Abstract
Immunocompromised persons with latent tuberculosis infection (LTBI) are at increased risk for tuberculosis reactivation compared with the general population. The tuberculin skin test, the traditional assay for diagnosing LTBI, has reduced accuracy in immunocompromised patients. IFN-γ release assays (IGRAs) are in vitro blood tests that measure T-cell release of IFN-γ after stimulation with antigens unique to Mycobacterium tuberculosis. Here we review the data for the use of QuantiFERON-TB Gold In-Tube and T-SPOT.TB, the two currently available IGRAs, in immunocompromised adults, including persons infected with HIV, patients with immune-mediated inflammatory disorders, candidates for treatment with tumor necrosis factor-α inhibitors, patients receiving hemodialysis, solid-organ transplant recipients, and patients with cancer. On the basis of the available data, IGRAs have advantages over the tuberculin skin test in specific patient populations and in certain situations. Further studies are needed to more accurately define the usefulness of IGRAs in immunocompromised patients.
Tuberculosis (TB) remains one of the most common infections worldwide (1). After initial infection, approximately 3 to 4% of patients go on to develop active TB within the first year (2). The rest develop latent tuberculosis infection (LTBI), and have a 5% lifetime risk of progressing to active TB (3, 4). The likelihood of progression to active TB can be substantially reduced by identification and treatment of patients with LTBI (5, 6). The long-established method to identify these patients has been the tuberculin skin test (TST). However, TST has several limitations, including false positive results due to prior bacillus Calmette-Guérin (BCG) vaccination or exposure to other nontuberculous mycobacteria, as well as variability in results due to the operator bias that is inherent to the test. False negative results can also occur because of reasons such as anergy, recent live virus vaccination (measles, mumps, polio), recent or overwhelming active TB infection, and improper administration of TST (7). Another important phenomenon that can occur when a patient is repeatedly tested by TST is boosting. Although boosting may increase the sensitivity of the test because of detection of prior false negative cases of LTBI, specificity is decreased because false positive results due to prior BCG vaccination/exposure to nontuberculous mycobacteria are also increased (7).
Immunocompromised persons with LTBI are at increased risk for progression to active TB (8), and treatment of LTBI in this population can reduce the risk of progression (9). However, many immunocompromised patients are already receiving complicated medical regimens, making empiric treatment for LTBI impractical. The situation is further compounded by the fact that TST performs particularly poorly in immunocompromised patients because of an increased likelihood for false negative results (7). For these reasons, alternative methods for diagnosing LTBI among immunocompromised persons have been sought.
IFN-γ release assays (IGRAs) are in vitro blood tests of cell-mediated immune response that measure T-cell release of IFN-γ after stimulation by antigens unique to Mycobacterium tuberculosis. The two IGRAs currently approved in many countries, including the United States, are the T-SPOT.TB assay (Oxford Immunotec, Abingdon, UK) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia). In immunocompetent persons, available data suggest that both assays have at least equal sensitivity to the TST, with improved specificity, for the diagnosis of LTBI (10, 11).
The QFT-GIT assay is a third-generation enzyme-linked immunosorbent assay that measures the amount of IFN-γ released in response to in vitro stimulation of whole blood with peptides from three TB-specific antigens (ESAT-6, CFP-10, and TB7.7). The result is reported as quantification of IFN-γ in international units (IU) per milliliter. Older versions of this test include the first-generation QuantiFERON-TB assay and the second-generation QuantiFERON-TB Gold assay. Neither is currently available in the United States.
T-SPOT.TB is an enzyme-linked immunospot (ELISPOT) assay that is used to count the number of IFN-γ–producing cells (spot-forming cells) in response to stimulation with the TB-specific antigens ESAT-6 and CFP-10. The assay is performed on separated and counted peripheral blood mononuclear cells.
Both T-SPOT.TB and QFT-GIT use negative and positive controls. The negative control measures response in the absence of antigen, whereas the positive control measures response in the presence of a known mitogen. An assay is classified as indeterminate if (1) the negative control tests positive regardless of the response to TB-specific antigens; or (2) the positive control tests negative, as does the response to TB-specific antigens. The response to TB-specific antigens cannot be interpreted in the presence of an indeterminate result.
The 2008 U.S. Food and Drug Administration–approved interpretation criteria for T-SPOT.TB included a borderline result category. The use of a borderline result category was meant to address test variation and uncertainty for results near the defined cut point, and to increase the certainty that a conversion from a negative to a positive result truly represents newly acquired infection. There is currently no borderline result category for QFT-GIT (12).
When used in the diagnosis of LTBI in immunocompetent persons, IGRAs offer several advantages in comparison with TST: the results are numerical, and thus less subject to reader bias; there is no need for a follow-up visit for reading of results; and they use TB-specific antigens that are not present in BCG and are therefore not affected by BCG vaccination status. Although there is no cross-reaction with BCG, cross-reactivity with some environmental mycobacterial species, including Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium szulgai, can occur (13).
One of the main disadvantages of IGRAs is their cost, which is due to more expensive reagents and the need for laboratory and blood-drawing equipment and expertise. However, cost–effectiveness models applied to certain populations, such as health care workers or contacts of patients with TB, suggest that use of IGRAs alone or in combination with TST may actually be cost-effective (14–17) because the test excludes persons with a positive test due to previous BCG vaccination and so prevents treatment of many persons needlessly. Cost–effectiveness studies are yet to be performed in immunocompromised patients.
Another disadvantage of IGRAs is that the clinical experience with them is relatively short. As such, their prognostic value with respect to the subsequent development of active TB is not as well defined as for TST, although new data continue to emerge supporting the predictive value of IGRAs (18–21).
Approximately 10 million persons in the United States are immunocompromised because of conditions that include HIV, immune-mediated inflammatory disorders (IMIDs), receipt of hemodialysis, solid-organ and hematopoietic stem cell transplantation, and hematologic malignancy (Table 1) (22–29). When latently infected with TB these persons have a considerably greater lifetime risk of progression to active TB than do immunocompetent persons. Unfortunately, LTBI can be more difficult to diagnose in immunocompromised patients, because TST is less sensitive in the presence of impaired immunity. Because of the high risk for TB reactivation and the low sensitivity of TST, IGRAs have been studied in various populations of immunocompromised patients in the hope that they would perform more reliably than TST.
| Condition | Estimated Number of Persons Living with Condition in the United States | Reference |
|---|---|---|
| HIV infection | 1.2 million | 22 |
| Immune-mediated inflammatory disorders | ||
| RA | 1.5 million | 23 |
| IBD | 1.1 million | 24 |
| SLE | 320,000 | 25 |
| Systemic sclerosis | 49,000 | 25 |
| Spondyloarthropathies | 2.4 million | 25 |
| Vasculitis | 1 million | 26 |
| End-stage renal disease | 0.87 million | 27 |
| Hematologic malignancies including HSCT recipients and candidates | 1 million | 28 |
| Solid organ transplant candidates | 120,000 | 29 |
| Total | 10 million |
One of the difficulties in assessing the performance of IGRAs is that there is no “gold standard” test for diagnosing LTBI. Investigators have, therefore, used one of four approaches: (1) using IGRAs concurrently with TST and comparing results; (2) using clinical risk factors for LTBI, such as exposure to a confirmed case of TB, occupational risk factors, or origin from a TB-endemic country as a surrogate for having LTBI (30); (3) longitudinal follow-up of patients after initial testing to document development of active TB (21); and (4) performing IGRAs with or without concurrent TST in patients with active TB, as a surrogate for LTBI. The problem with the first approach is that TST is itself an imperfect test by which to diagnose LTBI. Similarly, clinical risk factors for LTBI are not accurate markers for the presence of LTBI. Although the third approach is potentially the most accurate, these studies are frequently underpowered, as only a minority of even the most immunocompromised persons with LTBI will progress to active TB over the 1- to 2-year period of follow-up that is typically used. The issue with the fourth approach is that performance of the tests in patients with active TB may not accurately reflect their performance in patients with LTBI; it is known that active TB, particularly overwhelming disease, may result in a false negative TST (31, 32). With these limitations in mind, we review the current knowledge on using IGRAs to diagnose LTBI in various populations of immunocompromised patients.
HIV-infected patients with LTBI are one of the populations at highest risk for TB reactivation, with an estimated annual risk of TB reactivation as high as 10% (33). The risk of reactivation decreases in patients treated with antiretrovirals, but it is still twice that of the general population (4), underlining the importance of identifying and treating HIV-infected patients with LTBI. HIV-infected patients are frequently anergic to skin testing, particularly those with a CD4+ lymphocyte count lower than 100–200 cells/mm3, making TST an unreliable method of diagnosing LTBI in this population (34, 35). Both QFT-GIT and T-SPOT.TB have been evaluated as alternative methods to diagnose LTBI in HIV-infected patients.
QFT-GIT appears to suffer from the same problems as TST in HIV-infected persons. As with TST, HIV-infected patients are less likely to have a positive QFT-GIT than do HIV-negative patients with similar risk factors for TB infection (36, 37). Several studies have shown that the likelihood of a positive QFT-GIT result inversely correlates with CD4+ lymphocyte count (36–38), although this has not been a uniform finding (39, 40). Negative QFT-GIT results appear to increase in patients with CD4+ lymphocyte counts below 300 to 400 cells/mm3 (36–38). Similarly, negative TST results appear to increase at CD4+ lymphocyte counts below 200 to 500 cells/mm3 (34, 36–38, 41).
Similar to TST, QFT-GIT positivity correlates with traditional risk factors for TB, including birth or long-term residence in a TB-endemic country, contact with a patient with active TB, and lifestyle-related risk factors (homelessness, incarceration, injection drug use, or work in health care) (36, 38–40, 42). However, as in other populations, QFT-GIT is not affected by BCG vaccination status in HIV-infected persons (36).
An important concern in the use of QFT-GIT to diagnose LTBI in HIV-infected persons is the increase in indeterminate results. In various studies, the proportion of indeterminate QFT-GIT results in HIV-infected patients ranges from 1.5 to 16% of patients tested (36, 38, 40, 42–44). The risk of an indeterminate result is particularly increased in patients with lower CD4+ lymphocyte counts (38, 40, 43, 45). Other factors independently predicting an indeterminate QFT-GIT result in HIV-infected patients include injection drug use, an elevated viral load, and a clinical history of prior manifestations of acquired immunodeficiency syndrome (AIDS) (45). The increase in indeterminate results is mainly a result of the positive control of the assay testing negative (36, 38, 40, 44). Interestingly, one study found that indeterminate QFT-GIT results in HIV-infected patients independently predict progression to AIDS or death (45). This may be because an indeterminate IGRA provides indirect evidence of poor global T-cell function.
Although it has been evaluated less extensively than QFT-GIT in HIV-infected persons, available studies indicate that T-SPOT.TB correlates with risk factors for LTBI (46). In one study in which patients with HIV were monitored longitudinally, a positive T-SPOT.TB at baseline was associated with increased risk of subsequent active TB (47). T-SPOT.TB offers a distinct advantage compared with QFT-GIT and TST: Perhaps because it is normalized for peripheral blood mononuclear cell count, T-SPOT.TB remains sensitive in the face of low CD4+ lymphocyte counts (41, 44, 46). However, as for QFT-GIT, HIV-infected patients are less likely to have a positive T-SPOT.TB than their HIV-negative partners (37). Similar to QFT-GIT, T-SPOT.TB is not affected by BCG vaccination status, although this has not been formally evaluated in HIV-infected persons.
As with QFT-GIT, HIV-infected patients may have an increased proportion of indeterminate results; studies have reported indeterminate T-SPOT.TB results in 0 to 33% of HIV-infected persons tested (41, 44, 46). Once again, most indeterminate results were due to the positive control testing negative (41, 44).
Although TST and the two IGRAs all correlate with risk factors for LTBI, there is considerable discordance between tests when they are used simultaneously in the same patients. When QFT-GIT is compared head-to-head with TST, a similar proportion of patients is positive by either test, but the concordance between both tests is moderate at best, even in populations with low rates of BCG vaccination. Importantly, only a minority of patients positive by one test is positive by both (36–39, 42, 44). Similarly, the concordance between T-SPOT.TB and TST is poor to fair (37, 41, 44, 46), as is the concordance between QFT-GIT and T-SPOT.TB (37, 44). As patients positive by one test are frequently negative by others, concurrent testing by more than one modality could allow detection of more patients with LTBI. This may be particularly important in HIV-infected patients, in whom all tests perform poorly and the risk of TB reactivation is quite high if LTBI is not detected or treated. One piece of evidence that supports this approach is from a Swiss study in which patients with HIV who had developed active TB were tested by T-SPOT.TB, using stored blood samples collected in the 6 months before development of active TB. Although only 39% of patients were positive by T-SPOT.TB, and 50% of those tested were positive by TST, a combination of both tests, in which a positive result on either is considered diagnostic for LTBI, resulted in a sensitivity of 67% (41). Several professional guidelines have suggested testing HIV-infected persons by two modalities (see below). The advantage of such a strategy is increased sensitivity to detect cases of LTBI; although more false positives are likely, specificity is not as crucial as sensitivity in high-risk populations such as HIV-infected persons.
It is known that, in HIV-infected patients, a prior, presumably false negative, TST can become a positive test after immune reconstitution resulting from effective antiretroviral therapy (48). Although this issue has not been specifically examined, it is reasonable to assume that the same holds true for IGRAs. This has led the Centers for Disease Control and Prevention (CDC) to recommend retesting for LTBI in HIV-infected patients with previous negative testing and a CD4+ cell count less than 200/mm3 once antiretroviral therapy is started and a CD4+ cell count equal to or greater than 200 cells/mm3 is attained (49).
A systematic review and meta-analysis examined the usefulness of IGRAs for LTBI in HIV-infected persons (50). Studies reviewed were divided into three groups: (1) longitudinal studies evaluating the accuracy of IGRAs in prediction of future active TB; (2) studies in which IGRAs were used in patients with active TB, as a surrogate for diagnosis of LTBI; and (3) studies that correlated TST and IGRA results. The first group included three studies. Although the risk of active TB was higher in HIV-infected individuals with positive versus negative IGRA results, the duration of the follow-up and the numbers of active cases diagnosed were both low, making it difficult to draw clear conclusions. The second group included 18 studies, 16 of which were conducted in low- to middle-income countries. In this group, pooled sensitivity estimates were higher for T-SPOT.TB (72%) than for QFT-GIT (61%), but there was considerable heterogeneity between studies. Neither IGRA test was consistently more sensitive than TST. The authors concluded that IGRA performance is similar to TST performance for diagnosing LTBI. One important caveat of this study is that the studies included also evaluated the use of IGRAs to diagnose active TB. As mentioned previously, performance of TST or IGRAs in patients with active TB may not be a good surrogate for their performance in LTBI diagnosis because of the risk of false negative results associated with active TB.
The Tuberculosis Epidemiologic Studies Consortium will be conducting a study that might answer some of the questions regarding the relative usefulness of TST versus IGRAs in predicting the development of active TB among persons at high risk for TB, including HIV-infected persons. Patients enrolled will be tested for LTBI by TST, QFT-GIT, and T-SPOT.TB and will be monitored for 2 years to identify those who progress to active TB disease (51).
In summary, in the diagnosis of LTBI in HIV-infected persons, the current evidence suggests that IGRAs have comparable sensitivity to TST. TST and IGRAs appear less sensitive in HIV-infected patients than they are in HIV-negative persons, although this difference is likely less pronounced in patients with higher CD4+ lymphocyte counts. T-SPOT.TB may have an advantage over TST and QFT-GIT in patients with low CD4+ lymphocyte counts, owing to the methodology of the test. As with immune-competent populations, either IGRA is likely to be more specific than TST in populations with high rates of prior BCG vaccination; however specificity is not as important in HIV-infected persons as it is in immune-competent populations. TST and IGRAs are frequently discordant, and it is likely that some cases of LTBI are detected by one test but not by the other. A reasonable approach would be to use TST in patients with CD4+ lymphocyte counts greater than 200 cells/mm3, and to use T-SPOT.TB in those with lower CD4+ lymphocyte counts (Table 2).
| Patient Population | CDC Guidelines* | Comments | Suggested Approach |
|---|---|---|---|
| HIV-infected persons | • Consider sequential testing with TST and an IGRA in high-risk patients† | • TST performance is limited in patients with CD4+ cell count < 200 cells/mm3 | • Consider TST for patients with CD4+ cell count > 200 cells/mm3 |
| • Any positive result should be considered evidence of LTBI | • Correlation between IGRAs and clinical risk factors for LTBI: strong evidence | • Consider T-SPOT.TB in patients with lower CD4+ lymphocyte count | |
| • Increased likelihood of indeterminate results for both IGRAs | • Would not use QFT-GIT for routine screening | ||
| • T-SPOT.TB performance less affected by low CD4+ lymphocyte count | |||
| Candidates for therapy with a TNF-α inhibitor and patients with immune-mediated inflammatory disorders (RA, SLE, and other autoimmune diseases) | • Consider sequential testing with TST and an IGRA in high-risk patients† | • TST performance is limited in patients with Immune-mediated inflammatory disorders | • Test candidates for TNF-α inhibitor therapy for LTBI before initiating treatment with a TNF-α inhibitor |
| • Any positive result should be considered evidence of LTBI | • Correlation between IGRAs and clinical risk factors for LTBI: strong evidence | • Consider concurrent or sequential testing by TST and an IGRA in high-risk patients (candidates for TNF-α inhibitors)† | |
| • T-SPOT.TB less affected by use of immunosuppressive medications such as corticosteroids | • Consider T-SPOT.TB in patients receiving corticosteroids | ||
| Patients receiving dialysis | • Consider sequential testing with TST and an IGRA in high-risk patients† | • TST performance is limited | • Consider QFT-GIT as test of choice |
| • Any positive result should be considered evidence of LTBI | • Correlation between QFT-GIT and clinical risk factors for LTBI: strong evidence | • Would not use TST | |
| • T-SPOT.TB performance not well characterized | |||
| Patients with hematologic malignancy, including HSCT candidates | • Consider sequential testing with TST and an IGRA in high-risk patients† | • TST performance is limited | • Consider TST as test of choice |
| • Any positive result should be considered evidence of LTBI | • Correlation between IGRAs and clinical risk factors for LTBI: weak evidence | • Would not use IGRAs for routine screening | |
| • T-SPOT.TB may be less affected by presence of neutropenia and/or lymphopenia and may be preferable | |||
| Solid organ transplant candidates | • Consider sequential testing with TST and an IGRA in high-risk patients† | • TST of value if obtained before transplantation | • Test candidates for solid organ transplant for LTBI before transplantation |
| • Any positive result should be considered evidence of LTBI | • Correlation between IGRAs and clinical risk factors for LTBI: weak evidence | • Consider TST as test of choice | |
| • Underlying liver disease appears to increase likelihood of indeterminate results of both IGRAs in candidates for liver transplantation | • Would not use IGRAs for routine screening |
Patients with IMIDs such as systemic lupus erythematosus and rheumatoid arthritis are immunocompromised because of their disease or its treatment, and may have a greater risk of reactivation than the general population (52–54). Patients receiving tumor necrosis factor (TNF)-α inhibitors, which are used in an increasing number of IMIDs, are at particularly high risk of TB reactivation; the risk of reactivation TB in these patients can be as high as 12 times that of the normal population (55). The risk appears to be dependent on the specific TNF-α inhibitor used, with monoclonal antibody–based inhibitors, such as adalimumab and infliximab, conferring the greatest risk (56–58). As in HIV-infected persons, tuberculin skin testing in patients with IMIDs is associated with increased rates of false negative results (59). Importantly, treatment with isoniazid in patients with IMID who are diagnosed with LTBI before beginning TNF-α inhibitor therapy is associated with a 74% reduction in the risk of TB activation (59).
Both QFT-GIT and T-SPOT.TB have been studied in patients with IMID. As for TST, positive results in either IGRA correlate with the presence of clinical risk factors for LTBI, such as birth or residence in a TB-endemic country, history of close contact with a patient with active TB, chest X-ray findings suggestive of past TB or a history of prior active TB. In the various studies, patients who had at least one risk factor of LTBI were 2.5- to 23.8-fold more likely to have a positive QFT-GIT, and 4.8- to 8.7-fold more likely to have a positive T-SPOT.TB, compared with 1.6- to 6.2-fold for TST (60–67). As in other populations, a history of BCG vaccination does not appear to influence IGRA positivity (61, 67–69).
An important concern in patients with IMID is that immunosuppression due to the primary disease itself or due to its treatment will result in increased false negative results. Whereas one study showed that patients with IMID had reduced rates of positive TST and QFT-GIT compared with healthy persons with similar risk factors for LTBI (70), another did not (65). In patients with IMID, use of immunosuppressive medications, particularly corticosteroids, has been associated with negative and indeterminate QFT-GIT results (60, 62, 65, 71–73), but not with a negative or indeterminate T-SPOT.TB (62, 63, 66, 68, 74). As with HIV-infected patients, discordant results between IGRAs and TST in patients with IMID are common. Concordance between TST and QFT-GIT was fair to moderate, and concordance between TST and T-SPOT.TB was fair (60, 72, 74–76).
One strategy proposed in candidates for treatment with a TNF-α inhibitor is to retest for LTBI after initiation of therapy with the TNF-α inhibitor to detect patients whose initial result was false negative. The available data, although limited, do not seem to support this approach. In one study, patients with inflammatory bowel disease who were candidates for TNF-α inhibitor therapy were tested with TST and QFT-GIT before initiation of therapy and were retested after at least 5 months of therapy. None of the 184 patients retested with QFT-GIT exhibited conversion of a prior negative result (77). In a Taiwanese study patients with rheumatoid arthritis receiving TNF-α inhibitor therapy were tested serially (at Months 9, 18, and 24 after initiation of therapy) with the second-generation QuantiFERON-TB Gold test. Five of 233 patients had conversion of a previously negative QuantiFERON-TB Gold test; however, in all cases conversion occurred concomitantly with development of active tuberculosis, calling into question the value of serial testing in detection of LTBI (78).
Another important issue is reversion of a previously positive test, due to or in the absence of LTBI treatment. This issue has been examined in two studies of patients with IMID. In one study, reversion of a prior positive result occurred in 3 of 20 patients with a prior positive QFT-GIT or QuantiFERON-TB Gold test, 1 of whom had received LTBI treatment with isoniazid (79). Similarly, among patients with inflammatory bowel disease who tested positive by QFT-GIT before initiation of TNF-α inhibitor therapy and were treated with isoniazid, reversion occurred in 6 of 13 patients (77).
Overall, QFT-GIT and T-SPOT.TB appear to be at least as sensitive as TST in the diagnosis of LTBI in patients with IMID. Either test is more specific than TST in BCG-vaccinated patients. The sensitivity of QFT-GIT may be reduced in patients taking immunosuppressive medications, and indeterminate results may be increased. T-SPOT.TB appears to be less affected by immunosuppression, and its use should be considered in patients receiving corticosteroids. In patients at particularly high risk for TB reactivation, such as patients who are to receive TNF-α inhibitors, a strategy of sequential or simultaneous testing by TST and an IGRA may be optimal. In these high-risk populations, a patient who is positive by either test should be considered to have LTBI (Table 2).
Uremia is associated with impaired immunity. Patients with chronic renal failure, whether or not they are receiving dialysis, are at increased risk for reactivation of latent TB, estimated to be 2.4-fold higher than the risk of a healthy person (4, 80). Furthermore, patients receiving dialysis frequently exhibit anergy to skin testing, underscoring the need for better-performing tests to diagnose LTBI among them (81).
Interestingly, the current data indicate that, in patients receiving dialysis for end-stage renal disease, QFT-GIT may be more sensitive for diagnosing LTBI than TST, and perhaps T-SPOT.TB. In two studies in which patients receiving hemodialysis were tested by TST, QFT-GIT, and T-SPOT.TB, only QFT-GIT was significantly associated with clinical risk factors for LTBI (82, 83). Other studies confirmed that positive QFT-GIT was associated with the presence of risk factors for TB, whereas positive TST was associated only with a history of BCG vaccination, suggesting superior sensitivity and specificity of QFT-GIT over TST in this population (84–87). Only one study found T-SPOT.TB to be correlated with risk factors for LTBI (88).
The concordance between the various assays was similar to that seen in other immunocompromised populations. Studies showed poor to moderate agreement for QFT-GIT versus TST, and poor to fair agreement for T-SPOT.TB versus TST. Rates of indeterminate results are also similar to those in other populations, typically about 5% for either test (82–89).
A systematic review evaluated 30 studies comparing the IGRAs with TST in patients with end-stage renal disease. The authors concluded that the QuantiFERON assays were more strongly associated with clinical risk factors for TB than TST. T-SPOT.TB did not significantly differ from TST regarding association with clinical risk factors (90).
Risk factors for an indeterminate QFT-GIT among patients receiving dialysis were evaluated in one study in which 20 of 427 (4.7%) of patients studied had an indeterminate QFT-GIT result. Predictors of an indeterminate result included hemodialysis (as opposed to peritoneal dialysis), longer duration of having received dialysis, anemia, and hypoalbuminemia (91).
Serial testing with QFT-GIT and T-SPOT.TB among patients receiving dialysis was examined in a Korean study. Conversion of an initially negative test occurred in 17 of 55 patients (30%) tested with QFT-GIT and in 12 of 41 (29%) of those tested with T-SPOT.TB. Reversion of an initially positive test occurred in 9 of 43 (20%) of those tested with QFT-GIT and in 17 of 57 (29%) of those tested with T-SPOT.TB (92).
The available data suggest that in hemodialysis patients QFT-GIT is more sensitive than TST, and consideration should be given to using it among patients receiving hemodialysis (Table 2).
Several other immunocompromised patient populations have an increased risk of TB reactivation. Among patients with cancer, those with hematologic malignancies or head and neck cancers are at increased risk of developing active tuberculosis compared with the general population (93). Another population at risk is solid organ transplant recipients; among these patients the risk of developing active tuberculosis may be 20- to 74-fold higher than in the general population (94).
There are limited data to guide the use of QFT-GIT and/or T-SPOT.TB in these populations. Only two studies to date have evaluated IGRAs in patients with hematologic conditions (44, 95). One of the studies suggested that T-SPOT.TB may be more sensitive than TST in the presence of leukopenia, and that it may correlate better than TST with clinical risk factors for LTBI (95). A study of stem cell transplant recipients in South Korea (41% autologous and 59% allogeneic transplant) showed poor agreement between TST and QFT-GIT in this population; during a median follow-up period of 0.8 year, two patients developed active TB, one of whom was positive by QFT-GIT and both of whom were negative by TST (96).
Few studies have evaluated IGRAs in different populations of solid organ transplant recipients or candidates for solid organ transplant. In one study evaluating candidates for liver transplant, both TST and QFT-GIT were not associated with clinical risk factors for LTBI. In this study a high Model for End-Stage Liver Disease (MELD) score was associated with a negative TST, but did not significantly affect QFT-GIT, suggesting that the sensitivity of QFT-GIT may be better maintained even in the presence of advance liver disease (97). In another study, in which kidney transplant recipients were tested by T-SPOT.TB and TST and monitored longitudinally, some patients who were negative by TST but positive by T-SPOT.TB went on to develop active TB, suggesting that T-SPOT.TB might have a role, in addition to or in place of TST, in diagnosing LTBI in this population (98). A third study showed QFT-GIT, but not TST, to correlate with clinical risk factors for LTBI among candidates for kidney transplantation (99). In a fourth study all solid organ transplant candidates were tested by QuantiFERON Gold or QFT-GIT. In this study, IGRA positivity correlated with the presence of clinical risk factors for LTBI (100). Interestingly, more than 40% of liver transplant candidates had an indeterminate result, compared with only 10% of kidney transplant candidates. The indeterminate results were all due to a negative result in the positive control.
Given the paucity of data, it is difficult to make any definite recommendations regarding the use of IGRAs to diagnose LTBI in these populations. As TST remains the best studied test in these populations, we would suggest that it be the test of choice pending further data (Table 2).
The CDC, in conjunction with the American Academy of Pediatrics, the American Thoracic Society, and the Infectious Diseases Society of America, have published a guideline on the use of IGRAs to detect Mycobacterium tuberculosis infection (12) (Table 2). In general, the guideline allows use of IGRAs in place of (but not in addition to) TST in any situation in which TST is recommended. In immunocompromised patients, such as patients with HIV, the risk for TB infection, progression, and an eventual poor outcome are increased. For this reason, the guidelines recommend that, in a high-risk population, if initial testing by TST or IGRA is negative, performance of both tests should be considered, with a positive result on either sufficient to diagnose LTBI.
The European Centre for Disease Prevention and Control (ECDC) has also published guidelines on the use of IGRAs (101). In immunocompromised patients, including HIV-infected patients, the guidelines recommend using TST and IGRAs in combination to diagnose LTBI.
The CDC and the ECDC both define a range of results at which the T-SPOT.TB assay is considered borderline, although the definitions differ slightly. Both guidelines recommend repeating testing in the case of an indeterminate result (in either T-SPOT.TB or QFT-GIT) or a borderline result (in T-SPOT.TB) in all patients, including immunocompromised patients (12, 101).
The U.K. guidelines recommend concurrent testing by TST and an IGRA for persons with HIV and CD4+ cell counts less than 200 cells/mm3 (and to consider LTBI treatment if either test is positive). For persons with HIV and CD4+ cell counts of 200–500 cells/mm3 the same approach could be used, or IGRA alone could be used for testing. HIV-infected persons with higher CD4+ cell counts are treated as immunocompetent individuals. For other immunocompromised persons, the guidelines recommend testing by IGRA alone or concurrent IGRA and TST (and to consider LTBI treatment if either test is positive) (102).
The Canadian guidelines recommend that immunocompromised patients be tested initially by TST. If TST is negative, and the clinician is still concerned about the possibility of LTBI, an IGRA can be performed, with a positive result considered diagnostic for LTBI. T-SPOT.TB is suggested as preferable to QFT-GIT as it appears to retain sensitivity in immunocompromised patients (103).
The World Health Organization guidelines discourage the use of IGRAs among HIV-infected patients in resource-limited settings. The rationale for this approach is that neither IGRA is consistently more sensitive than the TST, and more data are available supporting the predictive value of TST (104). Also underlying this recommendation is the cost of IGRAs and the need for well-equipped laboratories with trained personnel, which may not be readily available in resource-limited settings.
Additional published guidelines regarding the use of IGRAs in various patient populations have been summarized in a review (105).
Although a systematic exploration of this topic is beyond the scope of this review, it is important to briefly mention the use of IGRAs to diagnose active tuberculosis among immunocompromised patients. The population that has been most studied in this regard is HIV-infected persons. Two meta-analyses showed that IGRAs were neither sensitive nor specific in diagnosing active TB among HIV-infected patients (106, 107). These findings are reflected in the recommendations of most of the current guidelines, which discourage use of IGRAs as stand-alone tests to diagnose active TB (101, 105).
Better tests are needed to diagnose LTBI in immunocompromised patients. Unfortunately, current data do not suggest that IGRAs have a clear across-the-board advantage over TST in these patients, and they are unlikely to entirely replace TST in this role. However, data do suggest that IGRAs have specific advantages in certain patient populations and in particular situations. For example, T-SPOT.TB may be less affected by low CD4+ cell count in HIV-infected persons, and by corticosteroid use in patients with IMID, compared with TST or QFT-GIT. Likewise, QFT-GIT may retain sensitivity in patients with dialysis compared with TST and, perhaps, T-SPOT.TB.
A summary of the advantages and disadvantages of IGRAs compared with TST in different populations of immunocompromised patients, and our suggested approach for LTBI testing in these patients, is shown in Table 2. It is important to mention that if concurrent or sequential testing by TST and an IGRA is performed, the IGRA should be performed first as TST can boost subsequent IGRA results (108).
Better studies are needed to more accurately define the usefulness of IGRAs in immunocompromised patients. In particular, longitudinal prospective studies monitoring for episodes of TB reactivation among immunocompromised patients tested by TST and the IGRAs would be highly valuable. In addition, more studies are needed in several immunocompromised populations that have been inadequately studied, principally transplant recipients and patients with cancer. A third issue that remains to be investigated is the cost-effectiveness of using IGRAs, in place of or in addition to TST, for the diagnosis of LTBI in different immunocompromised populations. Finally, the usefulness of serial IGRA testing in different populations of immunocompromised persons needs to be examined. As further studies are done, the role of IGRAs in immunocompromised patients will continue to be defined. In the meanwhile, one can hope that better understanding of latent tuberculosis infection will lead to the development of new and improved assays that will be more sensitive and specific than the tests currently in use.
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Originally Published in Press as DOI: 10.1164/rccm.201209-1621CI on December 21, 2013
Author disclosures are available with the text of this document at www.atsjournals.org.
