Dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon gamma response at the time of diagnosis.

OBJECTIVES: In the performance of interferon gamma release assays (IGRA) for the diagnosis of tuberculosis (TB) infection, false-negative results are a major obstacle. In active TB patients, treatment-dependent changes of the negative test results remain unknown. METHODS: The treatment course of 19 smear-positive/culture-confirmed TB patients who had IGRA-negative results by QuantiFERON-TB in-tube (QFT-IT) method at the time of diagnosis (month 0) in a previous study, were monitored in the present study. Blood was further collected at months 2 and 7, and the concentrations of 27 immune molecules were measured in the plasma supernatants remaining after performing the IGRA, using a suspension array system. RESULTS: After initiating treatment, eight of the 19 QFT-IT-negative patients showed positive conversion, whereas the remaining 11 (58%) did not; the interferon gamma (IFN-γ) response was restored to levels higher than 1 IU/ml in only three of the eight patients with positive conversion. Plasma concentrations of interleukin 1 receptor antagonist, interleukin 2, and interferon gamma-induced protein 10 remained low after Mycobacterium tuberculosis-specific antigen stimulation at months 2 and 7 in the continuously QFT-IT-negative group, whereas the parameters were elevated only in the transiently QFT-IT-negative group. CONCLUSIONS: It was demonstrated that a majority of active TB patients showing negative IGRA results did not regain sufficient levels of immune responsiveness despite successful treatment.

Use of the QuantiFERON®-TB Gold in Tube test for screening TB contacts and predictive value for active TB.

BACKGROUND: This study estimated the incidence of progression to active tuberculosis (TB) among contacts categorized by QuantiFERON(®)-TB Gold in Tube (QFT-GIT) test results and investigated other risk factors related to progression to TB. METHODS: Contacts of patients with TB were tested using QFT-GIT and were followed up every 6 months at public health centers to detect clinical progression to TB. RESULTS: Analysis of a retrospective cohort revealed that, of the 625 contacts, 168 were QFT-GIT positive and 457 were negative. Of these, 10 (6%) QFT-GIT-positive and two (0.4%) QFT-GIT-negative contacts progressed to TB during the follow-up period (p < 0.01, statistically significant). Multivariable logistic regression analysis revealed that QFT-GIT positivity (p < 0.01), contact of index patients with many other positive contacts (p < 0.01), household contact (p = 0.014), and untreated latent TB infection (p = 0.047) were independent risk factors for progression to TB during an average follow-up period of 637 days. CONCLUSIONS: Progression to TB among QFT-GIT-positive contacts was higher than among QFT-GIT-negative contacts. Other independent risk factors for progression to TB were index cases with more QFT-GIT-positive contacts as well as household contacts.

[Comparison of tests results between T-SPOT.TB and QuantiFERON-TB Gold In-Tube in a contact investigation].

BACKGROUND: We compared T-SPOT.TB (T-SPOT) and QuantiFERON-TB Gold In-Tube (QFT-GIT) test results in a contact investigation. SUBJECTS AND METHODS: The index case was a male lecturer at a vocational school in Tokyo. Chest X-ray examinations and T-SPOT tests were performed on all 397 contacts, and QFT-GIT was performed on a subset of these contact subjects. RESULTS: Chest X-ray examination showed no evidence of tuberculosis in any subjects. Among 389 contacts that underwent T-SPOT testing, 5 showed a positive reaction, 3 showed borderline reactions (1 positive borderline and 2 negative borderline), and 381 were negative. Among 56 contacts tested using both QFT-GIT and T-SPOT, 4 were positive, 1 was borderline, and 51 were negative by QFT-GIT. By T-SPOT, 2 contacts were positive, 1 was borderline positive, and 53 were negative. Preventive chemotherapy was indicated for the 5 positive and 1 borderline positive contacts identified by the T-SPOT test. DISCUSSION: Chest X-ray examination and the T-SPOT test did not identify the TB outbreak. CONCLUSION: The majority of contact subjects were negative by both tests, suggesting that both have a high specificity in contact investigations. However, the moderate concordance rate indicates that further testing is necessary to fully evaluate these tests.

Association between tuberculosis recurrence and interferon-γ response during treatment.

OBJECTIVES: We investigated the relationship between tuberculosis recurrence and Mycobacterium tuberculosis antigen-stimulated interferon-gamma (IFN-γ) responses during treatment. METHODS: Plasma IFN-γ levels in active pulmonary tuberculosis patients (n = 407) were analyzed using QuantiFERON-TB Gold In-Tube™ (QFT-IT) at 0, 2, and 7 months of the 8-month treatment received from 2007 to 2009 and the patients were followed up for another 16 months after treatment. Risk factors for recurrence were assessed using the log-rank test and Cox proportional hazard models. Random coefficient models were used to compare longitudinal patterns of IFN-γ levels between groups. RESULTS: QFT-IT showed positive results in 95.6%, 86.2%, and 83.5% at 0, 2, and 7 months, respectively. The antigen-stimulated IFN-γ responses varied significantly during the treatment course (P < 0.0001). Unexpectedly, positive-to-negative conversion of QFT-IT results between 0 and 2 months was significantly associated with earlier recurrence (adjusted hazard ratio, 5.57; 95% confidence interval, 2.28-13.57). Time-dependent changes in IFN-γ levels were significantly different between the recurrence and nonrecurrence groups (P < 0.0001). CONCLUSIONS: Although the IGRA response varies individually, early response during the treatment course may provide an insight into host immune responses underlying tuberculosis recurrence.

Expansion of functional human mucosal-associated invariant T cells via reprogramming to pluripotency and redifferentiation.

Mucosal-associated invariant T (MAIT) cells play an important physiological role in host pathogen defense and may also be involved in inflammatory disorders and multiple sclerosis. The rarity and inefficient expansion of these cells have hampered detailed analysis and application. Here, we report an induced pluripotent stem cell (iPSC)-based reprogramming approach for the expansion of functional MAIT cells. We found that human MAIT cells can be reprogrammed into iPSCs using a Sendai virus harboring standard reprogramming factors. Under T cell-permissive conditions, these iPSCs efficiently redifferentiate into MAIT-like lymphocytes expressing the T cell receptor Vα7.2, CD161, and interleukin-18 receptor chain α. Upon incubation with bacteria-fed monocytes, the derived MAIT cells show enhanced production of a broad range of cytokines. Following adoptive transfer into immunocompromised mice, these cells migrate to the bone marrow, liver, spleen, and intestine and protect against Mycobacterium abscessus. Our findings pave the way for further functional analysis of MAIT cells and determination of their therapeutic potential.

Global evidence directing regional preventive strategies in Southeast Asia for fighting TB/HIV.

Tuberculosis (TB) and human immunodeficiency virus (HIV) co-epidemics form a huge burden of disease in the Southeast Asia region. Five out of eleven nations in this region are high TB/HIV burden countries: Myanmar, Thailand, India, Indonesia and Nepal. The trends of TB incidence in these countries have been rising in recent years, in contrast to a falling global trend. Experts in the field of TB control and health service providers have been perplexed by the association of TB and HIV infections which causes a mosaic clinical presentation, a unique course with poor treatment outcomes including death. We conducted a review of contemporary evidence relating to TB/HIV control with the aims of assisting integrated health system responses in Southeast Asia and demystifying current evidence to facilitate translating it into practice.

Analysis of factors lowering sensitivity of interferon-γ release assay for tuberculosis.

BACKGROUND: Imperfect sensitivity of interferon-γ release assay (IGRA) is a potential problem to detect tuberculosis. We made a thorough investigation of the factors that can lead to false negativity of IGRA. METHODS: We recruited 543 patients with new smear-positive pulmonary tuberculosis in Hanoi, Viet Nam. At diagnosis, peripheral blood was collected and IGRA (QuantiFERON-TB Gold In-Tube) was performed. Clinical and epidemiological information of the host and pathogen was collected. The test sensitivity was calculated and factors negatively influencing IGRA results were evaluated using a logistic regression model in 504 patients with culture-confirmed pulmonary tuberculosis. RESULTS: The overall sensitivity of IGRA was 92.3% (95% CI, 89.6%-94.4%). The proportions of IGRA-negative and -indeterminate results were 4.8% (95% CI, 3.1%-7.0%) and 3.0% (95% CI, 1.7%-4.9%). Age increased by year, body mass index <16.0, HIV co-infection and the increased number of HLA-DRB1*0701 allele that patients bear showed significant associations with IGRA negativity (OR = 1.04 [95% CI, 1.01-1.07], 5.42 [1.48-19.79], 6.38 [1.78-22.92] and 5.09 [2.31-11.22], respectively). HIV co-infection and the same HLA allele were also associated with indeterminate results (OR = 99.59 [95% CI, 15.58-625.61] and 4.25 [1.27-14.16]). CONCLUSIONS: Aging, emaciation, HIV co-infection and HLA genotype affected IGRA results. Assessment of these factors might contribute to a better understanding of the assay.

[QFT test and TST test in diagnosis of TB infection].

At present, there are only two methods to diagnose tuberculosis infection in the world, tuberculin skin test (TST) and interferon gamma release assays (IGRAs). Since TST could show positive responses due to BCG vaccination or infection of non-tuberculous mycobacterium and BCG vaccination is widely done in Japan, TST has a critical problem in its specificity. QuantiFERON-TB Gold (QFT-G/QFT-3G) is one of IGRAs and uses M. tuberculosis-specific antigens (ESAT-6, CFP-10, TB7.7) for stimulation of whole blood to induce IFN-gamma production by antigen-specific T cells. Produced IFN-gamma is measured by ELISA system. IFN-gamma is produced by individuals with TB infection but not by BCG-vaccinated individuals without TB infection. As QFT can detect TB infection among BCG vaccinated individuals more accurately than TST, it is possible to diagnose TB infection efficiently in contact investigation so on. However, as same as TST, QFT cannot discriminate between remote infection and recent infection, nor between progressive infection and controllable recent infection. Since QFT is newly development TB diagnosis test, there are many subjects in the QFT test system. For example, one subject is that accurate QFT results among immunocompromised populations are difficult to obtain because of weak immune responses. After these many research data are accumulated, we will be able to have many solutions in QFT.

Analysis of an interferon-gamma release assay for monitoring the efficacy of anti-tuberculosis chemotherapy.

The reported effect of anti-tuberculosis chemotherapy on interferon-gamma (IFN-γ) release in response to specific Mycobacterium tuberculosis antigens has been inconsistent. The objective of this study was therefore to determine the effect of anti-tuberculosis chemotherapy on IFN-γ response to ESAT-6 and CFP-10. QuantiFERON®-TB Gold (QFT-G) was performed, and the IFN-γ response to ESAT-6 and CFP-10 were measured, for 50 people with culture-confirmed tuberculosis prior to initiating treatment and periodically for up to 120 weeks following initiation of said treatment. IFN-γ responses and bacteriological response were compared. The average IFN-γ response to ESAT-6 and CFP-10 and the proportion of QFT-G results that were positive decreased during chemotherapy and for several weeks thereafter, reaching lows at weeks 48 to 56. Furthermore, these measures were lower at 48 weeks for those with bacteriological reversion prior to the second monthly visit than for those with slower reversion. Although it was shown that anti-tuberculosis treatment generally reduced the specific release of IFN-γ, the effect is so variable that it could be used as a monitor of progress of chemotherapy with great care and reservation.

Performance of a Whole-Blood Interferon-Gamma Release Assay with Mycobacterium RD1-Specific Antigens among HIV-Infected Persons.

OBJECTIVE: To evaluate the usefulness of one of IGRAs, QuantiFERON-TB Gold (QFT-G), in human immunodeficiency virus- (HIV-) infected patients with various CD4(+) T cell counts. METHODS: The QFT-G assay was performed using QFT-G kits among 107 HIV-infected patients including 9 cases with active tuberculosis (TB). RESULTS: In HIV-infected patients with CD4(+) > 50/microL, QFT-G positive rate for active TB patients was 5/6 (sensitivity = 83%), and that for those without active disease was 1/69 (specificity = 99%). The frequency of indeterminate QFT-G test was significantly higher in those with CD4(+) less than 50/microL (P < .0001). At the same time there was a proportional relationship between CD4(+) and interferon-gamma response to mitogen (positive control) in QFT-G test (P = .0001). Conclusions. Our data suggested that QFT-G had high sensitivity and specificity in HIV-infected populations with CD4(+) greater than 50/microL. However, QFT-G did not perform well in HIV-positive patients with CD4(+) less than 50/microL.

Prevalence and risk factors for tuberculosis infection among hospital workers in Hanoi, Viet Nam.

BACKGROUND: Transmission of tuberculosis (TB) to health care workers (HCWs) is a global issue. Although effective infection control measures are expected to reduce nosocomial TB, HCWs' infection has not been assessed enough in TB high burden countries. We conducted a cross-sectional study to determine the prevalence of TB infection and its risk factors among HCWs in Hanoi, Viet Nam. METHODOLOGY/PRINCIPAL FINDINGS: A total of 300 HCWs including all staff members in a municipal TB referral hospital received an interferon-gamma release assay (IGRA), QuantiFERON-TB Gold In-Tube(TM), followed by one- and two-step tuberculin skin test (TST) and a questionnaire-based interview. Agreement between the tests was evaluated by kappa statistics. Risk factors for TB infection were analyzed using a logistic regression model. Among the participants aged from 20 to 58 years (median = 40), prevalence of TB infection estimated by IGRA, one- and two-step TST was 47.3%, 61.1% and 66.3% respectively. Although the levels of overall agreement between IGRA and TST were moderate, the degree of agreement was low in the group with BCG history (kappa = 0.29). Working in TB hospital was associated with twofold increase in odds of TB infection estimated by IGRA. Increased age, low educational level and the high body mass index also demonstrated high odds ratios of IGRA positivity. CONCLUSIONS/SIGNIFICANCE: Prevalence of TB infection estimated by either IGRA or TST is high among HCWs in the hospital environment for TB care in Viet Nam and an infection control program should be reinforced. In communities with heterogeneous history of BCG vaccination, IGRA seems to estimate TB infection more accurately than any other criteria using TST.

[Research agenda of interferon-gamma release assays].

Recently, new diagnostic tests for tuberculosis infection that are more specific than tuberculin skin tests have been developed and have become commercially available. These tests determine interferon-gamma production after stimulation with M. tuberculosis-specific antigens, ESAT-6 and CFP-10, and are named Interferon-Gamma Release Assays (IGRA). Currently, two IGRA formats are available. One is QuantiFERON TB-2G (QFT-2G, called Quanti FERON-TB Gold outside Japan), which uses the whole blood and has been approved as a diagnostic test for tuberculosis infection in Japan. The use of QFT-2G was recommended for contact investigations in the revised guidelines in 2006. The other format of IGRA is T-SPOT.TB (T-SPOT), which uses peripheral blood mononuclear cells. T-SPOT has not yet been approved in Japan. IGRA was developed just recently, so there are many research questions to be addressed. In 2007, Pai et al. reported a comprehensive research agenda on IGRA). We introduced a review of Pai et al. in Japanese with reference to our published reports. The references in the review of Pai et al. appear as they are, and our new references are numbered with Roman numerals.

Quality assessment of an interferon-gamma release assay for tuberculosis infection in a resource-limited setting.

BACKGROUND: When a test for diagnosis of infectious diseases is introduced in a resource-limited setting, monitoring quality is a major concern. An optimized design of experiment and statistical models are required for this assessment. METHODS: Interferon-gamma release assay to detect tuberculosis (TB) infection from whole blood was tested in Hanoi, Viet Nam. Balanced incomplete block design (BIBD) was planned and fixed-effect models with heterogeneous error variance were used for analysis. In the first trial, the whole blood from 12 donors was incubated with nil, TB-specific antigens or mitogen. In 72 measurements, two laboratory members exchanged their roles in harvesting plasma and testing for interferon-gamma release using enzyme linked immunosorbent assay (ELISA) technique. After intervention including checkup of all steps and standard operation procedures, the second trial was implemented in a similar manner. RESULTS: The lack of precision in the first trial was clearly demonstrated. Large within-individual error was significantly affected by both harvester and ELISA operator, indicating that both of the steps had problems. After the intervention, overall within-individual error was significantly reduced (P < 0.0001) and error variance was no longer affected by laboratory personnel in charge, indicating that a marked improvement could be objectively observed. CONCLUSION: BIBD and analysis of fixed-effect models with heterogeneous variance are suitable and useful for objective and individualized assessment of proficiency in a multistep diagnostic test for infectious diseases in a resource-constrained laboratory. The action plan based on our findings would be worth considering when monitoring for internal quality control is difficult on site.

Contact investigation in a primary school using a whole blood interferon-gamma assay.

OBJECTIVES: To evaluate the usefulness of QuantiFERON-TB Gold (QFT-G) for children. METHODS: Students in a primary school exposed to a tuberculosis patient were investigated using the tuberculin skin test (TST), chest X-ray examination and sequential QFT-G tests. RESULTS: The first QFT-G test was conducted one month after the end of exposure for 308 of the 313 children, with 6 (1.9%) positive. TST results were obtained from 306 of the students at 2 months after exposure, and 200 (65.4%) had induration > or =5mm. A second QFT-G test, a further month later, and a third QFT-G test, six months after exposure, found an additional 2 positive and one weakly positive, respectively. Overall, the rate of QFT-G positivity was 9.8% (4/41) for close contact children (> or =90h exposure), significantly higher than for casual contacts (< or =18h exposure; 1.8%, 5/272; p=0.020), whereas there was no significant difference in TST positive rates (p=0.078). CONCLUSIONS: These data suggest that QFT-G has the same performance characteristics in BCG vaccinated children as it does in adults. The observation that none of the 297 students who were QFT-G negative had developed active TB after 3 years of follow-up suggests that QFT-G has a very high negative predictive value.

Comparison of performance in two diagnostic methods for tuberculosis infection.

Performance of two diagnoses, T-SPOT.TB (T-SPOT) and QuantiFERON-TB Gold (QFT-G), was compared in Japanese subjects. Forty-seven confirmed tuberculosis patients and eighty-four healthy subjects were recruited. All samples were assessed for both T-SPOT and QFT-G, and the sensitivities and the specificities were compared between two methods. The sensitivity was 100% for T-SPOT, and 87.2% for QFT-G. The specificity was 83.3 and 98.8%, respectively. The overall agreement of two tests was substantially high (Kappa coefficient = 0.671). The sensitivity of T-SPOT appeared to be higher than that of QFT-G, whereas the specificity of T-SPOT was significantly lower than that of QFT-G. The difference in the performance between T-SPOT and QFT-G and biological relevance of each system in diagnosing M. tuberculosis infection should be further explored.

[Effects of prophylaxis on QuantiFERON TB-2G responses among children].

OBJECTIVE: To study the effect of treatment of latent tuberculosis infection (LTBI) on QuantiFERON TB-2G (QFT-2G) test results. SUBJECTS AND METHODS: QFT-2G was used for a contact investigation in a junior high school and those positive or doubtful positive (TB Antigen-Nil response > or = 0.1 and < 0.35 IU/ml) were indicated for treatment of LTBI with INH. All subjects who completed treatment of LTBI were re-tested with QFT-2G approximately 1 month after completion of treatment and a subset were again re-tested 8 to 11 months after the completion of treatment. The levels of IFN-gamma response in each QFT-2G test were compared. RESULTS: Initially, 43 subjects (28 QFT-2G positive and 15 doubtful positive) were indicated treatment of LTBI, and 41 (95%) completed 6-months treatment. These 41 subjects were re-tested with QFT-2G approximately 1 month after the completion of treatment. Among 28 pre-treatment positives, 19 remained positive, 6 became doubtful positive, and 3 reverted to negative. Among 13 pre-treatment doubtful positives, 1 converted to positive, 5 remained doubtful positive, and 7 reverted to negative. The QFT-2G responses after the completion of treatment significantly declined compared with the pre-treatment level (geometric means; before treatment ESAT-6: 0.30 IU/ml, CFP-10: 0.09 IU/ml, after treatment ESAT-6:0.18 IU/ml, CFP-10: 0.05 IU/ml, dependent t-test; ESAT-6: p = 0.020, CFP-10: p = 0.005). At 8 to 11 months after the completion of treatment, 30 randomly selected subjects received the third QFT-2G test. Among 19 positives at the completion of treatment, 14 remained positive, 4 become doubtful positive, and 1 reverted to negative. Among 8 doubtful positives at completion of treatment, 4 converted to positive, 3 remained doubtful positive, and 1 reverted to negative. A further decline of QFT-2G responses was not observed. Three subjects negative at the completion of treatment were re-tested and remained negative at the third test. CONCLUSION: QFT-2G responses significantly declined after the treatment of LTBI, despite the rate of reversion in QFT-2G being low. This low reversion rate suggests QFT-2G would not be useful as a marker to evaluate the success of treatment for LTBI. However, the finding that QFT-2G responses significantly decline after the treatment of LTBI suggests the possibility that this decline could be used as a marker of the susceptibility of the infective M. tuberculosis strain to the prophylactic drug used. The outbreak investigation has been carried out for over two years, and none of 229 students who were TST positive, but QFT-2G negative and because of this result not indicated treatment of LTBI, have developed TB, suggesting that QFT-2G reflects TB infection more accurately than the TST, even in school children.

Assessment of nosocomial transmission of tuberculosis in a psychiatric hospital using a whole blood interferon-gamma assay.

We conducted a contact investigation in a psychiatric hospital to evaluate the nosocomial transmission of tuberculosis (TB). Contacts included hospital healthcare workers (HCWs) and inpatients who had been exposed to an index case of pulmonary TB. Contacts were evaluated for Mycobacterium tuberculosis infection with standard screening methods as well as the QuantiFERONR-TB Gold (QFT-G) test. A tuberculin skin test (TST) was administered to 3 individuals who were under 30 years old, and all tests were negative. Chest X-ray examination was performed for all 46 contacts (9 HCWs and 37 patients). Five had abnormal chest X-ray results that were not compatible with TB, and 41 had normal chest X-rays. As regards the QFT-G test, 23 of the 46 (50%) contacts, 1 HCW (an 81year-old male) and 22 patients, were positive. The results suggest that there was significant nosocomial transmission of TB infection among inpatients in this psychiatric hospital. Moreover, these findings indicate that the use of chest X-ray and TST, i.e., conventional methods of detection will leave TB infection undetected in many individuals. Thus, introduction of screening for TB infection using the QFT-G test in long-term care facilities such as psychiatric hospitals may enable the detection and treatment of individuals with latent TB in whom the infection would otherwise be missed by other conventional screening methods.

[Results of repeated QFT-2G checkings at two-year interval and their comparison with TST results introduced into infection control program for staffs working at a hospital with isolation wards for tuberculosis].

OBJECTIVE: In Fukujuji Hospital, we have been conducting TST to tuberculosis (TB) non-infected staffs to find new latent TB Infection (LTBI) every year, although almost of them were BCG vaccinated, and the reliability of TST is controversial in BCG vaccinated group. Recently, a new technique, QFT-2G, is evaluated highly to detect TB infection, especially in BCG vaccinated individuals. We examined hospital staffs twice at two-year interval using QFT-2G and TST, and compared these data. MATERIAL & METHOD: About four hundreds fifty staffs in Fukujuji Hospital with isolation wards for tuberculosis, provided with high level program against nosocomial infection of TB were examined. Almost all of them were BCG vaccinated. Because one fifth to one seventh of them were supposed as TB non-infected, they had been examined with TST to find new LTBI every year. QFT-2G was applied for about 80-85% of staffs twice, 2003 Jan. and 2005 Jan., with each person's consent. We compared the sequential changes of TST reactions and QFT-2G data. RESULTS: (1) The positive rate of QFT-2G was approximately 10% in both two-year interval checkings. (2) Two hundreds twelve persons, about half of staffs, were sequentially checked QFT-2G twice at two-year interval. 19 persons were positive at both checkings, 4 converted to negative and 7 converted to positive, suggesting that the rate of new LTBI in staffs would be 3.7% [7/(212-19-4)] during 2 years, 1.85% per year by QFT-2G conversion. (3) In comparison with data between TST and QFT-2G, QFT-2G was positive only in 13% of staffs with strongly reactors to TST. Moreover, even in 13 staffs converted by TST reaction to strong positive and highly suspected of new LTBI at two-year interval, there were no positive and positive converted persons based on QFT-2G checkings. Lastly, out of 7 staffs who converted to positive by QFT-2G checkings, only one was tested with TST, and no increase in the intensity of TST was observed. CONCLUSION: The QFT-2G positive rate was about 10% and the new TB infection rate was estimated to be 1.85% par year in staffs of a hospital with TB wards provided with high level programs against nosocomial TB infection. In addition, there are apparent disagreements between the results of QFT-2G and TST reactions, presumably affected by prior BCG vaccination. Therefore we must be cautious to detect new LTBI by ordinary TST in BCG vaccinated group.

Interferon-gamma responses after isoniazid chemotherapy for latent tuberculosis.

BACKGROUND AND OBJECTIVE: Chemotherapy for Mycobacterium tuberculosis infection may decrease interferon (IFN)-gamma responses to early secretory antigenic target 6 and culture filtrate protein (CFP)-10; a reaction that could be useful to monitor the success of treatment. We investigated IFN-gamma responses in subjects with latent TB infection before and after isoniazid (INH) chemotherapy. METHODS: A total of 48 patients who had contact with a TB patient in a psychiatric hospital were suspected to have latent TB infection on the basis of a positive QuantiFERON-TB Gold (QFT-G) test and were offered INH treatment for 6 months. After INH chemotherapy, IFN-gamma responses were again quantified and compared with initial measurements. RESULTS: Thirty-four patients completed 6 months of therapy and 28 were retested. Seven (25%) had a negative test and the other patients showed an overall decline. Geometric mean for early secretory antigenic target 6 decreased from 1.398 to 0.362 (P < 0.001), and that for CFP-10 from 0.312 to 0.120 (P < 0.001). A subsequent QFT-G test carried out 18 months after chemotherapy showed no further decline of IFN-gamma responses. CONCLUSIONS: If the success of chemotherapy is defined as negative conversion in the QFT-G test, these results suggest that although the waning of QFT-G responses as a result of chemotherapy is an important characteristic of IFN-gamma responses, the extent of waning would not be sufficient to allow effective monitoring of the success of chemotherapy because a majority of contacts still showed positive responses in the QFT-G test even after chemotherapy.

Comparison of the sensitivity and specificity of two whole blood interferon-gamma assays for M. tuberculosis infection.

OBJECTIVES: To compare the sensitivity and the specificity of the QuantiFERON-TB Gold (QFT-G) and QuantiFERON-TB Gold In Tube (QFT-GIT) diagnostic tests for Mycobacterium tuberculosis infection. METHODS: One-hundred patients with culture and/or PCR confirmed M. tuberculosis infection and 168 volunteers with no risk factors for M. tuberculosis infection were tested to estimate sensitivity and specificity, respectively. RESULTS: Analysis of data from the tuberculosis (TB) patients with valid results found the sensitivity of QFT-GIT (92.6%, 87/94) to be significantly higher than that for the QFT-G test (81.4%, 79/97; p=0.023). The specificity of both QFT-GIT and QFT-G was 98.8% (CI: 95.1%-99.8%) with 2 of the 160 low risk subjects with valid results for both tests being positive. Data analysis confirmed the manufacturer's recommended test cut-off as being optimal, but identified higher sensitivity could be obtained by using a lower cut-off, with only a moderate decrease in specificity. CONCLUSIONS: The QFT-GIT test had enhanced sensitivity for detection of M. tuberculosis infection over the QFT-G test, whilst maintaining equivalent high specificity. The logistic benefits of the QFT-GIT test format, as well as its higher sensitivity, should enable enhanced TB control.