Quantitative IFN-γ and IL-2 Response Associated with Latent Tuberculosis Test Discordance in HIV-infected Pregnant Women

Abstract

Rationale: Pregnant women with latent tuberculosis infection (LTBI) are at high risk for development of TB, especially if infected with HIV.

Objectives: To assess the performance of LTBI tests in pregnant and postpartum women infected with HIV, investigate the immunology behind discordance in pregnancy, and explore the implications for the development of postpartum TB.

Methods: We screened pregnant women in their second/third trimester and at delivery for LTBI using the tuberculin skin test (TST) and IFN-γ release assay (IGRA) (QuantiFERON Gold). A subset of antepartum women had longitudinal testing, with repeat testing at delivery and postpartum and additional cytokines measured from the IGRA supernatant. The kappa statistic and Wilcoxon rank sum test were used to determine agreement and comparison of cytokine concentrations, respectively.

Measurements and main results: Of 252 enrolled, 71 (28%) women had a positive IGRA but only 27 (10%) had a positive TST (P < 0.005). There was 75% agreement (kappa, 0.25). When stratified by pregnancy versus delivery, 20% had IGRA(+)/TST(-) discordance at each time point. A positive IGRA was associated with known TB contact (odds ratio, 3.6; confidence interval, 1.2-11.1; P = 0.02). Compared with IGRA(+)/TST(+), women with IGRA(+)/TST(-) discordance had significantly less IFN-γ (1.85 vs. 3.48 IU/ml; P = 0.02) and IL-2 (46.17 vs. 84.03 pg/ml; P = 0.01). Five developed postpartum TB, of which three had IGRA(+)/TST(-) discordance during pregnancy.

Conclusions: Choice of LTBI test in pregnant women infected with HIV affects results. Pregnant women with IGRA(+)/TST(-) discordance had less IFN-γ and IL-2 than those with concordant-positive results and may represent an especially high-risk subset for the development of active TB postpartum.

Keywords: HIV; IFN-γ release assay; pregnancy; tuberculin skin test; tuberculosis.

Figure 1.

Prevalence of latent tuberculosis infection by stage of pregnancy in women infected with HIV. (A) Cross-sectionally, there was insignificantly lower percent positivity of TST and QGIT at delivery versus during pregnancy but significant discordance between TST and QGIT. (B) In the longitudinal cohort, there was a decrease in QGIT-positive results at delivery with rebound postpartum, although these were not significant changes. The TST, however, mirrored the changes in the QGIT with increased positivity at delivery and a decrease postpartum, suggesting that decreased TST performance is more related to HIV than pregnancy. QGIT = QuantiFERON TB Gold In-Tube test; TST = tuberculin skin test.

Figure 2.

Although percent of QuantiFERON TB Gold In-Tube test positive remained relatively constant, there was a trend for decreased median concentration of IFN-γ between antenatal and delivery (P = 0.07), and between delivery and postpartum (P = 0.19).

Figure 3.

Women with discordant QGIT⁺/TST⁻ had lower IFN-γ (A) and IL-2 (B) production as compared with concordant positive QGIT⁺/TST⁺, suggesting a difference in population and not just a difference in false-positive and -negative latent tuberculosis infection test results. QGIT = QuantiFERON TB Gold In-Tube test; TST = tuberculin skin test.