High annual risk of tuberculosis infection among nursing students in South India: a cohort study

Background

Nurses in developing countries are frequently exposed to infectious tuberculosis (TB) patients, and have a high prevalence of TB infection. To estimate the incidence of new TB infection, we recruited a cohort of young nursing trainees at the Christian Medical College in Southern India. Annual tuberculin skin testing (TST) was conducted to assess the annual risk of TB infection (ARTI) in this cohort.

Methodology/Principal Findings

436 nursing students completed baseline two-step TST testing in 2007 and 217 were TST-negative and therefore eligible for repeat testing in 2008. 181 subjects completed a detailed questionnaire on exposure to tuberculosis from workplace and social contacts. A physician verified the questionnaire and clinical log book and screened the subjects for symptoms of active TB. The majority of nursing students (96.7%) were females, almost 84% were under 22 years of age, and 80% had BCG scars. Among those students who underwent repeat testing in 2008, 14 had TST conversions using the ATS/CDC/IDSA conversion definition of 10 mm or greater increase over baseline. The ARTI was therefore estimated as 7.8% (95%CI: 4.3–12.8%). This was significantly higher than the national average ARTI of 1.5%. Sputum collection and caring for pulmonary TB patients were both high risk activities that were associated with TST conversions in this young nursing cohort.

Conclusions

Our study showed a high ARTI among young nursing trainees, substantially higher than that seen in the general Indian population. Indian healthcare providers and the Indian Revised National TB Control Programme will need to implement internationally recommended TB infection control interventions to protect its health care workforce.     

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.     

Sensitivity of the Quantiferon-Gold In-Tube Assay in Sputum Smear Positive TB Cases in Indonesia

Background

As part of a formal evaluation of the Quantiferon-Gold in-tube assay (QFT-IT) for latent TB infection we compared its sensitivity to the tuberculin skin test (TST) in confirmed adult TB cases in Indonesia. Smear-positive TB disease was used as a proxy gold standard for latent TB infection.

Methods and Findings

We compared the sensitivity of QFT-IT and TST in 98 sputum smear and chest x-ray positive TB cases and investigated risk factors for negative and discordant results in both tests. Both tests showed high sensitivity; (QFT-IT; 88.7%: TST; 94.9%), not significantly different from each other (p value 0.11). Very high sensitivity was seen when tests were combined (98.9%). There were no variables significantly associated with discordant results or with a negative TST. For QFT-IT which particular staff member collected blood was significantly associated with test positivity (p value 0.01). Study limitations include small sample size and lack of culture confirmation or HIV test results.

Conclusions

The QFT-IT has similar sensitivity in Indonesian TB cases as in other locations. However, QFT-IT, like the TST cannot distinguish active TB disease from LTBI. In countries such as Indonesia, with high background rates of LTBI, test specificity for TB disease will likely be low. While our study was not designed to evaluate the QFT-IT in the diagnosis of active TB disease in TB suspects, the data suggest that a combination of TST and QFT-IT may prove useful for ruling out TB disease. Further research is required to explore the clinical role of QFT-IT in combination with other TB diagnostic tests.     

Sensitivity of IFN-γ Release Assay to Detect Latent Tuberculosis Infection Is Retained in HIV-Infected Patients but Dependent on HIV/AIDS Progression

Background

Detection and treatment of latent TB infection (LTBI) in HIV infected individuals is strongly recommended to decrease morbidity and mortality in countries with high levels of HIV.

Objective

To assess the validity of a newly developed in-house ELISPOT interferon-γ release assay (IGRA) for the detection of LTBI amongst HIV infected individuals, in comparison with the Tuberculin Skin Test (TST).

Methodology/Principal Findings

ESAT6/CFP10 (EC) ELISPOT assays were performed, together with a TST, in 285 HIV infected individuals recruited in HIV clinics in Dakar, Senegal, who had no signs of active TB at time of enrolment. Thirty eight of the subjects (13.3%) failed to respond to PHA stimulation and were excluded from the analysis. In the 247 remaining patients, response to PHA did not vary according to CD4 cell count categories (p = 0.51). EC ELISPOT was positive in 125 (50.6%) subjects, while 53 (21.5%) had a positive TST. Concordance between EC ELISPOT and TST was observed in 151 patients (61.1%) (kappa = 0.23). The proportion of subjects with a positive response to the EC ELISPOT assay decreased with declining CD4 counts (p trend = 0.001), but were consistently higher than the proportion of TST responders. In multivariate analysis, the risk of being EC-ELISPOT positive in HIV infected individuals was associated with age, CD4 count and HIV-1 strain.

Conclusion

Our study indicates that IGRAs using M. tuberculosis specific antigens are likely to retain their validity for the diagnosis of LTBI among HIV positive individuals, but may be impaired by T-cell anergy in severely immuno-suppressed individuals.     

Latent Tuberculosis Infection and Occupational Protection among Health Care Workers in Two Types of Public Hospitals in China

Objective

To determine the impact factors of latent tuberculosis infection (LTBI) and the knowledge of TB prevention and treatment policy among health care workers (HCWs) in different types of hospitals and explore the strategies for improving TB prevention and control in medical institutions in China.

Methods

A cross-sectional study was carried out to evaluate the risk of TB infection and personnel occupational protection among HCWs who directly engage in medical duties in one of two public hospitals. Each potential participant completed a structured questionnaire and performed a tuberculin skin test (TST). Factors associated with LTBI were identified by logistic regression analysis.

Results

Seven hundred twelve HCWs completed questionnaires and 74.3% (n = 529) took the TST or had previous positive results. The TST-positive prevalence was 58.0% (n = 127) in the infectious disease hospital and 33.9% (n = 105) in the non-TB hospital. The duration of employment in the healthcare profession (6–10 years vs. ≤5 years [OR = 1.89; 95% CI = 1.10, 3.25] and>10 vs. ≤5[OR = 1.80; 95% CI = 1.20, 2.68]), type of hospital (OR = 2.40; 95% CI = 1.59, 3.62), and ever-employment in a HIV clinic or ward (OR = 1.87; 95% CI = 1.08, 3.26)were significantly associated with LTBI. The main reasons for an unwillingness to accept TST were previous positive TST results (70.2%) and concerns about skin reaction (31.9%).

Conclusion

A high prevalence of TB infections was observed among HCWs working in high-risk settings and with long professional experiences in Henan Province in China. Comprehensive guidelines should be developed for different types of medical institutions to reduce TB transmission and ensure the health of HCWs.     

Role of QuantiFERON-TB Gold,Interferon Gamma Inducible Protein-10 and Tuberculin Skin Test in Active Tuberculosis Diagnosis

Background

The measurement of Interferon gamma or Interferon gamma inducible protein (IP)-10 in antigen stimulated blood samples is suggested as an alternative method for latent tuberculosis (TB) diagnosis. Nonetheless, their role in active TB diagnosis, particularly in TB endemic settings is yet to be defined. In this study, the sensitivities and specificities of Interferon gamma release assay (IGRA), IP-10 assay and tuberculin skin test (TST) in detecting active TB cases were assessed in human immunodeficiency virus (HIV) sero-negative TB patients and healthy controls respectively.

Methods/Principal Findings

A total of 177 adult TB patients and 100 healthy controls were included for this study. QuantiFERON-TB Gold In-tube (QFT-IT) method was used to analyze the sensitivity and specificity of IGRA. QFT-IT, IP-10 and TST yielded the diagnostic sensitivities of 90.6% (95%CI: 86.3%–94.9%), 92.5% (95%CI: 88.6%–96.4%) and 68.9% (95%CI: 60.6%–77.2%) and specificities of 55% (95% CI: 35.2%–54.8%), 48% (95% CI: 38.2%–57.8%) and 75.5% (95% CI: 66.8%–84.2%), respectively. The extent of pulmonary involvement or presence of diabetes mellitus did not appear to influence the sensitivities of any of these tests. The combination of any of the two tests among QFT-IT, IP-10 and TST showed >98% sensitivity among smear negative cases and particularly the combination of IP-10, TST and smear microscopy showed 100% sensitivity, however, the specificity was decreased to 44.8%.

Conclusions/Significance

QFT-IT and IP-10 were highly sensitive in detecting active TB cases. The combination with TST improved the sensitivity of QFT-IT and IP-10 significantly. Although the higher sensitivity of combination of QFT-IT/IP-10 and TST may be useful in active TB diagnosis, they are limited by their poor specificity due to the high prevalence of latent TB in our settings.     

Evaluation of Interferon-Gamma Release Assays in the Diagnosis of Recent Tuberculosis Infection in Health Care Workers

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.     

Prevalence and Risk Factors for Tuberculosis Infection among Hospital Workers in Hanoi,Viet Nam

Background

Transmission of tuberculosis (TB) to health care workers (HCWs) is a global issue. Although effective infection control measures are expected to reduce nosocomial TB, HCWs'' infection has not been assessed enough in TB high burden countries. We conducted a cross-sectional study to determine the prevalence of TB infection and its risk factors among HCWs in Hanoi, Viet Nam.

Methodology/Principal Findings

A total of 300 HCWs including all staff members in a municipal TB referral hospital received an interferon-gamma release assay (IGRA), QuantiFERON-TB Gold In-Tube^TM, followed by one- and two-step tuberculin skin test (TST) and a questionnaire-based interview. Agreement between the tests was evaluated by kappa statistics. Risk factors for TB infection were analyzed using a logistic regression model. Among the participants aged from 20 to 58 years (median = 40), prevalence of TB infection estimated by IGRA, one- and two-step TST was 47.3%, 61.1% and 66.3% respectively. Although the levels of overall agreement between IGRA and TST were moderate, the degree of agreement was low in the group with BCG history (kappa = 0.29). Working in TB hospital was associated with twofold increase in odds of TB infection estimated by IGRA. Increased age, low educational level and the high body mass index also demonstrated high odds ratios of IGRA positivity.

Conclusions/Significance

Prevalence of TB infection estimated by either IGRA or TST is high among HCWs in the hospital environment for TB care in Viet Nam and an infection control program should be reinforced. In communities with heterogeneous history of BCG vaccination, IGRA seems to estimate TB infection more accurately than any other criteria using TST.     

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.     

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.     

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.     

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.     

High Utility of Contact Investigation for Latent and Active Tuberculosis Case Detection among the Contacts: A Retrospective Cohort Study in Tbilisi,Georgia, 2010–2011

Setting

The study was conducted at the National Center for Tuberculosis and Lung Diseases (NCTBLD) in Tbilisi, Georgia.

Objective

To assess the utility of contact investigation for tuberculosis (TB) case detection. We also assessed the prevalence and risk factors for active TB disease and latent TB infection (LTBI) among contacts of active pulmonary TB cases.

Design

A retrospective cohort study was conducted among the contacts of active pulmonary TB cases registered in 2010–2011 at the NCTBLD in Tbilisi, Georgia. Contacts of active TB patients were investigated according to an “invitation model”: they were referred to the NCTBLD by the index case; were queried about clinical symptoms suggestive of active TB disease; tuberculin skin testing and chest radiographs were performed. Demographic, laboratory, and clinical data of TB patients and their contacts were abstracted from existing records up to February 2013.

Results

869 contacts of 396 index cases were enrolled in the study; a median of 2 contacts were referred per index case. Among the 869 contacts, 47 (5.4%) were found to have or developed active TB disease: 30 (63.8%) were diagnosed with TB during the baseline period (co-prevalent cases) and 17 (36.2%) developed active TB disease during the follow-up period (mean follow up of 21 months) (incident TB cases). The incidence rate of active TB disease among contacts was 1126.0 per 100 000 person years (95% CI 655.7–1802.0 per 100,000 person-years). Among the 402 contacts who had a tuberculin skin test (TST) performed, 52.7% (95% CI 47.7–57.7%) had LTBI.

Conclusions

A high prevalence of LTBI and active TB disease was found among the contacts of TB cases in Tbilisi, Georgia. Our findings demonstrated that an “invitation” model of contact investigation was an effective method of case detection. Therefore, contact investigation should be scaled up in Georgia.     

Role of Interferon Gamma Release Assay in Active TB Diagnosis among HIV Infected Individuals

Background

A rapid and specific test is urgently needed for tuberculosis (TB) diagnosis especially among human immunodeficiency virus (HIV) infected individuals. In this study, we assessed the sensitivity of Interferon gamma release assay (IGRA) in active tuberculosis patients who were positive for HIV infection and compared it with that of tuberculin skin test (TST).

Methodology/Principal Findings

A total of 105 HIV-TB patients who were naïve for anti tuberculosis and anti retroviral therapy were included for this study out of which 53 (50%) were culture positive. Of 105 tested, QuantiFERON-TB Gold in-tube (QFT-G) was positive in 65% (95% CI: 56% to 74%), negative in 18% (95% CI: 11% to 25%) and indeterminate in 17% (95% CI: 10% to 24%) of patients. The sensitivity of QFT-G remained similar in pulmonary TB and extra-pulmonary TB patients. The QFT-G positivity was not affected by low CD4 count, but it often gave indeterminate results especially in individuals with CD4 count <200 cells/µl. All of the QFT-G indeterminate patients whose sputum culture were positive, showed ≤0.25 IU/ml of IFN-γ response to phytohemagglutinin (PHA). TST was performed in all the 105 patients and yielded the sensitivity of 31% (95% CI: 40% to 22%). All the TST positives were QFT-G positives. The sensitivity of TST was decreased, when CD4 cell counts declined.

Conclusions/Significance

Our study shows neither QFT-G alone or in combination with TST can be used to exclude the suspicion of active TB disease. However, unlike TST, QFT-G yielded fewer false negative results even in individuals with low CD4 count. The low PHA cut-off point for indeterminate results suggested in this study (≤0.25 IU/ml) may improve the proportion of valid QFT-G 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.     

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.     

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.     

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.     

Is IP-10 a Better Biomarker for Active and Latent Tuberculosis in Children than IFNγ?

Background

The blood based interferon-gamma release assays (IGRA) for the diagnosis of tuberculosis do not discriminate between active TB disease and latent TB infection (LTBI). The search for distinguishing biomarkers therefore continues, as the accurate diagnosis of tuberculosis is particularly challenging in children. IFN-γ-inducible protein 10 (IP-10/CXCL10) has recently been evaluated as a marker for active TB in adults with promising results.

Aim

To investigate this new biomarker for active TB and LTBI in paediatrics.

Method

We measured IP-10 levels using ELISA in supernatants of whole blood samples stimulated with TB-specific-antigens and negative control antigen.

Results

IP-10 is produced in high levels following mycobacterial antigen stimulation in active TB (n = 17) and LTBI (n = 16) compared to controls (n = 16) and to IFN-γ. The baseline levels of IP-10 are increased in active TB and in LTBI, but there is no significant difference of stimulated levels of IP-10 between active TB and LTBI.

Conclusions

IP-10 is a biomarker for tuberculosis in children. However like IFNγ, IP-10 also does not distinguish between active TB and LTBI.     

Interferon-gamma release assay for the diagnosis of latent TB infection--analysis of discordant results, when compared to the tuberculin skin test

Background

With the Interferon-γ release assays (IGRA) a new method for the diagnosis of latent tuberculosis infections (LTBI) is available. Due to the lack of a gold standard for the diagnosis of LTBI, the IGRA is compared to the Mantoux Tuberculin Skin Test (TST), which yields discordant results in varying numbers. Therefore we assessed to which extent discordant results can be explained by potential risk factors such as age, BCG vaccination and migration.

Methods and Findings

In this pooled analysis, two German studies evaluating the Quantiferon-Gold In-Tube test (QFT) by comparison with the TST (RT23 of SSI) were combined and logistic regressions for potential risk factors for TST+/QFT− as well as THT−/QFT+ discordance were calculated. The analysis comprises 1,033 participants. Discordant results were observed in 15.4%, most of them being TST+/QFT− combinations. BCG vaccination or migration explained 85.1% of all TST+/QFT− discordance. Age explained 49.1% of all TST−/QFT+ discordance. Agreement between the two tests was 95.6% in German-born persons younger than 40 years and not BCG-vaccinated.

Conclusions

After adjustment for potential risk factors for positive or negative TST results, agreement of QFT and TST is excellent with little potential that the TST is more likely to detect old infections than the QFT. In surveillance programs for LTBI in high-income, low TB incidence countries like Germany the QFT is especially suited for persons with BCG vaccination or migrants due to better specificity and in older persons due to its superior sensitivity.