Adults with Mycobacterium tuberculosis infection and pre-diabetes have increased levels of QuantiFERON interferon-gamma responses.
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ABSTRACT: Background
Diabetes is associated with increased prevalence of TB infection in the US. We assessed associations between diabetes and interferon-gamma (IFN-γ) TB antigen response among adults with TB infection using US representative data.Methods
National Health and Nutrition Examination (NHANES) participants >19 years from 2011 to 2012 with positive QuantiFERON®-TB Gold-In-Tube (QFT) results were eligible. Diabetes was defined by combination of self-report and glycated hemoglobin (HbA1c). Quantitative IFN-γ TB antigen was classified as high (≥10 IU/mL), intermediate (1.01-9.99 IU/mL), or low (0.35-1.00 IU/mL). Analyses accounted for NHANES weighted design.Results
Among NHANES participants >19 years, n = 513 had positive QFT (5.9%). Among those with positive QFT, diabetes prevalence was 22.2% and pre-diabetes was 25.9%. Overall, 16.7% of positive QFT participants had high IFN-γ TB antigen levels including 21.7% among those with diabetes, 20.8% among those with pre-diabetes, and 12.6% among euglycemic participants. In adjusted analyses, high IFN-γ TB antigen response was more common among those with pre-diabetes (aOR 1.9, 95%CI 1.0, 3.6) compared to euglycemic participants.Conclusion
Higher antigen responses may reflect immunopathy consistent with an exaggerated inflammatory but ineffectual response to TB or a reflection of more Mtb replication in participants with pre-diabetes or diabetes.
SUBMITTER: Magee MJ
PROVIDER: S-EPMC7275930 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWe previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru.MethodsWe analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis.ResultsData from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5-52.8 vs. 6.5 pg/mL, 4.5-15; P<0.01). LTBI remained associated with higher unstimulated interferon-gamma levels after controlling for age, sex, recent AMI, history of hypertension, diabetes mellitus, dyslipidemia, end stage renal disease, malignancy, obesity, and tobacco use (adjusted odds ratio, 2.93; 95% confidence interval, 1.8-4.9). In a sensitivity analysis that excluded participants with AMI, the association between unstimulated interferon-gamma and LTBI remained present (adjusted odds ratio; 3.93; 95% confidence interval, 1.9-8.2).ConclusionsLTBI was associated with higher unstimulated interferon-gamma levels. These data suggest ongoing immune activation in LTBI.
| S-EPMC6136705 | biostudies-literature
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Project description:Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.
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Project description:BackgroundData on the performance of Mycobacterium-tuberculosis-specific interferon-(IFN)-gamma release assays (IGRAs) in the serial testing of health care workers (HCWs) is limited. The objective of the present study was to determine the frequency of IGRA conversions and reversions and to identify predictors of persistent IGRA positivity among serially tested German HCWs in the absence of recent extensive tuberculosis (TB) exposure.MethodsIn this observational cohort-study HCWs were prospectively recruited within occupational safety and health measures and underwent a tuberculin skin test (TST) and the IGRA QuantiFERON-TB Gold In-Tube (QFT-GIT) at baseline. The QFT-GIT was repeated 18 weeks later in the median. QFT-GIT conversions (and reversions) were defined as baseline IFN-gamma < 0.35 IU/ml and follow-up IFN-gamma > or = 0.35 IU/ml (and vice versa). Predictors of persistently positive QFT-GIT results were calculated by logistic regression analysis.ResultsIn total, 18 (9.9%) and 15 (8.2%) of 182 analyzed HCWs were QFT-GIT-positive at baseline and at follow-up, respectively. We observed a strong overall agreement between baseline and follow-up QFT-GIT results (kappa = 0.70). Reversions (6/18, 33.3%) occurred more frequently than conversions (3/162, 1.9%). Age and positive prior and recent TST results independently predicted persistent QFT-GIT positivity. Furthermore, the chance of having persistently positive QFT-GIT results raised about 3% with each additional 0.1 IU/ml increase in the baseline IFN-gamma response (adjusted odds ratio 1.03, 95% confidence interval 1.01-1.04). No active TB cases were detected within an observational period of more than two years.ConclusionsThe QFT-GIT's utility for the application in serial testing was limited by a substantial proportion of reversions. This shortcoming could be overcome by the implementation of a borderline zone for the interpretation of QFT-GIT results. However, further studies are needed to clearly define the within-subject variability of the QFT-GIT and to confirm that increasing age, concordantly positive TST results, and the extend of baseline IFN-gamma responses may predict the persistence of QFT-GIT positivity over time in serially tested HCWs with only a low or medium TB screening risk in a TB low-incidence setting.
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Project description:Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection. IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.
| S-EPMC9241521 | biostudies-literature
Project description:BackgroundDevelopment of T-cells based-Interferon gamma (IFNgamma) assays has offered new possibilities for the diagnosis of latent tuberculosis infection (LTBI) and active disease in adults. Few studies have been performed in children, none in France. With reference to the published data on childhood TB epidemiology in the Paris and Ile de France Region, we considered it important to evaluate the performance of IGRA (QuantiFERON TB Gold In Tube(R), QF-TB-IT) in the diagnosis and the follow-up through treatment of LTBI and active TB in a cohort of French children.Methodology/principal findings131 children were recruited during a prospective and multicentre study (October 2005 and May 2007; Ethical Committee St Louis Hospital, Paris, study number 2005/32). Children were sampled at day 0, 10, 30, 60 (except Healthy Contacts, HC) and 90 for LTBI and HC, and a further day 120, and day 180 for active TB children. Median age was 7.4 years, with 91% of the children BCG vaccinated. LTBI and active TB children undergoing therapy produced significant higher IFNgamma values after 10 days of treatment (p = 0.035). In addition, IFNgamma values were significantly lower at the end of treatment compared to IFNgamma values at day 0, although the number of positive patients was not significantly different between day 0 and end of treatment.Conclusions/ significanceBy following quantitative IFNgamma values in each enrolled child with LTBI or active TB and receiving treatment, we were able to detect an increase in the IFNgamma response at day 10 of treatment which might allow the confirmation of a diagnosis. In addition, a decline in IFNgamma values during treatment makes it possible for clinicians to monitor the effect of preventive or curative therapy.
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