Diagnostic utility of quantitative interferon-gamma release assays in elderly patients with tuberculosis

ABSTRACT Evidence regarding the diagnostic value of quantitative interferon-gamma release assay (IGRA) results in elderly populations is limited, and large-scale data for QuantiFERON-TB Gold Plus (QFT-Plus) are scarce. We evaluated QFT-Plus and T-SPOT.TB (T-SPOT) for distinguishing active tuberculosis (ATB) from latent infection (LTBI) in elderly individuals in Japan, a super-aged country. We conducted a retrospective, cross-sectional diagnostic accuracy study of patients ≥65 years who underwent IGRA testing between 2015 and 2024 at two hospitals: a tuberculosis referral center (QFT-Plus and T-SPOT) and a tertiary hospital (T-SPOT only). ATB was defined as microbiologically confirmed TB. Quantitative IGRA values were compared between ATB and LTBI in all patients and in IGRA-positive subsets. Receiver operating characteristic (ROC) curves assessed discriminatory performance. Among 10,745 elderly patients (ATB: n = 310; LTBI: n = 1,158), values showed substantial overlap. For T-SPOT, the area under the curves (AUCs) improved at Tosei General Hospital (TGH) (ESAT-6: 0.679, CFP-10: 0.670) in IGRA-positive cases. In contrast, all-patient AUCs at Fujita Health University Hospital (FHUH) were low (ESAT-6: 0.367, CFP-10: 0.362), demonstrating an inverse association, though they improved (ESAT-6: 0.607 and CFP-10: 0.554) in IGRA-positive cases. For QFT-Plus, all-patient AUCs were low (TB1 antigen: 0.462, TB2 antigen: 0.470), but improved in the IGRA-positive cohort (TB1 antigen: 0.630, TB2 antigen: 0.645). The optimal quantitative cutoffs in IGRA-positive cases provided modest diagnostic accuracy. In elderly individuals, quantitative IGRA values alone have limited ability to distinguish ATB from LTBI, but QFT-Plus and T-SPOT show modest improvement in IGRA-positive cases. Although not suitable as a stand-alone diagnostic, quantitative IGRA may assist risk stratification and decision-making in selected scenarios. IMPORTANCE Tuberculosis remains a major health concern in aging societies, such as Japan, where most patients are elderly adults with impaired immune function. Interferon-gamma release assays (IGRA) are widely used for detecting infection, but the role of their quantitative values in differentiating active tuberculosis from latent tuberculosis infection has been uncertain. Our study is the first to evaluate the quantitative performance of the latest QuantiFERON-TB Gold Plus and T-SPOT.TB specifically in elderly patients, across both a tuberculosis referral hospital and a university hospital. Although absolute separation between active and latent disease was not achieved, we found that, in test-positive individuals, active cases tended to yield higher values, particularly with T-SPOT.TB. This indicates that quantitative information, when interpreted within the clinical context, can assist physicians in assessing risk and guiding further diagnostic steps, offering practical value for improving decision-making in the care of vulnerable elderly patients.