Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Veronique, Kaatje Smits

doi:10.4172/2155-9899.1000341

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…The diagnostic accuracy of this test was lower for disseminated compared to localized aTB, perhaps as a consequence of high immune suppression in disseminated aTB. A specific induction of CD8 + T cell responses by mycobacterial antigens during aTB is in line with previous reports (33, 34). The mechanisms of in vivo induction of these cells are still incompletely understood (33) This immunological signature was reported to be generated in response to a high bacillary load (35, 36), which was not always the case in our study, as less than half of children with aTB were culture confirmed.…”

Section: Discussionsupporting

confidence: 93%

Identification of Mycobacterium tuberculosis Infection in Infants and Children With Partial Discrimination Between Active Disease and Asymptomatic Infection

Dreesman¹,

Dirix

Smits

et al. 2019

Front. Pediatr.

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Background: Improved diagnostic tests are needed for the early identification of Mycobacterium tuberculosis- infected young children exposed to an active TB (aTB) index case. We aimed to compare the diagnostic accuracy of new blood-based tests to that of the tuberculin skin test (TST) for the identification of all infected children and for a potential differentiation between aTB and latent TB infection (LTBI). Methods: 144 children exposed to a patient with aTB were included, and those who met all inclusion criteria (130/144) were classified in three groups based on results from classical investigations: non-infected (NI: n = 69, 53%, median age 10 months), LTBI ( n = 28, 22%, median age 96 months), aTB disease ( n = 33, 25%, median age 24 months). The first whole blood assay consisted of a 7-days in vitro stimulation of blood with four different mycobacterial antigens (40 μl/condition), followed by flow cytometric measurement of the proportions of blast cells appearing among lymphocytes as a result of their specific activation. Thresholds of positivity were determined by Receiver Operating Characteristic (ROC) curve analysis (results of NI children vs. children with LTBI/aTB) in order to identify infected children in a first stage. Other cut-offs were determined to discriminate subgroups of infected children in a second step (results from children with aTB/LTBI). Analysis of blood monocytes and dendritic cell subsets was performed on 100 μl of blood for 25 of these children as a second test in a pilot study. Results: Combining the results of the blast-induced CD3 + T lymphocytes by Heparin-Binding Haemagglutinin and by Culture Filtrate Protein-10 identified all but one infected children (sensitivity 98.2% and specificity 86.9%, compared to 93.4 and 100% for the TST). Further identification among infected children of those with aTB was best achieved by the results of blast-induced CD8 + T lymphocytes by purified protein derivative (sensitivity for localized aTB: 61.9%, specificity 96.3%), whereas high proportions of blood type 2 myeloid dendritic cells (mDC) were a hallmark of LTBI. Conclusions: New blood-based tests requiring a very small volume allow the accurate identification of M. tuberculosis -infected young children among exposed children and are promising to guide the clinical classification of children with aTB or LTBI.

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Section: Discussionsupporting

confidence: 93%

Identification of Mycobacterium tuberculosis Infection in Infants and Children With Partial Discrimination Between Active Disease and Asymptomatic Infection

Dreesman¹,

Dirix

Smits

et al. 2019

Front. Pediatr.

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“…Since there are no early and accurate diagnostic tests currently available for detecting active TB and differentiate it from LTBI, immunodiagnostic biomarkers are urgently needed to monitor the progression from LTBI to clinical disease [9,28,29]. Studies [9,10,11,30,31] showed that one of the most promising biomarkers is HBHA. Although the existing studies explored the value of using IGRA with HBHA as a stimulating antigen to differentiate ATB from LTBI, they showed various results and it was difficult to obtain a consensus in deriving an accurate differential diagnosis [15,16,20,22,32].…”

Section: Plos Onementioning

confidence: 99%

“…A divergence was noted in the definition of the ATB groups between microbiologically confirmed TB and clinically confirmed TB. The inclusion of the LTBI groups had different selection criteria (TST or IGRA): the TST results are more often positive than the IGRAs, the LTBI groups in different studies exhibited varied risk stratifications [11,30,36,37]. Moreover, some studies specified neither the active TB type (pulmonary or extra-pulmonary TB) of the ATB subjects nor the treatment of the LTBI subjects.…”

Section: Plos Onementioning

confidence: 99%

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

et al. 2021

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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.

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“…It is estimated that 25% of the global population is latently infected with Mycobacterium tuberculosis, and 2 to 8% of these will develop the disease most of the time (50%) within the first 2 years after infection. Even though they are asymptomatic and do not transmit the infection, these subjects are a reservoir that sustains TB disease (3). Importantly, the risk of TB progression is much higher in children (30 to 40% progression rate if untreated) (4).…”

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confidence: 99%

Accuracy of QuantiFERON-TB Gold Plus Test for Diagnosis of Mycobacterium tuberculosis Infection in Children

et al. 2020

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Compared to its predecessor QuantiFERON-TB Gold In Tube (QFT-IT), QuantiFERON-TB Gold Plus (QFT-Plus) contains an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T cells. The ability to discriminate CD4+ and CD8+ responses is suggested to be useful in differentiating stages of Mycobacterium tuberculosis infection. While QFT-Plus has already been evaluated in adults, there are not enough data in children evaluated for suspected active tuberculosis (TB) or latent TB infection (LTBI). A prospective cross-sectional study was conducted among children aged 0 to 17 years who were evaluated for suspected active TB or screened for LTBI. All children underwent QFT-Plus and further clinical, radiological, and/or microbiological analyses according to clinical scenario. Of the 198 children enrolled, 43 (21.7%) were tested because of suspicion of active TB. A total of 12/43 (27.9%) were diagnosed with active TB, and among these, 10/12 (83.3%) had a positive QFT-Plus assay. Of the 155 children screened for LTBI, 18 (11.6%) had a positive QFT-Plus, and 5 (2.5%) had an indeterminate result. TB1 and TB2 quantitative responses were not able to discriminate active disease from latent infection. The percent agreement between TB1 and TB2 was 100%. QFT-Plus assay showed good sensitivity for active TB and was particularly useful for the evaluation of children with suspected LTBI, giving a low rate of indeterminate results in this group. More studies are needed to properly evaluate QFT-Plus ability in discriminating active disease from latent infection.

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Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Cited by 7 publications

References 34 publications

Identification of Mycobacterium tuberculosis Infection in Infants and Children With Partial Discrimination Between Active Disease and Asymptomatic Infection

Identification of Mycobacterium tuberculosis Infection in Infants and Children With Partial Discrimination Between Active Disease and Asymptomatic Infection

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

Accuracy of QuantiFERON-TB Gold Plus Test for Diagnosis of Mycobacterium tuberculosis Infection in Children

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