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Frontiers in Immunology 2020Latent tuberculosis infection (LTBI) is a subclinical mycobacterial infection defined on the basis of cellular immune response to mycobacterial antigens. The tuberculin... (Review)
Review
Latent tuberculosis infection (LTBI) is a subclinical mycobacterial infection defined on the basis of cellular immune response to mycobacterial antigens. The tuberculin skin test (TST) and the interferon gamma release assay (IGRA) are currently used to establish the diagnosis of LTB. However, neither TST nor IGRA is useful to discriminate between active and latent tuberculosis. Moreover, these tests cannot be used to predict whether an individual with LTBI will develop active tuberculosis (TB) or whether therapy for LTBI could be effective to decrease the risk of developing active TB. Therefore, in this article, we review current approaches and some efforts to identify an immunological marker that could be useful in distinguishing LTBI from TB and in evaluating the effectiveness of treatment of LTB on the risk of progression to active TB.
Topics: Animals; Biomarkers; Diagnosis, Differential; Disease Progression; Humans; Interferon-gamma; Latent Tuberculosis; Mycobacterium tuberculosis; Risk; Tuberculin Test
PubMed: 33013856
DOI: 10.3389/fimmu.2020.02006 -
The European Respiratory Journal Nov 2021Only the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs), QuantiFERON-TB Gold In-Tube and T-SPOT.TB, are currently endorsed by the World Health... (Review)
Review
BACKGROUND
Only the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs), QuantiFERON-TB Gold In-Tube and T-SPOT.TB, are currently endorsed by the World Health Organization as tests for tuberculosis (TB) infection. While IGRAs are more specific than the TST, they require sophisticated laboratory infrastructure and are costly to perform. However, both types of tests have limited performance to predict development of active TB. Tests with improved predictive performance and operational characteristics are needed.
METHODS
We reviewed the current landscape of tests for TB infection identified through a web-based survey targeting diagnostic manufacturers globally.
RESULTS
We identified 20 tests for TB infection: 15 tests and five skin tests. 13 of the tests are whole-blood IGRAs and 14 use early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10), with or without additional antigens. 10 of the tests are based on assays other than an ELISA, such as a fluorescent lateral flow assay that requires less manual operation and shorter assay time and hence is more suitable for decentralisation compared with the existing IGRAs. Four of the five skin tests use ESAT-6 and CFP-10 proteins, while the remaining test uses a new antigen that is specific to complex.
CONCLUSIONS
New tests have the potential to improve accuracy, operational characteristics and end-user access to tests for TB infection. However, published data in various populations and settings are limited for most new tests. Evaluation of these new tests in a standardised design would facilitate their endorsement and programmatic scale-up.
Topics: Humans; Interferon-gamma Release Tests; Latent Tuberculosis; Mycobacterium tuberculosis; Sensitivity and Specificity; Tuberculin Test; Tuberculosis
PubMed: 33875495
DOI: 10.1183/13993003.00167-2021 -
International Journal of Infectious... Nov 2022The World Health Organization estimated that a quarter of the global population is infected by Mycobacterium tuberculosis (Mtb). A better control of tuberculosis (TB) is... (Review)
Review
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.
OBJECTIVES
The World Health Organization estimated that a quarter of the global population is infected by Mycobacterium tuberculosis (Mtb). A better control of tuberculosis (TB) is based on the ability to detect Mtb infection, identifying the progressors to TB disease, undergoing to preventive therapy and implementing strategies to register the infections and treatment completion.
DESIGN
we reviewed the literature regarding the tests available for TB infection diagnosis, the preventive therapies options and the cascade of care for controlling TB at a public health level.
RESULTS
current tests for TB infection diagnosis as IFN-γ release assays or tuberculin skin tests are based on the detection of an immune response to Mtb in the absence of clinical disease. The main limit is their low accuracy to detect progressors to disease. New preventive treatments are available with short duration that are associated with better adherence. Options to register TB infections are presented.
CONCLUSIONS
Tests to diagnose TB infection are available but they lack accuracy to identify the progressors from infection to TB disease. Shorter preventive TB therapy are available but need to be implemented worldwide. A TB infection registry is crucial for improving the cascade of care leading to a better TB control.
Topics: Humans; Latent Tuberculosis; Tuberculosis; Tuberculin Test; Interferon-gamma Release Tests; Mycobacterium tuberculosis
PubMed: 35257904
DOI: 10.1016/j.ijid.2022.02.047 -
Journal of Clinical Microbiology Aug 2020QuantiFERON-TB Gold Plus (QFT-Plus) is the latest generation of interferon gamma release assays (IGRAs) to receive approval from the U.S. FDA, replacing its predecessor,... (Review)
Review
QuantiFERON-TB Gold Plus (QFT-Plus) is the latest generation of interferon gamma release assays (IGRAs) to receive approval from the U.S. FDA, replacing its predecessor, QuantiFERON-TB Gold In-Tube (QFT-GIT). The novelty of QFT-Plus is that it elicits a response from CD8 T cells, in addition to CD4 T cells, thus collecting a broader response from T-cell subsets than QFT-GIT. It was developed with the aim to improve the detection of latent tuberculosis infection (LTBI), especially among recently exposed contacts, immunocompromised hosts, and young children. In this minireview, we summarize the performance of QFT-Plus compared with that of QFT-GIT among active tuberculosis (TB) patients (a surrogate for LTBI patients), high-risk populations, and low-risk individuals based on recent publications. Studies comparing QFT-Plus to QFT-GIT currently do not support the superior performance of QFT-Plus in individuals with active TB and LTBI. The difference in sensitivity between QFT-Plus and QFT-GIT in active TB patients was not significant in nearly all studies and ranged from -4.0 to 2.0%. Among high-risk groups, the agreement between QFT-Plus and QFT-GIT was 89.9 to 96.0% (kappa coefficient range, 0.80 to 0.91). The specificity in the low-risk population was slightly lower for QFT-Plus than for QFT-GIT, with the difference ranging from -7.4 to 0%. Further studies are needed to accurately evaluate the sensitivity of QFT-Plus in immunocompromised hosts and children. In addition, further evidence is required to validate a modified interpretation of QFT-Plus for the identification of false-positive results in low-risk health care workers.
Topics: Child; Child, Preschool; Health Personnel; Humans; Immunocompromised Host; Interferon-gamma Release Tests; Latent Tuberculosis; Tuberculin Test; Tuberculosis
PubMed: 32493779
DOI: 10.1128/JCM.01950-19 -
La Medicina Del Lavoro Jun 2020Despite great efforts, tuberculosis (TB) is still a major public health threat worldwide. For decades, TB control programs have focused almost exclusively on infectious... (Review)
Review
INTRODUCTION
Despite great efforts, tuberculosis (TB) is still a major public health threat worldwide. For decades, TB control programs have focused almost exclusively on infectious TB active cases. However, it is evident that this strategy alone cannot achieve TB elimination. To achieve this objective a comprehensive strategy directed toward integrated latent tuberculosis infection (LTBI) management is needed. Recently it has been recognized that LTBI is not a stable condition but rather a spectrum of infections (e.g., intermittent, transient or progressive) which may lead to incipient, then subclinical, and finally active TB disease.
AIM
Provide an overview of current available LTBI diagnostic test including updates, future developments and perspectives.
RESULTS
There is currently no test for the direct identification of live MT infection in humans. The diagnosis of LTBI is indirect and relies on the detection of an immune response against MT antigens, assuming that the immune response has developed after a contact with the biological agent. Tuberculin skin test (TST) and interferon gamma release assays (IGRAs) are the main diagnostic tools for LTBI, however, both present strengths and limitations. The most ancient diagnostic test (TST) can be associated with several technical errors, has limited positive predictive value, is being influenced by BCG vaccination and several conditions can reduce the skin reactivity. Notwithstanding these limitations, prompt identification of TST conversion, should orientate indications for preventive therapy of LTBI. IGRAs have superior specificity, are not affected by M. bovis, BCG vaccination and other environmental mycobacteria. However, they present some logistical and organisational constraints and are more expensive. Currently, the WHO guidelines recommend that either a TST or an IGRA can be used to detect LTBI in high-income and upper middle-income countries with estimated TB incidences less than 100 per 100,000 population. Two skin tests (C-TB and Diaskintest), using only two specific M. tuberculosis antigens (ESAT-6 and CFP-10) instead of the tuberculin solution, have recently been developed but, to date, none of these tests is available on the European market.
CONCLUSION
Early identification and treatment of individuals with LTBI is an important priority for TB control in specific groups at risk within the population: this is of crucial meaning in recently infected cases both at the community level and in some occupational settings. Currently there is no gold standard test for LTBI: an improved understanding of the available tests is needed to develop better tools for diagnosing LTBI and predicting progression to clinical active disease.
Topics: Humans; Interferon-gamma; Latent Tuberculosis; Sensitivity and Specificity; Tuberculin Test; Tuberculosis
PubMed: 32624559
DOI: 10.23749/mdl.v111i3.9983 -
The European Respiratory Journal Sep 2019In 1999, the World Health Organization (WHO) estimated that one-third of the world's population had latent tuberculosis infection (LTBI), which was recently updated to... (Meta-Analysis)
Meta-Analysis
In 1999, the World Health Organization (WHO) estimated that one-third of the world's population had latent tuberculosis infection (LTBI), which was recently updated to one-fourth. However, this is still based on controversial assumptions in combination with tuberculin skin test (TST) surveys. Interferon-γ release assays (IGRAs) with a higher specificity than TST have since been widely implemented, but never used to estimate the global LTBI prevalence.We conducted a systematic review and meta-analysis of LTBI estimates based on both IGRA and TST results published between 2005 and 2018. Regional and global estimates of LTBI prevalence were calculated. Stratification was performed for low, intermediate and high TB incidence countries and a pooled estimate for each area was calculated using a random effects model.Among 3280 studies screened, we included 88 studies from 36 countries with 41 IGRA (n=67 167) and 67 TST estimates (n=284 644). The global prevalence of LTBI was 24.8% (95% CI 19.7-30.0%) and 21.2% (95% CI 17.9-24.4%), based on IGRA and a 10-mm TST cut-off, respectively. The prevalence estimates correlated well to WHO incidence rates (Rs=0.70, p<0.001).In the first study of the global prevalence of LTBI derived from both IGRA and TST surveys, we found that one-fourth of the world's population is infected. This is of relevance, as both tests, although imperfect, are used to identify individuals eligible for preventive therapy. Enhanced efforts are needed targeting the large pool of latently infected individuals, as this constitutes an enormous source of potential active tuberculosis.
Topics: Algorithms; Communicable Disease Control; Global Health; Humans; Incidence; Interferon-gamma Release Tests; Latent Tuberculosis; Prevalence; Tuberculin Test; World Health Organization
PubMed: 31221810
DOI: 10.1183/13993003.00655-2019 -
The New England Journal of Medicine Jul 2020Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitamin D metabolites support innate immune responses to . Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.
METHODS
We randomly assigned children who had negative results for infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.
RESULTS
A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.
CONCLUSIONS
Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).
Topics: Child; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Follow-Up Studies; Humans; Incidence; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Respiratory Tract Infections; Treatment Failure; Tuberculin Test; Vitamin D; Vitamins
PubMed: 32706534
DOI: 10.1056/NEJMoa1915176 -
The Clinical Respiratory Journal Feb 2023The diagnosis of latent tuberculosis infection (LTBI) relies largely on the tuberculin skin test (TST) or, more recently, on interferon-gamma release assays (IGRA)....
INTRODUCTION
The diagnosis of latent tuberculosis infection (LTBI) relies largely on the tuberculin skin test (TST) or, more recently, on interferon-gamma release assays (IGRA). Knowledge regarding these tests is essential to improve their usefulness in combating the tuberculosis epidemic.
OBJECTIVES
To characterize the agreement between the IGRA and TST tests by determining the kappa coefficient (K) and agreement rate between these two tests in patients with active tuberculosis (TB).
METHODS
Retrospective cohort study conducted with data from active TB patients notified in the Portuguese Tuberculosis Surveillance System (SVIG-TB), from 2008 to 2015. TST results were interpreted using a 5 mm (TST-5 mm) and 10 mm (TST-10 mm) cutoff. Kappa coefficient and agreement rate were calculated in order to evaluate the agreement between IGRA and TST (both cutoffs) test results.
RESULTS
A total of 727 patients with results for both tests were included in the study, of which 3.4% (n = 25) had HIV infection, 5.6% (n = 41) diabetes, 5.0% (n = 36) oncological diseases and 4.4% (n = 32) inflammatory diseases. Of the 727 patients, 16.5% (n = 120) presented different outcomes between IGRA and TST-5 mm, and 20.5% (n = 149) presented different outcomes between IGRA and TST-10 mm. Kappa coefficient between IGRA and TST-5 mm was 0.402 (p < 0.001) with an agreement rate of 83.5%. Between IGRA and TST-10 mm, the kappa coefficient was 0.351 (p < 0.001), with an agreement rate of 79.5%. Patients with HIV infection, diabetes, oncologic diseases and inflammatory diseases presented a substantial agreement between IGRA and TST-5 mm, while inflammatory diseases was the only variable that presented a substantial agreement between IGRA and TST-10 mm.
CONCLUSION
As both tests can present false-negative results, the low level of agreement between the tests can potentially help identify more cases of LTBI if the two tests are used in parallel, with infections not detected by IGRA possibly being detected by the TST and vice versa.
Topics: Humans; Interferon-gamma Release Tests; Tuberculin Test; HIV Infections; Retrospective Studies; Tuberculosis; Latent Tuberculosis
PubMed: 36526296
DOI: 10.1111/crj.13569 -
The Pediatric Infectious Disease Journal May 2023This review summarizes studies evaluating the performance of the QuantiFERON-TB Gold Plus (QFT-Plus) interferon-gamma release assay (IGRA) test for Mycobacterium... (Review)
Review
This review summarizes studies evaluating the performance of the QuantiFERON-TB Gold Plus (QFT-Plus) interferon-gamma release assay (IGRA) test for Mycobacterium tuberculosis ( Mtb ) infection in children. Literature searching was conducted using PubMed, MEDLINE and Embase (January 2017 to December 2021) and the terms "children" or "pediatric" and "IGRAs" or "QuantiFERON-TB Gold Plus." Selected studies (N = 14; 4646 subjects) enrolled children with Mtb infection, tuberculosis (TB) disease or healthy children with household TB contacts. Agreement between QFT-Plus and tuberculin skin test (TST) (kappa values) ranged from -0.201 (no agreement) to 0.83 (almost perfect agreement). Assay sensitivity of QFT-Plus (against reference standard of microbiologically confirmed TB disease) was 54.5%-87.3%, with no reported difference in children less than 5 versus greater than or equal to 5 years of age. In individuals less than or equal to 18 years of age, the rate of indeterminate results was 0%-33.3% (2.6% in children <2 years). IGRAs may overcome the limitations of TST in young, Bacillus Calmette-Guérin-vaccinated children.
Topics: Humans; Child, Preschool; Sensitivity and Specificity; Tuberculosis; Interferon-gamma Release Tests; Tuberculin Test; Mycobacterium tuberculosis; Latent Tuberculosis
PubMed: 36795574
DOI: 10.1097/INF.0000000000003877 -
JAMA Network Open May 2023
Topics: Humans; Latent Tuberculosis; Tuberculin Test; Mass Screening
PubMed: 37129898
DOI: 10.1001/jamanetworkopen.2023.12114