Screening for latent tuberculosis in migrants-status quo and future challenges.

OBJECTIVES: To review the evidence that migrants from tuberculosis (TB) high-incidence countries migrating to TB low-incidence countries significantly contribute to active TB cases in the counties of destination, primarily through reactivation of latent TB. METHODS: This is a narrative review. The different screening programs in the countries of destination are reviewed either based on screening and preventive treatment of latent TB pre or more commonly - post arrival. RESULTS: Screening can be performed using interferon-gamma release assays (IGRA) or tuberculin skin tests (TST). Preventive treatment of latent TB is using either monotherapy with isoniazid, or in combination with rifampicin or rifapentine. We discuss the ethical issues of preventive treatment in asymptomatic individuals and how these are addressed in different screening programs. CONCLUSION: Screening migrants from TB high endemic countries to TB low endemic countries is beneficial. There is a lack of standardization and agreement on screening protocols, follow up and treatment.

Incidence, risk factors for active tuberculosis infection and changes of IGRA in patients with Takayasu arteritis: a prospective cohort study.

There is limited evidence to support the association between tuberculosis (TB) and the occurrence of Takayasu arteritis (TAK). To investigate the incidence of active TB (ATB) in TAK and explore the impact of anti-rheumatic therapy on the occurrence of ATB or reactivation of Latent TB infection (LTBI) and their effect on interferon-γ release assay (IGRA) results, we conducted a prospective study based on the Chinese Registry for Systemic Vasculitis cohort. The standard incidence ratio (SIR) was calculated and stratified by age. Kaplan-Meier analysis was used to determine the effect of variables on ATB or LTBI reactivation in patients with TAK. Data from 825 patients with TAK in the registry were analysed. During a median follow-up of 5 years, 5 patients developed ATB with a crude incidence of 154 (95%CI:57-381) person-years/100,000. The SIR was 5.59 (95%CI:1.81-13.04). Glucocorticoids and conventional disease-modifying anti-rheumatic drugs (cDMARDs) did not increase the risk of ATB or LTBI reactivation (P > 0.05). However, the use of tumour necrosis factor inhibitor (TNFi) increased the risk of ATB in patients with LTBI (P < 0.001). Furthermore, the value of the IGRA assay decreased after treatment (P < 0.05). In conclusion, the incidence of TB infection is markedly increased in patients with TAK and patients with TAK are at high risk of developing ATB. Treatment with glucocorticoids and cDMARDs does not significantly increase the risk for ATB in patients with TAK. Moreover, IGRA may have limited effectiveness in monitoring ATB infection or LTBI reactivation in patients with TAK.

Interferon-Gamma-Release assay and absolute CD8 lymphocyte count for acquired immunosuppression monitoring in critically ill patients.

Guided biomarker-personalized immunotherapy is advancing rapidly as a means to rejuvenate immune function in injured patients who are the most immunosuppressed. A recent study introduced a fully automated interferon-γ release assay (IGRA) for monitoring the functionality of T lymphocytes in patients with septic shock. While a significant decrease in IFN-γ release capacity was observed, a significant correlation with CD8 lymphocyte absolute count was also reported, raising the question of whether ex-vivo IFN-γ production would be only a surrogate marker for lymphocyte count or if these two parameters conveyed distinct and complementary information. In a large cohort of more than 353 critically ill patients following various injuries (sepsis, trauma, major surgery), the primary objective of the present study was to simultaneously evaluate the association between ex vivo IFN-γ release and CD8 cell count with regard to adverse outcome. Our findings provide a clear-cut result, as they distinctly demonstrate that IGRA offers higher-quality information than CD8 count in terms of an independent association with the occurrence of an adverse outcome. These results strengthen the case for incorporating IGRA into the array of biomarkers of interest for defining endotypes in sepsis. This holds especially true given that fully automated tests are now readily available and could be used in routine clinical practice.

Tuberculosis and childhood cancer - A review of literature.

Tuberculosis and malignancy are major public health problems in developing countries like India and causes significant morbidity and mortality. Mycobacterium tuberculosis is an aerobic acid-fast bacilli which is an important pathogen especially complicating clinical status of paediatric oncology patients and treatment of infection with this bacilli is challenging in this subpopulation of patients because of ongoing immunosuppression and relative lack of published guidelines. Atypical presentations of tuberculosis in children also complicate the diagnosis and management. All the more, in tuberculosis endemic area lung cancer may be mistakenly diagnosed as tuberculosis or vice versa and this wrong diagnosis increases the burden on country's health status. It is noted that tuberculosis prevalence is high in children with haematological malignancy and head and neck tumours compared to other solid organ tumours. Moreover, it is found that morbidity and mortality from tuberculosis is more in children from WHO listed high TB burden countries who undergo hematopoietic stem cell and solid organ transplantation. Use of immune checkpoint inhibitors as novel therapy in treatment of childhood malignancies has led to modification of the body's immunological response and has resulted in increased latent tuberculosis infection reactivation as one immune-related infectious consequence. Latent TB infection screening is important concept in management of paediatric oncology patients. Currently, the tests employed as screening diagnostics for LTBI are interferon-gamma release assay (IGRA) blood test and the tuberculin skin test (TST). Various regimens have been suggested for the treatment of LTBI. But, after a positive IGRA or TST and prior to latent TB treatment, active tuberculosis should be ruled out by detailed history taking, examination and appropriate investigations so as to minimize the risk of drug resistance with anti-tuberculosis monotherapy used in LTBI treatment. To add on to literature, Non tuberculous mycobacteria are universally present environmental organisms. However, in immunocompromised children especially in subpopulation of malignancy, NTM is known to cause infections which needs protocol based management. Also importance has to given to implementation of adequate preventive and corrective measures to prevent such opportunistic infection in paediatric oncology subpopulation. In this review, we provide an overview of tuberculosis in paediatric oncology patients and summarize the expansive body of literature on the tuberculosis mimicking carcinoma, tuberculosis burden in transplantation patients and those receiving immune check point inhibitors, latent TB infection screening and management, and NTM infection in children with malignancy.

A five-year analysis of latent tuberculosis infection in Queensland, 2016-2020.

Background Australia is aiming to reach tuberculosis pre-elimination targets by 2035. As a low-incidence setting, control efforts will increasingly rely on the management of latent tuberculosis infection (LTBI). We undertook this descriptive analysis to assess the recent trends of LTBI testing in Queensland. Methods Our objective was to describe the features of LTBI testing in Queensland, and to estimate the range of possible annual notifications were it to be made a notifiable condition. We collated both state-wide and region-specific data on tuberculin skin testing (TST) and interferon gamma release assays (IGRA) conducted in Queensland during the five-year period 1 January 2016 - 31 December 2020. We used reports on Medicare-funded TST and IGRA testing in Queensland, as well as tuberculosis notification data, to understand the representativeness of our data and to derive state-wide estimates. Results We analysed 3,899 public TST, 5,463 private TST, 37,802 public pathology IGRA, and 31,656 private pathology IGRA results. The median age of people tested was 31 years; 57% of those tested were female. From our data sources, an annual average of 1,067 positive IGRA and 354 positive TST results occurred in Queensland. Building on this minimum value, we estimate possible latent tuberculosis notifications in Queensland could range from 2,901 to 6,995 per annum. Private laboratory TSTs are estimated to contribute the lowest number of potential notifications (range: 170-340), followed by private laboratory IGRA testing (range: 354-922), public laboratory IGRA testing (range: 706-1,138), and public setting TSTs (range: 1,671-4,595). Conclusion If LTBI were to be made notifiable, these estimates would place it among the ten most notified conditions in Queensland. This has implications for potential surveillance methods and goals, and their associated system and resource requirements.

Indeterminate results of interferon gamma release assays in the screening of latent tuberculosis infection: a systematic review and meta-analysis.

Objectives: We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI). Methods: On 15 November 2022, we searched the PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), and Cochrane Library databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators independently extracted the study data and assessed their quality using a modified quality assessment of diagnostic accuracy studies (i.e., QUADAS-2) tool. A random-effects model was used to calculate pooled results. Results: We included 403 studies involving 486,886 individuals and found that the pooled indeterminate rate was 3.9% (95% CI 3.5%-4.2%). The pooled indeterminate rate for QuantiFERON®-TB (QFT) was similar to that for T-SPOT®.TB (T-SPOT) [odds ratio (OR) = 0.88, 95% CI 0.59-1.32]; however, the indeterminate rate for a new generation of QFT (QFT-plus) was lower than that of T-SPOT (OR = 0.24, 95% CI 0.16-0.35). The indeterminate rate in the immunocompromised population was significantly higher than that in healthy controls (OR = 3.51, 95% CI 2.11-5.82), and it increased with the reduction of CD4+ cell count in HIV-positive patients. Children's pooled indeterminate rates (OR = 2.56, 95% CI 1.79-3.57) were significantly higher than those of adults, and the rates increased as the children's age decreased. Conclusion: On average, 1 in 26 tests yields indeterminate IGRA results in LTBI screening. The use of advanced versions of the QuantiFERON-TB assay (QFT-plus), may potentially reduce the occurrence of an indeterminate result. Our study emphasizes the high risk of immunosuppression and young age in relation to indeterminate IGRA, which should receive more attention in the management of LTBI. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020211363, CRD42020211363.

Active and latent TB screening in recently arrived persons from Afghanistan: feasibility and lessons learned.

We describe an active and latent tuberculosis (TB) screening programme undertaken in Manchester, UK in response to the arrival of a cohort of refugees from Afghanistan. In total, 217 adults and 347 children were offered screening, which involved a symptom questionnaire, Mantoux test or interferon gamma release assay, blood-borne virus screening and a chest X-ray in participants over the age of 11. We found a latent TB infection (LTBI) rate of 15% in adults and 1.5% in children, which is lower than global LTBI estimates. One case of active TB was detected. Screening was undertaken in the hotels where participants were temporarily housed, leading to high participant engagement levels. Attendance rates were almost doubled compared with a previous hospital-based screening programme. Hotel-based screening for TB presented several challenges, including transfer of information and results to secondary care. Understanding these challenges and learning from the programme has helped us refine our screening protocol to optimise migrant TB screening in Manchester in the future.

Tuberculin skin test and interferon-γ release assays: Can they agree?

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.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. CONCLUSION: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. WHAT IS KNOWN: • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. WHAT IS NEW: • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

The cascade of care in testing and treatment of latent tuberculosis infection in liver transplant candidates.

BACKGROUND: Testing and treatment for latent tuberculosis infection (LTBI) can mitigate risk of active tuberculosis (TB) post-liver transplant (LT). Testing and treatment completion rates have been reported low in this population. Our study aims to quantify the proportion of LT candidates who completed LTBI care cascade in our center. METHODS: A retrospective chart review was conducted on LT candidates from 2012 to 2021. Primary outcome was the proportion of patients who completed each cascade stage. Secondary outcome was an analysis of factors associated with positive and indeterminate LTBI testing. RESULTS: Of the 273 LT candidates, 265 (97.1%) were referred to transplant infectious disease (TID), 264 (96.7%) had orders for interferon-gamma release assay (IGRA), 262 (96%) underwent TID evaluation, and 259 (94.9%) completed IGRA. Twenty had LTBI, and 18 were treatment naïve and recommended for treatment. Of the 18, 15 (83.3%) agreed to therapy, 14 (77.8%) initiated treatment, and 12 (66.7%) completed treatment. No posttransplant TB reactivation occurred. Patients born in Asia, previous incarceration, past military service, and granuloma findings on chest imaging were likely to have positive IGRA (p < .05). Older age and travel to TB-endemic countries were likely to have indeterminate IGRA (p < .05). Indeterminate IGRAs were more common in QuantiFERON (QTF)-Gold Plus TB (15.3%) versus QTF-Gold TB (9.3%, p < .001). CONCLUSIONS: High rates of LTBI testing and treatment initiation and completion can be attributed to a standardized process that includes TID evaluation. Future studies in larger cohort are needed to better understand factors that can optimize the completion rates of LTBI treatment in LT candidates.

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.

Optimizing tuberculosis screening for immigrants in southern New Brunswick: A pilot study protocol.

INTRODUCTION: Immigrants from high tuberculosis-burdened countries have been shown to have an increased risk of latent tuberculosis infection (LTBI). To reduce the risk of increased tuberculosis cases in Canada, the country has a comprehensive immigration medical examination process that identifies individuals with active tuberculosis using chest X-ray; however, it fails to identify LTBI. The lack of LTBI identification is concerning because immigrants with LTBI are at an increased risk of developing active tuberculosis within their first few years of migration due to stressful experiences common to many immigrants. OBJECTIVES: The goal of this pilot study is to improve the current LTBI screening protocols among immigrants from high tuberculosis incidence countries and to better prevent and manage tuberculosis cases, by introducing an LTBI screening pilot program. The objectives are threefold: 1) to screen LTBI in immigrants from high tuberculosis incidence countries, including immigrants identified as being at risk of LTBI by the NB health care system, using the QuantiFERON-TB Gold Plus interferon-gamma release assay (IGRA); 2) to offer LTBI treatment and supports to those identified as having LTBI; and 3) to assess immigrant and health care providers (HCPs) satisfaction of the LTBI screening pilot program. METHODS: This cross-sectional study seeks to recruit 288 participants. Participants will be recruited via posters, social media platforms, invitations at immigrant wellness check-ups, presentations to local ethnocultural groups, and by snowball sampling. Consenting participants will be asked to submit a blood sample for LTBI screening; if positive, participants will be assessed and offered treatment for LTBI based on clinical assessment. Participants and HCPs' feedback will be gathered via short questionnaires. For the quantitative portion of the study, descriptive statistics will be used to summarize participant characteristics and feedback. Simultaneous logistic regression will be performed to identify variables associated with the IGRA test outcome and evidence of increased CD8 T-cell immune response among those found to be LTBI-positive. Qualitative results will be analyzed using inductive thematic analysis. DISCUSSION: The findings from this study will allow us to understand the role of the IGRA LTBI screening assay and its feasibility and acceptability by immigrants and HCPs in New Brunswick. The findings will additionally provide information on the enhancers and barriers of LTBI screening and management useful in determining how best to expand the LTBI screening program if deemed appropriate.

A systematic review of cost-utility analyses of screening methods in latent tuberculosis infection in high-risk populations.

BACKGROUND: The World Health Organisation (WHO) recommends that testing and treatment for latent tuberculosis infection (LTBI) should be undertaken in high-risk groups using either interferon gamma release assays (IGRAs) or a tuberculin skin test (TST). As IGRAs are more expensive than TST, an assessment of the cost-effectiveness of IGRAs can guide decision makers on the most appropriate choice of test for different high-risk populations. This current review aimed to provide the most up to date evidence on the cost-effectiveness evidence on LTBI testing in high-risk groups-specifically evidence reporting the costs per QALY of different testing strategies. METHODS: A comprehensive search of databases including MEDLINE, EMBASE and NHS-EED was undertaken from 2011 up to March 2021. Studies were screened and extracted by two independent reviewers. The study quality was assessed using the Bias in Economic Evaluation Checklist (ECOBIAS). A narrative synthesis of the included studies was undertaken. RESULTS: Thirty-two studies reported in thirty-three documents were included in this review. Quality of included studies was generally high, although there was a weakness across all studies referencing sources correctly and/or justifying choices of parameter values chosen or assumptions where parameter values were not available. Inclusions of IGRAs in testing strategies was consistently found across studies to be cost-effective but this result was sensitive to underlying LTBI prevalence rates. CONCLUSION: While some concerns remain about uncertainty in parameter values used across included studies, the evidence base since 2010 has grown with modelling approaches addressing the weakness pointed out in previous reviews but still reaching the same conclusion that IGRAs are likely to be cost-effective in high-income countries for high-risk populations. Evidence is also required on the cost-effectiveness of different strategies in low to middle income countries and countries with high TB burden.

Latent Tuberculosis Infection in Haematopoietic Stem Cell Transplant Recipients: A Retrospective Italian Cohort Study in Tor Vergata University Hospital, Rome.

The results of tuberculosis (TB) screening and reactivation in a cohort of 323 adult patients undergoing haematopoietic stem cell transplantation (HSCT) from 2015 to 2019 at the University Hospital of Tor Vergata, Rome, Italy, were reported. A total of 260 patients, 59 (18.3%) autologous and 264 (81.7%) allogeneic transplants, underwent Interferon Release (IFN)-γ (IGRA) test screening: 228 (87.7%) were negative, 11 (4.2%) indeterminate and 21 (8.1%) positive. Most of the IGRA-positive patients were of Italian origin (95.2%) and significantly older than the IGRA-negative (p < 0.001); 22 (8.5%) patients underwent a second IGRA during the first year after transplantation, and 1 tested positive for IGRA. Significantly lower monocyte (p = 0.044) and lymphocyte counts (p = 0.009) were detected in IGRA negative and IGRA indeterminate patients, respectively. All latent TB patients underwent isoniazid prophylaxis, and none of them progressed to active TB over a median follow-up period of 63.4 months. A significant decline in TB screening practices was shown from 2015 to 2019, and approximately 19% of patients were not screened. In conclusion, 8.1% of our HSCT population had LTBI, all received INH treatment, and no reactivation of TB was observed during the follow-up period. In addition, 19% escaped screening and 8% of these came from countries with a medium TB burden, therefore at higher risk of possible development of TB.

Significant difference in Th1/Th2 paradigm induced by tuberculosis-specific antigens between IGRA-positive and IGRA-negative patients.

False negative interferon-γ release assay (IGRA) results constitute the major dilemma for the diagnosis of tuberculosis (TB) infections. Herein, we conducted a cohort study to compare the host immunological response to TB-specific antigens between active TB patients with positive and negative IGRA results and control groups. A total of 274 laboratory-confirmed TB patients were included in our analysis, consisting of 221 were IGRA positive and 53 were IGRA negative. Patients with the elderly were identified as an independent risk factor for negative IGRA results. In addition, the elevated level of IL-4 and the decreased levels of IFN-γ, IL-2, IL-6, IL-1ß, and IL-12 in IGRA negative TB relative to IGRA positive TB group, demonstrating a significant difference in Th1/Th2 paradigm between two groups. The IFN-γ&IL-2 based assay could correctly identify 247 out of 307 MTB-infected individuals [271 TB patients and 36 individuals with latent TB infection (LTBI)], demonstrating a sensitivity of 80.5%. Then the IFN-γ and IL-4 were applied to distinguish healthy control and IGRA-negative group. When using the stepwise algorithm, the sensitivity for detecting Mycobacterium tuberculosis (MTB) infections was significantly increased from 80.5% to 89.6%. Additionally, patients with negative IGRA results had a conversion to culture-negative status longer than those with positive IGRA results. In conclusion, a stepwise algorithm outperforms IGRA assays to accurately identify MTB infections by the combination IFN-γ, IL-2, and IL-4. Further study is needed to evaluate the accuracy of our diagnostic algorithm in the LTBI population.

Detecting Mycobacterium tuberculosis Infection in Children Migrating to Australia.

In 2015, Australia updated premigration screening for tuberculosis (TB) disease in children 2-10 years of age to include testing for infection with Mycobacterium tuberculosis and enable detection of latent TB infection (LTBI). We analyzed TB screening results in children <15 years of age during November 2015-June 2017. We found 45,060 child applicants were tested with interferon-gamma release assay (IGRA) (57.7% of tests) or tuberculin skin test (TST) (42.3% of tests). A total of 21 cases of TB were diagnosed: 4 without IGRA or TST, 10 with positive IGRA or TST, and 7 with negative results. LTBI was detected in 3.3% (1,473/44,709) of children, for 30 applicants screened per LTBI case detected. LTBI-associated factors included increasing age, TB contact, origin from a higher TB prevalence region, and testing by TST. Detection of TB and LTBI benefit children, but the updated screening program's effect on TB in Australia is likely to be limited.

Screening for TB infection: the operator´s impact.

BACKGROUND: Accurate diagnosis of TB infection (TBI) is challenging due to the lack of a gold standard. Tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are currently useful in TBI diagnosis, but both have several limitations. This study aims to evaluate inter-operator variability in TST measurements and determine its impact on TBI diagnosis and treatment.METHODS: This was a retrospective analysis of patients screened for TBI using at least TST at a public outpatient clinic specialised in TB from January 2019 to August 2021. TST readings performed by five experienced nurses were compared.RESULTS: A total of 671 screenings were analysed. TST positivity rate (P < 0.001) and mean TST measurements obtained by our nurses were significantly different (P < 0.001). Concordance of TST and IGRA results was of 83.4% in the overall population (κ = 0.479). However, TST/IGRA agreement was significantly different among nurses (P = 0.003).CONCLUSION: Our analysis of TST measurements by experienced nurses shows significant differences in TST positivity rate, mean measured values and overall concordance with IGRA. This led to significant different outcomes in TBI diagnosis and subsequent treatment. TST measurement differences could potentially be more pronounced if we considered untrained operators or those with occasional reading experience.

Successes and challenges of latent TB screening and treatment in a high-prevalence US region.

BACKGROUND: South Texas has higher TB disease incidence than much of the United States. We evaluated a multi-site South Texas interferon-gamma release assay (IGRA)-based testing and latent TB infection (LTBI) treatment program targeting high-risk populations.METHODS: Number of IGRA tests, test results, LTBI confirmation, and treatment outcomes were collected over 2.5 years. Sixteen semi-structured patient interviews and 10 site-based focus groups were conducted with providers, nurses, and administrators. Grounded theory identified themes associated with successful outcomes.RESULTS: Of 9,050 IGRA tests, 687 (8%) were positive; 340 (49%) confirmed as LTBI; 191 initiated LTBI treatment; and 130 (68% of initiators) completed treatment. Patient barriers to treatment completion included lack of knowledge, misconceptions, and treatment toxicities. Clinic staff concurred that toxicity was a barrier to treatment and requiring new processes with limited resources were implementation barriers.CONCLUSIONS: Over 9,000 patients were screened with a high prevalence of IGRA positivity, but confirming LTBI, initiating, and completing treatment were challenging. Qualitative evaluation supports low literacy patient education on LTBI and toxicities and expanded support for process implementation and provider training. These findings highlight challenges at all levels of the LTBI care cascade and provide patient, staff, and provider perspectives on implementation of these programs.

Correlation between tuberculosis-specific interferon-γ release assay and intrathoracic calcification: A cross-sectional study.

BACKGROUND: Although persistent tuberculosis (TB) infection is known to cause calcification in the lungs, the relationship between intrathoracic calcification and the results of the interferon-γ release assay (IGRA) has not been fully elucidated. This study aimed to assess the association between intrathoracic calcification and IGRA results. METHODS: We retrospectively included consecutive patients who concurrently underwent chest X-ray, chest computed tomography (CT), and an IGRA. Patients with a current diagnosis of active TB or treatment history of active TB or latent tuberculosis infection (LTBI) were excluded. The association between calcification according to the chest X-ray or CT and IGRA results were analyzed using binomial logistic regression. RESULTS: This study included 574 patients, and 38 (7%) patients had a positive IGRA result. Patients with a positive result were significantly older and had a higher proportion of comorbidities, and history of tuberculosis exposure compared to those with a negative result. Calcification of the lung field and mediastinal lymph nodes according to chest CT was more frequently observed in patients with a positive IGRA result, whereas no significant difference was observed concerning the proportion of lung field calcification on chest X-ray between patients with positive and negative IGRA results. In multivariate analysis, calcification of mediastinal lymph nodes alone (adjusted odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.76-8.26) and the combination of lung field and mediastinal lymph node calcification (adjusted OR = 4.12, 95% CI = 1.51-11.76) on chest CT was independently associated with positive IGRA results. CONCLUSIONS: The finding of mediastinal lymph node calcification, with or without lung field calcification, on chest CT was associated with positive IGRA results independent of TB exposure history. Previous TB infection including eliminated TB infection and LTBI can be suspected when calcified lymph nodes in are observed the mediastinum on chest CT.

Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion.

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.