Performance Of Interferon-gamma Release Assay Research Articles

Development of lateral flow assays to detect host proteins in cattle for improved diagnosis of bovine tuberculosis.

Bovine tuberculosis (bTB), caused by Mycobacterium bovis (M. bovis) infection in cattle, is an economically devastating chronic disease for livestock worldwide. Efficient disease control measures rely on early and accurate diagnosis using the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), followed by culling of positive animals. Compromised performance of TST and IGRA, due to BCG vaccination or co-infections with non-tuberculous mycobacteria (NTM), urges improved diagnostics. Lateral flow assays (LFAs) utilizing luminescent upconverting reporter particles (UCP) for quantitative measurement of host biomarkers present an accurate but less equipment- and labor-demanding diagnostic test platform. UCP-LFAs have proven applications for human infectious diseases. Here, we report the development of UCP-LFAs for the detection of six bovine proteins (IFN-γ, IL-2, IL-6, CCL4, CXCL9, and CXCL10), which have been described by ELISA as potential biomarkers to discriminate M. bovis infected from naïve and BCG-vaccinated cattle. We show that, in line with the ELISA data, the combined PPDb-induced levels of IFN-γ, IL-2, IL-6, CCL4, and CXCL9 determined by UCP-LFAs can discriminate M. bovis challenged animals from naïve (AUC range: 0.87-1.00) and BCG-vaccinated animals (AUC range: 0.97-1.00) in this cohort. These initial findings can be used to develop a robust and user-friendly multi-biomarker test (MBT) for bTB diagnosis.

Use of Interferon-Gamma Release Assays in Children

While interferon-gamma release assays (IGRAs) are widely used for detecting tuberculosis (TB) infection, tuberculin skin tests (TSTs) remain preferred for children under the age of 2 years. The preference for TST stems from concern over IGRA sensitivity in young children. However, TSTs are susceptible to false-positive results following Bacille Calmette-Guérin (BCG) vaccination, which is common in infancy, and exposure to nontuberculous mycobacteria. We reviewed available data for IGRA performance in children under age 2 years. Across four cohorts of high-risk children under age 2 (mostly case contacts or those born in tuberculosis endemic regions), 0 of 575 untreated children with negative IGRA test results progressed to tuberculosis disease-including 0 of 70 who were TST positive but IGRA negative. While neither TSTs nor IGRAs are perfectly sensitive for the diagnosis of tuberculosis infection, IGRAs are an acceptable alternative to TST in children <2 years of age.

Evaluation of the IP-10 mRNA release assay for diagnosis of TB in HIV-infected individuals.

HIV-infected individuals are susceptible to Mycobacterium tuberculosis (M.tb) infection and are at high risk of developing active tuberculosis (TB). Interferon-gamma release assays (IGRAs) are auxiliary tools in the diagnosis of TB. However, the performance of IGRAs in HIV-infected individuals is suboptimal, which limits clinical application. Interferon-inducible protein 10 (IP-10) is an alternative biomarker for identifying M.tb infection due to its high expression after stimulation with M.tb antigens. However, whether IP-10 mRNA constitutes a target for the diagnosis of TB in HIV-infected individuals is unknown. Thus, we prospectively enrolled HIV-infected patients with suspected active TB from five hospitals between May 2021 and May 2022, and performed the IGRA test (QFT-GIT) alongside the IP-10 mRNA release assay on peripheral blood. Of the 216 participants, 152 TB patients and 48 non-TB patients with a conclusive diagnosis were included in the final analysis. The number of indeterminate results of IP-10 mRNA release assay (13/200, 6.5%) was significantly lower than that of the QFT-GIT test (42/200, 21.0%) (P = 0.000026). IP-10 mRNA release assay had a sensitivity of 65.3% (95%CI 55.9% - 73.8%) and a specificity of 74.2% (95%CI 55.4% - 88.1%), respectively; while the QFT-GIT test had a sensitivity of 43.2% (95%CI 34.1% - 52.7%) and a specificity of 87.1% (95%CI 70.2% - 96.4%), respectively. The sensitivity of the IP-10 mRNA release assay was significantly higher than that of QFT-GIT test (P = 0.00062), while no significant difference was detected between the specificities of these two tests (P = 0.198). The IP-10 mRNA release assay showed a lower dependence on CD4+ T cells than that of QFT-GIT test. This was evidenced by the fact that the QFT-GIT test had a higher number of indeterminate results and a lower sensitivity when the CD4+ T cells counts were decreased (P < 0.05), while no significant difference in the number of indeterminate results and sensitivity were observed for the IP-10 mRNA release assay among HIV-infected individuals with varied CD4+T cells counts (P > 0.05). Therefore, our study suggested that M.tb specific IP-10 mRNA is a better biomarker for diagnosis of TB in HIV-infected individuals.

Withdrawal Notice: The Performance of Interferon-gamma Release Assays and Tuberculin Skin Tests in the Diagnosis of Latent Tuberculosis Infection among Immune-mediated Inflammatory Diseases: A Meta-analysis Study

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Interferon-gamma release assay versus tuberculin test in diagnosis of latent tuberculosis infection among healthcare workers, Sana'a city Yemen

Background: Latent tuberculosis infection (LTBI) is the presence of Mycobacterium tuberculosis in the body without evidence of tuberculosis (TB) disease. Healthcare workers (HCWs) are at occupational risk of contracting &amp; transmitting TB. Therefore, identifying of persons with LTBI is an essential TB prevention &amp; control strategy. The aim of this study was to evaluate the performance of interferon-gamma release assay (IGRA) in diagnosis of LTBI among HCWs, in comparison to tuberculin skin test (TST); as well as identifying risk factors fortest positivity.Methods: A cross-sectional study was conducted in 2015 on 90 HCWs tested with TST and IGRA. All Participants were subjected to a questionnaire to assess their risk factors. Differences between categorical variables were analyzed by X2. Kappa coefficient used to detect the agreement between TST and IGRA. Also, accuracy of both tests was calculated. Results: Of the 90 HCWs; 54.4% were females and 45.6% were males with an age ranged between 20-60 years. The participants were classified as 38.9% nurses, 34.4% physicians, 16.7% technicians and 10% were administrators. The highest prevalence of LTBI was found in female 14.3% &amp; 28.6% by TST and IGRA, respectively. In general, the positivity by both tests increased with increasing age. 27.8% of HCWs were Bacille Calmette-Guérin (BCG) vaccinated and most of the positivity occurs among vaccinated HCWs. The crude prevalence for LTBI was 12.2% by TST and 20% by IGRA; overall agreement between TST and IGRA results was poor (k= 0.39).Conclusion: Most HCWs with LTBI were females, nurses, older age, BCG vaccinated and in a group of profession of close contact with TB patients'. The higher positivity was found by IGRA than by TST with poor agreement between them.Superior specificity was observed with IGRA; whereas TST had a higher sensitivity.

Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis

Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. We obtained data from 13 studies out of 40 that were considered eligible (N=32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15mm if BCG vaccinated and 5mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST5/15 mm) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST5/15 mm). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST5/15 mm) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST15 mm and p=0.68 for QFT-GIT). IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results. YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC_UU_00004/07].

Host, technical, and environmental factors affecting QuantiFERON-TB Gold In-Tube performance in children below 5 years of age

Interferon-gamma release assays performance can be impaired by host-related, technical and environmental factors, but data in young children are limited. We performed a cross-sectional study of children < 5 years-of-age at risk of tuberculosis (TB), using QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. The impact of the following was evaluated: (i) host-related [age; hematological parameters; erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and tobacco smoke exposure (TSE) based on serum cotinine concentrations], (ii) technical (pre-analytical delay) and (iii) environmental factors (annual season; monthly temperatures). Of 204 children, 35 (17.2%) were diagnosed with latent TB infection or TB disease. QFT-GIT results were indeterminate in 14 (6.9%) patients. In multivariate analysis, younger age and higher ESR were associated with lower positive control responses (beta: 0.247, p = 0.002 and − 0.204, p = 0.007, respectively), and increasing age was associated with lower rates of indeterminate QFT-GIT results [OR (95% CI) 0.948 (0.903–0.996) per month, p = 0.035]. In children with positive QFT-GIT results, average monthly temperatures correlated with antigen responses (r = 0.453, p = 0.020); also, antigen responses were lower in winter than in other seasons (p = 0.027). Serum cotinine concentrations determined in a subgroup of patients (n = 41) indicated TSE in 36 (88%), positive control responses being lower in children with TSE (p = 0.034). In children < 5 years-of-age, young age, elevated ESR, temperature, annual season and TSE can affect the performance of QFT-GIT assays.

Diagnostic Value of Interferon-Gamma Release Assays for Tuberculosis in the Immunocompromised Population.

Interferon-gamma release assays (IGRAs) are widely used in the diagnosis of Mycobacterium tuberculosis (M. tuberculosis) infection by detecting interferon-γ released by previously sensitized T-cells in-vitro. Currently, there are two assays based on either enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunospot (ELISPOT) technology, with several generations of products available. The diagnostic value of IGRAs in the immunocompromised population is significantly different from that in the immunocompetent population because their results are strongly affected by the host immune function. Both physiological and pathological factors can lead to an immunocompromised situation. We summarized the diagnostic value and clinical recommendations of IGRAs for different immunocompromised populations, including peoplewith physiological factors (pregnant and puerperal women, children, and older people), as well as people with pathological factors (solid organ transplantation recipients, combination with human immunodeficiency virus infection, diabetes mellitus, end-stage renal disease, end-stage liver disease, and chronic immune-mediated inflammatory diseases). Though the performance of IGRAs is not perfect and often requires a combination with other diagnostic strategies, it still has some value in the immunocompromised population. Hopefully, the newly developed IGRAs could better target this population.

Effect of the topical administration of corticosteroids and tuberculin pre-sensitisation on the diagnosis of tuberculosis in goats

BackgroundCaprine tuberculosis (TB) is a zoonosis caused by members of the Mycobacterium tuberculosis complex (MTBC). Caprine TB control and eradication programmes have traditionally been based on intradermal tuberculin tests and slaughterhouse surveillance. However, this strategy has limitations in terms of sensitivity and specificity. Different factors may affect the performance of the TB diagnostic tests used in goats and, subsequently, the detection of TB-infected animals. In the present study, the effect of two of the factors that may affect the performance of the techniques used to diagnose TB in goats, the topical administration of corticosteroids and a recent pre-sensitisation with tuberculin, was analysed.MethodsThe animals (n = 151) were distributed into three groups: (1) a group topically treated with corticosteroids 48 h after intradermal tuberculin tests (n = 53); (2) a group pre-sensitised with bovine and avian purified protein derivatives (PPDs) 3 days before the intradermal tuberculin test used for TB diagnosis (n = 48); and (3) a control group (n = 50). All the animals were tested using single and comparative intradermal tuberculin (SIT and CIT, respectively) tests, an interferon-gamma release assay (IGRA) and a P22 ELISA.ResultsThe number of SIT test reactors was significantly lower in the group treated with corticosteroids when compared to the pre-sensitised (p < 0.001) and control (p = 0.036) groups. In contrast, pre-sensitisation with bovine and avian PPDs did not cause a significant reduction in the number of SIT and CIT test reactors compared with the control group. In fact, a higher number of reactors was observed after the prior tuberculin injection in the pre-sensitised group (p > 0.05). No significant effect was observed on IGRA and P22 ELISA due to corticosteroids administration. Nevertheless, a previous PPD injection affected the IGRA performance in some groups.ConclusionsThe application of topical corticosteroid 24 h before reading the SIT and CIT tests can reduce the increase in skin fold thickness and subsequently significantly decrease the number of positive reactors. Corticosteroids used can be detected in hair samples. A previous pre-sensitisation with bovine and avian PPDs does not lead to a significant reduction in the number of intradermal tests reactors. These results are valuable in order to improve diagnosis of caprine TB and detect fraudulent activities in the context of eradication programs.

Role of Interferon-Gamma Release Assay for the Diagnosis and Clinical Follow up in Ocular Tuberculosis

ABSTRACT Purpose To assess the performance of interferon-gamma release assay (IGRA) associated with tuberculosis skin test (TST) for ocular tuberculosis (OTB) diagnosis and therapeutic decision making. Method One hundred and ninety-one patients with ocular inflammation were prospectively followed-up. Patients with clinical signs highly suspected of OTB, TST≥10 mm, and/or IGRA≥0.35 IU/mL received antitubercular therapy (ATT). Sensitivity (Se), specificity (Sp), and area under the curve (AUC) were assessed. Results Seventy-two (37.7%) patients received ATT for presumed OTB. Combining TST and IGRA had Se=89.6%, Sp=99.2%, and AUC (0.98) significantly higher compared to TST (0.85, Z=6.3, p<.001) or IGRA (0.95, Z=2.5, p=.01). Prior history of corticosteroids or immunosuppressant with concomitantly oral prednisone and baseline IGRA> 2.0 IU/mL was associated significantly with more recurrences in ATT patients (p=.01) . Conclusion Considering TST and IGRA together was more effective in assessing OTB diagnosis. The real value of the IGRA test to predict recurrences needs further studies.

Interferon-Gamma Release Assays Differentiate between Mycobacterium avium Complex and Tuberculous Lymphadenitis in Children

To assess the performance of interferon-gamma release assays (IGRAs) in the differential diagnosis between Mycobacterium avium complex (MAC) and tuberculosis (TB) in children affected with subacute/chronic submandibular/cervical lymphadenitis. Multicenter observational study comparing children with microbiologically confirmed MAC lymphadenitis from the European NontuberculouS MycoBacterial Lymphadenitis in childrEn study with children with TB lymphadenitis from the Spanish Network for the Study of Pediatric TB database. Overall, 78 patients with MAC and 34 with TB lymphadenitis were included. Among MAC cases, 44 out of 74 (59.5%) had positive tuberculin skin test (TST) results at the 5-mm cut-off, compared with 32 out of 33 (97%) TB cases (P<.001); at the 10-mm cut-off TST results were positive in 23 out of 74 (31.1%) vs 26 out of 31 (83.9%), respectively (P<.001). IGRA results were positive in only 1 out of 32 (3.1%) patients with MAC who had undergone IGRA testing, compared with 21 out of 23 (91.3%) TB cases (P<.001). Agreement between TST and IGRA results was poor in MAC (23.3%; κ=0.017), but good in TB cases (95.6%; κ=0.646). IGRAs had a specificity of 96.9% (95% CI 84.3%-99.8%), positive predictive value of 95.4% (95% CI 78.2%-99.8%), and negative predictive value of 93.9% (95% CI 80.4%-98.9%) for TB lymphadenitis. In contrast to TST, IGRAs have high specificity, negative predictive value, and positive predictive value for TB lymphadenitis in children with subacute/chronic lymphadenopathy, and consequently can help to discriminate between TB and MAC disease. Therefore, IGRAs are useful tools in the diagnostic work-up of children with lymphadenopathy, particularly when culture and polymerase chain reaction results are negative.

Performance of Interferon-Gamma Release Assays in the Diagnosis of Nontuberculous Mycobacterial Diseases-A Retrospective Survey From 2011 to 2019.

There is an urgent need for precise diagnosis to distinguish nontuberculous mycobacterial (NTM) diseases from pulmonary tuberculosis (PTB) and other respiratory diseases. The aim of this study is to evaluate the diagnostic performance of Interferon-gamma (IFN-γ) release assays (IGRAs), including antigen-specific peripheral blood-based quantitative T cell assay (T-SPOT.TB) and QuantiFERON-TB-Gold-Test (QFT-G), in differentiating NTM infections (N = 1,407) from culture-confirmed PTB (N = 1,828) and other respiratory diseases (N = 2,652). At specie level, 2.56%, 10.73%, and 16.49% of NTM-infected patients were infected by Mycobacterium kansasii, M. abscessus, and with M. avmm-intracellulare complex (MAC), respectively. Valid analyses of T-SPOT.TB (ESAT-6, CFP-10) and QFT-G were available for 37.03% and 85.79% in NTM-infected patients, including zero and 100% (36/36) of M. kansasii infection, 21.85% (33/151) and 92.05% (139/151) of M. abscessus infection, and 17.67% (41/232) and 91.24% (211/232) of MAC infection. Based on means comparisons and further ROC analysis, T-SPOT.TB and QFT-G performed moderate accuracy when discriminating NTM from PTB at modified cut-off values (ESAT-6 < 4 SFCs, CFP-10 < 3 SFCs, and QFT-G < 0.667 IU/ml), with corresponding AUC values of 0.7560, 0.7699, and 0.856. At species level of NTM, QFT-G effectively distinguished between MAC (AUC=0.8778), M. kansasii (AUC=0.8834) or M. abscessus (AUC=0.8783) than T-SPOT.TB. No significant differences in discriminatory power of these three IGRA tools were observed when differentiating NTM and Controls. Our results demonstrated that T-SPOT.TB and QFT-G were both efficient methods for differentiating NTM disease from PTB, and QFT-G possessed sufficient discriminatory power to distinguish infections by different NTM species.

Impact of comorbidities on the performance of interferon-gamma release assay in an elderly Greek population without overt immunodeficiency

Background The prevalence of latent tuberculosis infection (LTBI) increases with age. Interferon-gamma release assay (IGRA) is a T-cell based assay widely used for the detection of LTBI.Objectives To identify the prevalence of LTBI among an elderly Greek population using IGRA and to evaluate comorbidities associated with LTBI.Methods Individuals aged at least 65 years who were non-immunocompromised and had no history of active tuberculosis infection (TBI) underwent IGRA to identify LTBI. Participant characteristics were compared between the LTBI and non-LTBI groups. Interferon-gamma (INFγ) levels were analysed in each group.Results A total of 130 (38.7%) participants with LTBI and 206 (61.3%) participants without LTBI were included. Multivariate logistic regression analysis identified the following features that were independently associated with a positive IGRA result: female sex (odds ratio [OR]: 0.45; 95% confidence interval [CI]: 0.28-0.72; P=0.001), chronic heart failure (OR: 0.41; 95% CI: 0.22-0.77; P=0.005), history of major surgery (OR: 0.55; 95% CI: 0.33-0.92; P=0.022) and Charlson Comorbidity Index >3 (OR: 3.06; 95% CI: 1.46-6.40; P=0.003). Production of stimulated INFγ was significantly lower in the non-LTBI group.Conclusions Female sex, history of chronic heart failure and history of any surgical intervention were independently associated with a negative IGRA result, and CCI >3 was associated with a positive IGRA result. These results indicate careful interpretation of IGRA is required among elderly individuals with these characteristics.

Concordance between tuberculin skin test and interferon-gamma release assay for latent tuberculosis screening in inflammatory bowel disease.

Background/AimsLatent tuberculosis screening is mandatory prior to initiating anti-tumor necrosis factor (anti-TNF) medications. Guidelines recommend interferon-gamma release assays (IGRA) as first line screening method for the general population. Studies provided conflicting evidence on IGRA and tuberculin skin test (TST) performance in inflammatory bowel disease (IBD) patients. We assessed test concordance and the effects of immunosuppression on their performance in IBD patients.MethodsWe searched MEDLINE, Embase and Cochrane databases (2011–2018) for studies testing TST and IGRA in IBD. Primary outcome was TST and IGRA concordance. Secondary outcomes were effects of immunosuppressive therapy on performance. Immunosuppression defined as either steroids, thiopurine, methotrexate or cyclosporine use. We used the pooled random effects model to adjust for heterogeneity analyzed using (I2–Q statistics). We compared the fixed model to exclude smaller study effects.ResultsSixteen studies (2,488 patients) were included. Pooled TST and IGRA concordance was 85% (95% confidence interval [CI], 81%–88%; P=0.01). Effects of immunosuppression were reported in 8 studies (814 patients). The odds ratio of testing positive by IGRA decreased to 0.57 if immunosuppressed (95% CI, 0.31–1.03; P=0.06). The odds ratio of testing positive by TST if immunosuppressed was 1.14 (95% CI, 0.61–2.12; P=0.69). The fixed model yielded similar results, however the negative effect of immunosuppression on IGRA reached statistical significance (P=0.01).ConclusionsWhile concordance was 85% between TST and IGRA, the performance of IGRA seems to be negatively affected by immunosuppression. Given the importance of detecting latent tuberculosis prior to anti-TNF initiation, further randomized controlled trials comparing the performance of TST and IGRA in IBD patients are needed.

Can Interferon-γ Release Assays Be Useful for Monitoring the Response to Anti-tuberculosis Treatment?: A Systematic Review and Meta-analysis.

The number of studies which evaluated interferon-gamma release assays (IGRAs) results after anti-tuberculosis (TB) treatment has been rapidly increasing. The aim of this study was to investigate the potential use of IGRAs (QFT-GIT, T-SPOT.TB, QFT-Plus) in assessing the response to anti-TB treatment. We searched all studies in English language published from 1 October 2011 to 18 November 2018 in PubMed, Web of Science, and Scopus. Our search included the term "tuberculosis treatment AND interferon-γ release assay". We included studies evaluating the performance of commercial IGRAs (including QFT-GIT, T-SPOT.TB and QFT-Plus) before and after the anti-TB treatment. We performed subgroup analysis based on the age (children, adults), type of TB (active, latent, active and latent, and contacts exposed to MDR defined as MDR LTBI), type of IGRAs (QFT-GIT and T-SPOT.TB), and follow-up interval (2, 3, 4, 6, 9months). Of the 18 included studies, 12 used QFT-GIT for assessment of IGRA performance after therapy, 1 used T-SPOT.TB, and 3 used both QFT-GIT and T-SPOT.TB. Since then, only two studies have assessed the QFT-Plus performance during therapy. According to the results of the meta-analysis, the pooled rate of positive IGRAs (QFT-GIT and T-SPOT.TB) following anti-TB therapy was estimated at 76% [95% CI 70-81%] and no difference was found compared to the pooled positive rate of IGRAs before initiation of therapy which was 76% [95% CI 60-89%]. The subgroup analysis showed that the pooled rate of positive IGRAs (QFT-GIT and T-SPOT.TB) after anti-TB therapy was significantly higher in monitoring active TB subjects [80% (95% CI 74-88%)] than LTBI [71% (95% CI 70-81%)]. Available data are now sufficient to suggest that monitoring changes in the IGRAs (QFT-GIT and T-SPOT.TB) response during anti-TB treatment may have limited use in evaluating the effectiveness of treatment, while the monitoring changes in QFT-Plus during anti-tubercular treatment are recommended to determine treatment efficacy or for treatment monitoring. Further research is needed to establish the efficacy of this new assay as marker on a larger scale for treatment monitoring.

In reply to ‘Interferon-gamma release assays have suboptimal sensitivity in both latent and active tuberculosis'

[Extract] We thank Goetzinger et al. for their interest and comments about our work.1 They raise a number of valid points about the suboptimal performance of interferon-gamma release assays (IGRAs) in the diagnosis of tuberculous infection in pediatric populations. The tuberculin skin test (TST) and IGRA tests have known limitations for the diagnosis of latent tuberculous infection (LTBI).2 We propose, as suggested by Goetzinger et al., that these tests should be interpreted in the full clinical context.

High rates of indeterminate interferon-gamma release assays for the diagnosis of latent tuberculosis infection in liver transplantation candidates.

Screening for latent tuberculosis infection (LTBI) is recommended prior to solid organ transplantation. Interferon-gamma release assays (IGRAs) are the most widely used test for LTBI screening; however, assessment of IGRA performance in patients with end-stage liver disease is limited. The purpose of this study was to evaluate the prevalence and predictors of indeterminate (INDT) IGRA results in liver transplantation candidates. Between March 2011 and May 2018, we retrospectively analyzed 155 patients undergoing liver transplantation assessment, who underwent IGRA testing (Quantiferon-TB Gold, QFT-G) to exclude LTBI. Characteristics of patients, including age, gender, etiology of liver disease, MELD score, and absolute lymphocyte counts, were compared by QFT-G result (determinate vs INDT). Of the 155 patients screened, the rate of positive, negative, and INDT results were 5.2%, 69.8%, and 25%, respectively. The only variable independently associated with an indeterminate test on multivariate analysis was MELD score (odds ratio=1.07, 95% CI=1.01-1.14 per unit increase; P=0.014). In 95% of INDT tests, both TB antigen tube and the positive control tube were negative and repeat testing gave the same indeterminate result, suggestive of anergy rather than laboratory error. Our study suggests a high rate of INDT IGRA results during screening of liver transplant candidates for LTBI, associated with severity of liver disease and anergy. Because of the high rate of INDT QFT-G testing in this setting, individualized risk assessment is required including a thorough assessment of clinical risk factors and knowledge of local TB prevalence.

Recent Innovations in Diagnosis and Treatment of Pediatric Tuberculosis.

Tuberculosis is leading cause of global morbidity and mortality and a significant proportion of the burden of disease occurs in children. In the past 5years, a number of innovations have improved the diagnosis and treatment for children with both latent tuberculosis infection and active disease. This review discusses three key areas of innovation. First, we assess utilization and performance of interferon-gamma release assays (IGRAs) in different clinical and epidemiologic scenarios. Recent literature has demonstrated good performance of IGRAs for diagnosis of latent tuberculosis infection, particularly in low-incidence settings such as TB control programs in North America. For high-incidence populations, or when testing is done for possible active TB disease, IGRA performance has some important limitations, but IGRA sensitivity when measured against culture proven disease may be better than earlier studies suggested. The second area of innovation is in increased uptake of nucleic acid amplification (NAA) tests and broader application in non-sputum samples for both pediatric pulmonary and extrapulmonary tuberculosis. Finally, recent studies have provided solid evidence in support of shorter treatment courses for pediatric latent tuberculosis infection, such as 12weeks of weekly isoniazid and rifapentine or 4months daily rifampin, that improve compliance and may reduce resources required for TB control. Many recent innovations in pediatric tuberculosis relate to an improved understanding of how to optimally use existing tests and treatments. Until diagnostic tests and interventions such as vaccination are developed that can dramatically alter the paradigm of pediatric TB management and control, it is important for stakeholders to have a nuanced understanding of tools currently available.

Validation and Clinical Application of Interferon-Gamma Release Assay for Diagnosis of Latent Tuberculosis Infection in Children.

Background:India has the highest tuberculosis (TB) burden, accounting for one-fifth of the global incidence and two-third of the cases in Southeast Asia with an estimated 1.9 million new cases every year. Identifying and treating latent TB infection (LTBI) can reduce the risk of development of active disease by up to 90%, thereby decreasing a major burden to the prevalence of the disease, and thus reducing potential sources in future.Aim:Early diagnosis of LTBI by tuberculin skin test (TST) and a newer interferon-gamma release assay (IGRA).Materials and Methods:Seventy-seven clinically asymptomatic household contacts (≤18 years) of confirmed pulmonary TB patients were enrolled to compare the performance of TST and IGRA to diagnose LTBI. At baseline, all participants underwent testing for IGRA and TST.Results:TST showed positivity of 22%, while IGRA demonstrated positivity of 40% in the diagnosis of latent TB. Kappa value at 95% confidence interval was 0.4753, indicates a moderate agreement between the two tests. This indicates that IGRA is a better predictor of latent TB. Maximum positive percentage was in the age group of 16–18 years in both the tests followed by 1–5 years.Aim:Early diagnosis of LTBI by tuberculin skin test (TST) and a newer interferon-gamma release assay (IGRA).

Interferon-Gamma Release Assay-Based Screening for Pediatric Latent Tuberculosis Infection in an Urban Primary Care Network

To assess outcomes from a QuantiFERON-tuberculosis (TB) Gold (QFT)-based screening for pediatric latent TB infection (LTBI) in the Denver Health Community Health System (CHS), an urban primary-care network in the US. We retrospectively analyzed all QFTs (n = 6685) performed on children aged 2-18 years between January 5, 2011, and August 18, 2014. Risk factors for positive testing in the CHS population were identified by logistic regression, and further assessed using a case-control comparison. Results from CHS were compared with higher-TB-risk populations (refugee and TB clinics) in our health system. Positive QFT occurred in 79 of 3745 (2.1%) CHS patients. Positive rates increased with age (0.3% in age 2-5 years to 4.9% in age 13-18 years). Indeterminate results were uncommon (0.8%) including in children <5 (1.3%). Risk factors for positive tests in the CHS population included non-Medicaid insured/uninsured and non-English/Spanish preferred language. In the case-control analysis, birth/travel to/residence in a TB-endemic country was the only identified risk factor for positive testing (OR 5.2 [95% CI 1.04-25.5]). Rates of positive testing were lower in the CHS population than the refugee/TB clinic populations, including among children age 2-5. QFT-based LTBI screening was successfully introduced in our pediatric primary-care health system, and supported our programmatic goals of identifying LTBI cases while limiting unnecessary LTBI treatment courses. Increasing positive rates with age, and higher rates in the refugee/TB populations compared with CHS, add indirect evidence of adequate test sensitivity, even among young children, for whom data on interferon-gamma release assay performance are limited.