Indeterminate IGRA Research Articles

PTH-086 Effect of Immunosuppressive Treatment on Interferon-Gamma Release Assays Prior to Biologic Treated Inflammatory Bowel Disease

Introduction Indeterminate interferon-gamma release assay (IGRA) results when screening for latent tuberculosis infection (LTBI)prior to biologic use in inflammatory bowel disease (IBD) may delay biologic treatment initiation. Concomitant steroids affect IGRA result, however the impact of other immunosuppressive medications is less clear. We determine the effect of immunosuppressives on results of IGRAs. Methods All patients treated with biologics from July 2013-November 2015 were identified from a pharmacy database. Electronic and clinical records were reviewed for IGRA result and concomitant immunosuppressive use. X2 was used to compare categorical data and univariate logistic regression using SPSS was used to determine likelihood of indeterminate tests with different immunomodulator medications (IMM). Results 247 patients with IBD had an IGRA. Mean age: 36.9 years (range 8–85) and 54% were male. 78/247 (32%) had an indeterminate result and 35/78 (45%) patients had a repeat test; 17/35 (49%) had a second indeterminate result. 181/247 (73%) received at least one IMM prior to screening and 66 patients (27%) were not on any IMM (IMM-free). In the IMM group: 121/181 (67%) patients had thiopurines, 18/181 (10%) had corticosteroids, 25/181 (14%) had both, 9/181 (5%) had methotrexate and 7/181 (4%) had other IMMs at screening. 72/181 (40%) had a first indeterminate IGRA 59/181 (33%) had a second indeterminate result. In the IMM-free group: 6/66 (9.0%) had an indeterminate IGRA. Patients in IMM group were more likely to have an indeterminate results than patients in IMM-free group (33% v 9.0%, p = 0.00001). Each separate IMM group was more likely to be associated with an indeterminate IGRA result compared with those in IMM-free group: thiopurines (23%) p = 0.020, steroids (42%) p = 0.001, thiopurines and steroids (64%) p = 0.001, other (43%) p = 0.01 and methotrexate (44%) p = 0.008). The combination of steroids and thiopurines together was the strongest factor associated with an indeterminate result. High dose (Prednisolone >20 mg or intravenous Hydrocortisone) and low dose steroids (Prednisolone Conclusion A combination of thiopurines and steroids gave the highest likelihood of an indeterminate IGRA result, although significant results occurred with all IMMs. This has implications for LTBI screening in IBD patients. Guidelines to address indeterminate IGRA results, perhaps with more focus on epidemiological risk may be helpful. There is an unmet need to have improved assessment tools for TB in patients on IMMs. Disclosure of Interest None Declared

Study of the BCG Vaccine-Induced Cellular Immune Response in Schoolchildren in Antananarivo, Madagascar.

ObjectiveAlthough the Bacillus Calmette-Guérin vaccine (BCG) protects young children against serious forms of TB, protection against pulmonary TB is variable. We assessed BCG vaccine-induced cellular immune responses and determined for how long they could be detected during childhood in Antananarivo, Madagascar.MethodsWe assessed BCG vaccine-induced cellular immune responses by TST and IGRA (in-house ELISPOT assay) using BCG and PPD as stimulation antigen, and compared results between vaccinated and non-vaccinated schoolchildren of two age groups, 6-7 and 13-14 years old.ResultsThree hundred and sixty-three healthy schoolchildren were enrolled. TST was performed on 351 children and IGRA on 142. A high proportion (66%; 229/343) of the children had no TST reactivity (induration size 0 mm). TST-positive responses (≥15 mm) were more prevalent among 13-14 year-old (31.7%) than 6-7 year old (16.5%) children, both in the non-vaccinated (43% vs. 9%, p<0.001) and vaccinated (29% vs. 13%, p=0.002) subgroups. There were no significant differences in TST responses between vaccinated and non-vaccinated children in either of the age groups. The IGRA response to BCG and to PPD stimulation was not significantly different according to BCG vaccination record or to age group. A high rate (15.5%; 22/142) of indeterminate IGRA responses was observed. There was very poor agreement between TST and IGRA-PPD findings (k= 0.08) and between TST and IGRA-BCG findings (k= 0.02)ConclusionAnalysis of TST and IGRA response to stimulation with BCG and PPD revealed no difference in immune response between BCG-vaccinated and non-vaccinated children; also no decrease of the BCG vaccine-induced cellular immune response over time was observed. We conclude that TST and IGRA have limitations in assessing a role of BCG or tuberculosis-related immunity.

Isoniazid treatment to prevent TB in kidney and pancreas transplant recipients based on an interferon-γ-releasing assay: an exploratory randomized controlled trial.

We performed a randomized trial of isoniazid treatment based on interferon-γ-releasing assay (IGRA) in kidney transplant (KT) recipients in an intermediate-TB-burden country. All adult patients admitted to a KT institute between June 2010 and May 2013 were enrolled. The IGRA (T-SPOT.TB assay) was performed on all patients, and isoniazid treatment was given to those with clinical risk factors for latent TB infection (LTBI). Patients with positive IGRA who had no clinical risk factors for LTBI were randomly assigned to isoniazid treatment or a control group. The development of TB after KT was monitored between June 2010 and November 2013. The primary endpoint was the development of TB. Of the 784 patients who had no clinical risk factors for LTBI, 445 (57%) gave negative results in the IGRA, 76 (10%) indeterminate results and 263 (33%) positive results. Of the latter, 131 were allocated to isoniazid treatment and 132 to the control group. Three (2%) of the control group developed TB, whereas none of the isoniazid treatment group developed TB (rate difference 1.22 per 100 person-years, P = 0.09). Of the 521 patients with negative or indeterminate IGRA results, 4 [0.8%, 0.43 per 100 person-years (95% CI 0.12-1.09)] developed TB after KT. IGRA-based isoniazid treatment has a trend towards reducing TB development in KT recipients without clinical risk factors, but careful monitoring of TB development is needed in negative-IGRA KT recipients.

1685Screening for TB in Health Care Workers – QFT may not be the answer!

 Tuberculosis (TB) screening of healthcare workers (HCWs) is an important component of hospital infection control programs. Many institutions have replaced tuberculin skin tests (TSTs) with interferon-release gamma assays (IGRAs).  Challenges of IGRA tests include daily fluctuations of IGRA values, serial testing variability, higher conversion rates of IGRAs than TSTs, and indeterminate IGRA results. In addition, reversions of positive QuantiFERON® TB test (QFT) with low cut-off values (0.35 IU/mL to 1 IU/mL) to negative have also raised concerns.  Additional data is needed for IGRA use in HCWs.  An Employee Health algorithm was created prior to implementation of QFT testing at our institution (Figure 1). Background 1The Ohio State University College of Medicine, Columbus, Ohio.

S58 Prospective Health Economic Evaluation Of Different Recommended Strategies For Tb Testing In A Contemporary Hiv Positive Cohort

Introduction The risk of active tuberculosis (TB) disease is estimated to be increased 40-fold in people with HIV (PHIV). Effective antiretroviral treatment (ART) may reduce this significantly. UK national guidance recommends using blood interferon gamma release assay (IGRA) +/- tuberculin skin testing (TST) for latent TB (LTBI) diagnosis but there are little supporting health economic data. We sought to evaluate the cost-effectiveness of different testing strategies using data from a prospective contemporary cohort. Methods Subjects receiving ambulatory HIV care were recruited by stratified selection within our HIV centre. TST, IGRA (TSpot. TB), frontal chest radiograph (CXR) and single induced sputum for mycobacterial culture were performed. The yield was used to model a screening programme that utilised current UK HIV demographics (Public Health England). Costs were based on the BNF, local costs or published literature (TST £16, IGRA £60, CXR £50, induced sputum £42, treatment for latent and active TB £786 and £7619 respectively). Uptake and LTBI treatment efficacy were both estimated at 65%. We assumed a lifetime reactivation rate with TST+/IGRA+ of 10% and TST+/IGRA- of 2%; and that all those with evidence of LTBI would be given treatment. Results Over 13 months, 211 people were recruited. 26% were female and 26% black African. LTBI rates amongst subjects from sub-Saharan Africa, medium and low TB incidence countries were 8/55 (15%), 2/31 (6%) and 4/125 (3%) respectively. One patient had a persistently indeterminate IGRA. Subclinical TB disease was diagnosed in two (1%) subjects. Using these data to model TB testing nationally, the British HIV Association (BHIVA) testing algorithm was the most cost-effective with an incremental cost effectiveness ratio (ICER) of £21,475. The NICE algorithm both cost more and prevented fewer cases of active TB (Table 1). More comprehensive strategies were associated with increasing cost. Conclusion Testing only those at highest risk of progression to active TB disease in an HIV population with high ART use was cost-effective, whilst most strategies testing all comers and for active TB cost considerably more than the £20–30,000/QALY gained threshold used in the UK.

PTU-087 Indeterminate And Inconclusive Results Are Common When Using Interferon Gamma Release Assay As Screening For Tb In Patients With Ibd

IntroductionAnti-TNF treatment is widely used in inflammatory bowel disease (IBD) but has been linked with reactivation of tuberculosis (TB). Screening for active and latent TB prior to initiation of anti-TNF...

Su1101 Indeterminate and Inconclusive Results Are Common When Using Interferon Gamma Release Assay As Screening for TB in Patients With IBD

Introduction Anti-TNF treatment is widely used in inflammatory bowel disease (IBD) but has been linked with reactivation of tuberculosis (TB). Screening for active and latent TB prior to initiation of anti-TNF therapy is therefore mandated. ECCO recommends interferon gamma release assays (IGRAs) as, unlike tuberculin skin test, positive tests are not caused by previous Bacillus Calmette–Guerin (BCG) vaccine. However, immunosuppressive agents can result in indeterminate or unreportable results[i] and there is no clear guidance on managing them. We quantified the prevalence of indeterminate or unreportable TB IGRA Elispot results in a large tertiary centre cohort of patients with IBD. Methods A single centre retrospective study of IGRA tests performed on IBD patients prior to commencement of anti-TNF therapy between Oct 2010 and Oct 2013. Results We included 140 patients (median age 34, range 24–86, 50% males). 92% had Crohn’s disease, 4% ulcerative colitis, and 4% IBD-unclassified. At the time of IGRA testing, 115 patients were on immunomodulators and 6 on prednisolone. 3 were positive for latent TB and were referred to infectious disease (ID) department prior to anti-TNF therapy. 3 had indeterminate results; all were on immunosuppressants (2=azathioprine, 1=methotrexate). 2 had a lymphocyte count 10 had unreportable results, 9 of whom were on azathioprine. On repeat testing, 4 were negative, and the remainder were still unreportable, one of whom had risk factors for TB and was treated with isoniazid chemoprophylaxis on the advice of the ID team. The remaining 5 patients started anti-TNF based on the absence of risk factors for TB. No patient had reactivation of latent TB at follow up (range 1–18 months). Lymphopaenia was found to be associated with non-reportable cases as compared to the reported cases (median lymphocyte count unreportable = 0.4, reportable = 1.2; p = 0.015). Conclusion Our results demonstrate TB IGRA is a useful test to screen for latent infection before initiating anti-TNF therapy. However, a minority of results are indeterminate or unreportable. In such cases repeat testing can produce definitive results. Low lymphocyte counts in association with immunosuppression may contribute to unreportable and indeterminate results; clinical risk stratification appears to be a safe way of managing such cases in this small cohort. Reference Papay P et al . Predictors of indeterminate IFN-γ release assay in screening for latent TB in inflammatory bowel diseases. Eur J Clin Invest. 2011 Disclosure of Interest None Declared.

P32 When a test is neither positive nor negative: the impact of equivocal and indeterminate quantiferon TB IGRA in a UK population: Abstract P32 Table 1.

Introduction For the diagnosis of latent tuberculosis (LTBI), clinicians like interferon-gamma based assays (IGRA) to be either positive or negative. Tests can be indeterminate (failure of the positive or negative control); and recently an equivocal category has been introduced for QuantiFERON IGRA results that lie around the positive cut off, 0.35 IU/mL, covering the range 0.2–0.7 IU/mL. Within our hospital, it is recommended that indeterminate or equivocal results are initially repeated by the requesting clinician. We report our outcomes from March 2010, when the equivocal category was introduced. Methods Hospital pathology and clinical records were data-mined. Cost analysis used local NHS costs. Results Tests for 1964 individuals were processed (over one-third from Occupational Health, and another one-third pre-biological therapy). 92% of subjects had a definitive first result, with 6% (116) equivocal and 2% (42) indeterminate (Table 1). 60% of equivocal tests were below the positive cut off of 0.35. The demographics of those with an equivocal result were broadly comparable with the whole tested population. Almost half of the equivocal tests were not repeated (Table 1). 45% of repeats were negative and one-third still equivocal. 12 of 34 subjects referred to the TB service were treated for LTBI–10 with a positive IGRA on re-testing. One other patient with an initial equivocal test developed active TB during follow up. 43% of people with an indeterminate result had no repeat test (Table 1). 1 of 6 subjects referred to the TB service following an indeterminate IGRA received LTBI treatment. Cost-analysis indicated that equivocal and indeterminate results plus subsequent TB service management increased the cost of each initial QuantiFERON diagnostic test from £35 to £40.76 per patient. Conclusion 8% of subjects had an equivocal or indeterminate first IGRA result. The recommended subsequent action often was not followed by the requesting clinicians. When repeated, the test provided a definitive result in two-thirds of subjects - the majority being negative. This adds an appreciable cost to the test, and brings it in line with other commercial IGRA. Further education of referring clinicians is required to minimise avoidable waste and optimise patient care.

Screening for Latent Tuberculosis Infection in Patients with Chronic Inflammatory Arthritis: Discrepancies Between Tuberculin Skin Test and Interferon-γ Release Assay Results

Screening for latent tuberculosis infection (LTBI) is mandatory before initiating biologics in patients with chronic inflammatory arthritis (CIA). However, few studies have evaluated the discrepancies between the results of tuberculin skin test (TST) and interferon-γ release assays (IGRA) in these patients. The purpose of our study was to investigate factors associated with TST and IGRA results in a large cohort of patients with CIA before the introduction of biologics. A total of 563 consecutive patients with CIA (293 rheumatoid arthritis, 270 spondyloarthritis) and eligible for biologics were prospectively enrolled. Demographic, clinical, and biological data were recorded. Risk factors for LTBI were assessed. All patients underwent a TST, a chest radiograph, and an IGRA test (T-SPOT.TB). Agreement between the 2 tests was low (κ = 0.16). The bacillus Calmette-Guerin (BCG) status was significantly associated with discordance between the 2 tests (p = 0.004). The TST positivity rate was 34.8%. Factors associated with a negative TST were female sex (p = 0.02) and immunosuppressive treatment (p = 0.003). The only LTBI risk factor associated with TST positivity was an abnormal chest radiograph (p = 0.02). T-SPOT.TB was positive in 21.7% of patients and indeterminate in 15.6%. Previous active TB and chest radiograph abnormalities were associated with IGRA positivity (p = 0.008 and p = 3.9 × 10(-5), respectively). The BCG vaccination was associated with negative IGRA (p = 3 × 10(-4)). Indeterminate IGRA results were associated with age, C-reactive protein, and immunosuppressive treatment (p = 0.005, 0.007, and 0.004, respectively). Our data support the combined use of T-SPOT.TB and TST in patients with CIA before biologics introduction. However, despite these good diagnostic values, indeterminate results may complicate the use of IGRA.

Miliary Tuberculosis with Indeterminate Interferon Gamma Release Assay Results

Recently, interferon gamma release assays (IGRAs) have become an important clinical tool for detecting latent tuberculosis. However, IGRA results may impede making a diagnosis. We herein present an interesting case of miliary tuberculosis with a nonspecific IGRA reaction due to hemophagocytosis.

Negative effect of smoking on the performance of the QuantiFERON TB gold in tube test

BackgroundFalse negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively.MethodsPatients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results.ResultsSmokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02).ConclusionsCigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status.

P57 Comparative Cost-Effectiveness of IGRA to Detect Latent TB Infection in UK Inflammatory Bowel Disease Patients Initiating Anti-TNFα Agents

IntroductionTwo commercial Interferon Gamma release assays (IGRA) are approved in the UK by NICE to detect M tuberculosis (Mtb) infection. They use different test platforms. Both may provide borderline (neither...

Yield and cost effectiveness of mycobacterial infection detection using a simple IGRA-based protocol in UK subjects with inflammatory bowel disease suitable for anti-TNFα therapy

Background and aimsTesting for LTBI is recommended prior to anti-TNFα agents. This includes an assessment of TB risk factors, chest radiograph, and interferon-gamma release assay alone or with concurrent Tuberculin skin testing. Here we review our experience and cost-effectiveness of using T-SPOT.TB IGRA to detect mycobacterial infection in patients with IBD suitable for anti-TNFα therapy. MethodsThis was a single-centre, retrospective review and economic evaluation (compared to British Thoracic Society guidance) of 125 adult IBD patients (90 anti-TNFα naïve, 35 established on anti-TNFα) tested for LTBI using T-SPOT.TB IGRA. ResultsAll subjects had normal chest radiographs and no clinical evidence for TB. 109 (87%) were BCG vaccinated. 27 (22%) of all patients tested were not using immunomodulation at the time of testing. 66 (53%) were taking thiopurines, 22 (18%)corticosteroids, and 35 (28%) anti-TNFα agents. One hundred twenty two (98%) had a negative IGRA result, two (2%) had positive results, and one (1%) had an indeterminate IGRA. A strategy using IGRA to guide TB preventative treatment produced cost savings of £10.79 per person compared to the BTS guidance. Eighty eight percent of the anti-TNFα naïve group have subsequently received treatment with either infliximab or adalimumab (median follow-up of 24months, IQR 18–30) with no cases of TB disease occurring. ConclusionsThe use of a simple screening protocol for LTBI incorporating T-SPOT.TB IGRA in place of TST in a largely BCG vaccinated population, many using immunomodulatory agents, appears to work well and is a cost-effective strategy in our IBD service.

Screening for Mycobacterium tuberculosis Using an Interferon-Gamma Release Assay

The Centers for Disease Control and Prevention recommend analyzing characteristics of populations screened for Mycobacterium tuberculosis infection using interferon-gamma release assays (IGRAs). We characterized requests for IGRA analyses submitted to the first laboratory in Washington State that began to offer IGRAs as a tuberculosis screening test. In addition, we chronicled the process by which this program was launched. Through a retrospective record review we recorded the IGRA results, source of the request, and reason(s) for each request along with demographic information, risk factors, and prior exposure for each subject. Through dissemination and quality control measures, IGRA analyses began within the health district but quickly spread throughout the state and the West. A regional health district clinical laboratory in the Pacific Northwest received 4422 IGRA requests for 4218 unique subjects from January 2, 2008, through June 5, 2009. Most (96%) requests originated from public health clinics or centers, hospitals, private laboratories or practitioners, and Indian Health Centers. Community and migrant health centers had the highest rates of positive IGRA results (28%, Φc = 0.159, P = .000). About one-half of all requests were for employment or high-risk surveillance. Persons with a positive IGRA had a larger TST induration (M = 16.66 mm, 95% CI: 15.18-18.14) than those with a negative IGRA (M = 13.53 mm, 95% CI: 12.92-14.15) but did not differ for those with an indeterminate IGRA (M = 13.29 mm, 95% CI: 5.95-20.62). Public and private agencies use IGRAs for surveillance of persons employed, routinely screened, at high risk, or foreign-born. The TST induration varies widely for persons with an indeterminate IGRA. The process for implementing IGRA analyses serves as a model for other programs seeking to conduct similar reviews of test use and results.

Bronchoalveolar Lavage Enzyme-Linked Immunospot for Diagnosis of Smear-Negative Tuberculosis in HIV-Infected Patients

BackgroundPeripheral blood interferon-gamma release assays (IGRAs) have sub-optimal sensitivity and specificity for diagnosis of active pulmonary tuberculosis (TB). However, assessment of local immune responses has been reported to improve the accuracy of TB diagnosis.MethodsWe enrolled HIV-infected adults with cough ≥2 weeks’ duration admitted to Mulago Hospital in Kampala, Uganda and referred for bronchoscopy following two negative sputum acid-fast bacillus smears. We performed an ELISPOT-based IGRA (T-SPOT.TB®, Oxford Immunotec, Oxford, UK) using peripheral blood and bronchoalveolar lavage (BAL) fluid mononuclear cells, and determined the accuracy of IGRAs using mycobacterial culture results as a reference standard.Results94 HIV-infected patients with paired peripheral blood and BAL IGRA results were included. The study population was young (median age 34 years [IQR 28–40 years]) and had advanced HIV/AIDS (median CD4+ T-lymphocyte count 60 cells/µl [IQR 22–200 cells/µl]). The proportion of indeterminate IGRA results was higher in BAL fluid than in peripheral blood specimens (34% vs. 14%, difference 20%, 95% CI 7–33%, p = 0.002). BAL IGRA had moderate sensitivity (73%, 95% CI 50–89%) but poor specificity (48%, 95% CI 32–64%) for TB diagnosis. Sensitivity was similar (75%, 95% CI 57–89%) and specificity was higher (78%, 95% CI 63–88%) when IGRA was performed on peripheral blood.ConclusionsBAL IGRA performed poorly for the diagnosis of smear-negative TB in a high HIV/TB burden setting. Further studies are needed to examine reasons for the large proportion of indeterminate results and low specificity of BAL IGRA for active TB in high HIV/TB burden settings.

Interferon‐γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti–tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis

To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guérin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.

Risk Factors Associated with Indeterminate Gamma Interferon Responses in the Assessment of Latent Tuberculosis Infection in a High-Incidence Environment

The performance of gamma interferon (IFN-γ) release assays (IGRA) in the detection of latent tuberculosis (TB) infection is limited by the higher rates of indeterminate results in HIV-infected persons, who bear the brunt of TB disease in some high-burden settings. The objective of the study was to evaluate predictors of indeterminate IGRA results in the overall study population and in HIV-infected persons. The study setting is Khayelitsha, an informal township in the Western Cape of South Africa, with a high burden of TB and HIV infection. A total of 561 asymptomatic persons were recruited from the day hospital and youth centers. A questionnaire was used to collect demographic information, and blood tests, including CD4 counting and a 7-day in-house IGRA, were performed. The overall prevalence of indeterminate IGRA results was 8.6% (48/561), and this was higher in HIV-infected than in HIV-uninfected persons (11.5% [38/330] versus 4.3% [10/231], respectively; P = 0.003). In the overall study population, predictors of indeterminate IGRA results were the presence of HIV infection (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.10 to 5.08) and the presence of a Mycobacterium bovis BCG scar (OR, 2.48; 95% CI, 1.23 to 5.01). Long-term township residents were significantly less likely to have indeterminate results than recent migrants (OR, 0.30; 95% CI, 0.11 to 0.80). Among HIV-infected persons, participants with CD4 counts of >200 cells/mm(3) and long-term residents were significantly less likely to have indeterminate IGRA results (OR of 0.21 with a 95% CI of 0.09 to 0.48 and OR of 0.22 with a 95% CI of 0.07 to 0.68, respectively). We evaluated risk factors for indeterminate IGRA results and report a higher rate of indeterminate results among HIV-infected persons, particularly those with lower CD4 counts. Of note, a recent move to the township was associated with a higher risk of indeterminate IGRA results.

Factors Associated with the Performance of a Blood-Based Interferon-γ Release Assay in Diagnosing Tuberculosis

BackgroundIndeterminate results are a recognised limitation of interferon-γ release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees.MethodsA retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007.ResultsComplete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR = 0.93 [95% CI 0.91–0.95], P<0.001), iron deficiency anaemia (2.69 [1.51–4.80], P = 0.001), malaria infection (3.04 [1.51–6.09], P = 0.002), and helminth infection (2.26 [1.48–3.46], P<0.001), but not vitamin D deficiency or insufficiency, were associated with an indeterminate IGRA result.ConclusionsYounger age and a number of common co-morbidities are significantly and independently associated with indeterminate IGRA results in resettled predominantly African refugees.

Predictors of indeterminate IFN-γ release assay in screening for latent TB in inflammatory bowel diseases

IFN-γ release assays (IGRA), widely used for latent tuberculosis screening prior to anti-TNF-α treatment, are limited by indeterminate results in patients under immunomodulatory (IM) therapy. The aim of our observational study was to delineate factors associated with indeterminate IGRA results. A total of 190 patients with inflammatory bowel disease were included. IGRA was indeterminate if the result of IFN-γ concentration was < 0·35 IU mL(-1) for tuberculosis-specific antigens and < 0·5 IU mL(-1) for the positive control. Predictors for indeterminate results were delineated from multivariate logistic regression. IFN-γ release assays was indeterminate in 26/190 (13·7%) patients. Indeterminate IGRA were associated with lower serum albumin levels (odds ratio [OR] 0·88, 95% confidence interval [CI] 0·79-0·96), lower absolute lymphocyte count (OR 0·39, 95% CI 0·18-0·75) and double IM therapy (OR 2·98, 95% CI 0·95-8·90). Sub-analysis of IM therapy revealed an association of steroid therapy with indeterminate IGRA (OR 3·19, 95% CI 1·35-7·70). Hypoalbuminaemia increased the risk of indeterminate IGRA by (OR 2·97, 95% CI 1·03-8·61) and lymphopaenia by (OR 3·28, 95% CI 1·41-7·65). After a mean of 18·5 ± 14·4 days, retesting of IGRA in 18 patients with indeterminate results yielded 9 negative vs. 9 indeterminate results. Our results reveal associations of indeterminate IGRA with low serum albumin levels and absolute lymphocyte count and double IM therapy. IGRA testing appears best to be performed prior to initiation of IM therapy in patients with inflammatory bowel disease.

Latent Tuberculosis Detection by Interferon γ Release Assay during Pregnancy Predicts Active Tuberculosis and Mortality in Human Immunodeficiency Virus Type 1–Infected Women and Their Children

We evaluated the prognostic usefulness of interferon γ release assays (IGRAs) for active tuberculosis and mortality in Kenyan human immunodeficiency virus type 1 (HIV-1)-infected women and their infants. Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1-infected women. Hazard ratios, adjusted for baseline maternal CD4 cell count (aHR(CD4)), were calculated for associations between IGRA positivity and risk of active tuberculosis and mortality over 2-year postpartum follow-up among women and their infants. Of 333 women tested, 52 (15.6%) had indeterminate IGRA results. Of the remaining 281 women, 120 (42.7%) had positive IGRA results, which were associated with a 4.5-fold increased risk of active tuberculosis (aHR(CD4), 4.5; 95% confidence interval [CI], 1.1-18.0; P = .030). For immunosuppressed women (CD4 cell count, <250 cells/μL), positive IGRA results were associated with increased risk of maternal mortality (aHR(CD4), 3.5; 95% CI, 1.02-12.1;), maternal active tuberculosis or mortality (aHR(CD4), 5.2; 95% CI, 1.7-15.6; P = .004), and infant active tuberculosis or mortality overall (aHR(CD4), 3.0; 95% CI, 1.0-8.9; P = .05) and among HIV-1-exposed uninfected infants (aHR(CD4), 7.3; 95% CI, 1.6-33.5; P = .01). Positive IGRA results for HIV-1-infected pregnant women were associated with postpartum active tuberculosis and mortality among mothers and their infants.