Prevalence and Incidence of Latent Tuberculosis Infection in Georgian Healthcare Workers

Background

Tuberculosis is a major occupational hazard in low and middle-income countries. Limited data exist on serial testing of healthcare workers (HCWs) with interferon-γ release assays (IGRAs) for latent tuberculosis infection (LTBI), especially in low and middle-income countries. We sought to evaluate the rates of and risk factors for LTBI prevalence and LTBI test conversion among HCWs using the tuberculin skin test (TST) and QuantiFERON-TB Gold In-tube assay (QFT-GIT).

Methods

A prospective longitudinal study was conducted among HCWs in the country of Georgia. Subjects completed a questionnaire, and TST and QFT-GIT tests were performed. LTBI testing was repeated 6-26 months after baseline testing.

Results

Among 319 HCWs enrolled, 89% reported prior BCG vaccination, and 60% worked in TB healthcare facilities (HCFs). HCWs from TB HCFs had higher prevalence of positive QFT-GIT and TST than those from non-TB HCFs: 107/194 (55%) vs. 30/125 (31%) QFT-GIT positive (p<0.0001) and 128/189 (69%) vs. 64/119 (54%) TST positive (p = 0.01). There was fair agreement between TST and QFT-GIT (kappa = 0.42, 95% CI 0.31–0.52). In multivariate analysis, frequent contact with TB patients was associated with increased risk of positive QFT-GIT (aOR 3.04, 95% CI 1.79–5.14) but not positive TST. Increasing age was associated with increased risk of positive QFT-GIT (aOR 1.05, 95% CI 1.01–1.09) and TST (aOR 1.05, 95% CI 1.01–1.10). High rates of HCW conversion were seen: the QFT-GIT conversion rate was 22.8/100 person-years, and TST conversion rate was 17.1/100 person-years. In multivariate analysis, female HCWs had decreased risk of TST conversion (aOR 0.05, 95% CI 0.01–0.43), and older HCWs had increased risk of QFT-GIT conversion (aOR 1.07 per year, 95% CI 1.01–1.13).

Conclusion

LTBI prevalence and LTBI test conversion rates were high among Georgian HCWs, especially among those working at TB HCFs. These data highlight the need for increased implementation of TB infection control measures.     

Cost-Effectiveness of Quantiferon?-TB Gold-In-Tube Versus Tuberculin Skin Testing for Contact Screening and Treatment of Latent Tuberculosis Infection in Brazil

Background

Latent tuberculosis infection (LTBI) is a reservoir for new TB cases. Isoniazid preventive therapy (IPT) reduces the risk of active TB by as much as 90%, but LTBI screening has limitations. Unlike tuberculin skin testing (TST), interferon-gamma release assays are not affected by BCG vaccination, and have been reported to be cost-effective in low-burden countries. The goal of this study was to perform a cost-effectiveness analysis from the health system perspective, comparing three strategies for LTBI diagnosis in TB contacts: tuberculin skin testing (TST), QuantiFERON®-TB Gold-in-Tube (QFT-GIT) and TST confirmed by QFT-GIT if positive (TST/QFT-GIT) in Brazil, a middle-income, high-burden country with universal BCG coverage.

Methodology/Principal Findings

Costs for LTBI diagnosis and treatment of a hypothetical cohort of 1,000 adult immunocompetent close contacts were considered. The effectiveness measure employed was the number of averted TB cases in two years. Health system costs were US$ 105,096 for TST, US$ 121,054 for QFT-GIT and US$ 101,948 for TST/QFT-GIT; these strategies averted 6.56, 6.63 and 4.59 TB cases, respectively. The most cost-effective strategy was TST (US$ 16,021/averted case). The incremental cost-effectiveness ratio was US$ 227,977/averted TB case for QFT-GIT. TST/QFT-GIT was dominated.

Conclusions

Unlike previous studies, TST was the most cost-effective strategy for averting new TB cases in the short term. QFT-GIT would be more cost-effective if its costs could be reduced to US$ 26.95, considering a TST specificity of 59% and US$ 18 considering a more realistic TST specificity of 80%. Nevertheless, with TST, 207.4 additional people per 1,000 will be prescribed IPT compared with QFT.     

Tuberculin Skin Testing and Treatment Modulates Interferon-Gamma Release Assay Results for Latent Tuberculosis in Migrants

Background

Identifying latent tuberculosis infection (LTBI) in people migrating from TB endemic regions to low incidence countries is an important control measure. However, no prospective longitudinal comparisons between diagnostic tests used in such migrant populations are available.

Objectives

To compare commercial interferon (IFN)-gamma release assays (IGRAs) and the tuberculin skin test (TST) for diagnosing LTBI in a migrant population, and the influence of antecedent TST and LTBI treatment on IGRA performance.

Materials and Methods

This cohort study, performed from February to September 2012, assessed longitudinal IGRA and TST responses in Nepalese military recruits recently arrived in the UK. Concomitant T-SPOT.TB, QFT-GIT and TST were performed on day 0, with IGRAs repeated 7 and 200 days later, following treatment for LTBI if necessary.

Results

166 Nepalese recruits were prospectively assessed. At entry, 21 individuals were positive by T-SPOT.TB and 8 individuals by QFT-GIT. There was substantial agreement between TST and T-SPOT.TB positives at baseline (71.4% agreement; κ = 0.62; 95% CI:0.44–0.79), but only moderate concordance between positive IGRAs (38.1% agreement; κ = 0.46; 95% CI:0.25–0.67). When reassessed 7 days following TST, numbers of IGRA-positive individuals changed from 8 to 23 for QFT-GIT (p = 0.0074) and from 21 to 23 for T-SPOT.TB (p = 0.87). This resulted in an increase in IGRA concordance to substantial (64.3% agreement; κ = 0.73; 95% CI:0.58-0.88). Thus, in total on day 0 and day 7 after testing, 29 out of 166 participants (17.5%) provided a positive IGRA and of these 13 were TST negative. Two hundred days after the study commenced and three months after treatment for LTBI was completed by those who were given chemoprophylaxis, 23 and 21 participants were positive by T-SPOT.TB or QFT-GIT respectively. When individual responses were examined longitudinally within this population 35% of the day 7 QFT-GIT-positive, and 19% T-SPOT.TB-positive individuals, were negative by IGRA. When the change in the levels of secreted IFN-γ was examined after chemoprophylaxis the median levels were found to have fallen dramatically by 77.3% from a pre-treatment median concentration of IFN-γ 2.73 IU/ml to a post-treatment median concentration IFN-γ 0.62 (p = 0.0002).

Conclusions

This study suggests differences in the capacity of commercially available IGRAs to identify LTBI in the absence of antecedent TST and that IGRAs, in the time periods examined, may not be the optimal tests to determine the success of chemoprophylaxis for LTBI.     

The Clinical Usefulness of Tuberculin Skin Test versus Interferon-Gamma Release Assays for Diagnosis of Latent Tuberculosis in HIV Patients: A Meta-Analysis

BackgroundAccurate diagnosis of latent tuberculosis infection (LTBI) is becoming increasingly concerning due to the increasing the HIV epidemic, which have increased the risk for reactivation to active tuberculosis (TB) infection. LTBI is diagnosed by tuberculin skin test (TST) and interferon-gamma release assays (IGRAs).ObjectivesThe aim of the present study was to conduct a meta-analysis of published papers on the agreement (kappa) between TST and QuantiFERON-TB Gold In-Tube (QFT-GIT) tests for diagnosis of LTBI in HIV patient.MethodsElectronic databases including PubMed/Medline, Elsevier/Scopus and Embase/Ovid were reviewed up Jan. 2016. We performed a random effect model meta-analysis for estimation of pooled Kappa between the two methods of diagnosis. Meta regression was used for assessing potential heterogeneity and Egger’s test was used for assessing small study effect and publication bias.ResultsThe initial search strategy produced 6744 records. Of them, 23 cross-sectional studies met the inclusion criteria and 20 studies entered in meta-analysis. The pooled kappa was and prevalence-adjusted and bias-adjusted kappa (PABAK) were 0.37 (95% CI: 0.28, 0.46) and 0.59 (0.49, 0.69). The discordance of TST-/QFT-GIT+ was more than TST+/QFT-GIT-. Kappa estimate between two tests was linearly associated with age and prevalence index and inversely associated with bias index.ConclusionFair agreement between TST and QFT-GIT makes it difficult to know whether TST is as useful as the QFT-GIT in HIV-infected patients. The higher discordance of TST-/QFT-GIT+ in compared to TST+/QFT-GIT- can induce the higher sensitivity of QFT-GIT for diagnosis LTBI in HIV patients. Disagreement between two tests can be influenced by error in measurements and prevalence of HIV.     

Diagnostic Values of the QuantiFERON-TB Gold In-Tube Assay Carried out in China for Diagnosing Pulmonary Tuberculosis

Background

Interferon-release assays (IGRAs) for diagnosing active pulmonary tuberculosis (PTB) are not yet fully validated, particularly in high TB-endemic areas as the People''s Republic of China (PRC). The aim of this report was to assess the performance of the QuantiFERON-TB Gold In-tube (QFT-GIT) and tuberculin skin test (TST), in addition to microbiological results, as contributors for diagnosing active PTB in the PRC.

Methods/Principal Findings

A total of 300 PTB patients, 41 disease controls (DC) and 59 healthy community controls (HCC) were included prospectively between May 2010 and April 2011 from two provinces of the PRC (Heilongjiang and Zhejiang). The QFT-GIT and TST yielded an overall sensitivity for active TB of 80.9% and 86.2%, and a specificity of 36.6% and 26.8%, respectively. The province of origin and smear microscopy status did not significantly impact the diagnostic values for PTB. However, using the TST with a 10 mm cut-off point, a significantly higher proportion of LTBI was observed in the DC than the HCC (p=0.01). Discordant results between the QFT-GIT and TST were found among 1/3 of the PTB, HCC and DC. Two-thirds of the individuals presented TST-positive/QFT-GIT-negative discordant results. The TST-negative/QFT-GIT-positive result was not associated with age or bacillary load. Cumulative QFT-GIT and TST positive results increased the overall sensitivity (95.9%), but it was associated with a dramatic decrease of the overall specificity (24.8%) leading to a suboptimal PPV (80.1%) and a low NPV (61.1%).

Conclusions/Significance

The usefulness of the QFT-GIT to diagnose active TB in high TB-endemic countries remains doubtful because like the TST, the QFT-GIT cannot distinguish between LTBI and active TB. Used as single stand-alone tests, both the QFT-GIT and TST have very limited roles in the diagnosis of active PTB. However, the combined use of SM, the TST and QFT-GIT may allow for the exclusion of ATB.     

A Tuberculin Skin Test Survey and the Annual Risk of Mycobacterium tuberculosis Infection in Gambian School Children

Background

A Tuberculin skin test (TST) survey was conducted to assess the prevalence of latent TB Infection (LTBI) and to estimate the annual risk of M. tuberculosis infection (ARTI) in Gambian school children. The results are expected to contribute to understanding of Tuberculosis epidemiology in The Gambia.

Methods

This was a nationwide, multi-cluster survey in children aged 6–11 years. Districts, 20 of 37, were selected by probability proportional to size and schools by simple random sampling. All TST were performed using the Mantoux method. Height and weight measurements were obtained for all participants. We calculated prevalence of LTBI using cut-off points of 10mm, the mirror and mixture modelling methods.

Results

TST readings were completed 13,386 children with median age of 9 years (interquartile range [IQR] 8–10 years). Mixture analysis yielded a cut-off point of 12 mm, and LTBI prevalence of 6.9% [95%CI 6.47–7.37] and the ARTI was 0.75% [95%CI 0.60–0.91]. LTBI was associated gender and urban residence (p <0.01). Nutritional status was not associated with non-reactive TST or sizes of TST indurations. ARTI did not differ significantly by age, gender, BCG vaccination or residence.

Conclusions

This estimates for LTBI prevalence and ARTI were low but this survey provides updated data. Malnutrition did not affect estimates of LTBI and ARTI. Given the low ARTI in this survey and the overlapping distribution of indurations with mixture modelling, further surveys may require complementary tests such as interferon gamma release assays or novel diagnostic tools.     

Smoking,BCG and Employment and the Risk of Tuberculosis Infection in HIV-Infected Persons in South Africa

Background

The increased susceptibility to latent tuberculosis infection (LTBI) of HIV-1-infected persons represents a challenge in TB epidemic control. However few studies have evaluated LTBI predictors in a generalized HIV/TB epidemic setting.

Methods

The study recruited 335 HIV-infected participants from Khayelitsha, Cape Town between February 2008 and November 2010. Tuberculin skin tests and interferon-gamma release assays were performed on all participants and active TB excluded using a symptom screen, TB microscopy and culture.

Results

LTBI prevalence was 52.7% and 61.2% (TST and IGRA respectively). Being a recent TB contact (OR 2.07; 95% C.I. 1.15–3.69) was associated with TST positivity. Participants with a CD4>200 had a two-fold higher risk of IGRA positivity compared to those with CD4 counts <200 (OR 2.07; 95% C.I. 0.99–4.34). There was also a 19% increase in IGRA positivity risk for every additional year of schooling and a strong association between years of schooling and employment (p = 0.0004). A decreased risk of IGRA positivity was observed in persons with a BCG scar (OR 0.46; 95% C.I. 0.31–0.69) and in smokers (OR 0.47; 95% C.I. 0.23–0.96).

Conclusion

We report the novel findings of a decreased risk of IGRA positivity in HIV-infected smokers possibly due to decreased interferon production, and in the persons with a BCG scar suggesting a protective role for BCG in this population. We also found an increased risk of TST positivity in employed persons, possibly due to ongoing transmission in public modes of transport.     

TB Screening in Canadian Health Care Workers Using Interferon-Gamma Release Assays

Background

While many North American healthcare institutions are switching from Tuberculin Skin Test (TST) to Interferon-gamma release assays (IGRAs), there is relatively limited data on association between occupational tuberculosis (TB) risk factors and test positivity and/or patterns of test discordance.

Methods

We recruited a cohort of Canadian health care workers (HCWs) in Montreal, and performed both TST and QuantiFERON-TB Gold In Tube (QFT) tests, and assessed risk factors and occupational exposure.

Results

In a cross-sectional analysis of baseline results, the prevalence of TST positivity using the 10 mm cut-off was 5.7% (22/388, 95%CI: 3.6–8.5%), while QFT positivity was 6.2% (24/388, 95%CI: 4–9.1%). Overall agreement between the tests was poor (kappa = 0.26), and 8.3% of HCWs had discordant test results, most frequently TST−/QFT+ (17/388, 4.4%). TST positivity was associated with total years worked in health care, non-occupational exposure to TB and BCG vaccination received after infancy or on multiple occasions. QFT positivity was associated with having worked as a HCW in a foreign country.

Conclusions

Our results suggest that LTBI prevalence as measured by either the TST or the QFT is low in this HCW population. Of concern is the high frequency of unexplainable test discordance, namely: TST−/QFT+ subjects, and the lack of any association between QFT positivity and clear-cut recent TB exposure. If these discordant results are indeed false positives, the use of QFT in lieu of TST in low TB incidence settings could result in overtreatment of uninfected individuals.     

Strategy to Better Select HIV-Infected Individuals for Latent TB Treatment in BCG-Vaccinated Population

Objective

To evaluate the T-SPOT.TB interferon-γ releasing assay and the tuberculin skin test (TST), for the diagnosis of latent tuberculosis infection(LTBI) and the development of subsequent active tuberculosis, in BCG-vaccinated HIV-infected individuals.

Methods

HIV-infected individuals without clinical suspicion of active TB or a past history of TB were enrolled from 1 January 2008 to 30 November 2010. Both T-SPOT.TB test and TST were offered to the participants whom were followed up prospectively until April 30, 2012 for development of TB.

Results

Among the 909 participants, 25% had positive TST reactions with cut-off point of 5 mm and 15% had positive T-SPOT.TB results. After a median follow-up of 2.97 years, there were 5 cases developed culture-confirmed active TB (all had dual positive TST and T-SPOT.TB results), and the incidence was 0.17 per 100 person-years. The relative risks (RRs) for subsequent active TB in HIV-infected individuals with positive TST results, positive T-SPOT.TB results and dual positive results compared with the risk for individuals with negative results were 40.6 (95% CI 2.1–767.9), 73.9 (95% CI 3.9–1397.7) and 226.5 (95% CI 12.0–4284), respectively. The number needed to treat to prevent one subsequent TB case among patients with a positive TST, a positive T-SPOT.TB and dual positive results was 35, 22 and 8 respectively.

Conclusions

Adopting positive results of the TST and T-SPOT.TB to screen LTBI among BCG-vaccinated HIV-infected individuals might be feasible. Number needed to treat for isoniazid preventive therapy could be reduced significantly by using dual positive strategy.     

Comparison of the Tuberculin Skin Test and Interferon Gamma Release Assay for the Screening of Tuberculosis in Adolescents in Close Contact with Tuberculosis TB Patients

Background

The tuberculin skin test (TST) frequently yields false positive results among BCG-vaccinated persons thereby limiting its diagnostic value particularly in settings with high BCG vaccination rate. We determined the agreement between IGRA and TST using 2 cutoff values and identified possible relationships between the results of these tests and the development of active tuberculosis.

Methodology

Adolescents aged 11–19 years in close contact with smear-positive tuberculosis cases and with normal chest radiographs were recruited from middle and high schools in South Korea. The TST was conducted by trained nurses, and blood was drawn for the QuantiFERON-TB Gold In-Tube (QFT-GIT). Participants were followed up for 2 years to check for incidence tuberculosis.

Results

A total of 2,982 subjects were included in the study, the average age was 15.1 years (SD 1.3), 61% had BCG vaccination scars. The agreement of QFT-GIT and the TST was low (κ = 0.38, 95% CI 0.32 to 0.42) using 10 mm cutoff; however, when the 15 mm cutoff was used, the agreement was intermediate (κ = 0.56, 95% CI 0.50 to 0.61). The odds ratio (OR) for the development of active tuberculosis was 7.9 (95% CI 3.46 to 18.06) for QFT-GIT positive patients, 7.96 (95% CI 3.14-20.22) for TST/QFT-GIT+ and the OR 4.62 (95% CI 2.02 to 10.58) and 16.35 (95% CI 7.09 to 37.71) for TST 10 mm and 15 mm cutoff respectively.

Conclusions

The results of this study suggest that the TST cutoff point for patients aged 11–17 years would be 15 mm in other study. The OR of QFT-GIT for the development of active tuberculosis and its intermediate agreement with TST using 15 mm cutoff demonstrates its role as an adjunct diagnostic tool to current clinical practice. Positive responders to both TST and QFT-GIT at the outset may benefit from chemoprophylaxis.     

Longitudinal analysis of QuantiFERON-TB Gold In-Tube in children with adult household tuberculosis contact in South Africa: a prospective cohort study

Background

QuantiFERON-TB Gold In Tube (QFT-GIT) is a tool for detecting M. tuberculosis infection. However, interpretation and utility of serial QFT-GIT testing of pediatric tuberculosis (TB) contacts is not well understood. We compared TB prevalence between baseline and 6 months follow-up using QFT-GIT and tuberculin skin testing (TST) in children who were household contacts of adults with pulmonary TB in South Africa, and explored factors associated with QFT-GIT conversions and reversions.

Method

Prospective study with six month longitudinal follow-up.

Results

Among 270 enrolled pediatric contacts, 196 (73%) underwent 6-month follow-up testing. The 6-month prevalence estimate of MTB infection in pediatric contacts increased significantly from a baseline of 29% (79/270, 95%CI [24–35]) to 38% (103/270, 95% CI [32–44], p<0.001) using QFT-GIT; prevalence increased from a baseline of 28% (71/254, 95%CI [23–34]) to 33% (88/263, 95%CI [21–32], p = 0.002) using TST. Prevalence estimates were influenced by thresholds for positivity for TST, but not for QFT-GIT. Among 134 children with a negative or indeterminate baseline QFT-GIT, 24 (18%) converted to positive at follow-up; conversion rates did not differ significantly when using more stringent thresholds to define QFT-GIT conversion. Older age >10 years (AOR 8.9 95%CI [1.1–72]) and baseline TST positivity ≥5 mm (AOR 5.2 95%CI [1.2–23]) were associated with QFT-GIT conversion. Among 62 children with a positive baseline QFT-GIT, 9 (15%) reverted to negative; female gender (AOR 18.5 95%CI [1.1–321]; p = 0.04] was associated with reversion, while children with baseline positive TST were less likely to have QFT-GIT reversion (AOR 0.01 95%CI [0.001–0.24]).

Conclusion

Among pediatric contacts of adult household TB cases in South Africa, prevalence estimates of TB infection increased significantly from baseline to 6 months. Conversions and reversions occurred among pediatric TB contacts using QFT-GIT, but QFT-GIT conversion rates were less influenced by thresholds used for conversions than were TST conversion rates.     

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

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.     

QuantiFERON-TB Gold In-Tube Assay for Screening Arthritis Patients for Latent Tuberculosis Infection before Starting Anti-Tumor Necrosis Factor Treatment

Background

Patients undergoing anti-tumor necrosis factor (TNF) treatment are at an increased risk of reactivating a latent tuberculosis infection (LTBI). This study evaluated the effectiveness of the QuantiFERON-TB Gold In-Tube (QFT) assay for diagnosing LTBI in arthritis patients undergoing anti-TNF treatment.

Methods

We enrolled 342 consecutive patients from August 2007 to October 2013: 176 (51.5%) patients with ankylosing spondylitis and 166 (48.5%) with rheumatoid arthritis. Screening tests included tuberculin skin test (TST) and QFT assay. Positive QFT results, regardless of TST results, were considered an indicator for LTBI treatment.

Results

Bacillus Calmette-Guérin scars were found in 236 (69.0%) patients. Of 342 patients, TST and QFT were positive in 122 (35.7%) and 103 (30.1%) patients, respectively, and discordant in 101 (29.5%) patients. During a median follow-up duration of 41.7 months, five patients (1.5%) developed TB in a median of 20.8 months after initiation of anti-TNF treatment (428/100,000 person-years). TB did not occur in 62 TST+/QFT+ patients who received LTBI treatment. Of 41 TST−/QFT+ patients who received LTBI treatment, one (2.4%) developed TB 20.5 months after starting anti-TNF treatment (705/100,000 person-years). Of 60 TST+/QFT− patients who did not receive LTBI treatment, two (3.3%) developed TB 20.8 and 22.0 months after starting anti-TNF treatment (871/100,000 person-years). Of 179 TST−/QFT− patients, two (1.1%) developed TB 7.2 and 22.7 months, respectively, after initiating anti-TNF treatment (341/100,000 person-years). TB incidence rate during the follow-up period did not differ among TST−/QFT+, TST+/QFT−, and TST−/QFT− patients (P = 0.661).

Conclusion

QFT might be used instead of TST for diagnosing LTBI in patients before starting anti-TNF therapy in countries, such as Korea, where the TB prevalence is intermediate and the BCG vaccination is mandatory at birth. In the absence of a true gold standard test for LTBI, however, there is still a risk of TB development during anti-TNF treatment.     

Cough Aerosol Cultures of Mycobacterium tuberculosis: Insights on TST / IGRA Discordance and Transmission Dynamics

Rationale

The diagnosis of latent tuberculosis (TB) infection (LTBI) is complicated by the absence of a gold standard. Discordance between tuberculin skin tests (TST) and interferon gamma release assays (IGRA) occurs in 10–20% of individuals, but the underlying mechanisms are poorly understood.

Methods

We analyzed data from a prospective household contact study that included cough aerosol culture results from index cases, environmental and contact factors. We assessed contacts for LTBI using TST and IGRA at baseline and six weeks. We examined TST/IGRA discordance in qualitative and quantitative analyses, and used multivariable logistic regression analysis with generalized estimating equations to analyze predictors of discordance.

Measurements and Results

We included 96 TB patients and 384 contacts. Discordance decreased from 15% at baseline to 8% by six weeks. In adjusted analyses, discordance was related to less crowding (p = 0.004), non-cavitary disease (OR 1.41, 95% CI: 1.02–1.96; p = 0.03), and marginally with BCG vaccination in contacts (OR 1.40, 95% CI: 0.99–1.98, p = 0.06).

Conclusions

We observed significant individual variability and temporal dynamism in TST and IGRA results in household contacts of pulmonary TB cases. Discordance was associated with a less intense infectious exposure, and marginally associated with a BCG-mediated delay in IGRA conversion. Cough aerosols provide an additional dimension to the assessment of infectiousness and risk of infection in contacts.     

The Significance of Sensitive Interferon Gamma Release Assays for Diagnosis of Latent Tuberculosis Infection in Patients Receiving Tumor Necrosis Factor-α Antagonist Therapy

Objective

We compared two interferon gamma release assays (IGRAs), QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, for diagnosis of latent tuberculosis infection (LTBI) in patients before and while receiving tumor necrosis factor (TNF)-α antagonist therapy. This study evaluated the significance of sensitive IGRAs for LTBI screening and monitoring.

Methods

Before starting TNF-α antagonist therapy, 156 consecutive patients with rheumatic diseases were screened for LTBI using QFT-GIT and T-SPOT.TB tests. According to our study protocol, QFT-GIT-positive patients received LTBI treatment. Patients positive by any IGRAs were subjected to follow-up IGRA tests after completing LTBI-treatment and/or during TNF-α antagonist therapy.

Results

At the initial LTBI screening, 45 (28.9%) and 70 (44.9%) patients were positive by QFT-GIT and T-SPOT.TB, respectively. The agreement rate between IGRA results was 78.8% (k = 0.56; 95% confidence interval [95% CI] = 0.43 to 0.68). Of 29 patients who were positive only by T-SPOT.TB in the initial screening, 83% (19/23) were persistently positive by T-SPOT.TB, while QFT-GIT testing showed that 36% (9/25) had conversion during TNF-α antagonist therapy. By the end of the follow-up period (218 to 1,264 days), four patients (4/137, 2.9%) developed active tuberculosis (TB) diseases during receiving TNF-α antagonist therapy. Among them, one was Q-T+, one was Q+T-, and the remaining two were Q-T- at the initial screening (Q, QuantiFERON-TB Gold In-Tube; T, T-SPOT.TB; +, positive; -, negative). Two (2/4, 50%) patients with TB reactivation had at least one prior risk factor consistent with previous TB infection.

Conclusion

This study demonstrated the need to capitalize on sensitive IGRAs to monitor for LTBI in at-risk patients for a more sensitive diagnosis in countries with an intermediate TB burden.     

QuantiFERON-TB Gold Plus Test in Diagnostics of Latent Tuberculosis Infection in Children Aged 1–14 in a Country with a Low Tuberculosis Incidence

The aim of the study was to evaluate the QuantiFERON-TB Gold Plus (QFT-Plus) test usability in the identification of latent tuberculosis infection (LTBI) in children and the determination of features associated with tuberculin skin test (TST) and QFT-Plus-positive results concerning LTBI. Two-hundred thirteen children aged 1–14 were screened for LTBI due to household contact with TB, suspected TB, or were qualified for biological therapy. The objective of this study was to evaluate the QFT-Plus affectivity as a diagnostic test in the absence of a gold standard (GS) test for the diagnosis of LTBI. The children were diagnosed with QFT-Plus, TST, and culture of TB. The QFT-Plus results were analyzed depending on the children’s age, TST size, and type. In children aged 1–4, the positive predictive value of QFT-Plus was 1, the negative predictive value was 0.94, QFT-Plus sensitivity was 75%, and specificity was 100%. It was observed that in children aged 5–14 years, the level of agreement decreased to the substantial, i.e., 87.2%. Moreover, the negative predictive value was 0.83. QFT-Plus sensitivity was 64%, and specificity was 100%. Statistical analysis of QFT-Plus and TST results showed substantial and almost perfect agreements. Our study suggests that QFT-Plus is helpful in a pediatric practice showing good sensitivity and specificity for LTBI. The BCG vaccine, infections, and concomitant morbidities do not affect QFT-Plus results.     

Tuberculin Skin Test Distribution following a Change in BCG Vaccination Policy

Background

Epidemiologic data regarding tuberculin skin test (TST) responses are an important basis for TB control strategies. This study analyzed TST responses in Korea, which experienced a rapid change in BCG vaccination status.

Methods

TST responses in young adults were examined over 5 years. Participants with active TB lesions were excluded.

Results

A total of 5,552 participants were enrolled with median age of 21 years. When an induration diameter ≥10 mm was used as the criterion for a positive test, TST positivity fell (from 28.0% in 2005 to 15.3% in 2009); however, they remained steady when the criterion was ≥15–20 mm. A positive TST was associated with a personal or family of TB, the presence of a Bacille Calmette-Guérin (BCG) scar, and age (odds ratio [95% confidence interval] = 4.03 [2.61–6.22], 2.91 [1.80–4.71], 1.50 [1.31–1.72], and 1.15 [1.09–1.20], respectively). Among these factors, the decrease of participants with BCG scars was the most prominent change, which appeared to be associated with the change of TST positivity rate.

Conclusion

Overall, the rate of TST positivity in Korea decreased. However, this trend seems associated with the change of BCG vaccination strategy rather than successful control of LTBI. This study showed that change in BCG vaccination strategy can have great impact on TB epidemiologic survey based on TST.     

Interferon-gamma release assays for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis

Interferon -gamma release assays (IGRAs) provide a new diagnostic method for Mycobacterium tuberculosis (TB) infection. However, the diagnostic value of IGRAs for extrapulmonary TB (EPTB) has not been clarified. We searched several databases and selected papers with strict inclusion criteria, evaluated the evidence of commercially available IGRAs (QuantiFERON(?) -TB Gold QFT-G or QFT-GIT and T-SPOT(?) .TB) on blood and the tuberculin skin test (TST) using random effects models. Twenty studies with 1711 patients were included. After excluding indeterminate results, pooled sensitivity for the diagnosis of EPTB was 72% [95% confidence interval (CI) 65-79%] for QFT-G or GIT and 90% (95% CI, 86-93%) for T-SPOT; in high-income countries the sensitivity of QFT-G or GIT (79%, 95% CI 72-86%) was much higher than that (29%, 95% CI 14-48%) in low/middle-income countries. Pooled specificity for EPTB was 82% (95% CI 78-87%) for QFT-G or GIT and 68% (95% CI 64-73%) for T-SPOT. Pooled sensitivity of TST from four studies in high-income countries was lower than that of IGRAs. T-SPOT was more sensitive in detecting EPTB than QFT-G or GIT and TST. However, both IGRAs and TST have similar specificity for EPTB. IGRAs have limited value as diagnostic tools to screen and rule out EPTB, especially in low/middle-income countries. The immune status of patients does not affect the diagnostic accuracy of IGRAs for EPTB.     

Interferon gamma release assay in diagnosis of pediatric tuberculosis: a meta-analysis

Although interferon gamma release assays (IGRAs) have been widely used for the diagnosis of latent and active tuberculosis in adults, a relative lack of validation studies in children has led to caution in their clinical interpretation. This meta-analysis systematically evaluated two IGRAs (ELISA and ELISPOT) and the tuberculin skin test (TST). We searched databases (PubMed, MEDLINE, Ovid) between January 2000 and January 2011 using search terms of latent tuberculosis infection or tuberculosis and interferon gamma release assay, or T-SPOT.TB test, or QuantiFERON-TB Gold, or ESAT-6, or CFP-10, and child, or childhood, or pediatrics. We also collected data by performing a manual search of references from relevant articles and communicating with selected authors. The meta-analysis was conducted with random effects models to account for heterogeneity between selected studies. The sensitivities of all three tests in active tuberculosis were similar. The pooled sensitivity was 70% for ELISA studies, 62% for ELISPOT studies and 71% for TST. Calculated sensitivities for IGRAs and the TST differ in culture-confirmed tuberculosis [ELISA (85%) vs. ELISPOT (76%) vs. TST (85%)] and clinical diagnosed cases [ELISA (64%) vs. ELISPOT (58%) vs. TST (66%)]. The pooled specificity was 100% for ELISA and 90% for ELISPOT, but was much lower for TST [56% in all included studies and 49% in children with bacillus Calmette-Guerin (BCG) vaccination]. The agreement between the TST and IGRAs in non-BCG-vaccinated children is higher than that in BCG-vaccinated children. In the diagnosis of active tuberculosis in children, the TST and IGRAs have similar sensitivity. By contrast, the specificity of IGRAs is far greater than the TST, particularly in children with previous BCG vaccination.     

Risk factors associated with positive QuantiFERON-TB Gold In-Tube and tuberculin skin tests results in Zambia and South Africa

Introduction

The utility of T-cell based interferon-gamma release assays for the diagnosis of latent tuberculosis infection remains unclear in settings with a high burden of tuberculosis.

Objectives

To determine risk factors associated with positive QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results and the level of agreement between the tests; to explore the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST.

Methods

Adult household contacts of tuberculosis patients were invited to participate in a cross-sectional study across 24 communities in Zambia and South Africa. HIV, QFT-GIT and TST tests were done. A questionnaire was used to assess risk factors.

Results

A total of 2,220 contacts were seen. 1,803 individuals had interpretable results for both tests, 1,147 (63.6%) were QFT-GIT positive while 725 (40.2%) were TST positive. Agreement between the tests was low (kappa = 0.24). QFT-GIT and TST results were associated with increasing age (adjusted OR [aOR] for each 10 year increase for QFT-GIT 1.15; 95% CI: 1.06–1.25, and for TST aOR: 1.10; 95% CI 1.01–1.20). HIV positivity was less common among those with positive results on QFT-GIT (aOR: 0.51; 95% CI: 0.39–0.67) and TST (aOR: 0.61; 95% CI: 0.46–0.82). Smear positivity of the index case was associated with QFT-GIT (aOR: 1.25; 95% CI: 0.90–1.74) and TST (aOR: 1.39; 95% CI: 0.98–1.98) results. We found little evidence in our data to support our hypotheses.

Conclusion

QFT-GIT may not be more sensitive than the TST to detect risk factors associated with tuberculous infection. We found little evidence to support the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST.