Prevalence of positive IGRAs and innate immune system in HIV-infected individuals in Japan.

INTRODUCTION: Human immunodeficiency virus (HIV) infected individuals are at increased risk of developing active tuberculosis (TB). TB incidence remains higher than in non-HIV subjects after antiretroviral therapy (ART) initiation. This study was conducted to estimate the prevalence of positive IGRA, reflecting latent tuberculosis infection and/or a history of active TB, in HIV-infected individuals after ART initiation in Japan. METHODS: Two IGRAs (Interferon (IFN)-γ release assays), QuantiFERON®-TB Gold Plus (QFT-Plus) and T-Spot®.TB (TSPOT), were used. We also analyzed the TB associated risk factors for the IGRAs results and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. We also analyzed the risk factors for positive IGRA responses and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. RESULTS: One hundred eight-four subjects were prospectively enrolled. Median age was 49 years. The positivity rates of QFT-Plus and TSPOT were 7.6% [95%CI 4.6-12.4] and 2.7% [95%CI 1.2-6.2], respectively, with significant difference. TB-associated risk factors and NK cells ≥300/µL were selected as independently significant factors by multivariate logistic regression. The NK cell count revealed significant linear regression with IFN-γ production responding to TB-specific antigens. CONCLUSIONS: The prevalence of positive IGRAs was 2.7%-7.6%. QFT-Plus would be practical for a higher positivity rate and reflect TB risk factors. The innate immune system, referring to IFN-γ production, plays an important role in the immune response to TB-specific antigens even after initiating ART.

Role of CD8 T-cell in immune response to tuberculosis-specific antigen in QuantiFERON-TB Gold Plus.

Recent contacts with active TB (tuberculosis) patients were screened for latent tuberculosis infection (LTBI) because of their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) offers two TB-specific antigen tubes (TB1 and TB2). TB1 elicits CD4 T-cell responses, and TB2 is designed to elicit both CD4 and CD8 T-cell responses. These mechanisms could be useful for estimating the role of CD8 T-cell immune responses to TB-specific antigens. To estimate the QFT-Plus capability to diagnose LTBI, a prospective cross-sectional study was conducted. A total of 412 TB contacts (median age 44 years) were enrolled. The positivity rates of QFT-Plus, TB1 and TB2 were 7.5%, 6.3% and 7.2%, respectively. TB2 showed a higher positivity rate compared to TB1, but without significant difference. The interferon (IFN)-γ productions of TB1 and TB2 were well correlated (r = 0.934, P < 0.001). The ratio of IFN-γ production between TB1 and TB2 showed a median (interquartile range) of IFN-γ[QFT-Plus TB2]/IFN-γ[QFT-Plus TB1] of 1.09 (0.91-1.36). CD8 T-cell immune response to TB-specific antigens varied among subjects. CD8 T-cell potentially boosts IFN-γ productions in QFT-Plus and results in the detection of more persons with LTBI. However, there was no significant difference in the positivity rates of QFT-Plus TB1 and TB2 in our TB contact investigation. The contribution of CD8 T-cells might be small for the diagnosis of LTBI. The analysis of IFN-γ production in both TB1 and TB2 would lead to further analysis of the TB immune response, and especially that caused by CD8 T-cells.

Variation in interferon-γ production between QFT-Plus and QFT-GIT assays in TB contact investigation.

BACKGROUND: Individuals with recent contact with active tuberculosis (TB) patients were screened for latent tuberculosis infection (LTBI) considering their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) assay offers two TB-specific antigen tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses. This mechanism could lead to increased sensitivity as compared to the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay. Our objective was to compare the LTBI diagnostic capability of QFT-Plus with that of QFT-GIT. METHODS: A total of 412 TB contacts (median age 44 years) were prospectively enrolled. We conducted both QFT-Plus and QFT-GIT assays concurrently. We also analyzed production of interferon-γ (IFN-γ) in response to TB-specific antigens. RESULTS: The positivity rates in QFT-Plus and QFT-GIT were 7.5% (95% confidence interval (CI), 5.4-10.5) and 5.8% (CI, 3.9-8.5), respectively, showing a significant difference (P < 0.05). The median (inter-quartile range [IQR]) of IFN-γ[QFT-Plus]/IFN-γ[QFT-GIT] was 1.41 (1.00-2.00). QFT-Plus produced 1.4 times IFN-γ. CONCLUSIONS: QFT-Plus revealed significantly higher positivity rate compared with QFT-GIT, which might be attributed to increased IFN-γ production. The cut-off in both QFT-Plus and QFT-GIT was 0.35 IU/mL. These effects might resulted in the higher positivity rate in QFT-Plus.

Positivity rate of interferon-γ release assays for estimating the prevalence of latent tuberculosis infection in renal transplant recipients in Japan.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and developing active tuberculosis. QuantiFERON®-TB Gold Plus (QFT-Plus) has two TB-specific antigens tubes (TB1 and TB2). TB1 elicits CD4 T-cell response, and TB2 elicits both CD4 and CD8 T-cells responses, with expected increased sensitivity. The aim of this study was to estimate the prevalence of LTBI in renal transplant recipients in Japan. We conducted a cross-sectional study by using two interferon-γ release assays (IGRAs), QFT-Plus and T-SPOT®.TB (TSPOT). One hundred thirty-five recipients were prospectively enrolled. The median age was 49 years (range: 20 to 79). The positivity rates of QFT-Plus and TSPOT were 5.9% (95%CI 3.0-11.3) and 3.7% (95%CI 1.6-8.4), respectively, with no significant difference. The concordance rate was 95.5% (κ coefficient, 0.76). Age of 60 years and higher was related to the higher positivity rate in both QFT-Plus and TSPOT. The positivity rates of TB1 and TB2 were 5.1% (95%CI 2.5-10.2) and 5.9% (95%CI 3.0-11.2), respectively, with no significant difference. The concordance rate was 99.3% (κ coefficient, 0.93). TB2 did not show a higher positivity rate compared with TB1. The estimated prevalence of LTBI by using the both IGRAs was 3.7-5.9% in renal transplant recipients. These results were equivalent to the IGRAs positivity rate in the general Japanese population, even under the condition of immunosuppressive therapy. In consideration of the higher risk of developing active TB from LTBI, we can use both IGRAs as acceptable tools for LTBI diagnosis in renal transplant recipients.

Lymphocyte subset analysis in QuantiFERON-TB Gold Plus and T-Spot.TB for latent tuberculosis infection in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an immune mediated inflammatory disorder, and immune suppressive drugs are prescribed. RA patients receiving treatments are in a kind of immunosuppressive condition that presents increased risk of developing active tuberculosis. Accurate diagnosis of latent tuberculosis infection (LTBI) is recommended for RA. QuantiFERON®-TB Gold Plus (QFT-Plus), a novel IGRA, has two tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses, with expected increased sensitivity. We conducted a cross-sectional study to compare two IGRAs, QFT-Plus and T-SPOT®.TB (TSPOT), in RA. One hundred fifty-two RA patients (median age: 66.5 yrs) were enrolled. QFT-Plus and TSPOT were concurrently conducted. Lymphocyte subsets (CD4 T-cell and CD8 T-cell) were also measured. The positivity rates of QFT-Plus and TSPOT were 9.7% and 4.5%, respectively, with the difference being significant (P < 0.01). The positivity rates in TB1 and TB2 were 9.1% and 7.1%, respectively; the difference was not significant (P = 0.18). Patients with CD4 T-cell ≥650/µL and CD8 T-cell ≥400/µL had significantly higher positivity rates in both QFT-Plus and TSPOT in comparison with other groups (P < 0.01 and P < 0.05, respectively). QFT-plus demonstrated a higher positivity rate than TSPOT. However, there was little additional effect for detecting LTBI by TB2. Lymphocyte subsets were strongly associated with immune response in both QFT-Plus and TSPOT. LTBI should not be ruled out even with a negative IGRA result in patients with CD4 T-cell <650/µL or CD8 T-cell <400/µL.

Comparison of interferon-γ release assays, QuantiFERON TB-GIT and T-Spot.TB, in renal transplantation.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and progressing to active tuberculosis (TB). This study was conducted in National hospital for tuberculosis and renal transplantation (RT) in Japan. The purpose is to compare two interferon-γ release assays (IGRAs), QuantiFERON®-TB Gold in Tube (QFT) and T-SPOT®.TB (TSPOT), in patients after renal transplantation for detecting latent TB infection (LTBI). Total 92 renal transplant recipients (median age 46 years, range 17-75) were prospectively enrolled, and QFT and TSPOT were concurrently examined. Total subjects were 92 patients (median age 46 years, range 17-75). The positive rate in QFT and TSPOT were 6.5% (95% confidence interval (CI) 3.0-13.5) and 2.2% (95% CI 1.0-7.6), respectively. There was a significant difference in IGRAs positivity (P < 0.05). The negative rate in QFT and TSPOT were 91.3% (95% CI 83.8-95.5) and 95.7% (95% CI 89.3-98.3), respectively. There was no significant difference in IGRAs negativity. No patients among either IGRAs negative patients developed active TB during median follow-up of 994 days. Neither QFT nor TSPOT reaches estimated TB infection rate in Japan, especially elderly recipients aged 60 year-old or more. Therefore, both IGRAs might underestimate LTBI owing to immune suppressive therapy and aging. Physicians for renal transplantation need to understand the characteristics of both IGRAs and pay attention to the possibility of developing active TB even in patients of negative IGRAs results.