Repeat testing or additional tuberculin skin tests for management of indeterminate results of interferon-gamma release assays: a systematic review and meta-analysis

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BACKGROUND: Interferon-gamma release assays (IGRAs) are widely used for detecting latent tuberculosis infection (LTBI). However, these tests can yield indeterminate results, posing challenges for clinical management. The management of these indeterminate outcomes varies, creating uncertainty in clinical practice. This study systematically evaluates the effectiveness of repeat IGRA testing versus additional tuberculin skin testing (TST) in resolving indeterminate IGRA results during LTBI screening. METHODS: We conducted a systematic review and meta-analysis, searching PubMed, Embase, Web of Science, and the Cochrane Library databases on May 18, 2024, without start date or language restrictions. Studies were included if they screened for LTBI in healthy or high-risk populations using IGRA, reported indeterminate results, and managed these results with repeat IGRA testing and/or additional TST. A random-effects model was used to calculate pooled results. RESULTS: A total of 59 studies were included in this analysis. Among these, 40 studies assessed the use of additional TST in individuals with indeterminate IGRA results, yielding a pooled confirmation rate of 98.6% (95% CI: 96.2-99.8%). Additionally, 27 studies examined repeat IGRA testing, which resulted in a pooled confirmation rate of 68.9% (95% CI: 57.0-79.6%). Furthermore, eight studies evaluated both TST and repeat IGRA testing, with the pooled confirmation rate for the TST being 93.7% (95% CI: 78.7-99.9%), higher than the pooled confirmation rate for repeat testing at 76.5% (95% CI: 44.6-97.1%). However, there was no statistically significant difference in the confirmation rates between the two testing methods (OR = 2.13, 95% CI: 0.47-9.76). CONCLUSIONS: In managing indeterminate IGRA results during LTBI screening, head-to-head studies show no significant difference in confirmation rates between additional TST and repeat IGRA. Across nearly 60 studies, additional TST tends to have a slightly higher confirmation rate, though the difference is not statistically significant. Clinically, for patients with an initial indeterminate IGRA who are immunocompetent, with convenient sample collection or a need for rapid results, additional TST may help achieve more reliable outcomes. Selection of follow-up testing should consider the cause of indeterminate results, feasibility, and risk of patient loss to follow-up.

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