QuantiFERON TB Gold Plus for the diagnosis of tuberculosis: a systematic review and meta-analysis

Summary

Estimated 2017 tuberculosis (TB) incidence is 10 million and mainly depends on the reservoir of individuals with latent TB infection (LTBI). Quantiferon^Ⓡ-TB Gold in-Tube (QFT-GIT) is one of the tests used for LTBI detection. Since 2015 a new version, Quantiferon^Ⓡ-TB Gold Plus (QFT-Plus) is available.

Objectives

To perform a systematic review and meta-analysis to assess the diagnostic accuracy for TB of QFT-Plus compared to QFT-GIT.

Methods

PubMed and Scopus were used to detect records related to predefined strings from 2015 to 2018. Full text articles dealing with the sensitivity and/or specificity of the QFT-Plus vs. QFT-GIT for active-TB and LTBI detection were analyzed. Scientific quality and risk of bias were assessed using QADAS-2.

Results

We selected 15 articles. Studies were mainly observational and cross-sectional, performed in 8 countries. Sample size differed in the TB group (27 to 164) compared to LTBI group (29 to 1031). Pooled sensitivity of QFT-Plus for active-TB was 0.94 (0.91 and 0.95 for TB1 and TB2, respectively), whereas pooled specificity for healthy status was 0.96. Pooled sensitivity and specificity for LTBI was 0.91 and 0.95, respectively.

Conclusions

We show that QFT-Plus is more sensitive compared to QFT-GIT for detecting M. tuberculosis infection, mainly due to TB2 responses.

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is still an important global health problem with 10 million cases and 1.6 million deaths worldwide estimated in 2017 by the World Health Organization (WHO).1, 2, 3, 4, 5 Almost one-fourth of the world's population is latently infected with Mtb with a risk of progression to active disease of about 3–15% during their lifetimes.2, 6, 7 Being latent TB infection (LTBI) an important reservoir for TB disease progression, an effectively elimination of TB epidemic is feasible only diagnosing and treating LTBI.8, 9, 10, 11, 12, 13

Tuberculin skin test (TST) and T-cell interferon-γ release assays (IGRAs) are the routine tests used for LTBI diagnosis⁹; to note that no gold standard tests for LTBI diagnosis exist and therefore active TB is used as a surrogate to measure the sensitivity of these assays. The TST is based on an immune reaction to the intradermal injection of purified protein derivate (PPD) of tuberculin, a mixture of antigens that, however, is shared by Mtb and bacille Calmette–Guérin (BCG) as well as other mycobacteria, affecting the specificity of the test.14, 57, 58, 59

To overcome this limitation, IGRAs have been developed.60, 61, 62 Two IGRAs, Quantiferon^Ⓡ-TB Gold in Tube (QFT-GIT) and T-Spot^Ⓡ.TB (TSPOT), are available.^13,15, 16, 17, 18 IGRAs measure (by enzyme-linked immune-assay and by enzyme-linked immunospot, respectively) the IFN-γ production to Mtb specific peptides ESAT-6, CFP-10 and TB7.7 (one only in QFT-GIT) located in the region of difference (RD-1 and RD-11) of Mtb. However, also the IGRAs may show cross reactivity with mycobacteria containing antigens within the RD1 region¹⁹ and have higher costs compared to TST.17, 20 Furthermore, since both TST and IGRAs imply an immune reaction, these tests have a suboptimal diagnostic accuracy in immunocompromised patients as well as in children who have an immature immune system.11, 21, 22 Finally, TST and IGRAs do not differentiate between active TB and LTBI, between active TB and cured TB,23, 24, 25 and importantly, between recent and remote latent infections.^7,26, 27, 28 Such differentiation is greatly important, since the risk of progress to active disease is highest in the first two years after Mtb exposure.¹³

IGRAs are based on the assumption that CD4 T-cells play a critical role in the immune response to Mtb.²⁹ However, recent evidences support the idea that also CD8 T-cells are an important component of host immunity to Mtb.30, 31 Indeed, CD8 T-lymphocytes are able to mount an immune response producing IFN-γ in vitro after stimulation with Mtb antigens.32, 33, 34 Moreover, RD1-specific CD8+ T cells are more frequently detected in active TB patients than in subjects with LTBI30, 31, 35 and after recent infection compared to remote latent infection.¹⁸

A new version of QFT-GIT is available since 2015, the Quantiferon^Ⓡ-TB Gold Plus (QFT-Plus) which has been proposed as the 4th generation Quantiferon. QFT-Plus contains two TB-specific antigen tubes, called TB1 and TB2: the TB1 tube, contains long peptides derived from ESAT-6 and CFP-10 (TB-7.7, present in the previous QFT-GIT version has been removed), and it is designed to induce a specific CD4 T-cell response; TB2, besides the same long peptides of TB1, contains also shorter peptides able to stimulate CD8 T-cells.³⁶ This new test, overcoming the dependence on the CD4-mediated responses alone, could potentially have an increased sensitivity for the diagnosis of LTBI in HIV-infected subjects. Moreover, as CD8 T-cell responses seem to work at the early phase of Mtb infection and at a phase of reactivation from LTBI,18, 31, 37, 38 QFT-Plus test might be useful in differentiating recent and remote LTBI, helping in the decision to start LTBI treatment.

In the last 3 years, several studies were performed to assess the diagnostic accuracy of QFT-Plus over another routine immune diagnostic test (TST, QFT-GIT, T Spot TB). As reported above, active TB cases were used as a surrogate to evaluate the sensitivity of the test for LTBI diagnosis.

Aim of this study was to assess the diagnostic accuracy of QFT-Plus in TB and LTBI in comparison with QFT-GIT, carrying out a systematic review and meta-analysis.