Usefulness and limitations of QuantiFERON-TB Gold in Japanese rheumatoid arthritis patients: proposal to decrease the lower cutoff level for assessing latent tuberculosis infection

We aimed to determine the sensitivity and specificity of QuantiFERON-TB Gold (QFT-G) in Japanese rheumatoid arthritis (RA) patients with a past history of tuberculosis (TB). We assessed whether it is possible to decrease the cutoff using receiver operating characteristic (ROC) analysis. We evaluated chest computed tomography (CT) findings, prior history of treatment, and contact with active TB in 370 RA patients. Forty-nine patients before initiation of treatment with tumor necrosis factor (TNF) inhibitors were divided into two groups: 22 with a past history of TB and 27 without. We estimated the efficacy of QFT-G compared with the tuberculin skin test and antituberculosis (anti-TB) glycolipid antigen antibody. QFT-G was positive (≥0.35 IU/ml) in 13.6% with a past history of TB, increasing to 27.3% at the intermediate range cutoff of 0.1 IU/ml. The sensitivity and specificity of QFT-G was 0.27 and 1.00, respectively, at 0.1 IU/ml. Using ROC analysis, the area under the curve (AUC) of QFT-G but not for the other two tests was significantly large. QFT-G is a useful diagnostic method due to its superior specificity, but the use of a cutoff value of 0.35 IU/ml will likely result in an underestimate. We propose that a lower interferon-γ (IFN-γ) titer of 0.1 IU/ml be adopted when deciding to administer anti-TB drugs before initiation of TNF inhibitors.     

Comparison of the interferon- gamma release assay and the tuberculin skin test for contact investigation of tuberculosis in BCG-vaccinated health care workers

Health care workers are at increased risk of Mycobacterium tuberculosis infection. The tuberculin skin test (TST) is frequently false positive in BCG-vaccinated health care workers. QuantiFERON-TB GOLD (QFT-G) is a sensitive and specific interferon-gamma release assay unaffected by BCG vaccination. This study compared TST and QFT-G in the diagnosis of latent TB infection in BCG-vaccinated health care workers. 39 health care workers exposed to a smear-positive TB patient were enrolled. Initial TST was positive in 33 (84.6%) cases, but only 4 (10.2%) cases using QFT-G. TST conversion occurred in 2/6 (33.3%), compared to 4/32(12.5%), cases using QFT-G. A higher proportion of QFT converters was associated with intimate contact, although not reaching statistical significance. Face-to-face contact >1 h was significantly associated with QFT-G conversion >or=0.7 IU/ml (OR 8.63, 95%CI 1.08-69.07, p=0.04). Agreement between TST and QFT-G was 18.0%, (kappa: -0.03). Concordance between TST and QFT (>or=0.35 IU/ml) conversion was 40.0%(kappa=-0.40), and 60.0%(kappa=0.00) if QFT >or=0.7 IU/ml was used. Agreement increased with increasing TST cut-offs. TST is not useful in contact investigation among BCG-vaccinated health care workers, in an area with intermediate burden of TB. QFT may provide additional information for the diagnosis and strategic management of preventive treatment of LTBI in BCG-vaccinated health care workers in a country with intermediate burden of TB.     

High early death rate in tuberculosis patients in Malawi.

SETTING: Thirty-eight district and mission hospitals in Malawi. OBJECTIVES: In patients registered with all types of tuberculosis (TB) in 1997 to determine 1) treatment outcomes, and 2) when in the course of anti-tuberculosis treatment TB deaths occurred. DESIGN: A retrospective study using information from TB registers, health centre registers, TB treatment cards and TB ward admission books. RESULTS: A total of 16,004 patients were registered with all types of TB, 6471 with smear-positive pulmonary tuberculosis (PTB), 5305 with smear-negative PTB and 4228 with extra-pulmonary tuberculosis (EPTB). Of patients with all types of TB, 3720 (23%) died: death rates were 22% in smear-positive PTB, 26% in smear-negative PTB and 22% in EPTB. Month of death was known in 3371 patients (91% of those who died) and day of death in 3326 patients (89% of those who died). In patients who died, 19% of deaths occurred by day 7 and 41% by the end of the first month of treatment. A higher proportion of early deaths occurred in patients with smear-negative PTB and EPTB and in relation to increasing age. CONCLUSIONS: There was a high overall death rate in TB patients registered in 1997, with 40% of deaths occurring in the first month of treatment. Strategies to combat this problem are needed.     

Relationship between whole-blood interferon-gamma responses and the risk of active tuberculosis

We have analyzed the relationship between the responses to the diagnostic method for Mycobacterium tuberculosis (Mtb) infection, QuantiFERON-TB Gold (QFT-G), and the risk of developing active tuberculosis (TB). Contacts under 42 years old who were exposed to a patient with infectious pulmonary TB were tested using QFT-G during an investigation. Among 172 contacts, 111 (64.5%) were QFT-G positive. All subjects were evaluated for active TB by chest X-ray examination and, if needed, by CT scan at the time of the QFT-G test and 39 were diagnosed with active TB based on radiological abnormalities consistent with TB. Of these, 35 (89.7%) were QFT-G positive. Statistically the geometric mean of interferon-gamma (IFN-gamma) production levels of the active TB group was significantly larger than that of the latent TB infection group (p=0.013). The results of the multivariate analysis clearly showed that a combined parameter of ESAT-6 and CFP-10 significantly contributes to disease risk for the infected subjects. Our results suggest that subjects with high levels of IFN-gamma production in response to either ESAT-6 and/or CFP-10 in the QFT-G test have a higher possibility of developing active TB than QFT-G positive subjects with lower levels of IFN-gamma.     

Comparison of two commercial interferon-gamma assays for diagnosing Mycobacterium tuberculosis infection.

The clinical usefulness of ex vivo interferon-gamma assays may largely depend on the assay format and epidemiological status of tuberculosis (TB) in the region studied. From July 2004 to June 2005 a prospective comparison study was undertaken at a tertiary referral hospital in South Korea. The results of tuberculin skin tests (TST) and the commercially available QuantiFERON-TB Gold (QFT-G) and T SPOT-TB (SPOT) assays were compared in an intermediate TB-burden country. Of the 224 participants studied, results from all three tests (TST, QFT-G, and SPOT) were available in 218; 87 with active TB and 131 at a low risk for TB. Using 10 mm as a cut-off for TST, SPOT sensitivity (96.6%) was significantly higher than that seen for TST (66.7%) and QFT-G (70.1%). QFT-G showed superior specificity over TST (91.6 versus 78.6%). Although the specificity of QFT-G was higher than that of SPOT (91.6 versus 84.7%), the difference was not statistically significant. Whilst some differences were found in the performance of the two commercialised interferon-gamma assays, they seemed to be superior in their detection of Mycobacterium tuberculosis infection compared with tuberculin skin tests. The most appropriate choice of interferon-gamma assay to use may depend on the clinical setting.     

Extra-pulmonary manifestations in a large metropolitan area with a low incidence of tuberculosis.

BACKGROUND: The increases in extra-pulmonary tuberculosis (EPTB) have been largely due to human immunodeficiency virus co-infection. The rates of EPTB have remained constant despite the decline in pulmonary tuberculosis (PTB) cases. OBJECTIVE: To evaluate covariates associated with EPTB. METHODS: A 4-year cohort of EPTB patients was compared with PTB cases. Enrollees were assessed for TB risk, medical records were reviewed, and Mycobacterium tuberculosis isolates were fingerprinted. RESULTS: We identified 538 EPTB cases (28.6%) in a total of 1878 enrollees. The most common sites of infection were lymph nodes (43%) and pleura (23%). EPTB cases included 320 (59%) males, 382 (71%) patients were culture-positive, and 332 (86.9%) patient isolates were fingerprinted. Fewer EPTB than PTB patients belonged to clustered M. tuberculosis strains (58% vs. 65%; P = 0.02). A multivariate model identified an increased risk for EPTB among African Americans (OR = 1.9, P = 0.01), HIV-seropositive (OR = 3.1, P < 0.01), liver cirrhosis (OR = 2.3, P = 0.02), and age <18 years (OR = 2.0, P = 0.04). Patients with concomitant pulmonary and extra-pulmonary infections were more likely to die within 6 months of TB diagnosis (OR = 2.3, P < 0.01). CONCLUSIONS: African American ethnicity is an independent risk factor for EPTB. Mortality at 6 months is partly due to the dissemination of M. tuberculosis and the severity of the underlying co-morbidity.     

Clinical and epidemiological evaluation of tuberculosis in Serbia, 1990-2004.

SETTING: Republic of Serbia, excluding Kosovo. OBJECTIVE: To estimate the clinical and epidemiological pattern of tuberculosis (TB) in Serbia during the period 1990-2004. DESIGN: A retrospective analysis of clinical and epidemiological data on TB patients registered in annual TB reports. RESULTS: During the 15-year period, TB incidence levelled off in Serbia. The slightly decreasing trend occurred in both total pulmonary TB (PTB) and laboratory confirmed PTB (PTB+) incidence (P > 0.05), while the trend of extra-pulmonary TB (EPTB) incidence increased slightly (P > 0.05). During the same period, TB mortality showed a significantly decreasing trend (P < 0.05). The mean annual proportion of PTB+ cases among newly reported PTB cases was 62.7%. The mean proportion of EPTB cases among total TB cases was 6.1%. The mean percentage of cases with resistance to at least one anti-tuberculosis drug was 4.8%. CONCLUSION: Thanks to the good organisation and efficient work of anti-tuberculosis dispensaries in Serbia, as well as to the low incidence of AIDS and low frequency of Mycobacterium tuberculosis resistant strains, TB incidence did not increase during the period observed and TB mortality significantly decreased, despite markedly deteriorated socio-economic conditions during the 1990s.     

Effectiveness of the combination of a whole-blood interferon-gamma assay and the tuberculin skin test in detecting latent tuberculosis infection in rheumatoid arthritis patients receiving adalimumab therapy

OBJECTIVE: To investigate QuantiFERON-tuberculosis Gold (QFT-G) assay and tuberculin skin test (TST) for latent tuberculosis (TB) infection (LTBI) in patients with rheumatoid arthritis (RA) treated with adalimumab. METHODS: We prospectively followed up 43 RA patients who received adalimumab therapy and underwent serial TSTs and QFT-G assays. TST was performed using Mantoux method and QFT-G assay was examined by measuring interferon-gamma levels in whole blood samples that were incubated with early secretary antigenic target-6 and culture filtrate protein 10. RESULTS: Before starting adalimumab therapy, 8 RA patients (18.6%) had positive and 35 (81.4%) had negative TST results. All 8 RA patients with positive TST results were diagnosed as LTBI and received isoniazid prophylaxis (INHP) 1 month before starting adalimumab therapy. None of these 8 RA patients developed active TB 2 years after completing INHP. A high rate (10 [37.0%] patients) of TST conversion was observed among 27 patients who had completed 12-month adalimumab therapy. Of these 10 patients with TST conversion, 2 patients had positive QFT-G results and 1 developed active TB disease. Among 17 RA patients who did not have TST conversion after 12-month adalimumab therapy, 1 patient who had a positive QFT-G result developed active TB disease. Of all 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB after starting adalimumab therapy. CONCLUSION: The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy. Combined QFT-G assay and TST can aid in detecting LTBI in RA patients receiving adalimumab therapy.     

Comparison of two interferon-gamma assays and tuberculin skin test for tracing tuberculosis contacts

BACKGROUND: The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. OBJECTIVE: To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. METHODS: When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. RESULTS: Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. CONCLUSIONS: Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values.     

Comparison of extra-pulmonary and pulmonary tuberculosis cases: factors influencing the site of reactivation.

SETTING: Mycobacterium tuberculosis bacilli spread by the hematogenous route during primary infection and reactivate later. OBJECTIVE: To compare factors influencing the reactivation site. DESIGN: A total of 236 pulmonary tuberculosis (PTB) and 139 extra-pulmonary TB (EPTB) cases were compared in terms of age, co-morbid disease, immunosuppressive drug use, history of contact with a PTB case in a close relative, history of tuberculosis, smoking habit and alcohol intake. RESULTS: The sex ratio of EPTB and PTB cases was significantly different (P < 0.001): respectively 74% of EPTB cases and 34% of PTB cases were females; 53.3% of PTB cases and 23% of EPTB cases were smokers (P < 0.001); and the disease appeared within the first 5 years after contact in 23.7% of EPTB cases compared to 72.6% in PTB cases (P < 0.001). In logistic regression analysis, gender (OR = 3.69), smoking habit (OR = 0.54) and interval between contact and disease (OR = 1.07) were found to influence the reactivation site. CONCLUSION: The probability of PTB development was higher in males, in smokers and within the first 5 years of contact. In contrast, the probability of EPTB development was higher in females and after 5 years of contact.     

Waning of the specific interferon-gamma response after years of tuberculosis infection.

HYPOTHESIS: Memory T-cell responses to specific antigens wane over time in subjects with tuberculosis (TB) infection. SETTING: Accumulated evidence indicates that QuantiFERON-TB Gold (QFT-G), a specific whole-blood interferon-gamma (IFN-gamma) based assay, can detect recent TB infections with superior sensitivity and specificity. OBJECTIVE: We applied this technique to the adult population of a Japanese community to determine its epidemiological usefulness. METHOD: A total of 1559 subjects attending periodic health screening volunteered to participate in the study. RESULTS: The QFT-G positive rates were 3.1% for those aged 40-49 years, 5.9% for those aged 50-59 and 9.8% for those aged 60-69. The expected infection prevalence estimated by the authors from a series of studies was 11.1%, 29.6% and 53.1% for those aged 40-49, 50-59 and 60-69 years, respectively. This wide gap between the expected and observed positivity suggests that the IFN-gamma response waned substantially with time after infection. Those with X-rays suggestive of old TB lesions exhibited positivity rates well below 100%. CONCLUSION: The specific IFN-gamma response may wane considerably with time after infection. Longitudinal studies are required to investigate long-term dynamics of cell-mediated immunity in infected donors.     

Use of the QuantiFERON-TB Gold In-Tube test to monitor treatment efficacy in active pulmonary tuberculosis

SETTING: Cohort study at a tertiary care hospital. OBJECTIVE: To assess the potential use of QuantiFERON-TB Gold In-Tube (QFT-G) in monitoring clinical response to anti-tuberculosis treatment. DESIGN: We conducted a cohort study of 76 active pulmonary tuberculosis patients with serial testing by QFT-G at baseline and after 2 and 6 months of treatment. At these time points, we compared the performance of QFT-G with sputum culture status of the study subjects. RESULTS: Compared to baseline, 59 (77.6%) cases showed a decline whereas 17 (22.4%) showed persistent or stronger interferon-gamma (IFN-gamma) responses at 2 months. Using robust statistical methods, we observed that QFT-G assessment at 2 months independently and significantly predicted the likelihood of remaining sputum culture-positive at the end of the intensive phase of anti-tuberculosis treatment. A higher IFN-gamma concentration by 1 international unit (IU)/ml corresponded to a 45% (95%CI 8-97) higher likelihood of failing to convert to a negative culture, whereas a rising or persistent IFN-gamma response was associated with a 17.3 (P = 0.007) times higher likelihood of remaining culture-positive at 2 months. CONCLUSIONS: Our results suggest that QFT-G can potentially be used as a tool to monitor the efficacy of anti-tuberculosis treatment.     

Extra-pulmonary tuberculosis at a regional hospital in Thailand

The purpose of this study was to analyze the cases of extra-pulmonary tuberculosis (EPTB) at Maharat Nakhon Ratchasima Hospital, a tertiary care regional hospital in Northeast Thailand. There were 398 cases of EPTB (46.9%) and 450 cases of pulmonary tuberculosis (PTB) (53.1%). The mean age of EPTB patients (47.58 years) was lower than that of PTB patients (51.6 years) (p < 0.01). Human Immunodeficiency Virus (HIV) seropositivity was found in 50 cases of EPTB (12.6%) and 55 cases of PTB (12.2%) which was not significantly different. The common sites of extra-pulmonary involvement were the lymph nodes (29.7%), followed by the pleura (27.4%), the bones and spine (25.1%), the meninges and brain (4.5%), the pericardium (3.5%) and the gastrointestinal tract (3.0%). Disseminated TB occurred in only 8 cases (2.0%). HIV seropositivity rates were more common in disseminated TB (OR 41.51, 95% CI 4.98-34.5), TB of the meninges and brain (OR 4.47, 95% CI 1.57-12.6) and TB of the lymph nodes (OR 3.49, 95% CI 1.86-6.54) and were less common in TB of the bones and spine (OR 0.05, 95% CI 0.01-0.37) and TB of the pleura (OR 0.24, 95%CI 0.09-0.63).     

Extra-pulmonary tuberculosis: a biomarker analysis

Introduction

Studies on biomarkers in tuberculosis are focused on pulmonary forms of this disease (PTB), and only limited information is currently available on biomarkers of extra-pulmonary tuberculosis (EPTB).

Methods

Serum samples from 24 patients with PTB, 29 patients with EPTB and 27 healthy controls were obtained, and the levels of interferon-gamma, chemokine ligand 9, mannose-binding lectin (MBL), tumor marker Ca-125 and adenosine deaminase were determined.

Results

The circulating levels of all tested biomarkers in the serum were significantly higher in PTB and EPTB patients than in controls. However, there were no significant differences in the levels of the biomarkers between patients with PTB and EPTB, with the exception of serum levels of MBL which were significantly higher in patients with EPTB than in patients with PTB (p = 0.01). In patients with EPTB, no significant differences were observed in biomarker levels among patients with or without concomitant PTB involvement. Based on MBL serum levels, ROC curve analysis showed an AUC of 0.85 for EPTB versus non-EPTB. The optimal cut-off value of MBL serum levels for EPTB versus non-EPTB was 1,000 μg/ml, with a sensitivity and specificity of 79.3 and 78.0 %, respectively.

Conclusions

Biomarkers usually present as acute phase reactants and do not enable pulmonary forms to be differentiated from more serious or extra-pulmonary forms. MBL may be an exception.     

Prospective study of SEVA TB peroxidase assay for cocktail antigen and antibody in the diagnosis of Tuberculosis in suspected patients attending a tertiary care hospital located in rural area

ObjectiveTo evaluate inhouse developed SEVA TB peroxidase enzyme immunoassay using cocktail of mycobacterial excretory-secretory antigens (ES-31, ES-43 & EST-6) for antibody detection and their affinity purified antibodies for antigen detection in tuberculosis suspected patients.MethodsInhouse developed SEVA TB peroxidase enzyme immunoassay was evaluated prospectively in 73 suspected pulmonary and 46 extra-pulmonary tuberculosis patients during November 2008～March 2009 in a tertiary hospital located in rural area.ResultsAssay on prospective analysis showed 100% correlation of pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (EPTB) acid fast bacilli positivity and antitubercular treatment in 11 cases. Thirty nine PTB and 12 EPTB cases showed negative for ELISA test and were also not given antitubercular therapy. However 30 PTB and 27 EPTB cases showing ELISA positivity were neither acid fast bacilli positive nor antitubercular therapy treated. These cases may possibly have dormant infection and need further diagnosis. In EPTB cases ELISA was observed to be more useful than AFB smear test.ConclusionsThis inhouse developed user-friendly peroxidase ELISA can be used as an adjunct test of smear microscopy or culture techniques for routine screening of patients suspected of PTB or EPTB.     

Usefulness of whole-blood interferon-gamma assay and interferon-gamma enzyme-linked immunospot assay in the diagnosis of active pulmonary tuberculosis

PURPOSES: The aim of this study was to evaluate the usefulness of the whole-blood interferon-gamma assay (enzyme-linked immunosorbent assay [ELISA]) and interferon-gamma enzyme-linked immunospot assay (ELISPOT) based on early secretory antigenic target 6 and culture filtrate protein 10 in the diagnosis of active pulmonary tuberculosis (TB) in routine clinical practice. METHOD: We conducted a prospective study enrolling 144 participants with suspected pulmonary TB in a tertiary referral hospital in Seoul, South Korea, to investigate the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tests. Clinical assessment, tuberculin skin test (TST), whole-blood interferon-gamma ELISA (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia), and an ELISPOT assay (T SPOT.TB; Oxford Immunotec; Oxford, UK) were performed. Test results were compared with the final confirmed diagnoses. RESULTS: Active pulmonary TB was diagnosed in 67 of 144 participants (47%). Sensitivities of QFT-G and T SPOT.TB for active pulmonary TB were 89% (95% confidence interval [CI], 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%; 95% CI, 69 to 93%) and T SPOT.TB (87%; 95% CI, 73 to 96%) were higher than that of TST (64%; 95% CI, 51 to 76%) [p = 0.001 and p < 0.001, respectively]. CONCLUSION: High NPVs of QFT-G and T SPOT.TB for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB, although the low PPV limits their usefulness in routine clinical practice in South Korea, where the prevalence of latent TB infection is considerable.     

Risk factors for delay in the diagnosis and treatment of tuberculosis at a referral hospital in Rwanda.

SETTING: Kigali University Hospital, the main referral centre for TB in Rwanda. OBJECTIVE: To evaluate delays in the diagnosis and treatment of tuberculosis (TB) and associated risk factors. DESIGN: Prospective data collection of patients treated for pulmonary TB (PTB) or extra-pulmonary TB (EPTB) between June and September 2006. RESULTS: Of 104 patients with a mean age of 35 years (range 17-84) recruited into the study, 62% were HIV-positive. EPTB was diagnosed in 60 cases. The median total, health care and patient delays were respectively 57, 28 and 25 days. The health system delay before referral was significantly longer than the delay at our institution (18 vs. 6 days, P<0.0001). Risk factors for a longer health system delay at our institution were smear-negative PTB or EPTB (OR 5.12) and a trial of antibiotics (OR 2.96). The latter was also found to significantly prolong total delay (OR 2.85), as did rural residence (OR 4.86). No significant association was found between patient delay and age, sex, profession or health insurance status. CONCLUSION: Smear-negative PTB and EPTB were associated with longer health system delays. A trial of antibiotics significantly increased the health system delay. Its use, recommended by the World Health Organization in case of smear-negative TB and EPTB in developing countries, needs validation at the tertiary health care level.     

Sensitivity of a Whole-Blood Interferon-Gamma Assay Among Patients with Pulmonary Tuberculosis and Variations in T-Cell Responses During Anti-Tuberculosis Treatment

Abstract Background: Interferon-γ (IFN-γ) assays are new tests for tuberculosis (TB) infection, and T-cell responses may be correlated with antigen burden. However, it is unclear if IFN-γ assays can be used to monitor response to TB treatment. Materials and Methods: We measured T-cell responses to TB specific antigens in 60 Indian patients with microbiologically confirmed active pulmonary tuberculosis, before, during, and after TB treatment. Most patients were hospitalized and had moderate to advanced disease. IFN-γ responses were measured using the commercial whole-blood Quanti-FERON-TB Gold In Tube (QFT-G) assay at three time-points: at diagnosis (N = 60), after 2 months of intensive treatment (N = 47), and at 6 months (treatment completion) (N = 39). Results: At baseline, 44 of 60 (73%) patients were positive by QFT-G. At the second time-point, 38 of 47 (81%) patients were positive. At treatment completion, 31 of 39 (79%) patients were positive. Changes in IFN-γ responses over time were highly inconsistent - some individuals showed increases, while others showed decreases or no changes. Although the average IFN-γ levels decreased slightly during treatment (not significant), the QFT-G sensitivity remained mostly unchanged during therapy. Conclusions: Our data suggest that the QFT-G assay has modest sensitivity in patients with moderate to advanced pulmonary disease, but our results do not show a clear correlation between antigen burden and T-cell responses. Further research is needed to understand the kinetics of Tcell responses during TB treatment. M. Pai and R. Joshi contributed equally to this work.     

Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany

OBJECTIVES: To assess the cost-effectiveness of the new QuantiFERON-TB Gold In-Tube (QFT-G) [Cellestis; Carnegie, VIC, Australia] assay for screening and treating of persons who have had close contact with tuberculosis (TB) patients and are suspected of having latent tuberculosis infection (LTBI) [hereafter called close-contacts] in Germany. METHODS: The health and economic outcomes of isoniazid treatment of 20-year-old close-contacts were compared in a Markov model over a period of 20 years, using two different cutoff values for the tuberculin skin test (TST), the QFT-G assay alone, or the QFT-G assay as a confirmatory test for the TST results. RESULTS: QFT-G assay-based treatment led to cost savings of $542.9 and 3.8 life-days gained per LTBI case. TST-based treatment at a 10-mm induration size cutoff gained $177.4 and 2.0 life-days gained per test-positive contact. When the cutoff induration size for the TST was reduced to 5 mm, the incremental cost-effectiveness ratio fell below the willingness-to-pay threshold ($30,170 per life-years gained) but resulted in unnecessary treatment of 77% of contacts owing to false-positive TST results. Combination with the 5-mm induration size TST cutoff value compared to the results of the QFT-G assay alone reduced the total costs per 1,000 contacts by 1.8% to $222,869. The number treated to prevent 1 TB case was 22 for the two QFT-G assay-based procedures, 40 for the TST at a cutoff induration size of 10 mm, and 96 for the TST at a cutoff induration size of 5 mm. When the sensitivity rates of the TST and the QFT-G assay were compounded, the QFT-G assay strategy alone was slightly less costly (0.6%) than the two-step approach. CONCLUSIONS: Using the QFT-G assay, but especially combining the QFT-G assay following the TST screening of close-contacts at a cutoff induration size of 5 mm before LTBI treatment is highly cost-effective in reducing the disease burden of TB.     

Detection of Mycobacterium tuberculosis infection in United States Navy recruits using the tuberculin skin test or whole-blood interferon-gamma release assays.

BACKGROUND: Military personnel are at risk for acquiring Mycobacterium tuberculosis infection because of activities in close quarters and in regions with a high prevalence of tuberculosis (TB). Accurate tests are needed to avoid unnecessary treatment because of false-positive results and to avoid TB because of false-negative results and failure to diagnose and treat M. tuberculosis infection. We sought to estimate the specificity of the tuberculin skin test (TST) and 2 whole-blood interferon-gamma release assays (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) and to identify factors associated with test discordance. METHODS: A cross-sectional comparison study was performed in which 856 US Navy recruits were tested for M. tuberculosis infection using the TST, QFT, and QFT-G. RESULTS: Among the study subjects, 5.1% of TSTs resulted in an induration > or = 10 mm, and 2.9% of TSTs resulted in an induration > or = 15 mm. Eleven percent of QFT results and 0.6% of QFT-G results were positive. Assuming recruits at low risk for M. tuberculosis exposure were not infected, estimates of TST specificity were 99.1% (95% confidence interval [CI], 98.3%-99.9%) when a 15-mm cutoff value was used and 98.4% (95% CI, 97.3%-99.4%) when a 10-mm cutoff value was used. The estimated QFT specificity was 92.3% (95% CI, 90.0%-94.5%), and the estimated QFT-G specificity was 99.8% (95% CI, 99.5%-100%). Recruits who were born in countries with a high prevalence of TB were 26-40 times more likely to have discordant results involving a positive TST result and a negative QFT-G result than were recruits born in countries with a low prevalence of TB. Nineteen (50%) of 38 recruits with this type of discordant results had a TST induration > or = 15 mm. CONCLUSIONS: The QFT-G and TST are more specific than the QFT. No statistically significant difference in specificity between the QFT-G and TST was found using a 15-mm induration cutoff value. The discordant results observed among recruits with increased risk of M. tuberculosis infection may have been because of lower TST specificity or lower QFT-G sensitivity. Negative QFT-G results for recruits born in countries where TB is highly prevalent and whose TST induration was > or = 15 mm suggest that the QFT-G may be less sensitive than the TST. Additional studies are needed to determine the risk of TB when TST and QFT-G results are discordant.