Interferon gamma release assays for latent tuberculosis infection - CCDR Vol.33 ACS-10
Canada Communicable Disease Report
Volume 33 • ACS-10
1 November 2007
An Advisory Committee Statement (ACS)
Canadian Tuberculosis Committee†,††
18 Pages - 721 KB
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. It is disseminating this document 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 October 2006. 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. The updated Statements, along with a list of referenced studies grouped by category, will appear on the Public Health Agency of Canada Web site at www.publichealth.gc.ca/tuberculosis.
Recently, in-vitro T-cell based assays that measure interferon-gamma (IFN-γ) production have been developed for the diagnosis of latent tuberculosis infection (LTBI). These assays operate on the basis that T-cells previously sensitized to tuberculosis (TB) antigens produce high levels of IFN-γ when re-exposed to the same mycobacterial antigens(1). At the present time, two different types of IFN-γ release assays (IGRAs) are registered for use in Canada and present possible alternatives to the tuberculin skin test (TST). These are the QuantiFERON®-TB Gold In-Tube (Cellestis Limited, Carnegie, Victoria, Australia) and the T-SPOT.TB® (Oxford Immunotec, Oxford, UK) assays.
The first commercial IGRA was the QuantiFERON-TB assay, which used purified protein derivative (PPD) as the stimulating antigen. This assay was replaced by the QuantiFERON-TB Gold (QFT-G) assay, which uses TB-specific antigens. The T-SPOT.TB test, the first IGRA registered in Canada, is also currently CE marked, a requirement to market a product in the European Union (EU), indicating that the product meets the applicable requirements of the EU directives. As of January 2007, the T-SPOT.TB test has not been approved by the US Food and Drug Administration (FDA). Because of the rapid evolution of these assays and the variations in cut-points and technical methods used, it is important to note that this statement is based on published literature on QFT-G and QFT-G In-Tube, and research and commercial versions of the T-SPOT.TB assay.
The newer IGRAs use Mycobacterium tuberculosis specific proteins encoded by genes located within the region of difference 1 (RD-1) segment of the M. tuberculosis genome. These antigens are not found in Bacille Calmette-Guérin (BCG) vaccine and many non-tuberculous mycobacterial (NTM) species(1). The immunogenic antigens encoded within the RD-1 of M. tuberculosis are found in M. leprae, wild type M. bovis, and certain of the NTM (including M. kansasii, M. marinum, M. szulgai and M. flavescens). Theoretically, the presence in the host of these species could cause a false-positive IGRA. While M. leprae and M. bovis are uncommon species in Canada, and are therefore unlikely to cause cross reactions, the NTM M. kansasii, M. marinum, M. szulgai and M. flavescens (listed in approximate order of their frequency in Canada) are not uncommon. Cumulatively, as many as 1 or 2 isolates of these species are grown for every 10 isolates of M. tuberculosis (National Microbiology Laboratory, Public Health Agency of Canada: personal communication).
In 2005, the US Centers for Disease Control and Prevention (CDC) recommended that the FDA-approved version of the QFT-G assay may be used in place of the TST for all indications, including contact investigations, evaluation of immigrants and serial testing of health care workers(2). In 2006, the UK National Institute for Health and Clinical Excellence TB guidelines recommended a hybrid, two-step approach for LTBI diagnosis: initial screen with TST and subsequent IGRA testing, if available, of those who are TST positive (or in whom the TST may be unreliable), to confirm the TST results(3).
QuantiFERON-TB Gold In-Tube
The QFT-G assay is available in two formats, a 24-well culture plate format (approved by the FDA and currently used in the United States) and a newer, simplified In-Tube format (not FDA approved as yet but available in countries other than the United States). In Canada only the QFT-G In-Tube test is available. The QFT-G In-Tube assay uses peptides from early secreted antigenic target 6 (ESAT-6), culture filtrate protein 10 (CFP-10), and a portion of TB7.7. In this assay, 1 mL (one millilitre) of blood is drawn into each of three tubes: a negative control, a positive mitogen control, and a tube that contains the M. tuberculosis specific RD-1 antigens CFP-10, ESAT 6 and TB7.7. The tubes are incubated as soon as possible but within 16 hours at 37° C for 16-24 hours and then centrifuged. Plasma is removed and assayed for IFN-γ by enzyme-linked immunosorbent assay (ELISA). The plasma is stable for up to 4 weeks at 4° C or can be frozen at –20°C for 3 months. Using the software provided with the commercial kit, the ELISA read-out is used to calculate the amount of IFN-γ in international units per millilitre. After correction for the negative control, an IFN-γ value of > 0.35 IU/mL is considered positive.
The T-SPOT.TB test is an in-vitro diagnostic assay that measures IFN-γ release following T-cell exposure to ESAT-6 and CFP-10. The T-SPOT.TB test is available in two formats – a 96-well plate (T-SPOT.TB 96) or 8-well strips (T-SPOT.TB 8). In this assay, 8 mL of blood is collected in sodium citrate cell preparation tubes. Following isolation and washing of the peripheral blood mononuclear cells (PBMC), 2.5 × 105 viable cells are added to each of four microtitre plate wells: a negative (nil) control, a positive control and two patient test wells (containing ESAT-6 and CFP-10 respectively). The T-SPOT.TB assay incubates PBMCs with M. tuberculosis antigens and measures the number of T-cells producing IFN-γ using an enzyme linked immunospot (ELISPOT) assay. The results of the test are interpreted by comparing the number of spots produced in the patient test wells with the number in the corresponding negative and positive control wells. What constitutes a positive result depends upon the number of spots produced in the negative control well. The product insert or the manufacturer’s Web site should be consulted for further information on the interpretation of the test.
Uses of IGRAs in various population groups
The precise indications for use and interpretation of the results of IGRAs remain uncertain at this time. The following sections are meant to give guidance on the use and interpretation of these assays in various population groups and in various clinical settings.
(1) Serial testing
There are very few published studies of the results of serial testing with IGRA. Several small studies have examined the results of repeated IGRA in patients who were receiving treatment for active TB(4-9) or LTBI(10,11) . The results have been contradictory – in some studies IGRA responses increased(5,6), in others they decreased(4,7,8), and in others no change was seen following treatment(10,11). Thus, no clear conclusions can be drawn from these longitudinal studies. As well, the effect of treatment could not be distinguished from random and biologic variability. The only published study of serial IGRA testing in untreated but exposed persons was conducted among health care workers in India(12). In this study conversions, reversions, and non-specific variations occurred with serial testing with QuantiFERON-TB Gold In-Tube, as they do with TST. To meaningfully interpret repeat IGRA results, further studies are needed to determine the optimal thresholds for distinguishing new infections (i.e. conversions) from non-specific variations.
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(13).
(2) Diagnosis of LTBI in children
Evaluation of new tests for the diagnosis of LTBI in children is particularly difficult because of the lack of a gold standard, even in patients with active disease. As well, almost all of those identified with LTBI are treated because of their increased risk of disease development. Studies to date in pediatric populations have involved subjects with different clinical conditions who underwent different tuberculin and IGRA tests(14-21). In two studies, from high-incidence countries, an equal proportion of subjects were TST and IGRA positive(14,17), whereas in two studies, IGRAs were more frequently positive(20,21). In one study the proportion positive was not reported(18), and TST was more often positive in three studies, a difference that was not explained in two(16,19) but was related to BCG in the third(15). Of four studies, QFT results were indeterminate in 32%(18), 17%(16) and 0% of subjects(17,19); these differences in test performance are also unexplained. Given these heterogeneous methods and findings, no meaningful inferences can be drawn. It cannot even be stated whether IGRAs are equivalent, better or worse than TST in this population. Hence, at this time the most prudent action is to await further published evaluations of IGRA in children, as this is a very active area of investigation.
Use of IGRA is not recommended in children until published evidence is available consistently demonstrating the utility and accuracy of these tests in pediatric populations.
(3) Immigrant screening
In previously published statements, the Canadian Thoracic Society has not recommended routine or mass screening of new immigrants for LTBI using the TST(22). The vast majority of persons identified as having LTBI are at low risk of subsequent disease, making this TB prevention strategy much less cost-effective than other strategies, such as contact investigation(23). In addition, in published reports from large-scale screening programs the overall impact has been low because of substantial non-adherence, by patients and providers, to recommendations for screening, follow-up and LTBI treatment(23-28). The limited published experience of these tests under routine program conditions suggests that using new IGRAs will not significantly improve programmatic efficiency(29).
On the other hand foreign-born persons, because they have a higher prevalence of LTBI, SHOULD be targeted for LTBI screening if they have clinical conditions that increase the risk of reactivation of LTBI(30,31). These clinical conditions include the following(13):
- HIV infection
- transplantation (related to immunosuppressant therapy)
- chronic renal failure requiring hemodialysis
- carcinoma of head and neck
- recent TB infection (≤ 2 years)
- abnormal chest radiographic result – fibronodular disease or granuloma
- treatment with glucocorticoids
- treatment with tumor necrosis factor (TNF)-alpha inhibitors
- diabetes mellitus (all types)
- underweight (for TB purposes, this is a body mass index < 20 for most persons)
- cigarette smoker
- 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
- 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.
Note: A country is considered to have a high TB incidence if its World Health Organization estimated sputum smear-positive pulmonary TB incidence rate is 15/100,000 or higher (3 year average).
To view current rates, please see http://www.publichealth.gc.ca/tuberculosis.
Routine or mass screening for LTBI of all immigrants, with either TST or IGRA, is NOT recommended. However, targeted screening for LTBI after arrival in Canada is recommended among foreign-born individuals with clinical conditions that increase their risk of reactivation of LTBI. For these persons, the TST should be used.
(4) Contacts of a case of active infectious TB
There are seven published reports that compare IGRAs with TST in the context of contact investigation(32-38) . Two studies evaluated QFT-G versus a TST of ≥ 10 mm as a positive result in contacts of TB cases(33,35). These two studies suggest that QFT-G results were similar to those of the TST in non-BCG vaccinated contacts but correlated with exposure better than TST in BCG vaccinated contacts. There were five studies using ELISPOT-based assays versus TST in contacts(32,34,36-38). One used the Heaf test(33), and the other four studies used the Mantoux test, two designating ≥ 5 mm(36,37) and two designating ≥ 10 mm(34,38) as a positive result. Overall, the T-SPOT.TBI was similar to the TST in contacts, with better performance in BCG vaccinated persons. In the absence of BCG, the IGRAs and TST appeared to have similar rates of positivity, although there were discordant results. In the presence of BCG, there were significantly fewer positive results in the low-exposure groups with the IGRAs than with the TST. This is consistent with numerous studies demonstrating that the IGRAs have better specificity.
Given that several studies have found significant discordance between TST and IGRA results (both TST+/IGRA– and the reverse, TST–/IGRA+) and because the biological basis of this discordance is uncertain, the reliance on IGRA should depend on the clinical context. When the pretest probability of infection is high, as in a close contact of an active infectious case, it is important not to miss identifying recently infected persons. In such circumstances, a TST (or both TST and IGRA) should be used, and if either is positive, the contact should be considered to have LTBI. However, in contacts who are felt to have a low pretest probability of having acquired LTBI and who have no other significant risk factors for progression to active disease if infected (please refer to the previous section, Immigrant Screening, for a discussion of these risk factors), IGRA testing may be used in conjunction with the TST to improve the specificity of the TST. In such contacts with a known reason for a falsely positive TST (e.g. a prior history of BCG vaccination after infancy), the result of the IGRA can be used to reduce the likelihood of administering treatment for LTBI to persons with falsely positive TSTs.
Note about timing of simultaneous TST and IGRA:
When TST and IGRA are to be performed simultaneously, it is important to consider the issue of timing. Although one study in humans has shown that previous TST does not affect a subsequent ELISPOT result(39), there are animal studies suggesting that TST might boost subsequent measurements of IFN-γ(40,41). Given the paucity of data on this issue, it is recommended that, when possible, blood be drawn for IGRA before or on the same day as placing the TST. This will avoid any potential effect of PPD sensitization on subsequent IFN-γ measurements.
IGRAs may be used as a confirmatory test for a positive TST in contacts 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 or increased risk factors for progression to active disease if infected(13).
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.
If both TST and IGRA testing will be used, it is recommended that blood be drawn for IGRA before or on the same day as placing the TST.
(5) Immunocompromised persons
Published data on the use of IGRAs in immunocompromised populations are limited. Two studies have examined the sensitivity of the T-SPOT.TB test in this population(42,43). In one study, the T-SPOT.TB test had high sensitivity in detecting active TB in HIV-infected and uninfected Zambian adults(42). The results also suggested that compared with the TST it had greater sensitivity in the HIV-positive population. In a recent study comparing the performance of the T-SPOT.TB versus TST versus expert physician panel diagnosis (which included a TB epidemiologic survey, chest radiograph and two-step TST in patients with end-stage renal disease who were receiving hemodialysis), the T-SPOT.TB test was more closely correlated with known TB risk factors, such as prior active disease and an abnormal chest film, than the TST(43).
In a study involving 590 HIV-positive persons, QFT-G In-Tube was used to assess for LTBI(44) without a comparison TST. Overall, 4.6% of HIV-positive persons were found to have a positive IGRA result, and 78% had risk factors for LTBI. Only 20 (3.4%) of the study population had indeterminate results, with higher rates in those with CD4 counts < 100. In a second study(45), 318 hospitalized patients were tested with both QFT-G and TST. The concordance between QFT-G and TST was significantly lower in BCG vaccinated individuals. Of particular concern was the fact that the QFT-G gave an indeterminate result in 68 persons (21.4%).
1. In an immunocompromised person, 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 immunocompromised 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. The approach of accepting either test result (TST or IGRA) as positive will improve the sensitivity of detecting LTBI in immunocompromised populations, which would appear a desirable goal. However, in a meta-analysis of five randomized trials, all conducted in countries with a high TB incidence, isoniazid was of no benefit in TST-negative HIV-infected adults. 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 isoniazid treatment in such persons.
(6) “Low risk” persons with a positive TST result
TST-positive immunocompetent adults (persons > 14 years of age) at relatively low risk of being infected with TB and of progressing to active disease if infected may be referred to TB control physicians or clinics for consideration of treatment of LTBI. These would include (i) persons found to be TST positive on employment or post-secondary school screening but having no history of TB contact, no clinical condition that increases the risk of reactivation and a normal chest x-ray, and (ii) TST-positive immigrants from countries with high TB incidence (see the Immigrant Screening section for a definition of high TB incidence countries) having no clinical condition that increases the risk of reactivation and a normal chest x-ray. Their TSTs could be falsely positive on account of BCG vaccination or exposure to non-tuberculous mycobacteria. To improve the specificity of diagnosing LTBI and reduce the likelihood of administering treatment of LTBI to persons with false-positive TSTs, an IGRA may be performed.
IGRA may be performed in TST-positive, immunocompetent adults 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.
(7) The diagnosis of active TB disease
There are two reasons for evaluating IGRAs among patients with active TB: (i) to use active TB as a surrogate reference standard for LTBI (most studies would fit into this category); and (ii) to determine whether IGRAs would be helpful in diagnosing active TB per se. Both approaches have limitations. The first reason is based on the logic that anyone with active TB must have TB infection, albeit not latent. From an immunologic perspective, active TB occurs when the host immune response is unable to contain the latent infection, thus it is possible that the sensitivity of IGRAs in active disease may not reflect their sensitivity in LTBI. The second reason to perform the test is based on the assumption that evidence of TB infection (i.e. a positive IGRA result) is useful in diagnosing active disease. This is problematic because IGRAs, like the TST, are incapable of distinguishing between LTBI and active disease, and most cases of TB disease occur in populations with a high prevalence of LTBI.
It has been suggested that IGRAs have the potential to serve as useful tests to rule out active TB in selected populations (e.g. children, immunocompromised patients) when microbiologic diagnosis is hard to establish. In other words, while a positive IGRA may not always indicate active disease, a negative IGRA may indicate lack of TB infection and, therefore, disease. For IGRAs to be useful in excluding active disease, they must be highly sensitive in patients with active TB. As reviewed previously(46,47), the sensitivity of IGRA in active TB is comparable to the sensitivity of TST, and, by extension, both tests have suboptimal sensitivity in patients with active TB. This reflects the well-known diminished immune response in patients with active TB at the time of diagnosis, particularly in those with more advanced disease, malnutrition or older age(48,49). Thus, a negative IGRA or TST cannot be used alone to exclude the diagnosis of active TB.2
IGRAs are not recommended for the diagnosis of active TB. Clinicians who manage patients with suspected TB disease should align their practice with the Canadian TB Standards(13) and the International Standards for TB Care(50), and use sputum smear microscopy and culture to investigate patients with suspected active TB.
Interpretation in persons with both TST and IGRA positive test results
While the current recommendations for use of IGRA tests are limited, as already discussed, there may be situations in which IGRA testing has been performed outside of the above recommendations. If both IGRA and TST results are available and the clinician is unsure how to interpret the results, the following is recommended.
Risk of disease if infected with M. tuberculosis
|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 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, the reader is referred to chapters 4 and 6 of the Canadian Tuberculosis Standards(13).
The cost-effectiveness of IGRAs
At present there are few published studies comparing the cost-effectiveness of IGRA and TST(51-53). Available analyses have demonstrated that if the unit costs of the new IGRAs are substantially higher than those of TST, then these new tests will be cost-effective only when their specificity is substantially higher. The manufacturers’ retail prices for QFT-G In-Tube and for T-SPOT.TB will vary by clinical setting and the volume ordered. To this must be added $22.00 for ancillary costs per QFT-G In-Tube test for drawing blood, transport of specimens to the laboratory and technician time for performing and reporting the test; these estimates are based on a recently published programmatic experience(29). As the amount of technician time to perform the T-SPOT.TB test is greater than for the QFT-G In-Tube, the ancillary costs associated with the T-SPOT.TB test are slightly higher. By contrast, the total cost of TST is only $14 in public health settings(31,51,54,55), although it may be higher in primary care settings if not covered by provincial/territorial health insurance. Hence QFT-G In-Tube and T-SPOT.TB will be cost-effective, compared with the TST, only in populations in which a high proportion were BCG vaccinated after infancy(56).
Given their higher unit and labour costs, new IGRAs will be less cost-effective than TST in most clinical situations and populations. In low-risk populations that were BCG vaccinated after infancy, the most cost-effective strategy is initial TST followed by QFT-G In-Tube for those who are TST positive.
In the diagnosis of LTBI, IGRAs have a number of potential advantages over the TST. Current commercially available assays that are based on combinations of RD-1 antigens, such as ESAT-6 and CFP-10, have excellent specificity, with minimal false-positive test results due to vaccination with BCG and sensitization by certain NTM. Other benefits of these tests are that they require only a single visit by the patient and pose no risk of serious skin reactions.
A major advantage of the TST is that results have been validated through follow-up of large cohorts to determine subsequent incidence of active TB. On the basis of these studies, risk of disease in an individual with certain risk factors and a given TST reaction can be predicted with some accuracy. However, to date, none of the IGRAs has been validated prospectively in this way.
The initial material and ancillary costs of IGRAs are greater than those of the TST, and cost-benefit analyses have demonstrated that this means the tests will be less cost-effective in most populations. The occurrence of many reactions that are discordant with TST reactions is of concern, because this phenomenon of discordance remains largely unexplained. Therefore, individuals who are IGRA positive and TST negative will be difficult to manage appropriately.
It is important to note that, like the TST, IGRAs are not recommended for the diagnosis of active TB. The precise indications for use and interpretation of results, particularly with regard to future risk of active TB disease, remain uncertain at this time. Future research is needed to define the ability of these assays to predict the development of active disease, to demonstrate their reproducibility and to assess the health and economic implications of their use. Further studies, particularly prospective studies with simultaneous performance of TST and IGRAs, would be of great interest.
The authors acknowledge the members of the Canadian Tuberculosis Committee and the Provincial and Territorial Tuberculosis Programs for their contribution and participation in the Canadian Tuberculosis Reporting System:
Alberta Health and Wellness, Disease Control and Prevention Branch
Division of Tuberculosis Control, British Columbia Centre for Disease Control
Manitoba Tuberculosis Control Program
Department of Health and Wellness, New Brunswick
Department of Health and Community Services, Newfoundland and Labrador
Department of Health and Social Service, Government of Northwest Territories
Office of the Chief Medical Officer of Health, Nova Scotia Department of Health
Department of Health & Social Services, Government of Nunavut
Vaccine Preventable Diseases and TB Control Unit, Ontario Ministry of Health and Long-Term Care
Department of Health and Social Services, Prince Edward Island
Direction de la Protection de la Santé Publique, Ministère de la Santé et des Services Sociaux, Quebec
Tuberculosis Control Program, Saskatchewan Health
Department of Health and Social Services, Yukon
Association of Medical Microbiology and Infectious Disease Canada
Canadian Lung Association
Canadian Public Health Laboratory Network
Canadian Thoracic Society
Citizenship and Immigration Canada
Correctional Service Canada
First Nations and Inuit Health Branch, Health Canada
National Microbiology Laboratory, Public Health Agency of Canada
Stop TB Canada
Tuberculosis Prevention and Control, Public Health Agency of Canada
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†Members: Dr. R. Long (Chair); Dr. H. Akwar, Dr. A. Al-Azem, Ms. C. Case, Dr. E. Ellis (Executive Secretary), Dr. K. Elwood, Dr. B. Graham, Ms. C. Hemsley, Dr. V. Hoeppner, Dr. A. Kabani, Dr. M. Lem, Ms. J. Marshall, Dr. P. Orr, Ms. E. Randell, Dr. P. Rivest, Ms. S. Sarkesh, Dr. L. Scott, Dr. F. Stratton, Dr. L. Sweet, Dr. W. Wobeser, and Ms. J. Wolfe.
† †This statement was prepared by Drs. M. Gardam, D. Kunimoto, R. Long, D. Menzies and M. Pai (with secretariat support provided by Dr. R. Stirling). It has been approved by the Canadian Tuberculosis Committee.
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