Short Communication: Expression of APOBEC3G and Interferon Gamma in Pleural Fluid Mononuclear Cells from HIV/TB Dual Infected Subjects.
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ABSTRACT:
SUBMITTER: Toossi Z
PROVIDER: S-EPMC4505766 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Extra pulmonary manifestation of tuberculosis (TB) accounts for approximately one-half of TB cases in HIV-infected individuals with pleural TB as the second most common location. Even though mycobacteria are cleared, mycobacterial antigens may persist in infected tissues, causing sustained inflammation and chronicity of the disease. The aim of this study was to explore various mycobacterial antigens in pleural effusions, the impact of HIV infection and CD4+ T-cell depletion on the presence of antigens, and the diagnostic potential of antigens for improved and rapid diagnosis of pleural TB. METHODS:Pleural fluid specimens were collected from patients presenting with clinically suspected pleural TB, and processed routinely for culture, cytology, and adenosine deaminase activity analysis. HIV status and CD4+ T-cell counts were recorded. Pleural fluid mononuclear cells (PFMC) were isolated, and cell smears were stained with acid-fast staining and immunocytochemistry for various mycobacterial antigens. Real-time and nested-PCR were performed. Patients were categorized as pleural TB or non-TB cases using a composite reference standard. Performance of the mycobacterial antigens as diagnostic test was assessed. RESULTS:A total of 41 patients were enrolled, of which 32 were classified as pleural TB and 9 as non-TB. Thirteen patients had culture confirmed pleural TB, 26 (81%) were HIV-TB co-infected, and 64% had <?100 CD4+ T-cells/microL. Both secreted and cell-wall mycobacterial antigens were detected in PFMC. Lipoarabinomannan (LAM) was the most frequently detected antigen. There was no direct correlation between positive culture and antigens. Cases with low CD4+ T-cell counts had higher bacterial and antigen burden. By combining detection of secreted antigen or LAM, the sensitivity and specificity to diagnose pleural TB was 56 and 78%, respectively, as compared to 41 and 100% for culture, 53 and 89% for nested PCR, and 6 and 100% for real-time PCR. CONCLUSION:Mycobacterial antigens were detectable in PFMC from tuberculous pleural effusions, even in cases where viable mycobacteria or bacterial DNA were not always detected. Thus, a combination of secreted antigen and LAM detection by immunocytochemistry may be a complement to acid-fast staining and contribute to rapid and accurate diagnosis of pleural TB.
| S-EPMC7329517 | biostudies-literature
Project description:Unstimulated interferon gamma may be a useful pleural fluid biomarker in the diagnosis of tuberculous pleural effusion (TPE). However, the exact threshold of pleural fluid interferon gamma and its accuracy during routine clinical decision-making is not clear. We assessed the performance of pleural fluid interferon gamma in diagnosing TPE and tried to identify a useful assay threshold. We queried the PubMed and Embase databases for publications indexed until May 2020 that provided both sensitivity and specificity data on unstimulated pleural fluid interferon gamma for diagnosis of TPE. A bivariate random effects model was employed to compute summary estimates for diagnostic accuracy parameters, both overall as well as at threshold ranges of <2, 2 to 5, and >5 IU/ml. We retrieved 2,048 citations, of which 67 publications (7,153 patients) were assessed in our review. The summary estimates for sensitivity, specificity, and diagnostic odds ratio were 0.93 (95% confidence interval [CI], 0.91 to 0.95), 0.96 (95% CI, 0.94 to 0.97), and 310.72 (95% CI, 185.24 to 521.18), respectively. Increasing interferon gamma thresholds did not translate into any substantial change in diagnostic performance; however, eight studies using thresholds of >5 IU/ml showed poorer diagnostic accuracy estimates than other studies with lower thresholds. None of the prespecified subgroup variables significantly influenced relative diagnostic odds ratios in a multivariate meta-regression model. All publications demonstrated a high risk of bias. Unstimulated pleural fluid interferon gamma level provides excellent accuracy for diagnosing TPE and has the potential of becoming a first-line test for this purpose.
| S-EPMC8091832 | biostudies-literature
Project description:ObjectiveWe compared diagnostic accuracy of pleural fluid adenosine deaminase (ADA) and interferon-gamma (IFN-γ) in diagnosing tuberculous pleural effusion (TPE) through systematic review and comparative meta-analysis.MethodsWe queried PubMed and Embase databases to identify studies providing paired data for sensitivity and specificity of both pleural fluid ADA and IFN-γ for diagnosing TPE. We used hierarchical summary receiver operating characteristic (HSROC) plots and HSROC meta-regression to model individual and comparative diagnostic performance of the two tests.ResultsWe retrieved 376 citations and included 45 datasets from 44 publications (4974 patients) in our review. Summary estimates for sensitivity and specificity for ADA were 0.88 (95% CI 0.85-0.91) and 0.91 (95% CI 0.89-0.92), while for IFN-γ they were 0.91 (95% CI 0.89-0.94) and 0.96 (95% CI 0.94-0.97), respectively. HSROC plots showed consistently greater diagnostic accuracy for IFN-γ over ADA across the entire range of observations. HSROC meta-regression using test-type as covariate yielded a relative diagnostic odds ratio of 2.22 (95% CI 1.68-2.94) in favour of IFN-γ, along with better summary sensitivity and specificity figures. No prespecified subgroup variable significantly influenced the summary diagnostic accuracy estimates.ConclusionPleural fluid IFN-γ estimation has better diagnostic accuracy than ADA estimation for diagnosis of TPE.
| S-EPMC8224977 | biostudies-literature
Project description:BackgroundInterferon gamma release assays (IGRAs) are used to diagnose latent tuberculosis infection. Two IGRAs are commercially available: the Quantiferon TB Gold In Tube (QFT-IT) and the T-SPOT.TB. There is debate as to which test to use in HIV+ individuals. Previous publications from high TB burden countries have raised concerns that the sensitivity of the QFT-IT assay, but not the T-SPOT.TB, may be impaired in HIV+ individuals with low CD4+ T-cell counts. We sought to compare the tests in a low TB burden setting.Methodology/principal findingsT-SPOT.TB, QFT-IT, and tuberculin skin tests (TST) were performed in HIV infected individuals. Results were related to patient characteristics. McNemar's test, multivariate regression and correlation analysis were carried out using SPSS (SPSS Inc). 256 HIV infected patients were enrolled in the study. The median CD4+ T-cell count was 338 cells/µL (range 1-1328). 37 (14%) patients had a CD4+ T-cell count of <100 cells/µL. 46/256 (18% ) of QFT-IT results and 28/256 (11%) of T-SPOT.TB results were positive. 6 (2%) of QFT-IT and 18 (7%) of T-SPOT.TB results were indeterminate. An additional 9 (4%) of T-SPOT.TB results were unavailable as tests were not performed due to insufficient cells or clotting of the sample. We found a statistically significant association between lower CD4+ T-cell count and negative QFT-IT results (OR 1.055, p=0.03), and indeterminate/unavailable T-SPOT.TB results (OR 1.079, p=0.02).Conclusions/significanceIn low TB prevalence settings, the QFT-IT yields more positive and fewer indeterminate results than T-SPOT.TB. Negative results on the QFT-IT and indeterminate/unavailable results on the T-SPOT.TB were more common in individuals with low CD4+ T-cell counts.
| S-EPMC3559731 | biostudies-literature
Project description:The Republic of Ireland reports a relatively low prevalence of Johne's disease (JD) compared to international counterparts. Postulated reasons for this include a lower average herd size and a grass-based production system. Ireland also engages in high levels of bovine tuberculosis (bTB) testing. As interferon-gamma (IFN-γ) is believed to play a key role in protecting against JD, it is our hypothesis that administration of purified protein derivative (PPD), as part of the bTB test, is associated with a systemic increase in IFN-γ production, which may potentially limit clinical progression of the disease. We studied 265 cows (202 Friesian and 63 "Non-Friesian," e.g., JerseyX, Norwegian Red) to assess IFN-γ levels and Mycobacterium avium subspecies paratuberculosis (MAP) antibody response before and after the bTB test. As part of the compulsory annual bTB test, avian and bovine PPD were administered at two separate cervical sites. To assess IFN-γ production, blood samples were taken before and 72 h after PPD administration. MAP antibody response was assessed before and 10 days post-PPD administration. A significant increase in MAP antibody response was identified post-bTB compared to pre-bTB response (p < 0.001). Additionally, IFN-γ production significantly increased at the post-bTB time point (p < 0.001) compared to the pre-bTB test readings. This may indicate a beneficial effect of bTB testing in controlling JD.
| S-EPMC5660059 | biostudies-literature
Project description:IntroductionInterferon gamma (IFN-?) release assays, such as QuantiFERON®-TB Gold test (QFT-G) and QuantiFERON®-TB Gold In-Tube test (QFT-GIT) are designed to detect M. tuberculosis (Mtb) infection. Recognition of unusual IFN-? measurements may help indicate inaccurate results.MethodsWe examined QFT-G and QFT-GIT results from subjects who had two or more tests completed. We classified unusual IFN-? measurements as: 1) High Nil Concentration (HNC) when IFN-? concentration in plasma from unstimulated blood exceeded 0.7 IU/mL; 2) Low Mitogen Response (LMR) when Mitogen Response was <0.5 IU/mL; 3) Very Low Mitogen Response (VLMR) when Mitogen Response was ?-0.5 IU/mL; and 4) Very Low Antigen Response (VLAR) when the response to a Mtb antigen was ?-0.35 IU/mL and ?-0.5 times the IFN-? concentration in plasma from unstimulated blood.ResultsAmong 5,309 results from 1,728 subjects, HNC occurred in 234 (4.4%) tests for 162 subjects, LMR in 108 (2.0%) tests for 85 subjects, VLMR in 22 (0.4%) tests for 21 subjects, and VLAR in 41 (0.8%) tests for 39 subjects. QFT-GIT had fewer HNC, VLMR, and VLAR (p?=?0.042, 0.004, and 0.067 respectively); QFT-G had fewer LMR (p?=?0.005). Twenty-four (51.6%) of 47 subjects with positive results and HNC were negative or indeterminate by all other tests. Thirteen (61.9%) of 21 subjects with positive results and LMR were negative or indeterminate by all other tests.ConclusionUnusual IFN-? measurements including HNC, LMR, VLMR, and VLAR were encountered in small numbers, and in most instances were not seen on simultaneously or subsequently performed tests. To avoid erroneous diagnosis of Mtb infection, IGRAs with unusual IFN-? measurements should be repeated with another blood sample and interpreted with caution if they recur.
| S-EPMC3110578 | biostudies-literature
Project description:OBJECTIVE:Evaluate the performance of QuantiFERON ® -TB Gold In-Tube test (QFT-GIT), to improve the diagnosis of active tuberculosis (TB) in Human Immuno-Deficiency Virus (HIV)-infected children. METHOD:Sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV) of QFT-GIT were assessed in 58/63 HIV-infected children who were suspected of having TB. RESULTS:Sensitivity of QFT-GIT was 20.69%, specificity 96.55%, PPV/NPV respectively 85.71% and 54.90%. CONCLUSION:QFT-GIT appears to be of little contribution to the diagnosis of active TB in children living with HIV in a TB-endemic country.
| S-EPMC7647084 | biostudies-literature
Project description:The gamma interferon assay is used to identify Mycobacterium avium subsp. paratuberculosis-infected animals. It has been suggested that regulatory mechanisms could influence the sensitivity of the test when it is performed with cells from cattle and that the neutralization of interleukin-10 (IL-10) in vitro would increase the gamma interferon responses. To investigate the regulatory mechanisms affecting the gamma interferon assay with cells from goats, blood was collected from M. avium subsp. paratuberculosis-infected, M. avium subsp. paratuberculosis-exposed, and noninfected goats. Neutralization of IL-10 by a monoclonal antibody resulted in increased levels of gamma interferon production in M. avium subsp. paratuberculosis purified protein derivative (PPDj)-stimulated samples from both infected and exposed goats. However, the levels of gamma interferon release were also increased in unstimulated cells and in PPDj-stimulated cells from some noninfected animals following neutralization. Depletion of putative regulatory CD25(high) T cells had no clear effect on the number of gamma-interferon-producing cells. The IL-10-producing cells were identified to be mainly CD14(+) major histocompatibility complex class II-positive monocytes in both PPDj-stimulated and control cultures and not regulatory T cells. However, possible regulatory CD4(+) CD25(+) T cells produced IL-10 in response to concanavalin A stimulation. The numbers of CD4(+), CD8(+), and CD8(+) gammadelta T-cell receptor-positive cells producing gamma interferon increased following IL-10 neutralization. These results provide insight into the source and the role of IL-10 in gamma interferon assays with cells from goats and suggest that IL-10 from monocytes can regulate both innate and adaptive gamma interferon production from several cell types. Although IL-10 neutralization increased the sensitivity of the gamma interferon assay, the specificity of the test could be compromised.
| S-EPMC2708398 | biostudies-literature
Project description:Existing diagnostic tests for pleural tuberculosis (TB) have inadequate accuracy and/or turnaround time. Interferon-gamma (IFNg) has been identified in many studies as a biomarker for pleural TB. Our objective was to develop a lateral flow, immunochromatographic test (ICT) based on this biomarker and to evaluate the test in a clinical cohort. Because IFNg is commonly present in non-TB pleural effusions in low amounts, a diagnostic IFNg-threshold was first defined with an enzyme-linked immunosorbent assay (ELISA) for IFNg in samples from 38 patients with a confirmed clinical diagnosis (cut-off of 300 pg/ml; 94% sensitivity and 93% specificity). The ICT was then designed; however, its achievable limit of detection (5000 pg/ml) was over 10-fold higher than that of the ELISA. After several iterations in development, the prototype ICT assay for IFNg had a sensitivity of 69% (95% confidence interval (CI): 50-83) and a specificity of 94% (95% CI: 81-99%) compared to ELISA on frozen samples. Evaluation of the prototype in a prospective clinical cohort (72 patients) on fresh pleural fluid samples, in comparison to a composite reference standard (including histopathological and microbiologic test results), showed that the prototype had 65% sensitivity (95% CI: 44-83) and 89% specificity (95% CI: 74-97). Discordant results were observed in 15% of samples if testing was repeated after one freezing and thawing step. Inter-rater variability was limited (3%; 1 out of 32). In conclusion, despite an iterative development and optimization process, the performance of the IFNg ICT remained lower than what could be expected from the published literature on IFNg as a biomarker in pleural fluid. Further improvements in the limit of detection of an ICT for IFNg, and possibly combination of IFNg with other biomarkers such as adenosine deaminase, are necessary for such a test to be of value in the evaluation of pleural tuberculosis.
| S-EPMC3871622 | biostudies-literature
Project description:BACKGROUND:Peripartum immunologic changes may affect latent tuberculosis infection (LTBI) diagnostic performance among HIV-infected women. METHODS:HIV-infected women were serially tested with tuberculin skin test (TST) and interferon gamma release assay [QuantiFERON TB Gold In-tube (QFT)] in pregnancy and 6 weeks postpartum in Kenya. Prevalence, sensitivity and agreement, and correlates of QFT/TST positivity were assessed. Quantitative QFT mitogen and Mycobacterium tuberculosis antigen (Mtb-Ag) responses were compared by peripartum stage. Incidence of test conversion at 6 weeks postpartum was evaluated in baseline TST-/QFT- women. RESULTS:Among 100 HIV-infected women, median age was 26 years, median CD4 was 555 cells per cubic millimeter, and 88% were on antiretrovirals. More women were QFT+ than TST+ in both pregnancy (35.4% vs. 13.5%, P = 0.001) and postpartum (29.6% vs. 14.8%, P < 0.001). Among 18 consistently QFT+ women, 8 (44%) converted from TST- to TST+, with improved test agreement postpartum (56.9%, ? = 0.20 to 82.4%, ? = 0.60). Three initially QFT-/TST- women had test conversion (TST+ and/or QFT+), suggesting new infection (incidence 13.4/100 person-years). Mean QFT mitogen (4.46 vs. 7.64 IU/mL, P < 0.001) and Mtb-Ag (1.03 vs. 1.54 IU/mL, P = 0.03) responses were lower among all women retested in pregnancy vs. postpartum, and specifically among persistently QFT+ women (Mtb-Ag: 3.46 vs. 4.48 IU/mL, P = 0.007). QFT indeterminate rate was higher in pregnancy (16%) compared with postpartum (0%) because of lower mitogen response. CONCLUSIONS:QFT identified >2-fold more women with LTBI compared with TST in pregnancy and postpartum. Lower QFT Mtb-Ag and mitogen responses in pregnancy compared with postpartum suggest that pregnancy-associated immunologic changes may influence LTBI test performance.
| S-EPMC5388595 | biostudies-literature