J, Gideon HP, et al. Enhanced diagnosis of HIV-1 associated tuberculosis by relating T-SPOT.TB and CD4 counts. Eur Respir J. 2010;36(3):594–600
- Dheda K, Lalvani A, Miller RF, et al. Performance of a T-cell based diagnostic test for tuberculosis infection in HIV-infected individuals is independent of CD4 cell count. AIDS. 2005;19(17):2038–2041
- Wauters A, Peetermans WE, van den Brande PV, et al. The value of tuberculin skin testing in hemodialysis patients. Nephrol Dial Transplant. 2004;19:433–438
- Kantarci G, Altinöz H, Şahin S, Manga G, Taşan G. Tuberculin positivity: A serious problem before transplantation in Turkey. Transplant Proc. 2006;38:646–648
- Habesoglu MA, Torun D, Demiroglu YZ, et al. Value of tuberculin skin test in screening for tuberculosis in dialysis patients. Transplant Proc. 2007;39:883–886
- Lee SS, Chou KJ, Su IJ, et al. High prevalence of latent tuberculosis infection in patients with end-stage renal disease on hemodiaysis: Comparison of QuantiFERON-TB GOLD, ELISPOT, and tuberculin skin test. Infection. 2009;37(2):96–102
- Sester M, Sester U, Clauer P, et al. Tuberculin skin test underestimates a high prevalence of latent tuberculosis infection in hemodialysis patients. Kidney Int. 2004;65:1826–1834
- Passalent L, Khan K, Richardson R, Wang J, Dedier H, Gardam M. Detecting latent tuberculosis infection in hemodialysis patients: A head-to-head comparison of the T-SPOT.TB test, tuberculin skin test, and an expert physician panel. Clin J Am Soc Nephrol. 2007;2:68–73
- Chung WK, Zheng ZL, Sung JY, et al. Validity of interferon-γ-release assays for the diagnosis of latent tuberculosis in hemodialysis patients. Clin Microbiol Infect. 2010;16(7):960–965
- Soysal A, Toprak D, Koc M, Arikan H, Akoglu E, Bakir M. Diagnosing latent tuberculosis infection in hemodialysis patients: T-cell based assay (T-SPOT.TB) or tuberculin skin test. Nephrol Dial Transplant. 2012;27(4):1645–1650
- Pai M, Riley W, Colford JM. Interferon-gamma assays in the immunodiagnosis of tuberculosis: A systematic review. Lancet Infect Dis. 2004;4:761–776
- Dheda K, van Zyl Smith R, Badri M, Pai M. T-cell interferon-γ release assays for the rapid immunodiagnosis of tuberculosis: Clinical utility in high-burden vs. low-burden settings. Curr Opin Pulm Med. 2009;15:188–200
- Winthrop KL, Nyendak M, Calvet H, et al. Interferon-γ release assays for diagnosing Mycobacterium tuberculosis infection in renal dialysis patients. Clin J Am Soc Nephrol. 2008;3:1357–1363
- Inoue T, Nakamura T, Katsuma A, et al. The value of QuantiFERON®TB-Gold in the diagnosis of tuberculosis among dialysis patients. Nephrol Dial Transplant. 2009;24:2252–2257
- Triverio PA, Bridevaux PO, Roux-Lombard P, et al. Interferon-γ release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic hemodialysis patients. Nephrol Dial Transplant. 2009;24:1952–1956
- Soysal A, Torun T, Efe S, Gencer H, Tahaoglu K, Bakir M. Evaluation of cut-off values of interferon-gamma-based assays in the diagnosis of M. tuberculosis infection. Int J Tuberc Lung Dis. 2008;12(1):50–56
- Pathan AA, Wilkinson KA, Klenerman P, et al. Direct ex vivo analysis of antigen-specific IFN-γ secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: Associations with clinical disease state and effect of treatment. J Immunol. 2001;167:5217–5225
- Girndt M, Sester M, Sester U, Kaul H, Köhler H. Defective expression of B7-2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect. Kidney Int. 2001;59:1382–1389
- Shankar MSR, Aravindan AN, Sohal PM, et al. The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: Tuberculin test and the risk of post-transplant tuberculosis. Nephrol Dial Transplant. 2005;20:2720–2724
- Smirnoff M, Patt C, Seckler B, Adler JJ. Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest. 1998;113:25–27
- Vincenti D, Carrara S, Butera O, et al. Response to RD1 epitopes in HIV-infected individuals enrolled with suspected active tuberculosis: A pilot study. Clin Exp Immunol. 2007;150:91–98
- Kim SH, Lee SO, Park IA, et al. Diagnostic usefulness of a T cell-based assay for latent tuberculosis infection in kidney transplant candidates before transplantation. Transplant Infect Dis. 2009;12(2):113–119
- Shu CC, Wu VC, Yang FJ, et al. Predictors and prevalence of latent tuberculosis infection in patients receiving long-term hemodialysis and peritoneal dialysis. PLoS One. 2012;7:e42592