INT J TUBERC LUNG DIS 18(7):787–792 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0816
Interferon-gamma release assays piloted as a latent tuberculous infection screening tool in Canadian federal inmates I. S. Schwartz,* P. J. Bach,† B. Roscoe,‡ A. Majury,§¶ W. M. Hopman,#** E. Ellis,††‡‡ T. Garrahan,‡ J. Smith,‡ R. Barkley,‡ L. Panaro,‡,‡‡ F. Jamieson,§§¶¶ C. Froats,§ I. Gemmill,**## W. L. Wobeser** *Departments of Medical Microbiology & Infectious Diseases and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, †Department of Internal Medicine, University of British Columbia, Vancouver, British Columbia, ‡Correctional Services Canada, Health Services, Kingston, Ontario, §Laboratory Services, Public Health Ontario, Kingston, Ontario, ¶Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, #Clinical Research Centre, Kingston General Hospital, Kingston, Ontario, **Department of Public Health Sciences, Queen’s University, Kingston, Ontario, ††Public Health Agency of Canada, Ottawa, Ontario, ‡‡Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, §§Public Health Ontario, Laboratory Services, Toronto, Ontario, ¶¶Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, ##Kingston Frontenac Lennox & Addington Health Unit, Kingston, Ontario, **Department of Medicine, Queen’s University, Kingston, Ontario, Canada SUMMARY B A C K G R O U N D : Interferon-gamma release assays (IGRAs) may be useful in diagnosing latent tuberculous infection (LTBI) in inmates; however, published experience in these settings is limited. O B J E C T I V E : To identify variables associated with IGRA positivity among Canadian federal inmates with positive tuberculin skin test (TST) results. D E S I G N : On intake, TST-positive (710 mm) inmates were offered an IGRA (QuantiFERONw-TB Gold), and demographic and historical data were collected. IGRApositive and -negative inmates were compared using the v2 test and multivariable logistic regression; the final model’s goodness of fit was assessed using HosmerLemeshow test and area under the receiver operating characteristic curve (AUC). R E S U LT S : Of 96 TST-positive inmates, 31 (32.3%)
were IGRA-positive. Variables associated with positive IGRA were age .45 years (11/20 vs. 20/75, P ¼ 0.016) and previous LTBI treatment (9/20 vs. 13/55, P ¼ 0.032) in univariate analysis, and being from a country with a moderate or high estimated tuberculosis (TB) incidence (OR 3.5, 95%CI 1.3–9.4, P ¼ 0.013) and absence of bacille Calmette-Gu´erin (BCG) vaccination (OR 3.3, 95%CI 1.2–9.0, P ¼ 0.017) in multivariable analysis. The data fit the model well, classifying the group better than chance alone (AUC 0.67, P ¼ 0.007). C O N C L U S I O N : High discordance with TST, particularly among BCG-vaccinated inmates and those from low TB incidence countries, suggest that IGRA may be useful in Canadian federal penitentiary screening programmes. K E Y W O R D S : IGRA; LTBI; TST; prisons; TB
ALTHOUGH it has been used in screening for latent tuberculous infection (LTBI) for over a century, the Mantoux tuberculin skin test (TST) has several important limitations, including false-positive results in individuals with previous bacille Calmette-Gu´erin (BCG) vaccination or non-tuberculous mycobacteria (NTM) infection,1,2 the requirement for two separate visits for testing and interpretation, and poor reproducibility.1 Furthermore, inter-observer variability of as high as 6 mm has been reported.3,4 Interferon-gamma release assays (IGRAs) promise at least comparable sensitivity to TST, with improved specificity due to less cross-reaction with some NTM and previous BCG vaccination.5,6 IGRA appear to
have a higher sensitivity in human immunodeficiency virus (HIV) infected individuals,7 and require only a single visit. A meta-analysis found that IGRA had better positive predictive value than TST for the development of tuberculosis (TB) disease, although both were relatively low (2.7% and 1.5%, respectively).8 Two commercial assays are currently available on the market, the QuantiFERONw-TB Gold (QFT) test (Cellestis/Qiagen, Carnegie, VIC, Australia) and the T-SPOTw.TB test (Oxford Immunotec, Oxford, UK). Current Canadian recommendations are that IGRAs may be suitable for confirming positive TST results in health care workers, prison staff or inmates
Correspondence to: I S Schwartz, Departments of Medical Microbiology & Infectious Diseases and Internal Medicine, University of Manitoba, Basic Medical Sciences Building, 543–745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. Tel: (þ1) 204 789 3522. Fax: (þ1) 204 789-3926. e-mail: [email protected] Article submitted 13 November 2013. Final version accepted 19 March 2014.
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who are immunocompetent, considered to have a low pre-test probability of LTBI, and lack high-risk features for progression to active disease if infected.9 However, published experience with IGRA in these clinical settings is limited. In 1997, the Canadian federal prison system implemented a TB surveillance system to detect active disease at intake and identify individuals with LTBI on intake who might benefit from preventive therapy. To date, TST has been an integral part of the programme. Per this screening programme, 17.6% of inmates and 6.0–7.6% of staff were TST-positive in 2008 according to the standard Canadian definition for positivity of 710 mm induration.10 In 2010, an IGRA (QFT) was introduced into a pilot project to supplement TST in LTBI screening of Canadian federal inmates in Ontario on intake to the correctional facility. This study evaluated factors associated with a positive IGRA among TST-positive inmates.
STUDY POPULATION AND METHODS New inmates entering the Canadian federal penitentiary system are offered TST screening on intake. All inmates entering Millhaven Institution, Bath, ON, Canada, who screened positive for LTBI using TST (710 mm induration) at Millhaven Institution or with a previous positive TST from a provincial correctional institution between the months of April and October 2010 inclusive were offered IGRA (see the Figure for study algorithm). Of 107 inmates who met the eligibility criteria,
eight declined involvement or were unavailable for IGRA testing, and were eliminated from further analysis. IGRA testing was performed on 99 inmates. Blood was drawn according to protocol, and then couriered within the manufacturer’s recommended transport time to the Public Health Ontario Laboratory in Kingston, where samples were analysed using QFT according to the manufacturer’s instructions. Active TB disease was ruled out by symptom check, chest X-ray and sputum culture for all those enrolled. A questionnaire covering TB risk factors was administered to inmates at the time of phlebotomy, and further demographic information was gathered from chart review. HIV testing was offered at the time of phlebotomy. BCG vaccination status was inferred using public health policies in the inmate’s country of birth in his/her year of birth (http://www.bcgatlas. org).11 Estimated TB incidence in the country of birth was referenced from the World Health Organization.12 Data were entered into a spreadsheet and imported into IBM SPSS version 20.0 (IBM Corp, Armonk, NY, USA) for statistical analysis. v2 tests (Pearson’s or Fisher’s exact, as appropriate) were used to compare characteristics of inmates with positive and those with negative QFT. Variables with an association of P , 0.10 were entered into a backward, manual logistic regression model to facilitate inclusion of patients with any missing data for eliminated variables. Goodness of fit was assessed using the Hosmer and Lemeshow test, and probabilities for the logistic regression model were saved and used to populate a receiver operating characteristic (ROC) curve to
Figure Study algorithm. TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
IGRA for LTBI screening in Canadian inmates
additionally assess goodness-of-fit using the area under the curve (AUC). The criterion for statistical significance was P , 0.05. The impact of time between TST and QFT was analysed using the MannWhitney U-test. This study was approved by the Research Ethics Board at Queen’s University, Kingston, ON, Canada.
ment data were available for 60 (62.5%) inmates. The remaining 36 (37.5%) inmates were reported to be TST-positive at previous institutional screening, but induration measurements were unavailable. For those with a known TST measurement, the mean induration was 18.2 mm (range 10–46). Of 48 inmates (50%) tested for HIV, none were found to be positive. Overall, 31 individuals (32.3%) had positive (concordant) QFT results. In univariate analyses, variables associated with concordant QFT were age .45 years (11/20, 55.0% vs. 20/75, 26.7%; P ¼ 0.016) and any previous treatment for LTBI (9/20, 45.0% vs. 13/55, 23.6%; P ¼ 0.032). Factors that demonstrated a trend toward significance in predicting a positive QFT included birth in a country with a moderate or high estimated TB incidence (18/42, 42.9% vs. 13/54, 24.1%; P ¼ 0.051) and absence of BCG vaccination (27/46, 58.7% vs. 38/50, 76.0%; P ¼ 0.070). Having a larger TST result (.20 mm) also demonstrated a trend towards significance in predicting a positive QFT (10/23, 43.5% vs. 9/37, 24.3%; P ¼ 0.121). In a logistic regression analysis (Table 2), two variables were independently associated with a concordant QFT. Being from a country with a
RESULTS Of the 99 inmates who underwent QFT, three had indeterminate tests and were omitted from analysis; 96 inmates with a positive TST and either positive or negative QFT were included in further analysis. The characteristics of the inmates and bivariate analysis of the QFT results are shown in Table 1. The mean age was 35.8 years (range 20–67); 67 inmates (69.8%) were foreign-born, with a mean duration in Canada of 18.3 years (range 1–36), and were from the following world regions: Caribbean (n ¼ 22, 22.9%), Asia (n ¼ 20, 20.8%), sub-Saharan Africa (n ¼ 12, 12.5%), Latin America (n ¼ 7, 7.3%), Middle East (n ¼ 3, 3.1%) and Europe (n ¼ 3, 3.1%). Of all the Canadian-born inmates, five (5.2%) self-identified as aboriginal. TST measureTable 1
Bivariate analysis comparing IGRA-positive and IGRA-negative inmates IGRA-positive (n ¼ 31) n (%)
IGRA-negative (n ¼ 65) n (%)
Total (n ¼ 96) n (%)
Age group, years* 645 .45
20 (26.7) 11 (55.0)
55 (73.3) 9 (45.0)
75 (78.1) 20 (20.8)
0.016
TST group, mm Positive but measurement unavailable† 10–14 15–19 20–24 725
12 6 3 6 4
24 10 18 11 2
36 16 21 17 6
(37.5) (16.7) (21.9) (17.7) (6.3)
0.083
BCG‡ Yes No
12 (24.0) 19 (41.3)
38 (76.0) 27 (58.7)
50 (51.0) 46 (47.9)
0.070
TB incidence in country of birth§ Low Moderate to high
13 (24.1) 18 (42.9)
41 (75.9) 24 (57.1)
54 (56.3) 42 (73.8)
0.051
Birthplace Foreign-born Canadian-born
22 (32.8) 9 (31.0)
45 (67.2) 20 (69.0)
67 (69.8) 29 (30.2)
0.862
3 (60.0) 8 (38.1)
2 (40.0) 13 (61.9)
5 (5.2) 21 (21.9)
0.373
13 (23.6) 4 (30.8) 5 (71.4)
42 (76.4) 9 (69.2) 2 (70.7)
55 (57.3) 13 (13.4) 7 (7.3)
0.032
Ethnicity of Canadian-born inmates* Aboriginal Non-Aboriginal Previous treatment for LTBI* No Yes Partial
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(33.3) (37.5) (14.3) (35.3) (66.7)
(66.7) (62.5) (85.7) (64.7) (33.3)
P value
* Some data were missing for age (n ¼ 1), ethnicity (n ¼ 3), previous treatment for LTBI (n ¼ 21). † Individuals for whom a TST had been interpreted as positive at a referring institution, but for whom measurements were unavailable. ‡ BCG vaccination status was presumed according to the policy of the country and year of birth (www.bcgatlas.org). § Low refers to countries with estimated incidence rates of sputum-positive pulmonary TB ,15/100 000; moderate to high refers to those with estimated incidence 715/100 000.12 ´ IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection; WHO ¼ World Health Organization.
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Table 2 inmates
Multivariable analysis of IGRA results in TST-positive
Variable*
OR (95%CI)
P value
BCG† No Yes
3.3 (1.2–9.0) Reference
0.017
TB incidence in country of birth‡ Low Reference Moderate to high 3.5 (1.3–9.4)
0.013
* Variables initially entered into the model were removed manually in the following order, based on P value: TST category, age category, foreign-born, previous treatment (P ¼ 0.109 at removal). Hosmer and Lemeshow goodnessof-fit v2 ¼ 0.54, P ¼ 0.763. † BCG status was presumed according to the policy of the country and year of birth (www.bcgatlas.org). ‡ Low refers to countries with estimated incidence rates of sputum-positive pulmonary TB ,15/100 000; moderate to high refers to countries with estimated incidence 715/100 000.12 IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; OR ¼ odds ´ ratio; CI ¼ confidence interval; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; WHO ¼ World Health Organization.
moderate to high estimated TB incidence resulted in a 3.5-fold increase in the likelihood of a positive QFT (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.3–9.4, P ¼ 0.013). Furthermore, absence of previous BCG vaccination resulted in a 3.3-fold increase in the likelihood of a positive QFT (OR 3.3, 95%CI 1.2–9.0, P ¼ 0.017). The Hosmer and Lemeshow test indicates a v2 of 0.54 (P ¼ 0.76), suggesting that the data fit the final model quite well; the AUC was 0.67 (P ¼ 0.007), suggesting that the logistic regression classified the group significantly better than chance alone. Time between TST and QFT had no significant impact on the QFT results (P ¼ 0.75, Mann-Whitney U). Two additional analyses were conducted to assess the potential impact of including the 36 inmates for whom TST data was missing in the study. First, those with and those without documented TST results were compared using the v2 test: the two groups did not differ on any variable other than previous treatment (83% of those with and 56% of those without TST induration measurements received treatment, P ¼ 0.024). There were no differences in age, BGC vaccination, place of birth, TB incidence in country of birth, whether aboriginal or QFT results. The second analysis involved re-running both the bivariate and multivariate analyses without these 36 inmates. Tests of significance were attenuated due to the loss of power, but all results remained comparable (e.g., age: P ¼ 0.016 to P ¼ 0.035; BCG: P ¼ 0.070 to P ¼ 0.013; TB incidence in country of birth: P ¼ 0.051 to P ¼ 0.121; foreign birth: P ¼ 0.86 to P ¼ 0.42; aboriginal heritage: P ¼ 0.37 to P ¼ 0.46; and previous treatment: P ¼ 0.032 to P ¼ 0.081). Regression results changed slightly, in that the P value for BCG changed from P ¼ 0.017 to P ¼ 0.009 and TB incidence changed from P ¼ 0.013 to P ¼ 0.056.
DISCUSSION In this pilot project of an IGRA used as an adjunct to the current TB screening programme in a Canadian penitentiary, only a third of inmates who were TSTpositive were also positive using QFT. This study evaluated factors associated with concordant QFT results in this setting. Other studies have compared TST and IGRA results in correctional institutions, particularly in Europe. In a study of an IGRA and TST among 181 prisoners in Spain, Mourino ˜ et al. reported a concordance rate of 67.5% (27/40) among those with positive TST.13 In a contact tracing investigation in a prison in Germany, during which 149 male inmates received both tests, Scharlach et al. found a concordance rate of 45.5% (20/44) for QFT among TST-positive inmates.14 In the present study, factors associated on univariate analysis with concordant QFT results among TST-positive inmates included age .45 years and previous LTBI treatment. On multivariable analysis, these two factors fell out of the model, such that birth in a country with a moderate or high estimated TB incidence and absence of previous BCG vaccination were found to be the independent predictors of concordance. Data in the literature regarding the impact of BCG vaccination on TST results are conflicting.2,6 Neinhaus et al. found that BCG contributed to a large majority of TSTþ, IGRA– results in a German cohort.6 In contrast, a meta-analysis by Farhat et al. suggested that BCG was unlikely to cause falsepositive TST results.2 We found that previous BCG vaccination increased the likelihood of a discordant IGRA in those who were TST-positive: inmates with a positive TST in the absence of BCG vaccination had a .3 times higher likelihood of a positive IGRA than TST-positive inmates who had received BCG vaccination. This supports the view that BCG vaccination likely contributed to some of the discordance in this study. Our findings of improved concordance between positive TST and IGRA in older individuals are in agreement with those reported by Kunimoto et al. from their out-patient clinic,15 although the clinic and inmate populations likely have different tuberculous infection risks. In our study, the age at which a difference in concordance became significant was 45 years, whereas Kunimoto et al. found that those aged .65 years were significantly more likely to have a positive IGRA than those aged ,20 years. Improved concordance between TST and IGRA in older individuals might be explained by the fact that TST reactions to previous BCG vaccination wane over time, and thus older individuals are less likely to have a positive TST as a result of BCG vaccination.1 There are several important limitations of this
IGRA for LTBI screening in Canadian inmates
study. First, our population was exclusively male, although we know of no reason why our findings should not also apply to female inmates. Our study also did not include participants who were known to be HIV-positive, with negative HIV test results documented in half of our cohort. HIV prevalence among Canadian federal penitentiary inmates was 1.7% in 2010 (CSC WebIDSS, preliminary unpublished data). Also under-represented in this study were Canadian aboriginal persons, who comprise 10% of the inmate population of Ontario federal penitentiaries,16 but who made up just 5.2% of our cohort. BCG vaccination status for inmates was presumed based on the public health policy of their country and year of birth, as described by Zwerling et al.11 This method may have some important limitations, particularly for those from countries with regional variation in policy or where recommendations were based on certain high-risk features at birth, which may have resulted in an overestimation of BCG vaccination; thus, the strength of the association between BCG vaccination and discordant TST/IGRA may have been stronger than found here. Another potential limitation of the present study is that TST measurements were lacking for 37% of the inmates. In these cases, the TST had been performed at a referring correctional institution and were reported to be positive; however, the measurements had not been conveyed. The TST was not repeated for two reasons: 1) so that the study protocol reflected current practice in Canadian federal penitentiaries to maintain real-world applicability in this setting, and 2) because repeating TST was not felt to be in the interest of the inmate. It is possible that some of those enrolled may not have had true-positive readings, which may falsely reduce concordance with IGRA. However, with the exception of higher rates of previous LTBI treatment in those inmates with TST measurements missing, there were no significant differences between inmates for whom TST measurements were documented and those identified as TSTpositive but with measurements missing. Furthermore, aside from a loss of power, there were no significant changes in the results of the bivariate and multivariate analyses when excluding those inmates whose TST measurements were missing. We therefore conclude that this is unlikely to represent an important cause of bias. TST and IGRA are both dynamic tests, and there is evidence to suggest that TST administration could affect the IGRA results. In particular, the phenomenon of ‘boosting’ of IGRA by recent, prior TST has been described, although the clinical significance of this remains unclear.17 As such, current Canadian recommendations are for blood samples for IGRA to be obtained before, or on the day of, TST administration when both methods of testing are employed.9 As IGRA
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was offered only to inmates with TST-positive results, this was impractical in our study. Although this could theoretically result in false-positive IGRA results and an over-estimation of concordance, our analysis suggests that the time between tests had no significant impact on IGRA outcome. Like other cross-sectional studies of IGRA and TST, this study is limited by the lack of a gold standard for the identification of LTBI that would later progress to active TB.18 We do not therefore know which, if any, of the participants were truly infected with Mycobacterium tuberculosis and are at risk of developing future active disease. Given the availability of preventive LTBI therapy and the risks of progressing to active TB, both to the health of the individual and to other inmates and prison staff, inmates with positive IGRA and TST, in the absence of contraindications or prior therapy, were offered isoniazid preventive treatment (IPT). Those with discordant results (TSTþ, IGRA–) were not offered IPT, but were and will be followed with annual assessments, including symptom review, sputum cultures and chest X-ray, to monitor for the development of active disease. Finally, this study has shown that discordance between IGRA and TST is more likely in inmates with previous BCG vaccination and those from countries with low TB incidence. However, it is not able to conclude whether the optimal use of IGRA in Canadian federal prisons is in a confirmatory role for screening positive by TST vs. other methods, such as review of TB risk factors. Further study, in addition to cost analysis, is needed to understand the effectiveness of TST and the advisability of replacing TST with IGRA in correctional settings.
CONCLUSION The high rates of discordance in this study suggest that IGRAs may be more discerning than the TST for the diagnosis of LTBI in Canadian federal inmates, particularly in BCG-vaccinated inmates and those from low TB incidence countries, and that it may have an important role in screening programmes in this setting. Acknowledgements The authors gratefully acknowledge the federal inmates and Health Services staff of Millhaven Institution, Bath, ON, Canada, as well as the technologists of the Public Health Ontario laboratory in Kingston who performed the IGRA testing for this study. We are also grateful to the two anonymous reviewers for their constructive criticism of this manuscript. Funding was provided by Public Health Agency of Canada. Conflict of interest: none declared.
References 1 Huebner R E, Schein M F, Bass J B, Jr. The tuberculin skin test. Clin Infect Dis 1993; 17: 968–975.
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2 Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: What is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006; 10: 1192–1204. 3 Bearman J E, Kleinman H, Glyer V V, Lacroix O M. A study of variability in tuberculin test reading. Am Rev Respir Dis 1964; 90: 913–919. 4 Pouchot J, Grasland A, Collet C, Coste J, Esdaile J M, Vinceneux P. Reliability of tuberculin skin test measurement. Ann Intern Med 1997; 126: 210–214. 5 Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: Areas of uncertainty and recommendations for research. Ann Intern Med 2007; 146: 340–354. 6 Nienhaus A, Schablon A, Diel R. Interferon-gamma release assay for the diagnosis of latent TB infection—analysis of discordant results, when compared to the tuberculin skin test. PLOS ONE 2008; 3: e2665. 7 Cattamanchi A, Smith R, Steingart K R, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2011; 56: 230–238. 8 Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest 2012; 142: 63–75. 9 M, Kunimoto D, Jamieson F, Menzies D. Diagnosis of latent tuberculosis infection. In: Menzies D, ed. Canadian tuberculosis standards. 7th ed. Ottawa, ON, Canada: Public Health Agency of Canada and Canadian Thoracic Society, 2013. 10 Correctional Services Canada. Infectious disease surveillance in
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Canadian federal penitentiaries 2007–2008. Ottawa, ON, Canada: Minister of Public Works and Government Services, 2013. http://www.csc-scc.gc.ca/text/pblct/infdscfp-2007-08/ index-eng.shtml Accessed April 2014. Zwerling A, Behr M A, Verma A, Brewer T F, Menzies D, Pai M. The BCG world atlas: a database of global BCG vaccination policies and practices. PLOS MED 2011; 8 e1001012. World Health Organization. WHO report 2011. Global tuberculosis control. WHO/HTM/TB/2011.16. Geneva, Switzerland: WHO, 2011. Marco Mourino ˜ A, Orcau Palau A, Jane Galliga R, et al. Concordance of tuberculin tests and interferon gamma release assays in the prison population. Rev Esp Sanid Penit 2011; 13: 15–20. [Spanish] Scharlach M, Gross C, Wagner D, et al. Comparison of the tuberculin skin test with the interferon-gamma test in the framework of a surroundings investigation in a prison. Gesundheitswesen 2008; 70: 684–689. Kunimoto D, Der E, Beckon A, et al. Use of the QuantiFERONTB gold test to confirm latent tuberculosis infection in a Canadian tuberculosis clinic. Int J Tuberc Lung Dis 2009; 13: 726–730. Baboom A. The changing profile of adults in custody, 2006/ 2007. Report nr 28 (10). Ottawa, ON, Canada: Juristat, 2008. van Zyl-Smit R N, Zwerling A, Dheda K, Pai M. Within-subject variability of interferon-c assay results for tuberculosis and boosting effect of tuberculin skin testing: a systematic review. PLOS ONE 2009; 4: e8517. Pai M, Menzies D. The new IGRA and the old TST: making good use of disagreement. Am J Respir Crit Care Med 2007; 175: 529–531.
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RESUME C O N T E X T E : Les recommandations canadiennes actuelles sugge` rent que les tests de libe´ ration de l’interf´eron gamma (IGRA) pourraient eˆ tre utiles au diagnostic de tuberculose latente (LTBI) parmi les d´etenus, mais on dispose de peu d’exp´eriences publi´ees dans ce contexte. O B J E C T I F : Identifier les variables associ´ees a` un test IGRA positif parmi des d´etenus f´ed´eraux canadiens ayant un test positif a` la tuberculine (TST). S C H E M A : Les d´etenus f´ed´eraux canadiens ayant un TST tuberculine positif (710 mm) a` leur arriv´ee se sont vus offrir un test IGRA (QuantiFERON-TBw Gold). Des donne´ es d e´ mographiques et d’anamn e` se ont e´ te´ recueillies lors d’entretiens. On a ensuite compar´e ceux qui avaient des tests IGRA positifs et n´egatifs grace ˆ au test du v2 et a` une r´egression logistique multivari´ee ; l’ajustement du mod`ele final a e´ t´e e´ valu´e grace ˆ au test de Hosmer et Lemeshow et a` la surface sous la courbe ROC. R E S U LT A T S : Sur 96 d´etenus avec un r´esultat IGRA
d´etermin´e, 31 (32,3%) e´ taient positifs. En analyse univari´ee, un age ˆ .45 ans (11/20 contre 20/75 ; P ¼ 0,016) et un traitement ant´erieur de LTBI (9/20 contre 13/55 ; P ¼ 0,032) e´ taient associ´es a` un IGRA positif. En analyse multivari´ee, le fait de venir d’un pays a` incidence mod´er´ee ou e´ lev´ee de la tuberculose (TB) (OR 3,5 ; IC95% 1,3–9,4 ; P ¼ 0,013) et l’absence de vaccination par le bacille de Calmette-Gu´erin (OR 3,3 ; IC95% 1,2– 9,0 ; P ¼ 0,017) e´ taient ind´ependamment associ´es a` un IGRA positif. Le test d’ajustement a montr´e que les donn´ees s’ajustaient bien au mod`ele, en classant mieux le groupe que par le seul effet du hasard (AUC 0,67 ; P ¼ 0,007). C O N C L U S I O N : Un taux e´ lev´e de discordance avec le TST, surtout parmi les d´etenus non vaccin´es par le BCG et ceux provenant de pays a` faible incidence de TB, sugg`erent que l’IGRA pourrait eˆ tre un test utile dans les programmes de d´epistage de la TB dans les p´enitenciers f´ed´eraux du Canada.
RESUMEN M A R C O D E R E F E R E N C I A: Las pruebas de liberacion ´ de interferon ´ gama (IGRA) pueden ser utiles ´ en el diagnostico ´ de la infeccion ´ tuberculosa latente (LTBI), pero las publicaciones de investigaciones en estos entornos son escasas. O B J E T I V O: Determinar los factores que se asocian con la positividad de las IGRA en los reclusos del sistema federal canadiense que presentan una prueba cuta´nea positiva a la tuberculina (TST). M E´ T O D O S: Al ingreso, se propuso la IGRA (QuantiFERON-TB Goldw ) a los reclusos que presentaban una TST positiva (710 mm). Se recogieron datos demogra´ficos y cl´ınicos y se compararon los grupos de reclusos con IGRA positivas y negativas, mediante la prueba de la v2 y un ana´lisis de regresion ´ log´ıstica multifactorial; la bondad de ajuste del modelo se evaluo´ con la prueba de Hosmer-Lemeshow y la curva de eficacia diagnostica ´ (AUC). R E S U LT A D O S: De los 96 reclusos que obtuvieron una TST positiva, 31 presentaron una IGRA positiva
(32,3%). En el ana´lisis monofactorial, las variables que se asociaron con la positividad del IGRA fueron la edad .45 anos (11/20 contra 20/75; P ¼ 0,016) y el ˜ antecedente de tratamiento de la LTBI (9/20 contra 13/55; P ¼ 0,032); el ana´lisis multifactorial revelo´ como variables independientes la procedencia de un pa´ıs con una incidencia de tuberculosis (TB) moderada o alta (OR 3,5; IC95% de 1,3 a 9,4; P ¼ 0,013) y la falta de vacunacion ´ antituberculosa (OR 3,3; IC95% de 1,2 a 9,0; P ¼ 0,017). Los datos se adecuaron bien al modelo, pues clasificaron mejor al grupo que una distribucion ´ aleatoria (AUC 0,67; P ¼ 0,007). ´ N: La CONCLUSIO observacion ´ de una gran discordancia entre la TST y las IGRA, sobre todo en los reclusos con antecedente de vacunacion ´ antituberculosa y los que provienen de pa´ıses con una baja incidencia de TB, indica que estas pruebas pueden ser utiles ´ en los programas de deteccion ´ sistema´tica del sistema penitenciario federal en el Canada´.
Interferon-gamma release assays piloted as a latent tuberculous infection screening tool in Canadian federal inmates I. S. Schwartz,* P. J. Bach,† B. Roscoe,‡ A. Majury,§¶ W. M. Hopman,#** E. Ellis,††‡‡ T. Garrahan,‡ J. Smith,‡ R. Barkley,‡ L. Panaro,‡,‡‡ F. Jamieson,§§¶¶ C. Froats,§ I. Gemmill,**## W. L. Wobeser** *Departments of Medical Microbiology & Infectious Diseases and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, †Department of Internal Medicine, University of British Columbia, Vancouver, British Columbia, ‡Correctional Services Canada, Health Services, Kingston, Ontario, §Laboratory Services, Public Health Ontario, Kingston, Ontario, ¶Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, #Clinical Research Centre, Kingston General Hospital, Kingston, Ontario, **Department of Public Health Sciences, Queen’s University, Kingston, Ontario, ††Public Health Agency of Canada, Ottawa, Ontario, ‡‡Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, §§Public Health Ontario, Laboratory Services, Toronto, Ontario, ¶¶Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, ##Kingston Frontenac Lennox & Addington Health Unit, Kingston, Ontario, **Department of Medicine, Queen’s University, Kingston, Ontario, Canada SUMMARY B A C K G R O U N D : Interferon-gamma release assays (IGRAs) may be useful in diagnosing latent tuberculous infection (LTBI) in inmates; however, published experience in these settings is limited. O B J E C T I V E : To identify variables associated with IGRA positivity among Canadian federal inmates with positive tuberculin skin test (TST) results. D E S I G N : On intake, TST-positive (710 mm) inmates were offered an IGRA (QuantiFERONw-TB Gold), and demographic and historical data were collected. IGRApositive and -negative inmates were compared using the v2 test and multivariable logistic regression; the final model’s goodness of fit was assessed using HosmerLemeshow test and area under the receiver operating characteristic curve (AUC). R E S U LT S : Of 96 TST-positive inmates, 31 (32.3%)
were IGRA-positive. Variables associated with positive IGRA were age .45 years (11/20 vs. 20/75, P ¼ 0.016) and previous LTBI treatment (9/20 vs. 13/55, P ¼ 0.032) in univariate analysis, and being from a country with a moderate or high estimated tuberculosis (TB) incidence (OR 3.5, 95%CI 1.3–9.4, P ¼ 0.013) and absence of bacille Calmette-Gu´erin (BCG) vaccination (OR 3.3, 95%CI 1.2–9.0, P ¼ 0.017) in multivariable analysis. The data fit the model well, classifying the group better than chance alone (AUC 0.67, P ¼ 0.007). C O N C L U S I O N : High discordance with TST, particularly among BCG-vaccinated inmates and those from low TB incidence countries, suggest that IGRA may be useful in Canadian federal penitentiary screening programmes. K E Y W O R D S : IGRA; LTBI; TST; prisons; TB
ALTHOUGH it has been used in screening for latent tuberculous infection (LTBI) for over a century, the Mantoux tuberculin skin test (TST) has several important limitations, including false-positive results in individuals with previous bacille Calmette-Gu´erin (BCG) vaccination or non-tuberculous mycobacteria (NTM) infection,1,2 the requirement for two separate visits for testing and interpretation, and poor reproducibility.1 Furthermore, inter-observer variability of as high as 6 mm has been reported.3,4 Interferon-gamma release assays (IGRAs) promise at least comparable sensitivity to TST, with improved specificity due to less cross-reaction with some NTM and previous BCG vaccination.5,6 IGRA appear to
have a higher sensitivity in human immunodeficiency virus (HIV) infected individuals,7 and require only a single visit. A meta-analysis found that IGRA had better positive predictive value than TST for the development of tuberculosis (TB) disease, although both were relatively low (2.7% and 1.5%, respectively).8 Two commercial assays are currently available on the market, the QuantiFERONw-TB Gold (QFT) test (Cellestis/Qiagen, Carnegie, VIC, Australia) and the T-SPOTw.TB test (Oxford Immunotec, Oxford, UK). Current Canadian recommendations are that IGRAs may be suitable for confirming positive TST results in health care workers, prison staff or inmates
Correspondence to: I S Schwartz, Departments of Medical Microbiology & Infectious Diseases and Internal Medicine, University of Manitoba, Basic Medical Sciences Building, 543–745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. Tel: (þ1) 204 789 3522. Fax: (þ1) 204 789-3926. e-mail: [email protected] Article submitted 13 November 2013. Final version accepted 19 March 2014.
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The International Journal of Tuberculosis and Lung Disease
who are immunocompetent, considered to have a low pre-test probability of LTBI, and lack high-risk features for progression to active disease if infected.9 However, published experience with IGRA in these clinical settings is limited. In 1997, the Canadian federal prison system implemented a TB surveillance system to detect active disease at intake and identify individuals with LTBI on intake who might benefit from preventive therapy. To date, TST has been an integral part of the programme. Per this screening programme, 17.6% of inmates and 6.0–7.6% of staff were TST-positive in 2008 according to the standard Canadian definition for positivity of 710 mm induration.10 In 2010, an IGRA (QFT) was introduced into a pilot project to supplement TST in LTBI screening of Canadian federal inmates in Ontario on intake to the correctional facility. This study evaluated factors associated with a positive IGRA among TST-positive inmates.
STUDY POPULATION AND METHODS New inmates entering the Canadian federal penitentiary system are offered TST screening on intake. All inmates entering Millhaven Institution, Bath, ON, Canada, who screened positive for LTBI using TST (710 mm induration) at Millhaven Institution or with a previous positive TST from a provincial correctional institution between the months of April and October 2010 inclusive were offered IGRA (see the Figure for study algorithm). Of 107 inmates who met the eligibility criteria,
eight declined involvement or were unavailable for IGRA testing, and were eliminated from further analysis. IGRA testing was performed on 99 inmates. Blood was drawn according to protocol, and then couriered within the manufacturer’s recommended transport time to the Public Health Ontario Laboratory in Kingston, where samples were analysed using QFT according to the manufacturer’s instructions. Active TB disease was ruled out by symptom check, chest X-ray and sputum culture for all those enrolled. A questionnaire covering TB risk factors was administered to inmates at the time of phlebotomy, and further demographic information was gathered from chart review. HIV testing was offered at the time of phlebotomy. BCG vaccination status was inferred using public health policies in the inmate’s country of birth in his/her year of birth (http://www.bcgatlas. org).11 Estimated TB incidence in the country of birth was referenced from the World Health Organization.12 Data were entered into a spreadsheet and imported into IBM SPSS version 20.0 (IBM Corp, Armonk, NY, USA) for statistical analysis. v2 tests (Pearson’s or Fisher’s exact, as appropriate) were used to compare characteristics of inmates with positive and those with negative QFT. Variables with an association of P , 0.10 were entered into a backward, manual logistic regression model to facilitate inclusion of patients with any missing data for eliminated variables. Goodness of fit was assessed using the Hosmer and Lemeshow test, and probabilities for the logistic regression model were saved and used to populate a receiver operating characteristic (ROC) curve to
Figure Study algorithm. TST ¼ tuberculin skin test; IGRA ¼ interferon-gamma release assay.
IGRA for LTBI screening in Canadian inmates
additionally assess goodness-of-fit using the area under the curve (AUC). The criterion for statistical significance was P , 0.05. The impact of time between TST and QFT was analysed using the MannWhitney U-test. This study was approved by the Research Ethics Board at Queen’s University, Kingston, ON, Canada.
ment data were available for 60 (62.5%) inmates. The remaining 36 (37.5%) inmates were reported to be TST-positive at previous institutional screening, but induration measurements were unavailable. For those with a known TST measurement, the mean induration was 18.2 mm (range 10–46). Of 48 inmates (50%) tested for HIV, none were found to be positive. Overall, 31 individuals (32.3%) had positive (concordant) QFT results. In univariate analyses, variables associated with concordant QFT were age .45 years (11/20, 55.0% vs. 20/75, 26.7%; P ¼ 0.016) and any previous treatment for LTBI (9/20, 45.0% vs. 13/55, 23.6%; P ¼ 0.032). Factors that demonstrated a trend toward significance in predicting a positive QFT included birth in a country with a moderate or high estimated TB incidence (18/42, 42.9% vs. 13/54, 24.1%; P ¼ 0.051) and absence of BCG vaccination (27/46, 58.7% vs. 38/50, 76.0%; P ¼ 0.070). Having a larger TST result (.20 mm) also demonstrated a trend towards significance in predicting a positive QFT (10/23, 43.5% vs. 9/37, 24.3%; P ¼ 0.121). In a logistic regression analysis (Table 2), two variables were independently associated with a concordant QFT. Being from a country with a
RESULTS Of the 99 inmates who underwent QFT, three had indeterminate tests and were omitted from analysis; 96 inmates with a positive TST and either positive or negative QFT were included in further analysis. The characteristics of the inmates and bivariate analysis of the QFT results are shown in Table 1. The mean age was 35.8 years (range 20–67); 67 inmates (69.8%) were foreign-born, with a mean duration in Canada of 18.3 years (range 1–36), and were from the following world regions: Caribbean (n ¼ 22, 22.9%), Asia (n ¼ 20, 20.8%), sub-Saharan Africa (n ¼ 12, 12.5%), Latin America (n ¼ 7, 7.3%), Middle East (n ¼ 3, 3.1%) and Europe (n ¼ 3, 3.1%). Of all the Canadian-born inmates, five (5.2%) self-identified as aboriginal. TST measureTable 1
Bivariate analysis comparing IGRA-positive and IGRA-negative inmates IGRA-positive (n ¼ 31) n (%)
IGRA-negative (n ¼ 65) n (%)
Total (n ¼ 96) n (%)
Age group, years* 645 .45
20 (26.7) 11 (55.0)
55 (73.3) 9 (45.0)
75 (78.1) 20 (20.8)
0.016
TST group, mm Positive but measurement unavailable† 10–14 15–19 20–24 725
12 6 3 6 4
24 10 18 11 2
36 16 21 17 6
(37.5) (16.7) (21.9) (17.7) (6.3)
0.083
BCG‡ Yes No
12 (24.0) 19 (41.3)
38 (76.0) 27 (58.7)
50 (51.0) 46 (47.9)
0.070
TB incidence in country of birth§ Low Moderate to high
13 (24.1) 18 (42.9)
41 (75.9) 24 (57.1)
54 (56.3) 42 (73.8)
0.051
Birthplace Foreign-born Canadian-born
22 (32.8) 9 (31.0)
45 (67.2) 20 (69.0)
67 (69.8) 29 (30.2)
0.862
3 (60.0) 8 (38.1)
2 (40.0) 13 (61.9)
5 (5.2) 21 (21.9)
0.373
13 (23.6) 4 (30.8) 5 (71.4)
42 (76.4) 9 (69.2) 2 (70.7)
55 (57.3) 13 (13.4) 7 (7.3)
0.032
Ethnicity of Canadian-born inmates* Aboriginal Non-Aboriginal Previous treatment for LTBI* No Yes Partial
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(33.3) (37.5) (14.3) (35.3) (66.7)
(66.7) (62.5) (85.7) (64.7) (33.3)
P value
* Some data were missing for age (n ¼ 1), ethnicity (n ¼ 3), previous treatment for LTBI (n ¼ 21). † Individuals for whom a TST had been interpreted as positive at a referring institution, but for whom measurements were unavailable. ‡ BCG vaccination status was presumed according to the policy of the country and year of birth (www.bcgatlas.org). § Low refers to countries with estimated incidence rates of sputum-positive pulmonary TB ,15/100 000; moderate to high refers to those with estimated incidence 715/100 000.12 ´ IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; LTBI ¼ latent tuberculous infection; WHO ¼ World Health Organization.
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Table 2 inmates
Multivariable analysis of IGRA results in TST-positive
Variable*
OR (95%CI)
P value
BCG† No Yes
3.3 (1.2–9.0) Reference
0.017
TB incidence in country of birth‡ Low Reference Moderate to high 3.5 (1.3–9.4)
0.013
* Variables initially entered into the model were removed manually in the following order, based on P value: TST category, age category, foreign-born, previous treatment (P ¼ 0.109 at removal). Hosmer and Lemeshow goodnessof-fit v2 ¼ 0.54, P ¼ 0.763. † BCG status was presumed according to the policy of the country and year of birth (www.bcgatlas.org). ‡ Low refers to countries with estimated incidence rates of sputum-positive pulmonary TB ,15/100 000; moderate to high refers to countries with estimated incidence 715/100 000.12 IGRA ¼ interferon-gamma release assay; TST ¼ tuberculin skin test; OR ¼ odds ´ ratio; CI ¼ confidence interval; BCG ¼ bacille Calmette-Guerin; TB ¼ tuberculosis; WHO ¼ World Health Organization.
moderate to high estimated TB incidence resulted in a 3.5-fold increase in the likelihood of a positive QFT (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.3–9.4, P ¼ 0.013). Furthermore, absence of previous BCG vaccination resulted in a 3.3-fold increase in the likelihood of a positive QFT (OR 3.3, 95%CI 1.2–9.0, P ¼ 0.017). The Hosmer and Lemeshow test indicates a v2 of 0.54 (P ¼ 0.76), suggesting that the data fit the final model quite well; the AUC was 0.67 (P ¼ 0.007), suggesting that the logistic regression classified the group significantly better than chance alone. Time between TST and QFT had no significant impact on the QFT results (P ¼ 0.75, Mann-Whitney U). Two additional analyses were conducted to assess the potential impact of including the 36 inmates for whom TST data was missing in the study. First, those with and those without documented TST results were compared using the v2 test: the two groups did not differ on any variable other than previous treatment (83% of those with and 56% of those without TST induration measurements received treatment, P ¼ 0.024). There were no differences in age, BGC vaccination, place of birth, TB incidence in country of birth, whether aboriginal or QFT results. The second analysis involved re-running both the bivariate and multivariate analyses without these 36 inmates. Tests of significance were attenuated due to the loss of power, but all results remained comparable (e.g., age: P ¼ 0.016 to P ¼ 0.035; BCG: P ¼ 0.070 to P ¼ 0.013; TB incidence in country of birth: P ¼ 0.051 to P ¼ 0.121; foreign birth: P ¼ 0.86 to P ¼ 0.42; aboriginal heritage: P ¼ 0.37 to P ¼ 0.46; and previous treatment: P ¼ 0.032 to P ¼ 0.081). Regression results changed slightly, in that the P value for BCG changed from P ¼ 0.017 to P ¼ 0.009 and TB incidence changed from P ¼ 0.013 to P ¼ 0.056.
DISCUSSION In this pilot project of an IGRA used as an adjunct to the current TB screening programme in a Canadian penitentiary, only a third of inmates who were TSTpositive were also positive using QFT. This study evaluated factors associated with concordant QFT results in this setting. Other studies have compared TST and IGRA results in correctional institutions, particularly in Europe. In a study of an IGRA and TST among 181 prisoners in Spain, Mourino ˜ et al. reported a concordance rate of 67.5% (27/40) among those with positive TST.13 In a contact tracing investigation in a prison in Germany, during which 149 male inmates received both tests, Scharlach et al. found a concordance rate of 45.5% (20/44) for QFT among TST-positive inmates.14 In the present study, factors associated on univariate analysis with concordant QFT results among TST-positive inmates included age .45 years and previous LTBI treatment. On multivariable analysis, these two factors fell out of the model, such that birth in a country with a moderate or high estimated TB incidence and absence of previous BCG vaccination were found to be the independent predictors of concordance. Data in the literature regarding the impact of BCG vaccination on TST results are conflicting.2,6 Neinhaus et al. found that BCG contributed to a large majority of TSTþ, IGRA– results in a German cohort.6 In contrast, a meta-analysis by Farhat et al. suggested that BCG was unlikely to cause falsepositive TST results.2 We found that previous BCG vaccination increased the likelihood of a discordant IGRA in those who were TST-positive: inmates with a positive TST in the absence of BCG vaccination had a .3 times higher likelihood of a positive IGRA than TST-positive inmates who had received BCG vaccination. This supports the view that BCG vaccination likely contributed to some of the discordance in this study. Our findings of improved concordance between positive TST and IGRA in older individuals are in agreement with those reported by Kunimoto et al. from their out-patient clinic,15 although the clinic and inmate populations likely have different tuberculous infection risks. In our study, the age at which a difference in concordance became significant was 45 years, whereas Kunimoto et al. found that those aged .65 years were significantly more likely to have a positive IGRA than those aged ,20 years. Improved concordance between TST and IGRA in older individuals might be explained by the fact that TST reactions to previous BCG vaccination wane over time, and thus older individuals are less likely to have a positive TST as a result of BCG vaccination.1 There are several important limitations of this
IGRA for LTBI screening in Canadian inmates
study. First, our population was exclusively male, although we know of no reason why our findings should not also apply to female inmates. Our study also did not include participants who were known to be HIV-positive, with negative HIV test results documented in half of our cohort. HIV prevalence among Canadian federal penitentiary inmates was 1.7% in 2010 (CSC WebIDSS, preliminary unpublished data). Also under-represented in this study were Canadian aboriginal persons, who comprise 10% of the inmate population of Ontario federal penitentiaries,16 but who made up just 5.2% of our cohort. BCG vaccination status for inmates was presumed based on the public health policy of their country and year of birth, as described by Zwerling et al.11 This method may have some important limitations, particularly for those from countries with regional variation in policy or where recommendations were based on certain high-risk features at birth, which may have resulted in an overestimation of BCG vaccination; thus, the strength of the association between BCG vaccination and discordant TST/IGRA may have been stronger than found here. Another potential limitation of the present study is that TST measurements were lacking for 37% of the inmates. In these cases, the TST had been performed at a referring correctional institution and were reported to be positive; however, the measurements had not been conveyed. The TST was not repeated for two reasons: 1) so that the study protocol reflected current practice in Canadian federal penitentiaries to maintain real-world applicability in this setting, and 2) because repeating TST was not felt to be in the interest of the inmate. It is possible that some of those enrolled may not have had true-positive readings, which may falsely reduce concordance with IGRA. However, with the exception of higher rates of previous LTBI treatment in those inmates with TST measurements missing, there were no significant differences between inmates for whom TST measurements were documented and those identified as TSTpositive but with measurements missing. Furthermore, aside from a loss of power, there were no significant changes in the results of the bivariate and multivariate analyses when excluding those inmates whose TST measurements were missing. We therefore conclude that this is unlikely to represent an important cause of bias. TST and IGRA are both dynamic tests, and there is evidence to suggest that TST administration could affect the IGRA results. In particular, the phenomenon of ‘boosting’ of IGRA by recent, prior TST has been described, although the clinical significance of this remains unclear.17 As such, current Canadian recommendations are for blood samples for IGRA to be obtained before, or on the day of, TST administration when both methods of testing are employed.9 As IGRA
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was offered only to inmates with TST-positive results, this was impractical in our study. Although this could theoretically result in false-positive IGRA results and an over-estimation of concordance, our analysis suggests that the time between tests had no significant impact on IGRA outcome. Like other cross-sectional studies of IGRA and TST, this study is limited by the lack of a gold standard for the identification of LTBI that would later progress to active TB.18 We do not therefore know which, if any, of the participants were truly infected with Mycobacterium tuberculosis and are at risk of developing future active disease. Given the availability of preventive LTBI therapy and the risks of progressing to active TB, both to the health of the individual and to other inmates and prison staff, inmates with positive IGRA and TST, in the absence of contraindications or prior therapy, were offered isoniazid preventive treatment (IPT). Those with discordant results (TSTþ, IGRA–) were not offered IPT, but were and will be followed with annual assessments, including symptom review, sputum cultures and chest X-ray, to monitor for the development of active disease. Finally, this study has shown that discordance between IGRA and TST is more likely in inmates with previous BCG vaccination and those from countries with low TB incidence. However, it is not able to conclude whether the optimal use of IGRA in Canadian federal prisons is in a confirmatory role for screening positive by TST vs. other methods, such as review of TB risk factors. Further study, in addition to cost analysis, is needed to understand the effectiveness of TST and the advisability of replacing TST with IGRA in correctional settings.
CONCLUSION The high rates of discordance in this study suggest that IGRAs may be more discerning than the TST for the diagnosis of LTBI in Canadian federal inmates, particularly in BCG-vaccinated inmates and those from low TB incidence countries, and that it may have an important role in screening programmes in this setting. Acknowledgements The authors gratefully acknowledge the federal inmates and Health Services staff of Millhaven Institution, Bath, ON, Canada, as well as the technologists of the Public Health Ontario laboratory in Kingston who performed the IGRA testing for this study. We are also grateful to the two anonymous reviewers for their constructive criticism of this manuscript. Funding was provided by Public Health Agency of Canada. Conflict of interest: none declared.
References 1 Huebner R E, Schein M F, Bass J B, Jr. The tuberculin skin test. Clin Infect Dis 1993; 17: 968–975.
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2 Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: What is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006; 10: 1192–1204. 3 Bearman J E, Kleinman H, Glyer V V, Lacroix O M. A study of variability in tuberculin test reading. Am Rev Respir Dis 1964; 90: 913–919. 4 Pouchot J, Grasland A, Collet C, Coste J, Esdaile J M, Vinceneux P. Reliability of tuberculin skin test measurement. Ann Intern Med 1997; 126: 210–214. 5 Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: Areas of uncertainty and recommendations for research. Ann Intern Med 2007; 146: 340–354. 6 Nienhaus A, Schablon A, Diel R. Interferon-gamma release assay for the diagnosis of latent TB infection—analysis of discordant results, when compared to the tuberculin skin test. PLOS ONE 2008; 3: e2665. 7 Cattamanchi A, Smith R, Steingart K R, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2011; 56: 230–238. 8 Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest 2012; 142: 63–75. 9 M, Kunimoto D, Jamieson F, Menzies D. Diagnosis of latent tuberculosis infection. In: Menzies D, ed. Canadian tuberculosis standards. 7th ed. Ottawa, ON, Canada: Public Health Agency of Canada and Canadian Thoracic Society, 2013. 10 Correctional Services Canada. Infectious disease surveillance in
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Canadian federal penitentiaries 2007–2008. Ottawa, ON, Canada: Minister of Public Works and Government Services, 2013. http://www.csc-scc.gc.ca/text/pblct/infdscfp-2007-08/ index-eng.shtml Accessed April 2014. Zwerling A, Behr M A, Verma A, Brewer T F, Menzies D, Pai M. The BCG world atlas: a database of global BCG vaccination policies and practices. PLOS MED 2011; 8 e1001012. World Health Organization. WHO report 2011. Global tuberculosis control. WHO/HTM/TB/2011.16. Geneva, Switzerland: WHO, 2011. Marco Mourino ˜ A, Orcau Palau A, Jane Galliga R, et al. Concordance of tuberculin tests and interferon gamma release assays in the prison population. Rev Esp Sanid Penit 2011; 13: 15–20. [Spanish] Scharlach M, Gross C, Wagner D, et al. Comparison of the tuberculin skin test with the interferon-gamma test in the framework of a surroundings investigation in a prison. Gesundheitswesen 2008; 70: 684–689. Kunimoto D, Der E, Beckon A, et al. Use of the QuantiFERONTB gold test to confirm latent tuberculosis infection in a Canadian tuberculosis clinic. Int J Tuberc Lung Dis 2009; 13: 726–730. Baboom A. The changing profile of adults in custody, 2006/ 2007. Report nr 28 (10). Ottawa, ON, Canada: Juristat, 2008. van Zyl-Smit R N, Zwerling A, Dheda K, Pai M. Within-subject variability of interferon-c assay results for tuberculosis and boosting effect of tuberculin skin testing: a systematic review. PLOS ONE 2009; 4: e8517. Pai M, Menzies D. The new IGRA and the old TST: making good use of disagreement. Am J Respir Crit Care Med 2007; 175: 529–531.
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RESUME C O N T E X T E : Les recommandations canadiennes actuelles sugge` rent que les tests de libe´ ration de l’interf´eron gamma (IGRA) pourraient eˆ tre utiles au diagnostic de tuberculose latente (LTBI) parmi les d´etenus, mais on dispose de peu d’exp´eriences publi´ees dans ce contexte. O B J E C T I F : Identifier les variables associ´ees a` un test IGRA positif parmi des d´etenus f´ed´eraux canadiens ayant un test positif a` la tuberculine (TST). S C H E M A : Les d´etenus f´ed´eraux canadiens ayant un TST tuberculine positif (710 mm) a` leur arriv´ee se sont vus offrir un test IGRA (QuantiFERON-TBw Gold). Des donne´ es d e´ mographiques et d’anamn e` se ont e´ te´ recueillies lors d’entretiens. On a ensuite compar´e ceux qui avaient des tests IGRA positifs et n´egatifs grace ˆ au test du v2 et a` une r´egression logistique multivari´ee ; l’ajustement du mod`ele final a e´ t´e e´ valu´e grace ˆ au test de Hosmer et Lemeshow et a` la surface sous la courbe ROC. R E S U LT A T S : Sur 96 d´etenus avec un r´esultat IGRA
d´etermin´e, 31 (32,3%) e´ taient positifs. En analyse univari´ee, un age ˆ .45 ans (11/20 contre 20/75 ; P ¼ 0,016) et un traitement ant´erieur de LTBI (9/20 contre 13/55 ; P ¼ 0,032) e´ taient associ´es a` un IGRA positif. En analyse multivari´ee, le fait de venir d’un pays a` incidence mod´er´ee ou e´ lev´ee de la tuberculose (TB) (OR 3,5 ; IC95% 1,3–9,4 ; P ¼ 0,013) et l’absence de vaccination par le bacille de Calmette-Gu´erin (OR 3,3 ; IC95% 1,2– 9,0 ; P ¼ 0,017) e´ taient ind´ependamment associ´es a` un IGRA positif. Le test d’ajustement a montr´e que les donn´ees s’ajustaient bien au mod`ele, en classant mieux le groupe que par le seul effet du hasard (AUC 0,67 ; P ¼ 0,007). C O N C L U S I O N : Un taux e´ lev´e de discordance avec le TST, surtout parmi les d´etenus non vaccin´es par le BCG et ceux provenant de pays a` faible incidence de TB, sugg`erent que l’IGRA pourrait eˆ tre un test utile dans les programmes de d´epistage de la TB dans les p´enitenciers f´ed´eraux du Canada.
RESUMEN M A R C O D E R E F E R E N C I A: Las pruebas de liberacion ´ de interferon ´ gama (IGRA) pueden ser utiles ´ en el diagnostico ´ de la infeccion ´ tuberculosa latente (LTBI), pero las publicaciones de investigaciones en estos entornos son escasas. O B J E T I V O: Determinar los factores que se asocian con la positividad de las IGRA en los reclusos del sistema federal canadiense que presentan una prueba cuta´nea positiva a la tuberculina (TST). M E´ T O D O S: Al ingreso, se propuso la IGRA (QuantiFERON-TB Goldw ) a los reclusos que presentaban una TST positiva (710 mm). Se recogieron datos demogra´ficos y cl´ınicos y se compararon los grupos de reclusos con IGRA positivas y negativas, mediante la prueba de la v2 y un ana´lisis de regresion ´ log´ıstica multifactorial; la bondad de ajuste del modelo se evaluo´ con la prueba de Hosmer-Lemeshow y la curva de eficacia diagnostica ´ (AUC). R E S U LT A D O S: De los 96 reclusos que obtuvieron una TST positiva, 31 presentaron una IGRA positiva
(32,3%). En el ana´lisis monofactorial, las variables que se asociaron con la positividad del IGRA fueron la edad .45 anos (11/20 contra 20/75; P ¼ 0,016) y el ˜ antecedente de tratamiento de la LTBI (9/20 contra 13/55; P ¼ 0,032); el ana´lisis multifactorial revelo´ como variables independientes la procedencia de un pa´ıs con una incidencia de tuberculosis (TB) moderada o alta (OR 3,5; IC95% de 1,3 a 9,4; P ¼ 0,013) y la falta de vacunacion ´ antituberculosa (OR 3,3; IC95% de 1,2 a 9,0; P ¼ 0,017). Los datos se adecuaron bien al modelo, pues clasificaron mejor al grupo que una distribucion ´ aleatoria (AUC 0,67; P ¼ 0,007). ´ N: La CONCLUSIO observacion ´ de una gran discordancia entre la TST y las IGRA, sobre todo en los reclusos con antecedente de vacunacion ´ antituberculosa y los que provienen de pa´ıses con una baja incidencia de TB, indica que estas pruebas pueden ser utiles ´ en los programas de deteccion ´ sistema´tica del sistema penitenciario federal en el Canada´.
