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1.  Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update 
Annals of internal medicine  2008;149(3):177-184.
Background
Interferon-γ–release assays (IGRAs) are alternatives to the tuberculin skin test (TST). A recent meta-analysis showed that IGRAs have high specificity, even among populations that have received bacille Calmette–Guérin (BCG) vaccination. Sensitivity was suboptimal for TST and IGRAs.
Purpose
To incorporate newly reported evidence from 20 studies into an updated meta-analysis on the sensitivity and specificity of IGRAs.
Data Sources
PubMed was searched through 31 March 2008, and citations of all original articles, guidelines, and reviews for studies published in English were reviewed.
Study Selection
Studies that evaluated QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. For assessing sensitivity, the study sample had to have microbiologically confirmed active tuberculosis. For assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis. Studies with fewer than 10 participants and those that included only immunocompromised participants were excluded.
Data Extraction
One reviewer abstracted data on participant characteristics, test characteristics, and test performance from 38 studies; these data were double-checked by a second reviewer. The original investigators were contacted for additional information when necessary.
Data Synthesis
A fixed-effects meta-analysis with correction for overdispersion was done to pool data within prespecified subgroups. The pooled sensitivity was 78% (95% CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB. The pooled specificity for both QuantiFERON tests was 99% among non–BCG-vaccinated participants (CI, 98% to 100%) and 96% (CI, 94% to 98%) among BCG-vaccinated participants. The pooled specificity of T-SPOT.TB (including its precommercial ELISpot version) was 93% (CI, 86% to 100%). Tuberculin skin test results were heterogeneous, but specificity in non–BCG-vaccinated participants was consistently high (97% [CI, 95% to 99%]).
Limitations
Most studies were small and had limitations, including no gold standard for diagnosing latent tuberculosis and variable TST methods and cutoff values. Data on the specificity of the commercial T-SPOT.TB assay were limited.
Conclusion
The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non–BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.
PMCID: PMC2951987  PMID: 18593687 CAMSID: cams235
2.  Identifying Predictors of Interferon-γ Release Assay Results in Pediatric Latent Tuberculosis: A Protective Role of Bacillus Calmette-Guérin? 
Rationale: Interferon-γ (IFN-γ) release assays are widely used to diagnose latent infection with Mycobacterium tuberculosis in adults, but their performance in children remains incompletely evaluated to date.
Objectives: To investigate factors influencing results of IFN-γ release assays in children using a large European data set.
Methods: The Pediatric Tuberculosis Network European Trials group pooled and analyzed data from five sites across Europe comprising 1,128 children who were all investigated for latent tuberculosis infection by tuberculin skin test and at least one IFN-γ release assay. Multivariate analyses examined age, bacillus Calmette-Guérin (BCG) vaccination status, and sex as predictor variables of results. Subgroup analyses included children who were household contacts.
Measurements and Main Results: A total of 1,093 children had a QuantiFERON-TB Gold In-Tube assay and 382 had a T-SPOT.TB IFN-γ release assay. Age was positively correlated with a positive blood result (QuantiFERON-TB Gold In-Tube: odds ratio [OR], 1.08 per year increasing age [P < 0.0001]; T-SPOT.TB: OR, 1.14 per year increasing age [P < 0.001]). A positive QuantiFERON-TB Gold In-Tube result was shown by 5.5% of children with a tuberculin skin test result less than 5 mm, by 14.8% if less than 10 mm, and by 20.2% if less than 15 mm. Prior BCG vaccination was associated with a negative IFN-γ release assay result (QuantiFERON-TB Gold In-Tube: OR, 0.41 [P < 0.001]; T-SPOT.TB: OR, 0.41 [P < 0.001]). Young age was a predictor of indeterminate IFN-γ release assay results, but indeterminate rates were low (3.6% in children < 5 yr, 1% in children > 5 yr).
Conclusions: Our data show that BCG vaccination may be effective in protecting children against Mycobacterium tuberculosis infection. To restrict use of IFN-γ release assays to children with positive skin tests risks underestimating latent infection.
doi:10.1164/rccm.201201-0026OC
PMCID: PMC3443812  PMID: 22700862
interferon-γ release tests; latent tuberculosis; BCG vaccine; pediatrics
3.  Accuracy of Immunodiagnostic Tests for Active Tuberculosis Using Single and Combined Results: A Multicenter TBNET-Study 
PLoS ONE  2008;3(10):e3417.
Background
The clinical application of IFN-γ release assays (IGRAs) has recently improved the diagnosis of latent tuberculosis infection. In a multicenter study of the Tuberculosis Network European Trialsgroup (TBNET) we aimed to ascertain in routine clinical practice the accuracy of a novel assay using selected peptides encoded in the mycobacterial genomic region of difference (RD) 1 for the diagnosis of active tuberculosis in comparison with tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (Cellestis Ltd., Carnegie, Australia) and T-SPOT.TB (Oxfordimmunotec, Abingdon, UK).
Principal Findings
425 individuals from 6 different European centres were prospectively enrolled. We found that sensitivity of the novel test, TST, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB was respectively 73.1%, 85.3%, 78.1%, and 85.2%; specificity was respectively 70.6%, 48.0%, 61.9% and 44.3%; positive likelihood ratios were respectively 2.48, 1.64, 2.05, and 1.53; negative likelihood ratios were respectively 0.38, 0.31, 0.35, 0.33. Sensitivity of TST combined with the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB increased up to 92.4%, 97.7% and 97.1%, respectively. The likelihood ratios of combined negative results of TST with, respectively, the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB were 0.19, 0.07 and 0.10.
Conclusions
The assay based on RD1 selected peptides has similar accuracy for active tuberculosis compared with TST and commercial IGRAs. Then, independently of the spectrum of antigens used in the assays to elicit mycobacterial specific immune responses, the novel test, IGRAs, and the TST do not allow an accurate identification of active tuberculosis in clinical practice. However, the combined use of the novel assay or commercial IGRAs with TST may allow exclusion of tuberculosis.
doi:10.1371/journal.pone.0003417
PMCID: PMC2561073  PMID: 18923709
4.  Utility of QuantiFERON TB gold test in a south Indian patient population of ocular inflammation 
Indian Journal of Ophthalmology  2009;57(6):427-430.
Aim:
To study the utility of interferon-γ release assays (QuantiFERON TB gold test) in a south Indian patient population of intraocular inflammation.
Design:
Evaluation of a diagnostic test- a pilot study from January 2007 to October 2008.
Materials and Methods:
QuantiFERON TB gold test was performed on the following groups of patients following an informed consent. Group A included healthy volunteers without any exposure to tuberculosis (TB) or past history of TB (n=22). Group B included patients with active systemic TB diagnosed by the demonstration of acid-fast bacilli or by the histopathology finding of caseation with granuloma formation from the sputum, lymph node, skin or intestinal biopsies (n=26). Group C included patients with uveitis of known etiologies other than intraocular TB without any history of exposure to active TB (n=21). Group D included patients with a diagnosis of presumed intraocular TB, who responded to antitubercular therapy by decreased or no recurrences following treatment and with a minimum of nine months follow-up following initiation of antitubercular therapy (n=39).
Results:
The sensitivity and specificity of the QuantiFERON TB gold test to pick up active systemic TB was 58% and 77% respectively. The sensitivity and specificity of the QuantiFERON TB gold test to pickup intraocular TB was 82% and 76% respectively.
Conclusions:
QuantiFERON TB gold test alone may not be specific for intraocular TB. The significance of this test in a case scenario needs to be interpreted with clinical presentation and other evidences for intraocular TB.
doi:10.4103/0301-4738.57147
PMCID: PMC2812760  PMID: 19861743
Interferon-γ release assays; intraocular tuberculosis; QuantiFERON TB gold test
5.  IGRA tests perform similarly to TST but cause no adverse reactions: pediatric experience in Finland 
BMC Research Notes  2009;2:9.
Background
Two commercial interferon gamma release assays (IGRAs) (QuantiFERON®-TB Gold in Tube and T SPOT®-TB) to detect a contact with M. tuberculosis have recently become available. The majority of studies agree that the sensitivity and specificity of these methods are superior to the Tuberculin Skin Tests (TSTs) in detecting an exposure to bacteria in latently infected individuals and in clinical tuberculosis. However, the data in children remains limited.
Findings
Consecutively collected samples from children (n = 99) representing age range from zero to 18 years were analyzed in a retrospective non-blinded study. The two IGRAs were modified and adapted to the needs of Finland, a country of a low tuberculosis incidence. For 27 children, both tests were performed simultaneously and compared with the TST and clinician's diagnosis. The sensitivity, specificity, and accuracy of both IGRAs was determined. QuantiFERON TB Gold and T SPOT-TB performed (respectively) as follows: sensitivities 0.92 (95% confidence interval, CI, 0.67–0.99) and 0.85 (0.64–0.95); specificities 0.91 (0.77–0.97) and 1.00 (0.93–1.00); accuracies 0.91 (0.80–0.97) and 0.96 (0.88–0.99). This compares favorably to the TST whose known figures are 0.90, 0.95, and 0.95, respectively. The agreement between the IGRAs was high, k = 0.89. Finally, both methods agreed well with the TST, k = 0.86 for TST/QuantiFERON-TB Gold and k = 0.76 for TST/T SPOT-TB.
Conclusion
The sensitivity and specificity of IGRA methods compares well with the TST without the inconveniences and complications associated with TST, including exaggerated delayed type hypersensitivity reactions. These properties place them as acceptable substitutes for TST.
doi:10.1186/1756-0500-2-9
PMCID: PMC2637289  PMID: 19146687
6.  Serial Interferon-gamma Release Assays for the Diagnosis of Latent Tuberculosis Infection in Patients Treated with Immunosuppressive Agents 
Background
We assessed the efficacy of serial interferon-gamma release assays (IGRAs) for the diagnosis of latent tuberculosis infection (LTBI) in patients receiving immunosuppressive agents for treatment of rheumatic diseases in Korea.
Methods
Of 276 patients who underwent consecutive screening with one of two IGRAs [QuantiFERON-TB Gold or QuantiFERON-TB Gold In-Tube], 66 patients were evaluated by the serial IGRA for detection of LTBI during therapy with immunosuppressive agents. Information on clinical diagnosis, medication, previous TB, blood cell count, tuberculin skin test, and interferon-gamma (IFN-γ) level measured by IGRA was collected.
Results
Of the 66 patients, the initial IGRA was positive in 24.2%, negative in 65.2%, and indeterminate in 10.6%. Forty-six patients (69.7%) showed consistent IGRA results during follow-up, and 13 patients (19.7%) had consistently positive results. IGRA conversion rate was 12.1% (8/66) and reversion rate was 4.5% (3/66). Conversion of IGRA results was only observed in ankylosing spondylitis patients, and the median interval between the two tests in patients with conversion was 8.5 months. The mean IFN-γ level in the group of patients with consistently positive IGRA results was higher than that in the group with inconsistently positive results, although this trend was not statistically significant (P=0.293). Indeterminate results were observed most frequently in patients with systemic lupus erythematosus.
Conclusions
In patients receiving immunosuppressive agents, both IGRA conversions and reversions were observed. Serial IGRA testing may not be needed in patients with a positive initial IGRA result showing high IFN-γ levels, because of high consistency in the test results.
doi:10.3343/kjlm.2011.31.4.271
PMCID: PMC3190006  PMID: 22016681
Interferon-gamma release assay; Latent tuberculosis infection; Immunosuppressive agent; Conversion
7.  The Seasonality of Tuberculosis, Sunlight, Vitamin D, and Household Crowding 
The Journal of Infectious Diseases  2014;210(5):774-783.
Background. Unlike other respiratory infections, tuberculosis diagnoses increase in summer. We performed an ecological analysis of this paradoxical seasonality in a Peruvian shantytown over 4 years.
Methods. Tuberculosis symptom-onset and diagnosis dates were recorded for 852 patients. Their tuberculosis-exposed cohabitants were tested for tuberculosis infection with the tuberculin skin test (n = 1389) and QuantiFERON assay (n = 576) and vitamin D concentrations (n = 195) quantified from randomly selected cohabitants. Crowding was calculated for all tuberculosis-affected households and daily sunlight records obtained.
Results. Fifty-seven percent of vitamin D measurements revealed deficiency (<50 nmol/L). Risk of deficiency was increased 2.0-fold by female sex (P < .001) and 1.4-fold by winter (P < .05). During the weeks following peak crowding and trough sunlight, there was a midwinter peak in vitamin D deficiency (P < .02). Peak vitamin D deficiency was followed 6 weeks later by a late-winter peak in tuberculin skin test positivity and 12 weeks after that by an early-summer peak in QuantiFERON positivity (both P < .04). Twelve weeks after peak QuantiFERON positivity, there was a midsummer peak in tuberculosis symptom onset (P < .05) followed after 3 weeks by a late-summer peak in tuberculosis diagnoses (P < .001).
Conclusions. The intervals from midwinter peak crowding and trough sunlight to sequential peaks in vitamin D deficiency, tuberculosis infection, symptom onset, and diagnosis may explain the enigmatic late-summer peak in tuberculosis.
doi:10.1093/infdis/jiu121
PMCID: PMC4130318  PMID: 24596279
crowding; household; seasonality; sunlight; tuberculosis; vitamin D
8.  Comparison of T-Cell Interferon-γ Release Assays for Mycobacterium tuberculosis-Specific Antigens in Patients with Active and Latent Tuberculosis 
Lung  2010;188(4):283-287.
Through the use of QuantiFERON-TB Gold, a commercial IFN-γ assay, we compared differences in quantitative T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens [QuantiFERON TB-2G (QFT-2G)] between patients with active tuberculosis (TB) disease and those with latent TB infection (LTBI). The patient group consisted of 180 patients with active TB disease (culture-positive for MTB) and 50 screening contacts with LTBI-positive response to the QFT-2G test. We prospectively performed a tuberculin skin test (TST) and a QFT-2G test for all subjects. The median IFN-γ levels upon the application of both antigens, ESAT-6 and CFP-10, were significantly higher in patients with active TB disease than in those with LTBI. A combined positive response to both antigens occurred at a higher rate in patients with active TB disease than in those with LTBI. There were no significant relationships between the quantitative responses of IFN-γ to both antigens and the maximum induration on TST in both patient groups. We demonstrated significant differences in the quantitative responses of IFN-γ to MTB between patients with active TB disease and those with LTBI in this study. However, there was an overlap in the IFN-γ levels between active TB disease and LTBI groups. Therefore, it would be difficult to use the QFT-2G test to completely discriminate active TB disease from LTBI.
doi:10.1007/s00408-010-9238-3
PMCID: PMC2899021  PMID: 20422203
Active tuberculosis (TB) disease; Latent tuberculosis infection (LTBI); Tuberculin skin test (TST); QuantiFERON TB-2G (QFT-2G)
9.  TB Incidence in an Adolescent Cohort in South Africa 
PLoS ONE  2013;8(3):e59652.
Background
Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa.
Methods
We recruited adolescents aged 12 to 18 years from high schools in Worcester, South Africa. Demographic and clinical information was collected, a tuberculin skin test (TST) performed and blood drawn for a QuantiFERON TB Gold assay at baseline. Screening for TB cases occurred at follow up visits and by surveillance of registers at public sector TB clinics over a period of up to 3.8 years after enrolment.
Results
A total of 6,363 adolescents were enrolled (58% of the school population targeted). During follow up, 67 cases of bacteriologically confirmed TB were detected giving an overall incidence rate of 0.45 per 100 person years (95% confidence interval 0.29–0.72). Black or mixed race, maternal education of primary school or less or unknown, a positive baseline QuantiFERON assay and a positive baseline TST were significant predictors of TB disease on adjusted analysis.
Conclusion
The adolescent TB incidence found in a high burden setting will help TB vaccine developers plan clinical trials in this population. Latent TB infection and low socio-economic status were predictors of TB disease.
doi:10.1371/journal.pone.0059652
PMCID: PMC3606161  PMID: 23533639
10.  Differences in Tuberculin Reactivity as Determined in a Veterans Administration Employee Health Screening Program▿  
In response to a difference in pricing, the San Diego Veterans Administration Medical Center changed its tuberculin preparation from Tubersol to Aplisol in the fall of 2006. Following the change, an increased number of employee skin test conversions was noted. Employee tuberculin skin test converters from 2006 were screened with the QuantiFERON Gold (QFT-G) gamma interferon release assay. Those employees who tested negative by QFT-G were asked to repeat their skin test with both Tubersol and Aplisol tuberculin preparations. Of the new purified protein derivative converters, 12 of 14 returned for repeat testing with QFT-G, and the assay was negative for 83% (10/12), positive for 8% (1/12), and indeterminate for 8% (1/12) of the individuals. Nine of the individuals who were QFT-G negative agreed to repeat skin testing with both tuberculin preparations, and 7/8 (87.5%) demonstrated reactivity with the Aplisol preparation, while 0/8 (0%) reacted to the Tubersol preparation. A change from Tubersol to Aplisol resulted in elevated tuberculin skin test conversion rates that may be due to false-positive reactions. The differences in skin test reactivity between preparations support CDC guidelines that recommend that institutions should not change tuberculin preparations, as doing so may falsely increase the number of positive reactions.
doi:10.1128/CVI.00375-08
PMCID: PMC2668276  PMID: 19225075
11.  Selected RD1 Peptides for Active Tuberculosis Diagnosis: Comparison of a Gamma Interferon Whole-Blood Enzyme-Linked Immunosorbent Assay and an Enzyme-Linked Immunospot Assay 
We recently set up a gamma interferon (IFN-γ) enzyme-linked immunospot assay (ELISPOT), using selected early secreted antigenic target 6 (ESAT-6) peptides, that appears specific for active tuberculosis (A-TB). However, ELISPOT is difficult to automate. Thus, the objective of this study was to determine if the same selected peptides may be used in a technique more suitable for routine work in clinical laboratories, such as whole-blood enzyme-linked immunosorbent assay (WBE). For this purpose, 27 patients with A-TB and 41 control patients were enrolled. Our WBE, using the already described selected peptides from ESAT-6 plus three new ones from culture filtrate protein 10, was performed, and data were compared with those obtained by ELISPOT. Using our selected peptides, IFN-γ production, evaluated by both WBE and ELISPOT, was significantly higher in patients with A-TB than in controls (P < 0.0001). Statistical analysis showed a good correlation between the results obtained by WBE and ELISPOT (r = 0.80, P < 0.001). To substantiate our data, we compared our WBE results with those obtained by QuantiFERON-TB Gold, a whole-blood assay based on region of difference 1 (RD1) overlapping peptides approved for TB infection diagnosis. We observed a slightly higher sensitivity with QuantiFERON-TB Gold than with our WBE (89% versus 81%); however, our test provided a better specificity result (90% versus 68%). In conclusion, results obtained by WBE based on selected RD1 peptides significantly correlate with those generated by ELISPOT. Moreover, our assay appears more specific for A-TB diagnosis than QuantiFERON-TB Gold, and thus it may represent a complementary tool for A-TB diagnosis for routine use in clinical laboratories.
doi:10.1128/CDLI.12.11.1311-1316.2005
PMCID: PMC1287767  PMID: 16275946
12.  Rates of Latent Tuberculosis in Health Care Staff in Russia 
PLoS Medicine  2007;4(2):e55.
Background
Russia is one of 22 high burden tuberculosis (TB) countries. Identifying individuals, particularly health care workers (HCWs) with latent tuberculosis infection (LTBI), and determining the rate of infection, can assist TB control through chemoprophylaxis and improving institutional cross-infection strategies. The objective of the study was to estimate the prevalence and determine the relative risks and risk factors for infection, within a vertically organised TB service in a country with universal bacille Calmette-Guérin (BCG) vaccination.
Methods and Findings
We conducted a cross-sectional study to assess the prevalence of and risk factors for LTBI among unexposed students, minimally exposed medical students, primary care health providers, and TB hospital health providers in Samara, Russian Federation. We used a novel in vitro assay (for gamma-interferon [IFN-γ]) release to establish LTBI and a questionnaire to address risk factors. LTBI was seen in 40.8% (107/262) of staff and was significantly higher in doctors and nurses (39.1% [90/230]) than in students (8.7% [32/368]) (relative risk [RR] 4.5; 95% confidence interval [CI] 3.1–6.5) and in TB service versus primary health doctors and nurses: respectively 46.9% (45/96) versus 29.3% (34/116) (RR 1.6; 95% CI 1.1–2.3). There was a gradient of LTBI, proportional to exposure, in medical students, primary health care providers, and TB doctors: respectively, 10.1% (24/238), 25.5% (14/55), and 55% (22/40). LTBI was also high in TB laboratory workers: 11/18 (61.1%).
Conclusions
IFN-γ assays have a useful role in screening HCWs with a high risk of LTBI and who are BCG vaccinated. TB HCWs were at significantly higher risk of having LTBI. Larger cohort studies are needed to evaluate the individual risks of active TB development in positive individuals and the effectiveness of preventive therapy based on IFN-γ test results.
Gamma-interferon assays were used in a cross-sectional study of Russian health care workers and found high rates of latent tuberculosis infection.
Editors' Summary
Background.
Tuberculosis (TB) is a very common and life-threatening infection caused by a bacterium, Mycobacterium tuberculosis, which is carried by about a third of the world's population. Many people who are infected do not develop the symptoms of disease; this is called “latent infection.” However, it is important to detect latent infection among people in high-risk communities, in order to prevent infected people from developing active disease, and therefore also reduce the spread of TB within the community. 22 countries account for 80% of the world's active TB, and Russia is one of these. Health care workers are particularly at risk for developing active TB disease in Russia, but the extent of latent infection is not known. In order to design appropriate measures for controlling TB in Russia, it is important to know how common latent infection is among health care workers, as well as other members of the community.
Why Was This Study Done?
The researchers here had been studying the spread of tuberculosis in Samara City in southeastern Russia, where the rate of TB disease among health care workers was very high; in 2004 the number of TB cases among health care workers on TB wards was over ten times that in the general population. There was also no information available on the rates of latent TB infection among health care workers in Samara City. The researchers therefore wanted to work out what proportion of health care workers in Samara City had latent TB infection, and particularly to compare groups whom they thought would be at different levels of risk (students, clinicians outside of TB wards, clinicians on TB wards, etc.). Finally, the researchers also wanted to use a new test for detecting latent TB infection. The traditional test for detecting TB infection (tuberculin skin test) is not very reliable among people who have received the Bacillus Calmette-Guérin (BCG) vaccination against TB earlier in life, as is the case in Russia. In this study a new test was therefore used, based on measuring the immune response to two proteins produced by M. tuberculosis, which are not present in the BCG vaccine strain.
What Did the Researchers Do and Find?
In this study the researchers tested health care workers from all the TB clinics in Samara City, as well as other clinical staff and students, for latent tuberculosis. In total, 630 people had blood samples taken for testing. A questionnaire was also used to collect information on possible risk factors for TB. As expected, the rate of latent TB infection was highest among clinical staff working in the TB clinics, 47% of whom were infected with M. tuberculosis. This compared to a 10% infection rate among medical students and 29% infection rate among primary care health workers. The differences in infection rate between medical students, primary care health workers, and TB clinic staff were statistically significant and reflected progressively increasing exposure to TB. Among primary care health workers, past exposure to TB was a risk factor for having latent TB infection.
What Do These Findings Mean?
This study showed that there was a high rate of latent TB infection among health care workers in Samara City and that infection is increasingly likely among people with either past or present exposure to TB. The results suggest that further research should be carried out to test whether mass screening for latent infection, followed by treatment, will reduce the rate of active TB disease among health care workers and also prevent further spread of TB. There are concerns that widespread treatment of latent infection may not be completely effective due to the relatively high prevalence of drug-resistant TB strains and any new initiatives would therefore need to be carefully evaluated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040055.
The Stop TB Partnership has been set up to eliminate TB as a public health problem; its site provides data and resources about TB in each of the 22 most-affected countries, including Russia
Tuberculosis minisite from the World Health Organization, providing data on tuberculosis worldwide, details of the Stop TB strategy, as well as fact sheets and current guidelines
The US Centers for Disease Control has a tuberculosis minisite, including a fact sheet on latent TB
Information from the US Centers for Disease Control about the QuantiFERON-TB Gold test, used to test for latent TB infection in this study
doi:10.1371/journal.pmed.0040055
PMCID: PMC1796908  PMID: 17298167
13.  Evaluation of Interferon-Gamma Release Assays in the Diagnosis of Recent Tuberculosis Infection in Health Care Workers 
PLoS ONE  2009;4(8):e6686.
Background
Health care workers (HCWs) are a group at risk of latent tuberculosis infection (LTBI). The aims of this study were to determine IFN-γ response by QuantiFERON-TB GOLD In Tube (QFN-G-IT) and T-SPOT.TB in HCWs, comparing the results with tuberculin skin test (TST); and to analyze the capacity of IFN-γ tests to detect recent versus remote LTBI with a prolonged stimulation test (PST).
Methodology/Principal Findings
A total of 147 HCWs were enrolled; 23 of whom were BCG vaccinated. 95 HCWs (64.6%) had a previous positive TST and were not retested; and 52 HCWs had a previous negative TST or were tested for the first time. When we analysed individuals without previous positive TST, the number of positive results for T-SPOT.TB was 12/52 (23.1%); and for QFN-G-IT, 9/52 (17.3%). The global concordance (κ) between T-SPOT.TB and QFN-G-IT with TST was 0.754 and 0.929 respectively. Of individuals with previous positive TST, T-SPOT.TB and QFN-G-IT were negative in 51.6% (49/95) and 62.1% (59/95) respectively, decreasing the concordance to 0.321 and 0.288, respectively. In non-BCG vaccinated HCWs with previous positive TST a positive IFN-γ test was associated with degree of exposure and diameter of TST. PST was performed in 24 HCW with previous positive TST and negative IFN-γ tests. PST was developed in 3 cell cultures stimulated with medium alone, ESAT-6 and CFP-10, respectively. In the third and sixth day of incubation period, part of the supernatants were replaced with complete medium supplemented with (rIL)-2. On day 9, ELISPOT assay was performed. In 14 samples PST was not valid due to not having enough cells. In 8 cases, the response was negative, and in 2 cases positive, suggesting that these patients were infected with Mycobacterium tuberculosis in some point in the past.
Conclusions
Both IFN-γ tests showed a similar number of positive results, and concordance between the tests was excellent. None of the tests was affected by prior BCG vaccination. IFN-γ tests are a useful tool for detecting recent infection in HCW population.
doi:10.1371/journal.pone.0006686
PMCID: PMC2726945  PMID: 19701460
14.  QuantiFERON-TB gold in-tube implementation for latent tuberculosis diagnosis in a public health clinic: a cost-effectiveness analysis 
BMC Infectious Diseases  2012;12:360.
Background
The tuberculin skin test (TST) has limitations for latent tuberculosis infection (LTBI) diagnosis in low-prevalence settings. Previously, all TST-positive individuals referred from the community to Baltimore City Health Department (BCHD) were offered LTBI treatment, after active TB was excluded. In 2010, BCHD introduced adjunctive QuantiFERON-TB Gold In-Tube (QFT-GIT) testing for TST-positive referrals. We evaluated costs and cost-effectiveness of this new diagnostic algorithm.
Methods
A decision-analysis model compared the strategy of treating all TST-positive referrals versus only those with positive results on adjunctive QFT-GIT testing. Costs were collected at BCHD, and Incremental Cost-Effectiveness Ratios (ICERs) were utilized to report on cost-effectiveness.
Results
QFT-GIT testing at BCHD cost $43.51 per test. Implementation of QFT-GIT testing was associated with an ICER of $1,202 per quality-adjusted life-year gained and was considered highly cost-effective. In sensitivity analysis, the QFT-GIT strategy became cost-saving if QFT-GIT sensitivity increased above 92% or if less than 3.5% of individuals with LTBI progress to active TB disease.
Conclusions
LTBI screening with TST in low-prevalence settings may lead to overtreatment and increased expenditures. In this public health clinic, additional QFT-GIT testing of individuals referred for a positive TST was cost-effective.
doi:10.1186/1471-2334-12-360
PMCID: PMC3546858  PMID: 23253780
Tuberculosis; Diagnosis; Interferon-gamma release assay; Latent tuberculosis; Implementation
15.  Discordance among Commercially Available Diagnostics for Latent Tuberculosis Infection 
Rationale: There is uncertainty regarding how to interpret discordance between tests for latent tuberculosis infection.
Objectives: The objective of this study was to assess discordance between commercially available tests for latent tuberculosis in a low-prevalence population, including the impact of nontuberculous mycobacteria.
Methods: This was a cross-sectional comparison study among 2,017 military recruits at Fort Jackson, South Carolina, from April to June 2009. Several tests were performed simultaneously with a risk factor questionnaire, including (1) QuantiFERON-TB Gold In-Tube test, (2) T-SPOT.TB test, (3) tuberculin skin test, and (4) Battey skin test using purified protein derivative from the Battey bacillus.
Measurements and Main Results: In this low-prevalence population, the specificities of the three commercially available diagnostic tests were not significantly different. Of the 88 subjects with a positive test, only 10 (11.4%) were positive to all three tests; 20 (22.7%) were positive to at least two tests. Bacille Calmette-Guérin vaccination, tuberculosis prevalence in country of birth, and Battey skin test reaction size were associated with tuberculin skin test–positive, IFN-γ release assay–negative test discordance. Increasing agreement between the three tests was associated with epidemiologic criteria indicating risk of infection and with quantitative test results.
Conclusions: For most positive results the three tests identified different people, suggesting that in low-prevalence populations most discordant results are caused by false-positives. False-positive tuberculin skin test reactions associated with reactivity to nontuberculous mycobacteria and bacille Calmette-Guérin vaccination may account for a proportion of test discordance observed.
doi:10.1164/rccm.201107-1244OC
PMCID: PMC3297098  PMID: 22161162
tuberculosis screening; interferon-γ release assays; nontuberculous mycobacteria
16.  Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals – A systematic review and meta-analysis 
OBJECTIVE
To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from LTBI therapy.
DESIGN
Systematic review and meta-analysis.
METHODS
We searched multiple databases through May2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-Gold In-tube [QFT-GIT] and T-SPOT. TB [TSPOT])in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in pre-specified sub-groups using forest plots, and where appropriate, calculated pooled estimates using random effects models.
RESULTS
The search identified 37 studies that included 5736 HIV-infected individuals. In3 longitudinal studies, the risk of active TB was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the 2 studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active TB(a surrogate reference standard for LTBI), pooled sensitivity estimates were heterogeneous, but higher for TSPOT (72%, 95% CI 62–81%) than for QFT-GIT (61%, 95% CI 41–75%). However, neither IGRA was consistently more sensitive than the tuberculin skin test (TST) in head-to-head comparisons. While TSPOT appeared to be less affected by immunosuppression than QFT-GIT and TST, overall, differences between the three tests were small or inconclusive.
CONCLUSIONS
Current evidence suggests that IGRAs perform similarly to the TST at identifying HIV-infected individuals with LTBI. Given that both tests have modest predictive value and sub-optimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistical considerations.
doi:10.1097/QAI.0b013e31820b07ab
PMCID: PMC3383328  PMID: 21239993
latent tuberculosis infection; systematic review; interferon-gamma release assay; HIV infection; tuberculin skin test
17.  Reproducibility of QuantiFERON-TB Gold In-Tube Assay▿  
Studies are needed to characterize the reproducibility of QuantiFERON-TB Gold (QFT-G) for targeted U.S. screening populations. Members of northern California households were tested with the QFT-G in-tube assay (QFT-G-IT) at two home visits 3 months apart. Reproducibility and agreement with the tuberculin skin test (TST) were assessed. Monte Carlo simulation was used to evaluate the role of test-related error. Of 63 individuals (49 adults and 14 children) completing QFT-G-IT at both time points, 79% were foreign-born (98% from Latin America) and 68% reported Mycobacterium bovis BCG vaccination. At the baseline visit, 23 (37%) were TST positive and 15 (24%) were QFT-G-IT positive (κ = 0.48 [± 0.11]). At 3 months, 3/48 (6.3%; 95% confidence interval [95CI], 2 to 17) of those initially QFT-G-IT negative converted, and 5/15 (33%; 95CI, 15 to 58) of those initially QFT-G-IT positive reverted. Among the 8 individuals with inconsistent QFT-G-IT results, the maximum gamma interferon response at either visit was 0.68 IU/ml versus means of 4.99 (± 3.74) and 6.95 (± 5.6) for 10 persistent positives at the first and second visits, respectively. Expected false-reversion and -conversion rates were 32% (90CI, 25 to 39%) and 6.95% (90CI, 4.6 to 9.8%) when the sensitivity and specificity were assumed to average 70% and 98%, respectively. Transient responses to QFT-G-IT are common, and low positive results need to be interpreted with caution. Further studies are needed to characterize the predictive value of the test for U.S. foreign-born and other targeted screening populations.
doi:10.1128/CVI.00398-07
PMCID: PMC2268272  PMID: 18199741
18.  Isoniazid prophylaxis differently modulates T-cell responses to RD1-epitopes in contacts recently exposed to Mycobacterium tuberculosis: a pilot study 
Respiratory Research  2007;8(1):5.
Rationale
Existing data on the effect of treatment of latent tuberculosis infection (LTBI) on T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens are contradictory. Differences in technical aspects of the assays used to detect this response and populations studied might explain some of these discrepancies. In an attempt to find surrogate markers of the effect of LTBI treatment, it would be important to determine whether, among contacts of patients with contagious tuberculosis, therapy for LTBI could cause changes in MTB-specific immune responses to a variety of RD1-antigens.
Methods and results
In a longitudinal study, 44 tuberculin skin test+ recent contacts were followed over a 6-month period and divided according to previous exposure to MTB and LTBI treatment. The following tests which evaluate IFN-gamma responses to RD1 antigens were performed: QuantiFERON TB Gold, RD1 intact protein- and selected peptide-based assays. Among the 24 contacts without previous exposure that completed therapy, we showed a significant decrease of IFN-gamma response in all tests employed. The response to RD1 selected peptides was found to be more markedly decreased compared to that to other RD1 antigens. Conversely, no significant changes in the response to RD1 reagents were found in 9 treated subjects with a known previous exposure to MTB and in 11 untreated controls.
Conclusion
These data suggest that the effect of INH prophylaxis on RD1-specific T-cell responses may be different based on the population of subjects enrolled (recent infection versus re-infection) and, to a minor extent, on the reagents used.
doi:10.1186/1465-9921-8-5
PMCID: PMC1794408  PMID: 17257436
19.  Clinical Utility of Two Interferon-gamma Release Assays on Pleural Fluid for the Diagnosis of Tuberculous Pleurisy 
Background
The release of interferon-gamma (IFN-γ) by T lymphocytes increases after rechallenge with Mycobacterium tuberculosis antigen, especially, at a localized site of tuberculosis (TB) infection. We aimed to compare the clincial efficacy of two commercial IFN-γ release assays from pleural fluid for the diagnosis in tuberculous pleurisy.
Methods
We performed T-SPOT.TB and QuantiFERON-TB Gold tests simultaneously on pleural fluid and peripheral blood samples from patients with pleural effusion, in South Korea, an area with intermediate TB burden.
Results
Thirty-six patients were enrolled prospectively, and tuberculous pleurisy was found in 21 patients. Both the numbers of IFN-γ secreting T cells and the concentration of IFN-γ were greater in the pleural tuberculous group, comparing with the non-tuberculous group. Moreover, in the tuberculous group, there was a significant difference in IFN-γ producing spot-forming cells using the T-SPOT.TB method between pleural fluid and peripheral blood. The receiver operating characteristic (ROC) curve, was the greatest for pleural fluid T-SPOT.TB test, followed by peripheral blood T-SPOT.TB test, peripheral blood QuantiFERON-TB Gold test, and pleural fluid QuantiFERON-TB Gold test (area under the ROC curve of 0.956, 0.890, 0.743, and 0.721, respectively). The T-SPOT.TB assay produced less indeterminate results than did QuantiFERON-TB Gold assay in both pleural fluid and peripheral blood.
Conclusion
These findings suggest that the pleural fluid T-SPOT.TB test could be the most useful test among the IFN-γ release assays for diagnosing tuberculous pleurisy in an area with an intermediate prevalence of TB infection.
doi:10.4046/trd.2012.73.3.143
PMCID: PMC3492399  PMID: 23166547
Interferon-gamma Release Tests; Tuberculosis, Pleural
20.  Impact of Targeted Testing for Latent Tuberculosis Infection Using Commercially Available Diagnostics 
As with the tuberculin skin test, testing with interferon gamma release assays will result in false positives when employed in low-prevalence populations. Regardless of the test used, targeted testing is critical in reducing unnecessary testing and treatment.
Background. The interferon-γ release assays (IGRAs) are increasingly being used as an alternative to the tuberculin skin test (TST). Although IGRAs may have better specificity and certain logistic advantages to the TST, their use may contribute to overtesting of low-prevalence populations if testing is not targeted. The objective of this study was to evaluate the accuracy of a risk factor questionnaire in predicting a positive test result for latent tuberculosis infection using the 3 commercially available diagnostics.
Methods. A cross-sectional comparison study was performed among recruits undergoing Army basic training at Fort Jackson, South Carolina, from April through June 2009. The tests performed included: (1) a risk factor questionnaire; (2) the QuantiFERON Gold In-Tube test (Cellestis Limited, Carnegie, Victoria, Australia); (3) the T-SPOT.TB test (Oxford Immunotec Limited, Abingdon, United Kingdom); and (4) the TST (Sanofi Pasteur Ltd., Toronto, Ontario, Canada). Prediction models used logistic regression to identify factors associated with positive test results. RFQ prediction models were developed independently for each test.
Results. Use of a 4-variable model resulted in 79% sensitivity, 92% specificity, and a c statistic of 0.871 in predicting a positive TST result. Targeted testing using these risk factors would reduce testing by >90%. Models predicting IGRA outcomes had similar specificities as the skin test but had lower sensitivities and c statistics.
Conclusions. As with the TST, testing with IGRAs will result in false-positive results if the IGRAs are used in low-prevalence populations. Regardless of the test used, targeted testing is critical in reducing unnecessary testing and treatment.
Clinical Trial Registration. NCT00804713.
doi:10.1093/cid/cir321
PMCID: PMC3202318  PMID: 21765072
21.  Poor agreement between QuantiFERON-TB Gold test and tuberculin skin test results for the diagnosis of latent tuberculosis infection in rheumatoid arthritis patients and healthy controls 
Background/Aims
We investigated the agreement between the QuantiFERON-TB Gold (QFT-Gold) test and the tuberculin skin test (TST) in the diagnosis of latent tuberculosis infection in patients with rheumatoid arthritis (RA), compared with healthy controls, in Korea.
Methods
We recruited 64 patients with RA and 79 healthy controls at two university hospitals in South Korea. The participants underwent both the QFT-Gold test and the TST simultaneously between August 2006 and February 2009. All patients were diagnosed using the classification criteria for RA revised in 1987 by the American College of Rheumatology. Bacillus Calmette-Guérin vaccination status and current medications were evaluated, and disease activities were assessed using the Disease Activity Score in 28 joints. Eleven patients with RA produced indeterminate QFT-Gold test results and were thus excluded from the kappa analysis.
Results
Based on an induration of 10 mm in diameter as the TST cutoff value, the QFT-Gold test and TST demonstrated 75.0% agreement (κ = 0.23) in patients with RA and 75.9% agreement (κ = 0.19) in healthy controls. Among the 56 patients with RA who had negative TST results, 11 patients (17.2%) also yielded indeterminate QFT-Gold results.
Conclusions
Our study showed poor agreement between the results of the QFT-Gold test and the TST in both RA patients and healthy controls. Based on these findings, we emphasize the importance of making clinical decisions in the diagnosis of latent tuberculosis in Koreans with or without RA.
doi:10.3904/kjim.2014.29.1.76
PMCID: PMC3932398  PMID: 24574836
QuantiFERON-TB Gold test; Tuberculin skin test; Latent tuberculosis; Arthritis, rheumatoid
22.  Evaluation of the diagnostic utility of a whole blood interferon-γ assay for determining the risk of exposure to Mycobacterium tuberculosis in BCG-vaccinated individuals 
We evaluated the utility of the “QuantiFERON®-TB Gold in tube” (QuantiFERON®) test that uses TB-specific antigens for the diagnosis of latent infection in such individuals. We also examined the correlation between the IFN-γ response to these antigens and the exposure risk to TB by evaluating antigen-specific IFN-γ release in comparison with IFN-γ release in response to PPD in three groups; medical students, nurses in a TB hospital, and TB patients. All nurses and TB patients responded to PPD whereas 79.2 % (p=0.04) and 52 % (p<0.0001) responded to QuantiFERON®, respectively. In the medical students, only 10.4 % responded to QuantiFERON® while 85.2 % were positive to PPD (p < 0.0001). There was also a significant correlation between the levels of IFN-γ production and the duration of employment in the group of nurses at the TB hospital suggesting on-going exposure in this high risk group. Thus these results demonstrate that Mycobacterium tuberculosis-specific IFN-γ release assay accurately discriminates low and high risk healthy subjects and might therefore be a useful diagnostic tool for the diagnosis of latent infection in BCG-vaccinated individuals.
doi:10.1016/j.diagmicrobio.2008.01.002
PMCID: PMC2475550  PMID: 18296002
Tuberculosis; latent infection; IFN-γ; “QuantiFERON®-TB Gold in tube”
23.  Comparison of two interferon-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) in testing for latent tuberculosis infection among HIV-infected adults 
International Journal of STD & AIDS  2013;24(10):775-779.
There is currently no ‘gold standard’ for diagnosis of latent tuberculosis infection (LTBI), and both the tuberculin skin test and interferon-gamma release assays (IGRAs) are used for diagnosis; the latter have a higher sensitivity than tuberculin skin tests for diagnosis of LTBI in HIV-infected individuals with lower CD4 counts. No evidence base exists for selection of IGRA methodology to identify LTBI among human immunodeficiency virus-infected patients in the UK. We prospectively evaluated two commercially available IGRA methods (QuantiFERON-TB Gold In Tube [QFG] and T-SPOT.TB) for testing LTBI among HIV-infected patients potentially nosocomially exposed to an HIV-infected patient with ‘smear-positive’ pulmonary tuberculosis. Among the exposed patients median CD4 count was 550 cells/µL; 105 (90%) of 117 were receiving antiretroviral therapy, of who 104 (99%) had an undetectable plasma HIV load. IGRAs were positive in 12 patients (10.3%); QFG positive in 11 (9.4%) and T-SPOT.TB positive in six (5.1%); both IGRAs were positive in five patients (4.3%). There was one indeterminate QFG and one borderline T-SPOT.TB result. Concordance between the two IGRAs was moderate (κ = 0.56, 95% confidence interval = 0.27–0.85). IGRAs were positive in only 4 (29%) of 14 patients with previous culture-proven tuberculosis. No patient developed tuberculosis during 20 months of follow-up.
doi:10.1177/0956462413486459
PMCID: PMC4107858  PMID: 23970606
Interferon-gamma release assays; latent tuberculosis infection; HIV; screening; tuberculin skin test; AIDS; IGRA; Mycobacterium tuberculosis
24.  The Feasibility of the Interferon Gamma Release Assay and Predictors of Discordance with the Tuberculin Skin Test for the Diagnosis of Latent Tuberculosis Infection in a Remote Aboriginal Community 
PLoS ONE  2014;9(11):e111986.
Background
The tuberculin skin test (TST) is the standard test used to screen for latent TB infection (LTBI) in the northern Canadian territory of Nunavut. Interferon gamma release assays (IGRA) are T cell blood-based assays to diagnose LTBI. The Bacillus Calmette-Guerin (BCG) vaccine is part of the routine immunization schedule in Nunavut. The objective of this study was to test the feasibility, and predictors of discordance between the Tuberculin Skin Test (TST) and the IGRA assay in a medically under-serviced remote arctic Aboriginal population.
Methods
Both the TST and QuantiFERON-TB Gold (Qiagen group) IGRA tests were offered to people in their homes as part of a public health campaign aimed at high TB risk residential areas in Iqaluit, Nunavut, Canada. Feasibility was measured by the capacity of the staff to do the test successfully as measured by the proportion of results obtained.
Results
In this population of predominantly young Inuit who were mostly BCG vaccinated, the use of IGRA for the diagnosis of LTBI was feasible. IGRA testing resulted in more available test results reaching patients (95.6% vs 90.9% p = 0.02) but took longer (median 8 days (IGRA) vs 2 days (TST), p value <0.0001). 44/256 participants (17.2%) had discordant results. Multivariable regression analysis suggested that discordant results were most likely to have received multiple BCG vaccinations (RR 20.03, 95% CI, 3.94–101.82)), followed by BCG given post infancy (RR 8.13, 95% CI, 2.54–26.03)) and then to a lesser degree when BCG was given in infancy (RR 6.43, 95% CI, 1.72–24.85).
Interpretation
IGRA is feasible in Iqaluit, Nunavut, a remote Arctic community. IGRA testing results in more test results available to patients compared to TST. This test could result in fewer patients requiring latent TB treatment among those previously vaccinated with BCG in a region with limited public health human resources.
doi:10.1371/journal.pone.0111986
PMCID: PMC4227715  PMID: 25386908
25.  Interferon-γ Release Assays for Active Pulmonary Tuberculosis Diagnosis in Adults in Low- and Middle-Income Countries: Systematic Review and Meta-analysis 
The Journal of Infectious Diseases  2011;204(Suppl 4):S1120-S1129.
Background. The diagnostic value of interferon-γ release assays (IGRAs) for active tuberculosis in low- and middle-income countries is unclear.
Methods. We searched multiple databases for studies published through May 2010 that evaluated the diagnostic performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB (T-SPOT) among adults with suspected active pulmonary tuberculosis or patients with confirmed cases in low- and middle-income countries. We summarized test performance characteristics with use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models.
Results. Our search identified 789 citations, of which 27 observational studies (17 QFT-GIT and 10 T-SPOT) evaluating 590 human immunodeficiency virus (HIV)–uninfected and 844 HIV-infected individuals met inclusion criteria. Among HIV-infected patients, HSROC/bivariate pooled sensitivity estimates (highest quality data) were 76% (95% confidence interval [CI], 45%–92%) for T-SPOT and 60% (95% CI, 34%–82%) for QFT-GIT. HSROC/bivariate pooled specificity estimates were low for both IGRA platforms among all participants (T-SPOT, 61% [95% CI, 40%–79%]; QFT-GIT, 52% [95% CI, 41%–62%]) and among HIV-infected persons (T-SPOT, 52% [95% CI, 40%–63%]; QFT-GIT, 50% [95% CI, 35%–65%]). There was no consistent evidence that either IGRA was more sensitive than the tuberculin skin test for active tuberculosis diagnosis.
Conclusions. In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection.
doi:10.1093/infdis/jir410
PMCID: PMC3192542  PMID: 21996694

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