Risk Factors for Indeterminate Interferon-Gamma Release Assay for the Diagnosis of Tuberculosis in Children-A Systematic Review and Meta-Analysis

Abstract

Background: Interferon-gamma release assays (IGRA) are well-established immunodiagnostic tests for tuberculosis (TB) in adults. In children these tests are associated with higher rates of false-negative and indeterminate results. Age is presumed to be one factor influencing cytokine release and therefore test performance. The aim of this study was to systematically review factors associated with indeterminate IGRA results in pediatric patients. Methods: Systematic literature review guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) searching PubMed, EMBASE, and Web of Science. Studies reporting results of at least one commercially available IGRA (QuantiFERON-TB, T-SPOT.TB) in pediatric patient groups were included. Random effects meta-analysis was used to assess proportions of indeterminate IGRA results. Heterogeneity was assessed using the I² value. Risk differences were calculated for studies comparing QuantiFERON-TB and T-SPOT.TB in the same study. Meta-regression was used to further explore the influence of study level variables on heterogeneity. Results: Of 1,293 articles screened, 133 studies were included in the final analysis. These assessed QuantiFERON-TB only in 77.4% (103/133), QuantiFERON-TB and T-SPOT.TB in 15.8% (21/133), and T-SPOT.TB only in 6.8% (9/133) resulting in 155 datasets including 107,418 participants. Overall 4% of IGRA results were indeterminate, and T-SPOT.TB (0.03, 95% CI 0.02-0.05) and QuantiFERON-TB assays (0.05, 95% CI 0.04-0.06) showed similar proportions of indeterminate results; pooled risk difference was-0.01 (95% CI -0.03 to 0.00). Significant differences with lower proportions of indeterminate assays with T-SPOT.TB compared to QuantiFERON-TB were only seen in subgroup analyses of studies performed in Africa and in non-HIV-infected immunocompromised patients. Meta-regression confirmed lower proportions of indeterminate results for T-SPOT.TB compared to QuantiFERON-TB only among studies that reported results from non-HIV-infected immunocompromised patients (p < 0.001). Conclusion: On average indeterminate IGRA results occur in 1 in 25 tests performed. Overall, there was no difference in the proportion of indeterminate results between both commercial assays. However, our findings suggest that in patients in Africa and/or patients with immunocompromising conditions other than HIV infection the T-SPOT.TB assay appears to produce fewer indeterminate results.

Keywords: Clinical studies; IGRA; QuantiFERON; T cell response; T-SPOT.TB; latent; pediatrics; risk difference.

Figure 1

Flow chart outlining selection of articles included in the review.

Figure 2

Proportion of indeterminate results with 95% CI by type of IGRA. Studies arranged according to year of publication.

Figure 3

Risk difference (RD) with 95% CI in studies that included a head-to-head comparison of QuantiFERON-TB and T-SPOT.TB assays. Studies arranged according to year of publication.

Figure 4

Risk differences (RD) with 95% CI in studies that included a head-to-head comparison of QuantiFERON-TB and T-SPOT.TB assays stratified by age. Studies sorted according to year of publication.

Figure 5

Risk differences (RD) with 95% CI in studies that included a head-to-head comparison of QuantiFERON-TB and T-SPOT.TB assays stratified by continent. Studies arranged according to year of publication.

Figure 6

Risk differences (RD) with 95% CI in studies that included a head-to-head comparison of QuantiFERON-TB and T-SPOT.TB assays stratified by African/Non-African origin of the study. Studies arranged according to year of publication.

Figure 7

Risk differences (RD) with 95% CI in studies that included a head-to-head comparison of QuantiFERON-TB and T-SPOT.TB assays stratified by immune status. Studies arranged according to year of publication.