Mycobacterial heparin-binding hemagglutinin (HBHA)-induced interferon-γ release assay (IGRA) for discrimination of latent and active tuberculosis: A systematic review and meta-analysis

Abstract

Background The Mycobacterial heparin-binding hemagglutinin (HBHA) is an important latency-associated antigen that can be used to distinguish between latent tuberculosis infection (LTBI) and active tuberculosis (ATB). Although many studies were explored the efficiency of the HBHA-induced interferon-γ release assay (IGRA) in different populations, the clinical differential value of HBHA-IGRA is still controversial. Therefore, the aim of this study was to determine whether the HBHA-IGRA can be used as an efficient test for the discrimination of LTBI and ATB by a systematic review and meta-analysis. Methods Relevant articles were retrieved from PubMed, Embase, Web of Science, and the Cochrane Library on Oct 18, 2020, with no start date limitation. The quality of each study was evaluated using Review Manager 5.4. The Stata MP v.14.0 software was used to combine sensitivity, specificity, likelihood ratio (LR), diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curve, and area under SROC (AUC) to evaluate the diagnostic value of HBHA-IGRA for discrimination of LTBI and ATB. Meta-regression and subgroup analysis were performed for the sources of heterogeneity based on the selection criteria for active TB, the population, the TB burden, the type of antigen, the type of sample, and the time of antigen stimulation. Results A total of 13 studies (14 results) were included in this meta-analysis, including 603 ATB patients and 514 LTBI individuals. The pooled sensitivity and specificity of the HBHA-IGRA for discrimination of the LTBI and ATB were 0.70 (95% CI, 0.57~0.80) and 0.78 (95% CI, 0.71~0.84), respectively. The pooled positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 3.15 (95%CI, 2.43~4.09), 0.39 (95% CI, 0.27~0.56), and 8.11 (95% CI, 4.81~13.67), respectively. The AUC was 0.81 (95% CI, 0.77~0.84). The subgroup analysis showed that the main source of heterogeneity was due to the HIV-infected population incorporated, and the different selection criteria of active TB subjects would also lead to the variation of the pooled sensitivity and specificity. Different TB burdens, HBHA antigen types, sample types, antigen stimulation time and BCG vaccination did not affect the heterogeneity in this analysis. Conclusion The HBHA-IGRA is a promising immunodiagnostic test for discrimination of latent and active TB, which can be added in commercial IGRAs to enhance the differential diagnostic performance.

The role of IGRA in the diagnosis of tuberculosis infection, differentiating from active tuberculosis, and decision making for initiating treatment or preventive therapy of tuberculosis infection

“…Preventive therapy to HIV-infected participants reduced the prevalence of PCR-detected Mtb from 95% at baseline to 54% post-treatment (Belay et al, 2021). Experimental in vitro tests based on the detection of IFN-γ to heparin-binding hemagglutinin antigen (HBHA) have been shown interesting results as associated with Mtb containments and as tools to monitor active TB clinical states in children (Sali et al, 2018) confirming results from the adults (Delogu et al, 2011;Chedid et al, 2021;Chiacchio et al, 2017;Tang et al, 2021). Further studies to evaluate the ability of these approaches to predict TB development are needed (Table 1).…”

Optimal Detection of Latent Mycobacterium tuberculosis Infection by Combined Heparin-Binding Hemagglutinin (HBHA) and Early Secreted Antigenic Target 6 (ESAT-6) Whole-Blood Interferon Gamma Release Assays

“…The lack of a commercialized WB-HBHA-IGRA used here limits standardization of the assay for larger studies. Interest in the HBHA-IGRA was reported independently by several groups, mostly as an option to differentiate LTBI from aTB ( 10 – 13 , 15 , 30 – 32 ). However, technical differences between those studies, including different sources of HBHA, make comparisons of the results difficult.…”

“…However, technical differences between those studies, including different sources of HBHA, make comparisons of the results difficult. This might be mitigated by using a standardized, commercial WB-HBHA-IGRA, as recently stressed ( 32 ).…”

Tuberculosis Diagnosis: Updates and Challenges

“…Even though IGRA evaluation studies and its recommendations required many years, effort, funding, and resources across the globe, it did not have a major contribution to successful tuberculosis control [13]. A recent meta-analysis has shown that heparin-binding hemagglutinin (HBHA) is a latency-associated Mtb antigen and HBHA-induced IGRA can be a promising diagnostic test to differentiate latent and active TB [29]. IGRA testing is also a cost-effective screening method [30].…”