Recommendations on Interferon Gamma Release Assaysfor the Diagnosis of Latent Tuberculosis Infection—2010 Update Updated Literature Reviews and Summary of Evidence

Preamble The Canadian Tuberculosis Committee provides the Public Health Agency of Canada (PHAC) with ongoing, timely and scientifically based advice on national strategies and priorities with respect to tuberculosis prevention and control in Canada. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best currently available scientific knowledge and medical practice. This document is disseminated for information purposes to the medical and public health communities involved in tuberculosis prevention and control activities. Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use. The following recommendations are based in general upon a review of the literature and expert opinion as of June 2009. With more research results related to interferon gamma Une déclaration d'un comité consultatif (DCC) Le Comité canadien de lutte antituberculeuse (CCLA)* † Recommandations sur les tests de libération d'interféron-gamma pour la détection de l'infection tuberculeuse latente – †Cette déclaration a été rédigée par le D r Dennis Kunimoto (auteur principal et président du Groupe de travail d'experts) et les membres suivants du Groupe de travail d'experts (en ordre alphabétique) : 2 release assays being published all the time, the field is quickly evolving. As a result, this Advisory Committee Statement will be periodically updated as warranted and made available at www.publichealth.gc.ca/tuberculosis. Introduction Until recently, the diagnosis of tuberculosis infection depended solely on the tuberculin skin test (TST), an imperfect test with known limitations. The most significant advance in recent times has been the development of T-cell-based interferon-gamma release assays (IGRAs). IGRAs are in-vitro blood tests that are based on interferon-gamma (IFN-γ) release after stimulation by TB specific antigens (e.g. ESAT-6 and CFP-10). Two IGRAs are currently registered for use in Canada – the QuantiFERON®-TB Gold In-Tube (QFT) assay (1). This was the first official recommendation from Canadian tuberculosis authorities on IGRAs, based on scientific literature published up to October 2006. The recommendations have been incorporated into …


Recommendations on Interferon Gamma Release Assaysfor the Diagnosis of Latent
Tuberculosis Infection-2010 Update  (1) .This was the first official recommendation from Canadian tuberculosis authorities on IGRAs, based on scientific literature published up to October 2006.The recommendations have been incorporated into the recently published 6 th edition of the Canadian Tuberculosis Standards (2007) (2) .
Since the publication of the original ACS, a large number of IGRA studies have been published.In October 2008, updated version of the 2007 guidelines was published (Can Commun Dis Rep. 2008 October, 34(ACS-6):1-13.) (3).In December 2008, an expert group was constituted to prepare this second update.

Updated literature reviews and summary of evidence
To facilitate the preparation of this revised ACS, the Expert Work Group primarily used the evidence summarized in a meta-analysis on IGRAs published in 2007 (4) and an updated version of this meta-analysis published in 2008 (5) .Together, these two meta-analyses synthesized evidence from a large number of studies.Most original references are not included in this ACS because of length consideration.
Readers are asked to refer to the references used in the meta-analyses.

Sensitivity and specificity of IGRAs
Sensitivity figures are in the context of active TB disease since there is no gold standard for LTBI.Specificity refers to active TB and LTBI.
• IGRAs and TST cannot distinguish between LTBI and infection in active TB.
• Both IGRAs have very high specificity (93% -99%) and are unaffected by prior BCG vaccination.While several QFT studies have consistently shown very high specificity, data are limited on the specificity of the commercial T-SPOT.TB assay.Much of the specificity data on T-SPOT.TB are derived from published information on its pre-commercial ELISPOT version.
• In populations where BCG is given, TST specificity is low and variable (~60%).This is true especially in populations where BCG is given after infancy or when multiple (booster) BCG vaccines are administered.
• Head to head comparisons among patients with active TB suggest that T-SPOT.TB is more sensitive than QFT and TST but slightly less specific than the QFT.

IGRA performance in immunocompromised populations
• Immunocompromised populations are highly heterogeneous and most studies are small.
• There are few studies on sensitivity and specificity of IGRAs in immunocompromised populations.
• TST sensitivity is modest to poor in immunocompromised individuals.
• The sensitivity of T-SPOT.TB appears to be maintained in immunocompromised individuals.
• T-SPOT.TB appears to have a higher rate of positivity than the TST in immunocompromised populations.This trend, however, is not clearly evident in the QFT studies.
• In immunocompromised with low CD4+ counts (i.e.severe immune suppression), there appears to be a correlation between degree of immunosuppression and rates of indeterminate QFT results (mainly due to lack of response to the positive mitogen control).This correlation is not clearly evident in the T-SPOT.TB studies.

IGRA performance in contacts and outbreak investigations
• IGRAs correlate well with surrogate markers of exposure in contact and outbreak settings, but not necessarily better than TST in all populations.
• Correlation between IGRA results and surrogate markers of exposure is better than TST in low incidence settings where BCG has been commonly used; this is not evident in high incidence countries.
• Discordance between TST and IGRAs is almost always found.However, not all discordance is explainable.Extreme discordance is also documented (i.e.strongly positive TST result, but negative IGRA result and vice-versa) and the biological basis for such discordance is unknown.Concordance levels seem to vary when IGRA and TST cut-off points are changed.The very limited outcome data on discordant results suggests that persons with a negative IGRA result are at low risk of developing active TB (6,7) .

IGRA performance in healthcare workers and employee screening programs
• Significant discordance is found between TST and IGRA positivity rates in healthcare workers (HCWs), with a large proportion of TST+/IGRA-type of discordance, especially in low incidence countries that administer repeated BCG vaccinations.
• IGRAs seem to correlate with markers of exposure in HCWs, but correlation with age is not consistent across studies.
• Serial testing studies of HCWs are limited, but suggest that IGRA conversions and reversions can occur, just as they occur with TST; rates of conversions and reversions depend a lot on the definition used for conversions and reversions.

IGRA performance in children (under age 18)
• In school outbreaks and contact studies, IGRAs correlate well with surrogate markers of exposure, but not necessarily better than TST in all populations.
• IGRA sensitivity in active TB is variable, with higher sensitivity reported for T-SPOT.TB or ELISPOT than QFT.
• TST+/IGRA-pattern of discordance is frequently reported in children.
• While IGRAs appear to be feasible in children, a few studies have found high rates of phlebotomy failure and indeterminate results in children.

IGRA performance in serial testing and predictive value of IGRAs
• IGRAs are dynamic and both conversions and reversions occur when serial testing is done; this has been shown to occur among contacts as well as HCWs.
• There is no consensus on what the best definition for conversion is -different definitions appear to produce different rates of conversions.
• Reversion rates are higher when baseline interferongamma levels are just above the cut-off point and when baseline results are discordant (i.e.TST-/IGRA+); reversion rates low when baseline interferon-gamma levels are high and when baseline results are concordantly positive (TST+/IGRA+).
• Prognosis of conversions and reversions are unknown.
• The studies on the predictive value of IGRAs have small numbers of active TB cases and are not consistent in their results.
• Les études sur la valeur prédictive des TLIG portent sur un petit nombre de cas de TB active et leurs résultats sont contradictoires.

Cost effectiveness
The unit costs of the new IGRAs are substantially higher than those of TST (with the T-SPOT.TB having a higher unit cost than the QFT).T-SPOT.TB is also technically more demanding than the QFT and this also has cost implications in terms of technician time and expertise.Unless the lab is able to batch the tests, unit costs become even higher.
• These new tests are more cost-effective than the TST only when their specificity is substantially higher thereby reducing the number of persons needing treatment for LTBI.
• Overall the studies suggest that a sequential TST/ IGRA approach is usually the most cost effective (8,9) .
• In specific settings where the rate of false positive TSTs would be high, (e.g.BCG vaccinated, particularly after infancy), IGRA alone may be cost effective (9)(10)(11) .
• In specific situations, other factors may make an IGRA more attractive than a TST such as where historical return rates for a TST reading are low (e.g.homeless person or IV drug users) (12) .However, regardless of the test used, treatment completion and adherence rates are likely to be poor in these situations.
• If untreated IGRA negative, TST positive patients develop active TB at a rate higher than TST negative patients, then IGRA testing may not be cost effective due to the cost of treating patients with active TB and their contacts.Longitudinal data are lacking for such patients.

Revised recommendations
Based on the updated reviews and expert opinion, the Expert Work Group made several recommendations.These are summarized in the Table 1, presented alongside the previous ACS recommendations.• Ces nouveaux tests sont plus rentables que le simple TCT uniquement lorsque leur spécificité est beaucoup plus grande, ce qui a pour effet de réduire le nombre de personnes devant être traitées pour une ITL.
• Si des patients positifs au TCT mais négatifs au TLIG qui ne sont pas traités développent en plus grand nombre une TB active que les patients négatifs au TCT, le TLIG peut ne pas être alors rentable, en raison du coût du traitement des patients souffrant d'une TB active et de leurs contacts..An updated version was published in October 2008 (3) based on updated literature reviews and expert opinion (as of March 2008).An updated literature review to June 2009 and expert opinion were used to develop these revised recommendations on IGRAs which are presented in this statement.

N°Sous-groupe ou indication clinique spécifique
Despite the substantial body of literature on IGRAs, several questions still remain unanswered, including the prognostic ability of these tests to accurately identify those individuals with latent tuberculosis infection that are at highest risk for progressing to active tuberculosis disease, and therefore most likely to benefit from preventive therapy (4,5,13) .Emerging data suggest that IGRAs appear to have dynamic characteristics that increase the likelihood of conversions and reversions over time (14) .At present, there is no consensus on the interpretation of IGRA conversions and reversions.Data are still limited on high-risk populations such as children and immunocompromised persons.Ongoing studies should resolve these issues within the next few years and inform evidence-based guidelines on how to implement IGRAs in clinical practice.
For The Canada Communicable Disease Report (CCDR) presents current information on infectious diseases for surveillance purposes.Many of the articles contain preliminary information and further confirmation may be obtained from the sources quoted.The Public Health Agency of Canada (PHAC) does not assume responsibility for accuracy or authenticity.Contributions are welcome (in the official language of your choice) from anyone working in the health field and will not preclude publication elsewhere.

un comité consultatif (DCC) Le Comité canadien de lutte antituberculeuse (CCLA)* † Recommandations sur les tests de libération d'interféron-gamma pour la détection de l'infection tuberculeuse latente - Mise à jour de 2010 Préambule Le
PreambleThe Canadian Tuberculosis Committee provides the Public Health Agency of Canada (PHAC) with ongoing, timely and scientifically based advice on national strategies and priorities with respect to tuberculosis prevention and control in Canada.PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best currently available scientific knowledge and medical practice.This document is disseminated for information purposes to the medical and public health communities involved in tuberculosis prevention and control activities.Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use.Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s).Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.The following recommendations are based in general upon a review of the literature and expert opinion as of June 2009.With more research results related to interferon gammaUne déclaration d'Comité canadien de lutte antituberculeuse (CCLA) donne à l'Agence de la santé publique du Canada (ASPC) des conseils constants, à jour et fondés sur des données scientifiques en ce qui concerne les stratégies et les priorités canadiennes en matière de prévention et de lutte contre la tuberculose au pays.L'ASPC reconnaît que les conseils et les recommandations figurant dans la présente déclaration reposent sur les connaissances scientifiques et la pratique médicale les plus récentes.Elle diffuse ce document à des fins d'information aux intervenants en médecine et en santé publique qui cherchent à prévenir et à contrer la tuberculose.Les personnes qui administrent ou utilisent des médicaments, des vaccins ou d'autres produits devraient bien connaître la monographie des produits ainsi que toute autre norme ou instruction approuvée concernant leur usage.Les recommandations relatives à l'usage des produits et les autres renseignements présentés ici peuvent différer de ceux figurant dans les monographies ou dans toute autre norme ou instruction approuvée pertinente qui a été établie par les fabricants autorisés.Rappelons que les fabricants font approuver leurs produits et démontrent l'innocuité et l'efficacité de ces derniers uniquement lorsqu'ils sont utilisés conformément à la monographie ou à toute norme ou instruction approuvée semblable.Les recommandations qui suivent se fondent en général sur un examen des publications et de l'opinion d'experts en date de juin 2009.C'est un domaine qui évolue rapidement, de nouveaux résultats de recherche Ces deux méta-analyses combinées ont synthétisé les données tirées d'une multitude d'études.La plupart des références originales ne sont pas incluses dans la présente DCC, faute d'espace.Le lecteur est prié de se reporter aux références utilisées dans les méta-analyses.LTBI), cross-sectional design, use of sensitivity and specificity as surrogates for patient-important outcomes, and lack of adequate data on important outcomes such as accuracy of diagnostic algorithms (rather than single tests), incremental or added value of IGRAs, impact of IGRAs on clinical decision-making and therapeutic choices, and the prognostic ability of IGRAs to accurately identify individuals with LTBI who are at the highest risk for progressing to active tuberculosis and therefore most likely to benefit from preventive therapy.Thus, available evidence on IGRAs cannot be considered high quality, and further research is likely to have an important impact on the recommendations made in this ACS and may change the recommendations.
Bien qu'aucune classification en bonne et due forme en fonction de la qualité des preuves n'ait été effectuée, presque toutes les études disponibles sur les TLIG comportent des limites, notamment les infection ( Table 1 also provides information on what has changed and why.Les coûts unitaires des nouveaux TLIG sont beaucoup plus élevés que ceux des TCT ( le coût unitaire du T-SPOT.TB dépassant celui du QFT).Le T-SPOT.TB demande plus de ressources techniques que le QFT, ce qui a des incidences sur les coûts (heures de travail et expertise du technicien).Si le laboratoire n'est pas en mesure d'exécuter les tests par lots, les coûts unitaires augmentent encore davantage.

Recommandations sur les tests de libération d'interféron-gamma pour certaines indications ou certains sous-groupes N°Sous-groupe ou indication clinique spécifique Recommandation antérieure dans la DCC [RMTC 2008]
While the updated recommendations for use of IGRA tests are shown in Table1, there may be situations where IGRA testing has been performed outside of the above recommendations.If both IGRA and TST results are available and the clinician is unsure as to how to interpret the results, the approach in Table 2 is recommended.However, there are limited longitudinal data on prognosis of discordant IGRA and TST results.Therefore, the recommendations in Table2are primarily based on expert opinion and accumulated evidence on the prognostic value of the TST.

Table 2 . Interpretation of results when both TST and IGRA results are available Risk of developing disease if infected with M. tuberculosis
Disclaimer: this table is offered in the context of this Statement and is NOT meant to be a comprehensive guide to the management of LTBI.For comprehensive guidance on the management of LTBI, please see chapters 4 and 6 of the Canadian Tuberculosis Standards

Interprétation des résultats lorsque tant un TCT qu'un TLIG ont été effectués Risque de développer la maladie après une infection par M. tuberculosis
Pour le moment, on ne s'entend pas sur l'interprétation des positivations et négativations des TLIG.En outre, les données sur les populations à risque élevé, telles que les enfants et les sujets immunodéprimés, demeurent limitées.Les études en cours devraient résoudre ces problèmes d'ici quelques années et faciliter l'élaboration de lignes directrices fondées sur des preuves qui précisent comment intégrer les TLIG dans la pratique clinique.Avis de non-responsabilité : ce tableau est offert dans le cadre de la présente déclaration et ne prétend PAS être un guide exhaustif pour la prise en charge de l'ITL.Pour obtenir des recommandations complètes sur la prise en charge de l'ITL, le lecteur est prié de se reporter aux chapitres 4 et 6 des Normes canadiennes pour la lutte antituberculeuse specific provincial/territorial information on which health professionals can order IGRA tests, what laboratories process the tests, which tests are publicly funded and whether positive test results are legally reportable, contact the respective provincial/territorial/ local TB control program.Dr. Michael Gardam performed two investigatordriven studies sponsored by Oxford Immunotec using the T-SPOT.TB assay.• Dr. Dennis Kunimoto applied for and received materials from Cellestis Ltd. for a research project in 2006.• Dr. Madhukar Pai has no financial conflicts.However, he consults for the Foundation for Innovative New Diagnostics (FIND), a non-profit agency that collaborates with several industry partners, including Cellestis Ltd., for the development and evaluation of new diagnostics for neglected infectious diseases.4. 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(5):340-54. 5. Pai M, Zwerling A, Menzies D. Systematic Review: T-cell-Based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update.Ann Intern Med.Présidents des sous-comités chargés de la surveillance, de l'immigration, des questions liées à la tuberculose en milieu métropolitain et de la tuberculose chez les Autochtones du Comité canadien de lutte antituberculeuse • Lutte antituberculeuse, Agence de la santé publique du Canada •