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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 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.
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 (Cellestis Ltd., Carnegie, Australia), and the T-SPOT®.TB assay (Oxford Immunotec, Oxford, U.K.).
"Interferon Gamma Release Assays for Latent Tuberculosis Infection" was published in Canada Communicable Disease Report 2007; 33 (ACS-10) on 1 November, 2007 as an Advisory Committee Statement (ACS) of the Canadian Tuberculosis Committee (CTC)Footnote 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 6th edition of the Canadian Tuberculosis Standards (2007)Footnote 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.)Footnote 3. In December 2008, an expert group was constituted to prepare this second update.
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 2007Footnote 4 and an updated version of this meta-analysis published in 2008Footnote 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.
In addition, all relevant English language literature up to June 30, 2009 was reviewed and considered. A specific focused subgroup literature review on IGRA performance in immunocompromised populations was also performed.
Although no formal grading of the quality of evidence was done, almost all the available studies on IGRAs have limitations, namely lack of a gold standard for latent TB infection (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.
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.
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.
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. Table 1 also provides information on what has changed and why.
|No.||Specific subgroup or clinical indication||Previous ACS recommendation [CCDR 2008]||Updated recommendation ||Comments|
|1||Diagnosis of active TB in adults with suspected TB disease||IGRAs are not recommended for the diagnosis of active TB in adults. Clinicians who manage patients with suspected TB disease should align their practice with the Canadian Tuberculosis Standards and the International Standards for Tuberculosis Care, and use sputum smear microscopy and culture to investigate adult patients with suspected active TB.||Same||No change|
|2||Diagnosis of active TB in children (under age 18) with suspected TB disease||Evidence of TB infection in children is often used in making a diagnosis of active TB, in addition to symptoms, radiological abnormalities, history of exposure, and microbiological investigations such as microscopy and culture. While collection of clinical specimens for definitive micro biologic diagnosis remains paramount, IGRAs may be used as a supplementary diagnostic aid in combination with the TST and other investigations to help support a diagnosis of TB. However, IGRA should not be a substitute for, or obviate the need for, appropriate specimen collection.||Evidence of TB infection in children is often used in making a diagnosis of active TB, in addition to symptoms, radiological abnormalities, history of exposure, and microbiological investigations such as microscopy and culture. While collection of clinical specimens for definitive micro biologic diagnosis remains paramount, IGRAs may be used as a supplementary diagnostic aid in combination with the TST and other investigations to help support a diagnosis of TB. However, IGRA should not be a substitute for, or obviate the need for, appropriate specimen collection. In addition, IGRAs (and the TST) may fail to detect patients with active TB. A negative IGRA (or TST) does NOT rule out active TB at any age and especially not in young children.||This revised recommendation emphasizes that although IGRAs may be useful as a supplementary diagnostic aid in children with suspected TB disease, a negative test does not rule out active TB.|
|3||Adult and childhood contacts of a case of active infectious tuberculosis||1. IGRAs may be used as a confirmatory test for a positive TST in contacts (adult or child) who, on the basis of an assessment of the duration and degree of contact with an active infectious case, are felt to have a low pretest probability of recently acquired LTBI and who have no other high risk factors for progression to active disease if infected.
2. For close contacts or those contacts who have high or increased risk of progression to active disease if infected, a TST (or both TST and IGRA) should be used, and if either is positive the contact should be considered to have LTBI.
3. If both TST and IGRA testing will be used, it is recommended that blood be drawn for IGRA on or before the day when the TST is read whenever possible.
|4||"Low risk' adults and children age 5-17 years with a positive TST result||IGRA may be performed in TST-positive, immunocompetent adults and children who are at relatively low risk of being infected with TB and of progressing to active disease if infected. Persons with a positive IGRA result may be considered for treatment of LTBI.||IGRA may be performed as a confirmatory test in a TST positive, immunocompetent adult or child age 5-17 years who is considered to have a low pretest probability of LTBI and EITHER has no high risk factor, per the Canadian Tuberculosis Standards, Chapter 4, Table 2, for progression to active disease if infected, OR is not on treatment with glucocorticoids or tumor necrosis factor (TNF)-alpha inhibitors, does not have diabetes mellitus and is not age 0-4 years.||IGRA may be used as a confirmatory test when the only increased risk factor for progression to active disease is cigarette smoking, underweight or abnormal chest x-ray due to granuloma.|
|5||Immunocompromised adults and children (under age 18)||1. In an immunocompromised person (adult or child), the TST should be the initial test used to detect LTBI. If the TST is positive, the person should be considered to have LTBI.
2. However, in light of the known problem with false-negative TST results in immunocompromised populations, a clinician still concerned about the possibility of LTBI in an immuno-compromised person with a negative initial TST result may perform an IGRA test. If the IGRA result is positive, the person might be considered to have LTBI. If the IGRA result is indeterminate, the test should be repeated to rule out laboratory error. If the repeat test is also indeterminate, the clinician should suspect anergy and rely on the person's history, clinical features, and any other laboratory results to make a decision as to the likelihood of LTBI. Although both IGRAs may be used as described above, there is evidence that the T-SPOT.TB assay may be more sensitive than the QFT assay in active TB, and this characteristic might be especially relevant in immunocompromised populations.
While the approach of accepting either test result (TST or IGRA) as positive will improve the sensitivity of detecting LTBI in immunocompromised populations, there are no data supporting the efficacy of preventive therapy in TST-negative but IGRA-positive individuals. Thus the clinician must weigh the potential benefit of detecting more persons with positive test results against the lack of evidence for the benefit of preventive therapy in such persons.
|Same||Immunocompromised refers to HIV infection
Organ transplantation (related to immune suppressant therapy)
Other immunosuppressive drugs, e.g. corticosteroids (equivalent of ≥ 15 mg/day of prednisone for 1 month, risk of TB disease increases with higher dose and longer duration)
|6||Routine immigrant screening||Routine or mass screening for LTBI of all immigrants (adults and children), with either TST or IGRA, is not recommended. However, targeted screening for LTBI after arrival in Canada is recommended among foreign-born individuals and Travellers (adults and children) with risk factors for reactivation of LTBI (these risk groups are listed below and aside from 14 and 15 are the same as those for non-immigrant Canadians). For these persons, recommendations 1, 2, 3 and 5 apply.
Immigrants who should receive targeted screening:
1. HIV infection
2. transplantation (related to immunosuppressant therapy)
4. chronic renal failure requiring hemodialysis
5. carcinoma of head and neck
6. recent TB infection (≤ 2 years)
7. abnormal chest radiographic result - fibronodular disease
8. treatment with glucocorticoids
9. treatment with tumor necrosis factor (TNF)-alpha inhibitors
10. diabetes mellitus (all types)
11. underweight (for TB purposes, this is a body mass index < 20 for most persons)
12. cigarette smoker
13. abnormal chest radiographic result-granuloma
14. children under the age of 15 years who have lived in a country with high TB incidence and have immigrated within the past 2 years
15. persons aged 15 years and older who have lived in a country with high TB incidence, have immigrated within the past 2 years and have either been living with or in known contact with a TB case in the past or are at high risk of development of active TB.
|The word "Travellers" was removed.||See Recommendation No. 7 regarding Travellers. Recommendations for routine immigrant screening remain unchanged from 2008.|
|7||Travellers||Recommendation No. 6||See specific TST recommendations in "Risk Assessment and Prevention of Tuberculosis Among Travellers," published by the Committee to Advise on Tropical Medicine and Travel (CATMAT) at http://www.phac-aspc.gc.ca/ publicat/ccdr-rmtc/09vol35/ acs-dcc-5/index-eng.php.
For IGRA testing, Recommendations 1, 2 and 5 apply. Confirmatory IGRA testing is not recommended as travellers with a positive TST post-travel are considered recent converters or at high risk of reactivation.
|The publication of specific TST recommendations for travellers by CATMAT since the 2008 version of IGRA recommendations necessitates this clarification.|
|8||Serial testing of healthcare workers, prison inmates and staff, and in employee screening programs||There is insufficient published evidence to recommend serial IGRA testing in populations exposed to TB, such as health care workers or prison staff and inmates. Serial screening for LTBI should continue to be done using the TST, as recommended by the Canadian Tuberculosis Standards
IGRAs may be used as a confirmatory test for a positive baseline TST in an immunocompetent health care worker or prison staff/inmate who is felt to have a low pretest probability of LTBI and who has no other high or increased risk factor for progression to active disease if infected. Persons with a positive IGRA result may be considered for treatment of LTBI. If an IGRA is negative, this person could be tested again with IGRA, if an exposure occurs (i.e. post-exposure testing). In the absence of data on optimum timing for post-exposure IGRA testing, the time-window recommended by the Canadian Tuberculosis Standards for repeating TST after exposure (i.e. at least 8 weeks after the last exposure) may be used for IGRA as well.
|There is insufficient published evidence to recommend serial IGRA testing in populations exposed to TB, such as health care workers or prison staff and inmates. Serial screening for LTBI should continue to be done using the TST, as recommended by the Canadian Tuberculosis Standards
IGRAs may be used as a confirmatory test for a positive baseline TST in an immunocompetent health care worker or prison staff/inmate who is considered to have a low pretest probability of LTBI and EITHER has no high risk factor, per the Canadian Tuberculosis Standards, Chapter 4, Table 2, for progression to active disease if infected, OR is not on treatment with glucocorticoids or tumor necrosis factor (TNF)-alpha inhibitors, does not have diabetes mellitus.
Persons with a positive IGRA result may be considered for treatment of LTBI. If an IGRA is negative, this person could be tested again with IGRA, if an exposure occurs (i.e. post-exposure testing). In the absence of data on optimum timing for post-exposure IGRA testing, the time-window recommended by the Canadian Tuberculosis Standards for repeating TST after exposure (i.e. at least 8 weeks after the last exposure) may be used for IGRA as well.
|9||Population (or community-based) surveys for prevalence of LTBI||While IGRAs may be useful research tools for prevalence estimation, there is insufficient published evidence to recommend the routine use of IGRAs in population or community-based surveys for estimating the prevalence of LTBI. Prevalence surveys should continue to be done using the TST.||Same||No change|
While the updated recommendations for use of IGRA tests are shown in Table 1, 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 Table 2 are primarily based on expert opinion and accumulated evidence on the prognostic value of the TST.
|Risk of developing disease if infected with M. tuberculosis|
|IGRA positive||IGRA negative||IGRA indeterminate||IGRA positive||IGRA negative||IGRA indeterminate|
|TST positive||Consider treatment for LTBI||Consider treatment for LTBI||Treatment for LTBI is not necessary||Repeat IGRA test or base interpretation on TST result|
|TST negative||Consider treatment for LTBI||Treatment for LTBI is not necessary if immunocompetent||Repeat IGRA test or base interpretation on TST result||Consult a TB specialist||Treatment for LTBI is not necessary|
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 (2).
Interferon-gamma release assays have emerged as promising alternatives to the tuberculin skin test. The first official recommendation from Canadian tuberculosis authorities on IGRAs was published in 2007, based on literature published up to October 2006Footnote 1. An updated version was published in October 2008Footnote 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.
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 Footnote 4, Footnote 5, Footnote 13. Emerging data suggest that IGRAs appear to have dynamic characteristics that increase the likelihood of conversions and reversions over timeFootnote 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 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.
The authors acknowledge the members of the Canadian Tuberculosis Committee: