CJASN ePress. Published on April 22, 2010 as doi: 10.2215/CJN.09231209 In-Depth Review

Diagnosis of in Dialysis Patients: Current Strategy

Liviu Segall and Adrian Covic Nephrology Department, “Dr. C. I. Parhon” Hospital, University of Medicine and Pharmacy “Gr. T. Popa,” Ias¸i, Romania

Patients with ESRD undergoing chronic dialysis are much more prone to develop tuberculosis (TB) than the general population. In these patients, the diagnosis of TB disease is often difficult because of prevailing extrapulmonary involvement and nonspecific symptoms. The prevalence of latent TB infection (LTBI) in ESRD patients is elevated, and those who become infected are at high risk of developing active disease. Therefore, screening for LTBI in this population is recommended, aiming to prevent progression to active TB and secondary contamination of others. The skin test (TST), the classic diagnostic tool for LTBI, has several major drawbacks, including poor sensitivity (because of a high prevalence of anergy in dialysis patients) and specificity [with false-positive tests in those vaccinated with bacille Calmette–Gue´rin (BCG)]. In the past 10 years or so, new immunological tests using IFN-␥ release assays (IGRAs) have become available and have shown superior sensitivity and specificity for the diagnosis of TB compared with the TST in several studies, some very recent ones including ESRD patients. Therefore, current strategy in dialysis patients should use these tests instead of TST for LTBI screening and as an aid for the diagnosis of active TB. Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010. doi: 10.2215/CJN.09231209

atients with ESRD undergoing chronic dialysis are 6 to monly associated with fatigue, malnutrition, and other nonspe- 25 times more likely to develop tuberculosis (TB) than cific complaints, possibly concealing the course of an underly- P the general population, mainly because of the impaired ing TB disease (7,11,12). cellular immunity characteristic of this condition (1–3). Noso- This atypical presentation may often lead to a delay in accu- comial transmission of TB has also been reported in hemodial- rate diagnosis and therapy, sometimes resulting in patients’ ysis (HD) centers (4). In a U.S. Renal Data System (USRDS) death. Therefore, nephrologists should always have a high retrospective analysis, age, unemployment, Asian and Native degree of suspicion and consider the possibility of TB whenever American race, smoking, reduced body mass index, low serum confronted with an ESRD patient presenting with general albumin, ischemic heart disease, and anemia were all signifi- symptoms such as fever, weight loss, and/or lymphadenopa- cant risk factors for HD patients to develop TB (5). thy (10). The diagnosis would then require the isolation of The mortality rate of TB in dialysis patients is high, ranging acid-fast bacilli, the finding of typical caseating granuloma on from 17% to 75% (6). In the USRDS analysis mentioned above, biopsy, or the recovery of tubercle bacilli from the culture of the TB was independently associated with a 42% increased mortal- biopsy material (7). ity (5). Difficulties in Diagnosing Latent TB Active TB in ESRD Patients: Atypical Infection: The Limitations of the TST Clinical Presentation According to several studies using different diagnostic ap- In ESRD, the diagnosis of TB disease is often difficult because proaches, the prevalence of latent TB infection (LTBI) in chronic of prevailing extrapulmonary involvement and nonspecific dialysis patients is high, ranging between 20% and 70% symptoms. Extrapulmonary TB has been reported in as many (2,13,14), and those who become infected are at high risk of as 60% to 80% of cases, either alone or associated with pulmo- developing active disease (15,16). Therefore, screening for LTBI nary TB. The most common forms of presentation are lymph- in this population is recommended, aiming to prevent progres- adenitis, gastrointestinal, bone, genitourinary, peritonitis, pleu- sion to active TB and secondary contamination of other patients ral effusion, pericardial effusion, miliary TB, and pyrexia of and healthcare workers (15). It has been shown that preventive unknown origin (7–10). On the other hand, uremia is com- treatment of latently infected people diminishes the risk of subsequent development of active TB by approximately 90% (17).

Published online ahead of print. Publication date available at www.cjasn.org. In persons with LTBI, the very low bacterial burden makes it impossible to directly detect tuberculosis: acid- Correspondence: Dr. Liviu Segall, Clinica a IV-a Medicala˘—Nefrologie, Spitalul “Dr C. I. Parhon,” B-dul Carol I nr. 50, Ias¸i, Romania. Phone: 00-40-232-211834; fast bacilli are rarely seen on sputum smear examination and Fax: 00-40-232-211752; E-mail: [email protected] tubercle bacilli are not found in cultures of respiratory speci-

Copyright © 2010 by the American Society of Nephrology ISSN: 1555-9041/●●●●–0001 2 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 mens. Serologic testing is unreliable and the chest radiograph is between TST and chest radiograph results: patients with posi- usually normal (15,18). tive TST had negative chest x-rays and vice versa. The authors The classic diagnostic tool for LTBI is the tuberculin skin test suggest that this lack of correlation could be due to the high (TST), which is based on the strong cell-mediated immune anergy rate in HD patients, causing a false-negative TST with a response induced by LTBI. The TST measures the delayed-type positive chest x-ray. On the other hand, chest radiography hypersensitivity response to intradermal inoculation of tuber- could be false-negative in the presence of only small scars, or culin purified protein derivative (PPD), a crude mixture of false positive due to sequel lesions of previous pulmonary Ͼ200 M. tuberculosis proteins (18). In 1995, the Centers for diseases other than TB. Because they found no correlation Disease Control and Prevention (CDC) recommended screen- between chest radiography and TST, the authors conclude that ing for LTBI with TST in persons with a medical condition that none of these methods can be used as the “gold standard,” and increases the risk of TB, including those with ESRD. A skin recommend that both of them should be performed in every induration over 10 mm in diameter is considered positive (19). HD patient at the start of dialysis and repeated every year or However, the high-risk groups that are targeted for screening whenever active TB disease is diagnosed in the unit. and preventive therapy are also those in which the TST most An interesting new diagnostic approach was tried a few often fails to detect LTBI (15,20). The prevalence of anergy to years ago by Sester et al. in 127 HD patients and 218 controls TST in the ESRD population is significantly higher than in the (24): in vitro quantitation of PPD-specific T cells using a rapid general population (44% versus 16%) (21). This same limitation 6-hour assay. Specific T cells toward PPD were flow-cytometri- of the skin test applies to its use as a diagnostic aid in the cally quantified from whole blood, and results were compared evaluation of patients with suspected active TB (when micro- with skin testing. Whereas 85.7% of control patients with PPD biological confirmation is awaited or not possible). In one study reactivity in vitro were skin-test positive, the respective percent- in HD patients diagnosed with active TB, anergy to TST was age among HD patients was significantly lower—51.4%. The found in over 50% of patients (7). Thus, because of its poor authors concluded that, unlike the skin test, measurement of sensitivity, a negative TST in these patients cannot be used to PPD reactivity by in vitro quantitation of PPD-specific T cells eliminate the possibility of latent or active TB (15). was not affected by uremia-associated immunosuppression, Various strategies to improve the sensitivity of the TST in and they suggested that this assay might thus be a valuable dialysis patients have been advocated, including two-step test- alternative to TST. However, the method did not receive further ing to induce a “booster phenomenon.” In a study by Dogan et attention from researchers because other more specific blood al. (22), 11.3% of 124 chronic HD patients showed a positive assays for the diagnosis of LTBI have subsequently been devel- reaction with the first test, whereas the second test added 12.1% oped and introduced in clinical practice. more. Multiple (Ͼ2) testing does not seem to add significant benefit. Wauters et al. administered four consecutive TSTs (at The IFN-␥ Release Assays: Advantages over 7-day intervals) to 224 HD patients (1): after the first test, 14.7% the TST of the patients showed a positive reaction; the second test These new tests use two proteins encoded by a unique added 13.1% more TST-positive patients; and the third and the genomic segment (stretch of DNA) termed “Region of Differ- fourth TST only resulted in an additional 4.2% and 4.4% new ence 1,” which is absent from all strains of , positive patients, respectively. However, repeated testing most BCG, and most nontuberculous mycobacteria but is present in likely increases sensitivity at the expense of specificity. Also, M. tuberculosis (25). These proteins, early secretory antigenic repeated testing has operational limitations linked to the need target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), are of many return visits. Setting a lower TST threshold (e.g., 5-mm major targets of T-helper type 1 cells in patients with M. tuber- induration instead of 10) would also increase the sensitivity of culosis infection (26,27). Therefore, a T cell response to these the test, but again it would do so at the cost of a larger number antigens could serve as a specific marker of M. tuberculosis of false-positive TST reactions, meaning many individuals pos- infection, avoiding the antigenic crossreactivity of PPD, the sibly exposed to unnecessary preventive treatment (18). main cause of poor specificity of the TST. The second major drawback of TST is its low specificity. The T-SPOT.TB test (Oxford Immunotec, Abingdon, United Because PPD is a culture filtrate of tubercle bacilli containing Kingdom) was developed by A. Lalvani and co-workers in the many antigens shared with the bacille Calmette–Gue´rin (BCG) late 1990s (28). T cells from individuals with M. tuberculosis vaccine and most nontuberculous mycobacteria (20), individu- infection become sensitized to ESAT-6 or CFP-10 in vivo; when als vaccinated with BCG but not infected with M. tuberculosis the T cells re-encounter these antigens ex vivo in the overnight can test falsely positive using the TST. However, in the study of T-SPOT.TB assay, they release a cytokine, IFN-␥. By the next Wauters et al., a history of BCG vaccination did not correlate morning, each such T cell gives rise to a dark spot, which is the with positive TST, and some guidelines recommend ignoring “footprint” of an individual M. tuberculosis-specific T cell (26). the effect of BCG on TST (15,23). The readout is thus the number of spots that are counted using The low sensitivity and specificity of the TST may explain the a magnifying lens or automated reader. The QuantiFERON-TB reported poor correlation of its results with the patients’ history Gold (QFT-G) test (Cellestis, Carnegie, Australia) is a whole- and chest radiographs. In the aforementioned study of Wauters blood ELISA that measures the IFN-␥ concentration in the et al. (1), positive TST results were only weakly correlated with supernatant of a sample of diluted whole blood after 24 hours previous TB disease, and there was no significant correlation of incubation with ESAT-6 and CFP-10 (29). Originally devel- Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 Diagnosis of Tuberculosis in Dialysis Patients 3 oped in the 1980s for detecting TB in cattle, the assay was 34). A case-control study on 216 Japanese BCG-vaccinated adapted for human use in the 1990s. The U.S. Food and Drug adults showed a 98% specificity of QFT-G, much higher than Administration has approved it for in vitro diagnostics, and a for TST (35%) (29). guideline from the CDC has been published (30). A newer On the other hand, establishing the diagnostic accuracy for version of the QuantiFERON-TB Gold assay, the so-called “In- LTBI of the IGRAs is a major challenge because a gold standard Tube” test (QFT-GIT), uses tubes prefilled with antigens; this is lacking. However, when testing patients with active TB, simplifies the laboratory procedures, making it more suitable T-SPOT.TB showed sensitivity ranging from 83% to 97% in five for “on-field” usage in settings with limited resources (18). The studies on 266 cumulative patients, whereas in another five three of these assay platforms are sometimes collectively re- studies on 330 cumulative patients the sensitivity of QFT-G ferred to as “T cell-based IFN-␥-release assays” (IGRAs). A ranged from 70% to 89%. When these results were pooled, the summary of the characteristics of the IGRAs in comparison sensitivity of T-SPOT.TB seemed to be significantly higher com- with the TST is presented in Table 1. pared with QFT-G (18). The sensitivity of the IGRAs is at least In theory, the T-SPOT.TB-based test should be more sensitive equivalent to that of TST and, in certain studies, superior with because it detects IFN-␥ in the immediate vicinity of the T cell T-SPOT.TB. Finally, several studies in contacts have been un- from which it is released (where it is still at a locally high dertaken with the aim of measuring the concordance between concentration), whereas the ELISA detects IFN-␥ after it has these biologic tests and the TST. The essential finding was a diffused into the supernatant and become diluted in the total very good correlation between positivity of the blood tests and volume of the test sample (18). the degree of exposure of the contacts (31). Reviews of several studies in various populations (18,31) Studies in immunocompromised populations confirmed suggested similar levels of specificity for the two IGRAs and the superiority of IGRAs for the diagnosis of LTBI in com- these were statistically higher than those for TST, particu- parison with TST, which has notoriously low sensitivity in larly in subjects vaccinated by BCG. Four case-control stud- these settings (35). In HIV-seropositive persons, it has been ies on 127 BCG-vaccinated low-risk individuals in aggregate demonstrated that T-SPOT.TB has a higher sensitivity than showed that T-SPOT.TB has a specificity of 100% (26,27,32– the TST (27,36–39). However, the results with QFT-G seem to

Table 1. Characteristics of the TST and of the IGRAs (18)

T-SPOT.TB QFT-G TST

Antigens ESAT-6 and CFP-10 ESAT-6 and CFP10 PPD Positive internal Yes Yes No control Uniformity of methods Yes Yes Noa and reagents Potential for boosting No No Yes effect in repeated tests Need for return visit No No Yes Time required for 16 to 20 hours 16 to 24 hours 48 to 72 hours results Setting of test In vitro In vitro In vivo Interpretation of test Objective (instrument- Objective (instrument- Subjective (operator-based) based) based) Readout units IFN-␥ spot-forming International units of Millimeters of induration cells IFN-␥ Technological platform T-SPOT.TB ELISA NA Test’s substrate PBMC Whole blood NA Outcome measure Number of IFN-␥- Serum concentration of NA producing T cells IFN-␥ produced by T cells Readout system Enumeration of spots Measurement of optical Palpable induration by naked eye, density values using magnifying lens, or an automated reader automated counter

NA, not applicable; PBMC, peripheral blood mononuclear cells. aMantoux test versus Heaf test, induration versus erythema, PPD-S versus PPD RT-23. 4 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 be less convincing. For example, Raby et al. (40) evaluated among those with a false-negative TST result. More true- the QFT-G in a cross-sectional study of Zambian adults with positive results in infected people would increase the rate of smear-positive TB and found that the sensitivity of the QFT-G was diagnosis and treatment of LTBI before progression to active significantly lower in HIV-positive than in HIV-negative individ- TB (18). uals. Subsequent studies have also confirmed that with decreasing Nevertheless, it is of paramount importance to also under- CD4 count, false-negative and indeterminate results are seen more stand the limitations of the IGRAs: lower sensitivity in severe frequently, which may affect the diagnostic utility of the QFT-G in disease, unknown predictive value for future development this population (37,41,42). In patients with autoimmune diseases of active TB (because no studies have been performed on this treated with immunosuppressive agents, the experience with subject), and lack of distinction between LTBI and active TB IGRAs in diagnosing LTBI is rather limited and is mainly drawn (31). Limited availability of IGRAs (in contrast with the from small-scale cross-sectional studies (35). In general, these worldwide readily accessible TST) is another important is- studies have found that agreement between the TST and IGRAs is, sue. A 2008 survey of the Infectious Disease Society of Amer- at best, fair (43–45) and that, although false-negative IGRA results ica’s Emerging Infections Network (IDSA EIN) showed that may occur, the diagnostic sensitivity of IGRAs is more robustly QFT-G was available for use in only 63% of U.S. regions, maintained than that of the TST (35). with the lowest availability reported in the southern and The IGRAs have an internal positive control (i.e., a sample eastern states (50). Most likely, the availability of these tests well stimulated with a potent nonspecific stimulator of IFN-␥ is even lower in low-income countries. However, the single production by T cells). Although a negative TST in immuno- major disadvantage of IGRAs is their high cost, which is suppressed individuals can be a false negative, the failure of the approximately $30 for QFT-G, $25 for QFT-GIT, and $57 for positive control in the blood tests provides the important in- T-SPOT.TB in the United States. Most of this cost is related to formation that the test’s result cannot be reliably interpreted the laboratory, but other procedures, such as phlebotomy, because it may reflect an underlying in vivo immunosuppres- specimen transport, and processing also count (51). In com- sion, negatively affecting T cell function in the in vitro stimu- parison, the PPD used in the TST is only about $10; however, lation (18). Studies suggest that indeterminate results are rela- additional costs of the follow-up visit for reading the TST tively common with the ELISA, occurring in 5% to 40% of reaction must be considered (52). The introduction of blood patients with QFT-G but less frequently with the newer QFT- tests in clinical practice is expected to initially increase the GIT (46–48). Indeterminate QFT results seem to be associated cost of TB control. However, the fact that most of the costs with extremes of age (Ͻ5 and Ͼ80 years) and immunosuppres- for TB control are incurred during diagnosis and treatment sion, especially HIV infection (41). In contrast, indeterminate of patients with active TB suggests that higher diagnostic results are more rare with the T-SPOT.TB, occurring in 0% to sensitivity and higher specificity could induce cost savings in 5.4% (49). the medium and long term by reducing the future burden of Other important advantages of the IGRAs compared with the cases of active TB and decreasing the number of uninfected TST include lack of boosting effect in repeated tests, no need for BCG-vaccinated people inappropriately treated for LTBI return visit, shorter time required for results (16 to 24 hours (18). Studies in Switzerland and Germany have shown that versus 48 to 72 hours), and objective (instrument-based) inter- the most cost-effective method for LTBI screening is the pretation of the test (18). two-step strategy (TST followed by IGRA in TST-positive It is generally thought that the higher diagnostic accuracy patients) (53,54). The cost-effectiveness of this strategy is together with the operational advantages of the IGRAs probably related to low prevalence of LTBI and high preva- should improve the effectiveness of TB control programs. lence of BCG history in these countries. IGRA testing alone is Higher specificity will reduce false-positive test results, thus only cost-effective at LTBI rates Ͼ40% (55). Furthermore, the avoiding unnecessary chemoprophylaxis. On the other hand, costs of IGRAs are likely to decline with increasing usage of higher sensitivity would identify more infected persons these tests.

Table 2. Summary of studies on the value of IGRAs for the diagnosis of TB in ESRD patients

Indeterminate Study (Reference) n Objective IGRA Sensitivity Specificity Results (%) (%) (%)

Inoue et al. (56) 162 HD Diagnosis of active TB QFT-G 100 89.7 24.1 Zoccali et al. (57) 29 HD Diagnosis of active TB T-SPOT.TB 91.7 64.7 NA Passalent et al. (3) 203 HD Diagnosis of LTBI T-SPOT.TB 73.1 to 78.6 NA 5.1 Triverio et al. (14) 62 HD Diagnosis of LTBI T-SPOT.TB 22 61.2 11.0 QFT-G 46 75.5 8.0 Chung et al. (58) 167 HD Diagnosis of LTBI T-SPOT.TB 65.7 41.9 4.8 QFT-G 62.5 63.5 12.6 Hoffmann et al. (59) 39 HD Diagnosis of LTBI QFT-GIT 71.4 100 2.6 Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 Diagnosis of Tuberculosis in Dialysis Patients 5

Table 3. National guidelines on detection of LTBI

Country (Reference) Immunocompetent Individuals Immunocompromised Individuals

United States-CDC (30) QFT-G can be used in all circumstances – in which the TST is used. QFT-G usually can be used in place of (and not in addition to) the TST. Canada (61) IGRA may be performed in TST- In an immunocompromised person (adult or positive, immunocompetent adults child), the TST should be the initial test and children who are at relatively used to detect LTBI. If TST is negative, an low risk of being infected with TB IGRA test may be performed. and of progressing to active disease if infected. Australia (62) TST remains the preferred method of – screening for LTBI. IGRAs may be used as a supplementary test in individualized clinical assessment. Japan (63) QFT is preferred over TST in adults (18 In high-risk groups QFT is preferred and to 49 years old) can be used for deciding on LTBI treatment. Even when QFT is preferred TST may be done first, followed by QFT in TST-positive patients, to be cost- effective (especially in case of mass screening). United Kingdom NICE (64) A two-step strategy is currently – recommended: using a TST, and those with positive results (or in whom TST may be less reliable) should then be considered for IGRA testing, if available. HPA (65) TST should generally be used as the IGRA testing, if available, can be considered first-line test for LTBI. as the sole test for LTBI in individuals in whom the result of TST may be falsely negative because immunocompromised. Switzerland (66) Confirm a positive TST with an IGRA. Use only an IGRA in immunocompromised subjects. Italy (67) TST should be carried out and when In immunosuppressed patients, an IGRA positive an IGRA should be should be carried out without a prior TST. performed. Netherlands (68) TST is the initial test, and if 5 mm or In subjects in whom the TST “may be less more followed by IGRA. reliable” perform an IGRA without a prior TST. France (69) IGRAs should be used instead of TST. – Ireland (70) IGRAs can be used in conjunction with IGRAs, if available, can be considered as the a TST. sole test for LTBI when the TST may be falsely negative because of immunosuppression.

NICE, U.K. National Institute for Clinical Excellence; HPA, Health Protection Agency.

The Value of IGRAs in ESRD Patients For the diagnosis of active TB, the sensitivity and the speci- In recent years, only a few studies have been published that ficity of the IGRAs were found to be 100% and 89.7%, respec- tried to assess the value of the blood assays for the diagnosis of tively, for QFT-G (56) and 91.7% and 64.7%, respectively, for TB in HD patients. A summary of these studies is presented in T-SPOT.TB (57). Table 2. On the other hand, the value of the IGRAs for the diagnosis 6 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 of LTBI in dialysis patients, as well as in the general population, recommend a two-step approach (i.e., TST followed by IGRA to is difficult to estimate in the absence of a gold standard. In a confirm TST-positive cases), which seems to be the most cost- study by Passalent et al. (3), LTBI was diagnosed by an expert effective strategy. On the other hand, in immunocompromised panel of physicians on the basis of three elements: patient individuals in whom the TST may be falsely negative, almost self-reported history of active TB, radiographic findings consis- all existing guidelines recommend using IGRAs, if available, as tent with previous TB infection, and a TST of induration Ͼ10 the sole test for LTBI. mm. The T-SPOT.TB was positive in 78.6%, 72.7%, and 73.1% of Summarizing the findings in ESRD patients described above, patients, respectively, whereas TST was positive in only 21.4% we may point out that (1) these patients are at high risk for M. of participants with positive history and in 18.2% of those with tuberculosis infection, and, once infected, they are very prone to suggestive x-rays. Defining “probable LTBI” as chest radiogra- develop active disease, which may be severe and difficult to phy suggestive of prior infection and/or established “at risk” diagnose; (2) screening for LTBI is therefore recommended, but contact with a patient with contagious TB, Triverio et al. (14) the anergy rate to TST is high; (3) the IGRAs are more sensitive found a higher sensitivity (46%) for QFT-G than for T-SPOT.TB and specific than the TST for detecting LTBI; (4) the IGRAs also (22%) and TST (25%). Similarly, Chung et al. (58) defined pa- have operational advantages over the TST; and (5) the rate of tients as being at “high-risk for LTBI” if they had a history of indeterminate results of IGRA tests is rather low. close contact with TB patients, old TB lesions on chest x-rays, or Therefore, we suggest that chronic dialysis patients should a history of TB infection. They showed that QFT was indepen- be screened for LTBI by using an IGRA test, if available, instead dently associated with the high-risk group (adjusted odds ratio of TST. Any of the three types of assays may be used, but QFTs 2.58; P ϭ 0.036), whereas TST and T-SPOT.TB were not. Finally, are less expensive and probably more sensitive in these pa- Hoffmann et al. (59) found that, in comparison with TST of tients. However, cost-effective studies are desirable to support induration Ն10 mm, QFT-GIT was more closely related to “TB the implementation of this strategy in dialysis units. exposure” (i.e., previous TB-disease, chest x-ray suggestive for A positive IGRA test requires excluding active disease before LTBI, or origin from a medium TB-prevalence region) as a affirming LTBI, and this should include checking for specific proxy for LTBI. symptoms and signs, a chest radiograph, and sometimes exam- Winthrop et al. (60) reported that patients in a dialysis center ination of sputum or other clinical samples for the presence of with TB case contact were likely to have a positive QFT-G (P ϭ M. tuberculosis. After TB has been excluded, treatment of LTBI 0.02) and T-SPOT.TB (P ϭ 0.04), but not a positive TST (P ϭ 0.7). should be considered. On the other hand, a negative test cannot Furthermore, Lee et al. (13) performed TST, T-SPOT.TB, and exclude TB when suggestive history, symptoms, or physical QFT-G in 32 ESRD patients that were subsequently followed up signs are present. The high susceptibility to TB infection of for 2 years. They found that only QFT-G but neither T-SPOT.TB dialysis patients must always be kept in mind, particularly in nor TST predicted the development of active TB in these pa- endemic areas. In symptomatic patients, further evaluation (in- tients. cluding chest radiographs and microbiologic or pathologic ex- When QFT-G and T-SPOT.TB were used, in three of the ams) is necessary, and IGRAs may also be used in difficult previously mentioned studies in HD patients the agreement situations as an aid for diagnosis. Indeterminate IGRA results between the two tests has been found to be fair or moderate cannot be interpreted; they may entail repeated testing in pa- (␬ ϭ 0.27 to 0.60), whereas the agreement between TST and tients with a high probability of having TB, but not in those IGRAs was only poor or fair (␬ ϭ 0.16 to 0.27 for QFT-G and with a low probability (30). 0.16 to 0.32 for T-SPOT.TB) (13,14,58). On the other hand, in the study of Winthrop et al. (60), the concordance between results Disclosures was better, ranging from 71% (TST versus T-SPOT.TB) to 79% None. (TST versus QFT-G) to 87% (QFT-G versus T-SPOT.TB). The rate of indeterminate results in HD patients varies be- tween 2% and 24% for QFT-G and 3% and 11% for T-SPOT.TB References according to different studies (Table 2). 1. Wauters A, Peetermans WE, Van Den Brande P, De Moor In the study of Chung et al. (58), previous BCG vaccination B, Evenepoel P, Keuleers H, Kuypers D, Stas K, Vanwal- significantly increased the rate of positive TST results, but did leghem J, Vanrenterghem Y, Maes BD: The value of tuber- not affect the QFT and T-SPOT.TB results. culin skin testing in haemodialysis patients. Nephrol Dial Transplant 19: 433–438, 2004 Screening for LTBI in Dialysis Patients: 2. Habesoglu MA, Torun D, Demiroglu YZ, Karatasli M, Sen Current Strategy N, Ermis H, Ozdemir N, Eyuboglu FO: Value of the tuber- culin skin test in screening for tuberculosis in dialysis With all of their limitations, the superiority of the new blood patients. Transplant Proc 39: 883–886, 2007 assays over the TST is indisputable and their introduction in 3. Passalent L, Khan K, Richardson R, Wang J, Dedier H, clinical practice is certainly a major progress in the diagnosis of Gardam M: Detecting infection in he- LTBI. Many countries (at least 17 so far) have developed new modialysis patients: A head-to-head comparison of the national guidelines for the detection of LTBI, including the T-SPOT.TB test, and an expert physician panel. Clin J Am place of IGRAs in this process (30,61–70) (Table 3). In immu- Soc Nephrol 2: 68–73, 2007 nocompetent persons, the vast majority of these guidelines 4. Centers for Disease Control and Prevention: Tuberculosis Clin J Am Soc Nephrol ●●: ●●●-●●●, 2010 Diagnosis of Tuberculosis in Dialysis Patients 7

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