Indeterminate IGRA Research Articles

Predictors of interferon-gamma release assay results and their association with COVID-19 infection outcomes.

An 'indeterminate' interferon-gamma release assay (IGRA) result used in the diagnosis of latent TB infection (LTBI) is most commonly due to an inadequate control (or 'mitogen') response, which may reflect underlying T-cell dysfunction. We performed a single-centre, retrospective study on COVID-19 patients admitted to a tertiary referral hospital who had IGRA testing conducted over a 5-month period. The primary outcomes included predictors of indeterminate IGRA results and associations with COVID-19 outcomes. A total of 181 patients were included for analysis. Approximately one-third of patients hospitalised with COVID-19 with IGRA testing performed (60/181) had an indeterminate result. The likelihood of an indeterminate IGRA was increased in patients with a history of solid organ transplant and a higher severity of COVID-19 at the time of testing. An indeterminate IGRA was associated with a higher risk of severe COVID-19 and a higher risk of admission to the ICU during admission to the hospital. No difference in mortality between the two subgroups was found. Our study demonstrated that COVID-19 patients on immunosuppression had a high likelihood of an indeterminate IGRA result, which was associated with markers of disease severity and immunosuppression. In this cohort, an indeterminate result was associated with worse COVID-19 outcomes.

Agreement between Mycobacterium tuberculosis antigen-based skin test and interferon-gamma release assay in elderly individuals aged ≥65 years in China

ObjectivesTo determine the agreement of Mycobacterium tuberculosis (TB) antigen-based skin test (TBST) with interferon-gamma release assay (IGRA) in elderly individuals aged ≥65 years beyond instruction for use in China. MethodsBased on the baseline survey of randomized controlled trial with the objective of exploring suitable regimens for TB preventive treatment, M. tuberculosis infection was tested using TBST and IGRA in parallel in rural residents aged 50–70 years using a cross-sectional study design. ResultsA total of 21 219 participants with both TBST and IGRA results were included in this analysis. The concordance between TBST and IGRA was 89.4% (95% CI, 89.0–89.8%) with a kappa coefficient of 0.61 (95% CI, 0.60–0.62). In those aged ≥65 years, the concordance was 86.5% (95% CI, 85.6–87.4%) with a kappa coefficient of 0.55 (95% CI, 0.52–0.58). 21.2% (35/165) of the participants with indeterminate IGRA results were TBST positive, and nine of them were aged ≥65 years. Discussion: The consistent agreement between TBST and IGRA in individuals aged ≥65 years suggests that TBST has the potential to be used in the elderly with age beyond instruction for use in China. The respective diagnostic performance of each test will be analysed when the longitudinal data on incident TB is obtained in the future.

Intravitreal faricimab as an adjuvant in the management of tubercular uveitis.

To report the use of intravitreal faricimab used as an adjunct in the management of intraocular tuberculosis (IOTB) in a patient with occlusive retinal vasculitis (ORV) and choroiditis. A case report. A 27-year-old Asian male presented with bilateral choroiditis and ORV complicated by retinal neovascularization and vitreous hemorrhage in one eye. The patient had a positive tuberculin skin test, indeterminate interferon-gamma release assay, and Ghon's focus on chest radiography. With a diagnosis of IOTB, the patient was treated with anti-tubercular therapy. Due to the significant vitreous hemorrhage, he underwent pars plana vitrectomy in one eye. The patient received bilateral faricimab. Within a week of the injection, he had a near-complete resolution of the extensive choroidal and retinal vascular inflammation. Intravitreal faricimab, given its angiopoietin-2 (ang2) inhibition and anti-vascular endothelial growth factor action, maybe a helpful adjunct in IOTB. Whether ang2 inhibition provides any additional benefit needs further evaluation in extensive studies.

Prevalence of Latent Tuberculosis Infection Among Rheumatology Patients and Management Practices in the United Arab Emirates: A Single-Center Retrospective Cohort Study.

Introduction Prior to immunosuppression, rheumatology patients are routinely screened for latent tuberculosis (TB) infection using interferon-gamma release assays (IGRAs). Variability in the management of latent and indeterminate IGRA results across institutionslimited long-term outcome data. A retrospective study was conducted at Tawam Hospital, United Arab Emirates, to investigate the incidence and management protocols associated with positive and indeterminate IGRAresults, as well as TBinfection, among patients with rheumatic conditions. Methods A single-center retrospective observational study was performed at Tawam Hospital, Abu Dhabi, UAE. Ethical approval for this study was obtained from the Tawam Human Research Ethics Committee. Laboratory records and the hospital's electronic medical system were used to obtain information about IGRA results over a 12-year period (April 2010-April 2022). The hospital's electronic medical system was used to obtain patient information and subsequent management approaches of positive and indeterminate IGRAs.Moreover, long-term follow-up data were collected to determine the risk of TB reactivation in the cohort. Results We found a total of 1,012 positive and 223 indeterminate IGRA test results within the 12-year period. Within the rheumatology department, 123 positive and 39 indeterminate IGRA results were identified. In the indeterminate IGRA group, the majority were women (n = 24, 61.5%) and UAE nationals (n = 22, 56.4%), and their mean age was 38.6 years. Systemic lupus erythematosus was the most prevalent rheumatologic condition (n = 21, 53.8%). Thirteen (33.3%) were on disease-modifying anti-rheumatic drugs (DMARDs) and 26 (66.7%) were on corticosteroids during IGRA testing. A total of eight patients (20.5%) received anti-TB medications. In the positive IGRA group, the mean age was 55.7 years and the female-to-male ratio was 3:1. The most common rheumatologic condition was rheumatoid arthritis (n = 69, 56%). Sixty-five (52.8%) patients were on conventional DMARDs, 43 (34.9%) were on corticosteroids during IGRA testing, and 74 (60%) received anti-TB medications. Two cases (1.6%) of active TB infections were detected among patients with positive IGRA tests, both of whom were receiving anti-tumor necrosis factor alpha inhibitor treatment in combination with methotrexate. No cases of active TB infection were observed in the indeterminate IGRA group. Conclusion Long-term data on the risk of TB activation in positive and indeterminate IGRA results for rheumatological conditions are low. It is recommended to reassess the choice of using anti-TNF-α, with a positive IGRA result if no other feasible alternatives can be offered. Our findings stress the importance of age, underlying diseases, and immunosuppressive treatments in interpreting IGRA results and guiding patient management. A large multicenter study is needed to understand the differences and outcomes of such patients in TB endemic and nonendemic geographical areas.

Interferon-gamma release assay for screening of tuberculosis infection in children

BackgroundInterferon-gamma release assay (IGRA) is the main tool for the diagnosis of latent tuberculosis (TB) infection (LTBI). However, the indeterminate results were more frequent in children, and the underlying reasons were largely speculative. We aimed to compare QuantiFERON-TB Gold In-Tube (QFT-GIT) with X.DOT-TB (XDOT) for diagnosing LTBI, and to identify the risk factors associated with indeterminate results in children.MethodsA retrospective study for children<18 years old, at risk for LTBI or progression to TB disease, received either QFT-GIT or X.DOT-TB tests was performed at Beijing Children’s Hospital from August 2019 to August 2022.ResultsA total of 33,662 children were recruited, including 15,129 (44.9%) tested with X.DOT-TB and 18,533 (55.1%) with QFT-GIT. Proportion of positive and indeterminate results in children with respiratory disease was significantly higher than did that with other diseases, respectively (P < 0.001). The indeterminate rate of X.DOT-TB and QFT-GIT results decreased with increasing age (P < 0.001). Proportion of QFT-GIT indeterminate results was higher than that of X.DOT-TB across age groups. Male, age and disease classification all presented a statistically significant association with indeterminate IGRA results.ConclusionsThe positive rates of X.DOT-TB and QFT-GIT in children were 3.1% and 1.8%, respectively. The X.DOT-TB assay performed better than QFT-GIT in children, and male, age and underlying diseases were associated with an increased risk of indeterminate IGRA results.

Prevalence of indeterminate tuberculosis interferon-gamma release assays in COVID-19 patients: Systematic review and meta-analysis.

The reliability of interferon-gamma-release-assays (IGRAs) for tuberculosis (TB) testing in coronavirus disease 2019(COVID-19) patients is unknown. This study aimed to systematically review the prevalence of indeterminate TB-IGRA following SARS-CoV-2 infection or vaccination and to review associated factors. This systematic literature review was guided according to the PRISMA guidelines by searching PubMed, Scopus, Web of Science, Clinicalkey, and Cochrane Library. Studies reporting results of TB-IGRA tests (QuantiFERON [QFT]-TB, T-SPOT.TB) in COVID-19 patients or vaccines were included. The random effects model was used to assess the prevalence of indeterminate IGRA results. Heterogeneity was evaluated using the Τ 2 and 95% predictive interval. Of the 273 citations screened, 12 articles were included in the final analysis including a total of 2107 patients. The overall pooled effect size proportion of indeterminate QFT-TB results, estimated in eightstudies using the QFT-TB Plus assay, was 0.26 (95%CI: 0.205-0.324, Τ 2 = 0.158). The mean true effect size was 0.26 (95% predictive interval: [0.110-0.500]). A subgroup analysis was not undertaken due to the small number of studies. Indeterminate QFT-TB rates were associated with COVID-19 severity, steroid treatment, inflammation-related parameters, neutrophilia, and lymphopenia. Indeterminate QFT-TB results in COVID-19 patients occur in almost one-quarter of tests performed. Further studies are needed to assess associated factors.

Abstract 27 — Prevalence and Management Approach of Latent Tuberculosis Infection in Rheumatology Patients

Prior to immunosuppression, rheumatology patients are routinely screened for latent tuberculosis infection (LTBI) using Interferon-Gamma Release Assays (IGRA). The management of latent and indeterminate IGRA results varied among institutions and long-term outcome data is lacking. We conducted a retrospective study at Tawam Hospital, United Arab Emirates, to examine the frequency and management of positive and indeterminate IGRA results and tuberculosis infection in rheumatic patients. Methods Laboratory records and hospital electronic medical system were used to obtain information about IGRA results over a 12 years period (April 2010-April 2022). Results In our hospital record over a 12-year period, we found a total of 1012 positive and 223 indeterminate IGRA test results. Within the rheumatology department, 123 positive and 39 indeterminate IGRA results were identified. In the indeterminate IGRA group, the majority were female (n=24, 61.5%), UAE nationals (n=22, 56.4%), and had a mean age of 38.6 years. Systemic lupus erythematosus (SLE) was the most prevalent rheumatologic condition (n=21, 53.8%). 33.3% (n=13) were on disease modifying anti-rheumatic drugs (DMARDs) and 66.7% (n=26) were on corticosteroid during IGRA testing. A total of 8 patients (20.5%) received anti-TB medications. In a positive IGRA group, the mean age of 55.7 years and a female-to-male ratio of 3:1. The most common rheumatologic conditions were RA (n=67, 54.4%). Approximately 52.8% (n=65) of patients were on conventional DMARDs, 66.7% (n=26) were on corticosteroids during IGRA testing, and 60% (n=74) received anti-TB medications. Two cases (1.6%) of active TB infections were detected among patients with positive IGRA tests, both of whom were receiving anti-TNFa inhibitor treatment in combination with methotrexate. No cases of active TB infection were observed in the indeterminate IGRA group. Conclusion Tuberculosis risk in positive and indeterminate IGRA results for rheumatological conditions is low. Further multicenter studies are required to analyze patient outcomes and differences in TB-endemic and non-endemic regions.

Performance of two interferon-gamma release assays for tuberculosis infection screening in Kawasaki children before immunosuppressive therapy.

We aimed to compare QuantiFERON-TB Gold In-Tube (QFT-GIT) and X.DOT-TB for screening latent tuberculosis infection (LTBI) in kawasaki patients, and to identify the risk factors associated with indeterminate IGRA results. We conducted a retrospective study on children with KD, who were screened for mycobacterium tuberculosis (Mtb) infection by either ELISA-based QFT-GIT or ELISPOT-based X.DOT-TB tests, admitted in Department of Cardiology, Beijing Children's Hospital from July 2019 to April 2022. A total of 1327 cases were included. Among them, 932 cases were tested by QFT-GIT and 395 cases by X.DOT-TB. The positive rate of children was 0.1% and 0.2%, and the indeterminate rate was 68.2% and 6.1% for QFT-GIT and X.DOT-TB, respectively. Patients with hypoproteinemia had a higher risk of indeterminate X.DOT-TB result. Female, critical ill, shock or hypoproteinemia presented statistically significant associations with an increased risk of indeterminate QFT-GIT result. High-dose of IVIG inhibited the release of IFN-γ by more than 90%, which might account for the high indeterminate incidence. It is recommended to perform X.DOT-TB rather than QFT-GIT to screen LTBI in patients with high level of the mitogen that can inhibit IFN-γ release. For KD children with positive IGRA results, it has a higher risk of activation TB infection when treated with immunosuppressive therapy in the future. Children with KD aged <5 years old had higher frequency of indeterminate IGRA results.

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

We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI). 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. 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. 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. PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020211363, CRD42020211363.

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

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. 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. 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). 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.

1438. Latent tuberculosis infection (LTBI) in hematopoietic stem cell transplantation (HSCT) recipients: a retrospective Italian cohort study in Tor Vergata University Hospital, Rome.

Abstract Background Patients undergoing haematopoietic stem cell transplantation (HSCT) have severe and prolonged immunodeficiency and the incidence of tuberculosis (TB) disease in those patients is 10 to 40 times higher than the general population Methods This retrospective study performed at Tor Vergata University Hospital in Rome (Italy) included all adult patients who underwent a HSCT in the Hematologic Transplant Unit from January 2015 to December 2019. Data on TB screening, performed through interferon-γ release assay (IGRA), were collected; patients were observed for TB reactivation in a follow up period of at least 3 years Results 323 HSCT recipients were enrolled in this study. Patients’ characteristics are summarized in table 1. 63 patients (19.5%) were not screened for TB, of which 6.3% were born overseas. 260 HSCT recipients (80.5%) were screened: 228 patients (87.7%) had a negative IGRA result, 21 (8.1%) tested positive, and 11 (4.2%) had an indeterminate result. 98.5% were screened before the HSCT. Of the 21 patients with a positive pre-HSCT IGRA test, 14 (66.7%) were males and significantly (p&amp;lt; 0.001) older (median age 60 [IQR] 58-65 years) than those with negative or indeterminate results. Almost all patients (95.2%) were Italian. Patients with a positive IGRA showed a higher monocyte count compared to the other groups (p=0.044), while those with indeterminate IGRA showed a tendence to lower lymphocyte absolute counts, compared to the other groups (p=0.060) (Table 2). All the 21 patients with a pre-HSCT positive IGRA test were radiologically and clinically screened for active TB and, once it was ruled out, treated for latent TB (LTBI) with isoniazid (INH) for 6 months. No events of toxicity or treatment interruption were reported. None of the patients was treated with rifampin. None of the 21 patients with pre-HSCT positive IGRA test developed active TB during the follow up period. Table 1.Characteristics of the study population, overall and divided according to IGRA testingTable 2.Characteristics of the IGRA tested patients, overall and divided by IGRA test results Conclusion To our knowledge, this is the first Italian study on the prevalence of LTBI in patients undergoing HSCT. 8.1% of the 260 patients screened with an IGRA tested positive. The great majority (95.2%) of LTBI patients were Italian and significantly older than IGRA-negative patients. All LTBI HSCT patients received INH treatment and no drug toxicity, nor TB reactivation was observed during the follow-up period Disclosures All Authors: No reported disclosures.

Are interferon-gamma release assays reliable to detect tuberculosis infection in patients with rheumatoid arthritis treated with Janus kinase inhibitors?

BackgroundScreening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs.ObjectivesTo compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki.MethodsRA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed.ResultsTwenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (p<0.0001).ConclusionA response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation.

CD69 flow cytometry to complement interferon-γ release assay for active tuberculosis.

The interferon-γ (IFN-γ) release assay (IGRA) is widely used to diagnose tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb). However, indeterminate IGRA results due to "high Nil" or "low PHA" responses limit its clinical utility. We developed a novel assay using CD69 flow cytometry (FC) to complement IGRA. CD69 FC measures the surface CD69 expression on T cells prior to centrifugation to harvest the plasma for IGRA. T cell responses against Mtb antigen 1 (Ag1) or Ag2 were measured using three-color FC (CD3, CD4, and CD69) in TB (n=140) and non-TB groups (n=117). The cutoff values of Δ%CD69bright cells (stimulated minus unstimulated) for CD4+ and CD4- T cells were established based on healthy individuals (n=63). The assay performances of CD69 FC and IGRA were compared. In subjects with determinate IGRA results ("positive" or "negative"; n=216), the diagnostic accuracies of CD69 FC (90.3%) and IGRA (87.0%) were not significantly different (p=0.31). For indeterminate IGRA results (n=40), CD69 FC attained a diagnostic accuracy of 92.5%. The CD4+ /CD4- ratio within CD69bright T cells measured by CD69 FC was significantly higher (p < 0.05) in the active TB group (6.39 ± 132.05; n=72) than in other CD69 FC-positive subjects (2.84 ± 15.36; n=63) (p < 0.05), whereas CD8 responses expected by IGRA (difference of IFN-γ levels between Mtb Ag tubes) did not differ significantly (0.00 ± 9.18 and 0.00 ± 4.25, respectively, IU/ml; p=0.58). We demonstrated the potential of CD69 FC as a simple, rapid assay for clarifying indeterminate IGRA results and identifying active TB. With further improvements, CD69 FC may complement the IGRA to enhance TB risk stratification in the routine diagnostic workup.

Serial interferon-gamma release assay in lung cancer patients receiving immune checkpoint inhibitors: a prospective cohort study.

Recent advancements in cancer immunotherapy using immune checkpoint inhibitors (ICIs) have received considerable attention. Although advantageous, ICI therapies cause unique immune-related adverse events (irAEs) in some patients. Moreover, infectious diseases, such as tuberculosis, have been recognized as emerging concerns during immunotherapy. We aimed to evaluate the interferon-gamma release assay (IGRA) conversion rate and active tuberculosis incidence during immunotherapy to elucidate the incidence of tuberculosis reactivation after ICI therapy induction.We prospectively assessed IGRA results in lung cancer patients who received ICI monotherapy before ICI treatment and at 6 and 12months after ICI treatment. We also assessed computed tomography findings to determine the presence of active tuberculosis when positive IGRA results were obtained. The ICIs used were nivolumab, pembrolizumab, atezolizumab, and durvalumab.In all, 178 patients were prospectively recruited between March 2017 and March 2020. Of these, 123 completed serial IGRAs, of whom 18, 101, and 4, respectively, had positive, negative, and indeterminate IGRAs at baseline. Three and four patients, respectively, showed IGRA reversion and conversion during immunotherapy. One patient with a sustained, stable positive IGRA and one with IGRA conversion developed active pulmonary tuberculosis during immunotherapy.We found that 3.3% and 1.6% of the patients developed IGRA conversion and active tuberculosis, respectively. Of the four patients who developed IGRA conversion, one developed active pulmonary tuberculosis during immunotherapy. Another patient with sustained, stable positive IGRA developed active tuberculosis. Physicians should be alert to tuberculosis development during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis.

Risk factors of latent tuberculosis among chronic kidney disease with routine haemodialysis patients

IntroductionSince immune system alteration occurs, chronic kidney disease (CKD) on routine haemodialysis (HD) patients have a greater risk for latent tuberculosis (LTB). LTB needs special attention so that it does not develop into an active form, because infection in CKD patients increases the mortality. This study aims to determine the risk factors that associated with LTB among CKD on routine HD patients. MethodsThis was a cross-sectional study conducted in Haemodialysis Unit, Hasan Sadikin General Hospital, Bandung. The subjects were recruited from March–May 2020. Subjects aged > 18 years at least have undergoing HD in 3 months and twice a week HD were included in this study. Patients with active tuberculosis (TB) suspected, malignancy, or immunocompromised were excluded. LTB was diagnosed using interferon-γ release assays (IGRA). All data including age, sex, CKD etiologies, smoking status, HD adequacy that assessed using KT/V and urea reduction ratio (URR), and contact status with TB patients were obtained and recorded in case report form. ResultsA total of 120 subjects were involved. LTB based on IGRA was occurred in 39.2% subjects, while 56.7% and 4.1% subjects had negative and indeterminate IGRA, respectively. Adequacy of HD based on KT/V value was not significantly different between positive and negative IGRA subjects. Positive IGRA subjects had lower URR (p = 0.042). Smoking status had significant association with LTB (OR = 2.5[95%CI 1.2–5.4, p = 0.017). Furthermore, URR < 73% also had significant association with LTB (OR = 2.6[1.2–5.6, p = 0.013). ConclusionSmoking status and HD adequacy based on URR < 73% are associated factors that contribute to LTB among CKD on HD patients.

Assessment of latent tuberculosis infection pre-immunomodulatory therapy; 5 year experience in a UK centre

• A 5 year retrospective review of 367 LTBI referrals to a UK TB service. • 51% were referred pre-immunomodulatory therapy with 25 different agents. • They were older and had more negative & indeterminate screening IGRAs than ‘traditional’ LTBI referrals. • 57% either didn’t initiate or couldn’t complete chemoprophylaxis. An ever greater variety of immunomodulatory agents with potential to reactivate latent TB infection are being used in clinical practice. We set out to describe the experience of assessing and mitigating TB reactivation risk for patients planning to start immunomodulatory biological or small molecule inhibitor (SMI) therapies referred to a TB service in a high income low TB prevalence setting. Retrospective clinical case note review of patients referred to the infectious diseases TB service of Sheffield Teaching Hospitals following LTBI screening between 1 September 2015 and 30 September 2020. 367 patients had been referred and assessed. 179 patients referred for new entrant or contact screening and 188 (51%) patients were being worked up pre-immunomodulatory therapy with 25 different biologic/SMIs for more than 20 conditions. This group were older (median age 56.2 vs 32.6 years, p < 0.0001), and more likely to have had a negative or indeterminate screening IGRA (25.5% vs 4.1%, p < 0.0001). 155/188 were diagnosed with LTBI, of whom 58% commenced chemoprophylaxis (50 isoniazid, 40 rifampicin/isoniazid) and they were significantly younger than those who did not (median age 48.7 vs 70.6 years, p = 0.0004). 75% completed chemoprophylaxis with 7% stopping early due to altered liver function tests and 10% due to other adverse effects. No differences were observed between isoniazid or rifampicin/isoniazid treated groups. Increased age, less reliable screening IGRAs and adverse effects of chemoprophylaxis in the face of a widening variety of agents make management of LTBI in patients pre-immunomodulatory therapy complex. Better tests and treatments are required.

In-hospital blood collection increases the rate of indeterminate results in interferon-gamma release assays.

Background:The interferon (IFN)-γ release assay (IGRA) has recently been established as a method to evaluate the infection status of tuberculosis instead of the tuberculin skin test. However, indeterminate results can create challenges to interpretation. The IGRA has been available in Japan since 2005, including the recently launched QuantiFERON-TB Gold Plus (QFT-plus) assay.Objectives:The aim of this study was to investigate the clinical features and predictors of indeterminate results by the QFT-plus test in routine practice.Methods:This was a cross-sectional study of 1258 patients. Multivariate logistic regression models were employed to investigate the clinical factors related to indeterminate results by the QFT-plus.Results:Overall, 91.8% of results were found to be conclusive and 8.2% were indeterminate. The QFT-plus indeterminate results were predominantly due to a low level of IFN-γ production by mitogens. Multivariate analysis indicated that an indeterminate result was significantly associated with age, sex, corticosteroid use, autoimmune disease, and inpatient setting.Conclusion:Certain types of individuals are at higher risk of an indeterminate IGRA result. The QFT-plus test for hospitalized patients should be avoided as much as possible, and it is better to perform the test for those patients in outpatient settings.

Interferon Gamma Release Assay Mitogen Responses in COVID-19

Background Elevated cytokine release and T cell exhaustion have been associated with COVID-19 disease severity. T cell activity may be indirectly measured through interferon gamma release assays (IGRAs), which use mitogen stimulation of T lymphocytes as a positive control. In our institution, an unexpectedly high rate of indeterminate IGRAs was noted in COVID-19–positive patients. We aimed to evaluate the clinical characteristics associated with indeterminate IGRA results and the difference in mitogen responses between COVID-19–positive and COVID-19–negative patients. Methods We reviewed all patients, regardless of COVID status, who were admitted between March 1, 2020, and May 31, 2020, and for whom an IGRA was collected. For COVID-19–positive individuals, we evaluated the statistical association of their IGRA results and clinical characteristics, including demographics, laboratory values, comorbidities, and hospitalization-related outcomes. For both COVID-19–positive and COVID-19–negative individuals, we evaluated IGRA mitogen control values relative to COVID-19 status as stratified by absolute lymphocyte count. Results In COVID-19–positive patients, indeterminate IGRA results were statistically associated with white blood cell count and other markers of inflammation. When comparing COVID-19–positive and COVID-19–negative patients, we noted a statistically significant difference in IGRA mitogen control values when stratified by absolute lymphocyte count. Conclusions Indeterminate IGRA results were associated with higher levels of inflammatory markers. Furthermore, when comparing mitogen responses between COVID-19–positive and COVID-19–negative patients, there was an observed difference in T cell reactivity between the groups. The mitogen response in IGRAs may serve as a surrogate for T cell function and a marker of disease severity in COVID-19.

The impact of age when screening for latent tuberculosis infection - is it a problem?

Abstract Background Older population in developed countries represents a large reservoir of tuberculosis (TB) infection. Knowledge if age can contribute to false negative results in the immunological tests available for screening latent TB infections (LTBI) is critical to improve their usefulness in Public Health strategies for TB control. The aim of this study was to ascertain whether age was a risk factor for false negative (FN) results in the tuberculin skin test (TST) and in an interferon gamma release assay (IGRA). Methods Retrospective cohort study carried out using data from the Portuguese National Tuberculosis Surveillance system (2008-2015). Were included all active pulmonary TB cases with an IGRA (n = 597) and/or TST (n = 6185) result. TST outcomes were interpreted using a 5mm (TST-5mm) and 10mm (TST-10mm) cutoff. Logistic regression analysis crude and sex-adjusted was used to evaluate the association of age to the risk of FN results. Results Patients with a TST result presented a mean age of 42.7 years and patients with an IGRA result presented a median age of 45.5 years. TST-5mm, TST-10mm and IGRA had 36.5%, 43.9% and 24.5% FN results, respectively. Older patients presented a statistically significant association with the risk of FN TST results, regardless of using a 5mm [71-80years: OR 2.209; &amp;gt;80years: OR 2.491; p &amp;lt; 0.001] or 10mm [71-80years: OR 1.986; &amp;gt;80years: OR 2.308; p &amp;lt; 0.001] cut-off. Age was not a predictive factor for FN IGRA results. However, older patients presented a significant association with indeterminate IGRA results [71-80years: OR 3.808; &amp;gt;80years: OR 5.214; p &amp;lt; 0.001]. Conclusions When using TST as part of the Public Health strategies for screening elderly patients, healthcare professionals should bear in mind that there is an increased risk of obtaining a FN result. On the other hand, age did not show an association with the occurrence of FN IGRA results, which suggests that this test could perform better when screening for LTBI in older patients. Key messages TST in elderly people is associated with false negative results thus, when using this test for screening for LTBI, a negative result should be interpreted with caution. IGRA was not associated with false negative results in elderly people, however indeterminate results can occur more frequently, thus performing better in this population group.

Screening for TB in Hospitalised Patients with Inflammatory Bowel Disease before Anti-TNF Therapy: Is QuantiFERON® Gold Testing Useful?

Background—Tumour necrosis factor alpha (TNFα) plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and in immunity to Mycobacterium tuberculosis. Patients should be tested for latent tuberculosis infection using interferon-gamma release assays (IGRA/QF) prior to anti-TNFα therapy. Indeterminate QF results can delay anti-TNFα therapy. We sought to investigate factors associated with indeterminate QF results. Method—Retrospective study of all IGRA tests requested for gastroenterology patients in 2017. We compared inpatients and outpatients and investigated factors potentially associated with QF usefulness (steroid exposure, C-reactive protein (CRP), hypoalbuminaemia, thrombophilia). Results—We included 286 outpatients and 74 inpatients with IBD. Significantly more inpatients had an indeterminate IGRA (52.7% vs. 3.14% in outpatients; p < 0.0001). Laboratory parameters reflecting inflammation (high CRP, low albumin, low haemoglobin and high platelets) were also associated with an indeterminate QF (p < 0.0001). Exposure to steroids was more common in patients with an indeterminate QF (p < 0.0001). A binary logistic regression analysis revealed inpatient status and steroid exposure to be independently predictive of an indeterminate QF (p < 0.0001). Conclusion—There is a high chance of indeterminate QF results in inpatients. QF testing should ideally be performed in the outpatient setting at diagnosis.