Quantiferon Indeterminate Results: Understanding Their Impact on Tuberculosis Screening for SOT Candidates

The risk of tuberculosis (TB) is significantly increased among solid organ transplant (SOT) patients, and particularly among lung recipients.1,2 Posttransplant TB rates ranges from 0.05% to 13.27%3 and are strongly influenced by the disease prevalence in the local population. In this context, TB may present atypically and may also be associated with higher severity, including higher rates of extrapulmonary and disseminated presentation. Active TB has been associated with increased risk of graft failure and mortality as compared with non-SOT patients.2 Posttransplant TB may result from donor-transmitted infection, acquisition through community exposure after transplantation, or reactivation of a latent tuberculosis infection (LTBI). This latter accounts for the majority of TB cases, especially in countries with low TB prevalence.4 The detrimental impact of TB on patient outcomes underscores the critical importance of implementing preventive strategies within this population. Therefore, different panels of specialists and guidelines have recommended the treatment of LTBI as the main preventive intervention for SOT candidates and recipients.5,6 With no direct methods available for diagnosing LTBI, the selection of patients for treatment relies on the application of risk prediction rules, which include epidemiologic factors; radiologic evidence of fibrotic lesions compatible with pulmonary TB in patients that did not receive adequate treatment and positive results from biomarkers such as tuberculin skin test (TST) and interferon gamma release assays (IGRAs). This set of prediction rules identifies a subset of patients at higher risk for posttransplant TB, but its accuracy remains limited in this population, especially concerning its positive predictive value.7 IGRAs, particularly, offer the advantage of higher specificity compared with TST, as they are not influenced by prior Bacille Calmette-Guérin (BCG) vaccination and have a lower risk of false-positive reactions because of exposure to nontuberculous mycobacteria. However, much like TST, patients’ immune response status could increase the risk of false-negative results. Another factor that may limit the interpretation of IGRAs is the considerable proportion of indeterminate results associated with immunosuppressed individuals.8 These results, for the most part, indicates a failure of T cells to respond to the positive control of the test. In this issue of Transplantation, Chiu et al9 present interesting data regarding pretransplant TB screening of transplant candidates with an indeterminate result after IGRA (QuantiFERON-TB [QFT] Gold In-Tube and QFT Gold Plus; Qiagen, Germantown, MD). The main strength of the study is the large sample of patients with pretransplant indeterminate IGRA in which the risk of posttransplant TB was assessed. In addition, based on their findings, the authors propose an algorithm that may help to address this diagnostic limitation in low-prevalence settings, while more solid data on this issue is awaited. In brief, among 13 008 candidates screened, 736 (6%) patients had an indeterminate result. This frequency was indeed slightly higher than the proportion of tests with positive results (629; 5%). This finding highlights the relevance of this particular issue for the interpretation of TB screening in this population. Thirty-nine patients with indeterminate results underwent treatment for LTBI. It bears noting that the risk factors that led to LTBI treatment in these cases were not detailed in the article. Among the 697 patients with indeterminate results who were not treated, 2 (0.3%) developed TB after transplantation. This cumulative incidence was higher than that observed among patients with negative results (1/11 641; 0.009%), but lower than that observed among patients with positive results (7/629; 1.1%). These findings align with the results of a recent meta-analysis, which suggests that patients with indeterminate results tend to have an intermediate risk of posttransplant TB, falling between the risk levels observed in patients with positive and negative test results.10 On the other hand, the low rate of posttransplant TB detected in patients with indeterminate IGRA results in this low-prevalence area suggests that, in the absence of other risk factors, further screening of these candidates may not be necessary. In their conclusions, the authors appropriately recommend that the decision to treat LTBI in patients with indeterminate IGRA test results “should account for epidemiological risk factors, and shared decision making is recommended.” Nonetheless, additional studies, preferably with a prospective design and a larger geographic span, would be important to confirm this observation and to assess whether such conclusions would also hold for other populations with higher prevalence of TB. Another issue analyzed in the study concerns results obtained with repeat biomarker testing. Among the 736 patients who had an indeterminate result at initial evaluation with the QFT assay, 247 were evaluated using different tests (QFT in 185; 75%, T-SPOT.TB assay (Oxford Diagnostic Laboratories, Memphis, TN) in 48; 19%, and TST in only 14; 6%). The criteria that determined both the selection of candidates to be retested and the method to be used in each case were not detailed by the authors. Most patients retested with QFT maintained an indeterminate result, while all those allocated to be retested with the T-SPOT.TB assay had negative results. Based on these results, the authors conclude that “opting for T-SPOT.TB as a second test may be preferable to repeating the QFT.” Although the probability of uninterpretable results is lower with the T-SPOT.TB assay, the results of the study do not allow a reliable conclusion regarding this point, given the inherent limitations of its retrospective observational design and the lack of statistical power to assess the risk of posttransplant TB in the subset of retested patients. It is also worth mentioning that the interpretation of serial IGRA testing results remains an unresolved issue, considering the higher frequency of conversions and reversals observed with IGRAs as compared with TST.8 Overall, future studies are needed to improve the LTBI screening in SOT recipients. The development of more accurate biomarkers for the diagnosis of LTBI in transplant candidates and recipients would be highly desirable. However, given the nature of the latency of the infection, developing a direct diagnostic test that does not rely on the host’s immune response to the pathogen appears to be a distant goal at this time. Nonetheless, appropriately designed, large multicenter studies could clarify several issues that might help to optimize screening protocols based on the currently available resources. Key issues to be addressed may include (1) the interpretation of serial testing after an initially negative or indeterminate IGRA result and (2) the performance of combined use of biomarkers (TST and IGRA) to tailor selection criteria for LTBI treatment among transplant candidates and recipients that live or were born in areas with higher epidemiologic risk, as well as for transplant modalities with different risks of posttransplant TB reactivation (eg, lung transplants versus other SOT).1,2