IGRA for diagnosis of LTBI: 2010 

Volume 36 ACS-5, June 2010

An Advisory Committee Statement (ACS)
Canadian Tuberculosis Committee (CTC)*^†

Recommendations on Interferon Gamma Release Assays for the Diagnosis of Latent Tuberculosis Infection—2010 Update

Contributors

*Members: Ms. C. Case (Chair), Ms. R. Appl, Dr. E. Ellis (Executive Secretary), Dr. K. Elwood, Dr. S. Field, Ms. T. Garrahan, Dr. F. Jamieson, Dr. J. Kettner, Dr. R. Long, Dr. S. Martin (ex-officio), Ms. E. McQuade, Ms. D. Mombourquette, Dr. H. Morrison, Dr. P. Orr, Ms. E. Randell, Dr. E. Rea, Dr. P. Rivest, Dr. G. Samuel, Dr. L. Scott, Ms. D. Smith, Ms. C. Stannard, Dr. G. Verma, Dr. K. Wilson (ex-officio), Dr. W. Wobeser, Ms. J. Wolfe, Ms. M. Yetman and Dr. L. Yuan.

† This statement was prepared by Dr. Dennis Kunimoto (lead author and chair of the Expert Work Group), and the following Expert Work Group members (in alphabetical order): Drs Michael Gardam, Ian Kitai, Dick Menzies, Muhammad Morshed, Madhukar Pai, Heather Ward, Duncan Webster and Wendy Wobeser.

DOI

https://doi.org/10.14745/ccdr.v36i00a05

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 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 (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.

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^{Footnote 4} and an updated version of this meta-analysis published in 2008^{Footnote 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 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.
• TST specificity is high (~97%) in populations not vaccinated with BCG.
• 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.
• The sensitivity of IGRAs in active TB is about 75% - 90%, with QFT showing lower sensitivity (~75 - 80%) than T-SPOT.TB (~90%). QFT appears to be more sensitive (~80%) in low-incidence countries than high-incidence countries (~70%).
• 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.
• Sensitivity of TST is variable, but on average ~75 - 80% (similar to QFT, but lower than T-SPOT.TB).

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^{Footnote 6, Footnote 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.

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^{Footnote 8, Footnote 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^{Footnote 9}-^{Footnote 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)^{Footnote 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. Table 1 also provides information on what has changed and why.

Table 1. Recommendations on Interferon Gamma Release Assays (IGRAs) for specific indications or subgroups

No.	Specific subgroup or clinical indication	Previous ACS recommendation [CCDR 2008]	Updated recommendation [2010]	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.	Same	No change
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) Extracted from Canadian Tuberculosis Standards, Chapter 6, Table 6
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) 3. silicosis 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

Interpretation in persons with both TST and IGRA test results

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.

Table 2. Interpretation of results when both TST and IGRA results are available

Risk of developing disease if infected with M. tuberculosis
	High			Low
	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 (^{Footnote 2}).

Conclusions

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 2006^{Footnote 1}. An updated version was published in October 2008^{Footnote 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 time^{Footnote 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.

Statement of Disclosure of Interests

• 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.

Acknowledgements

The authors acknowledge the members of the Canadian Tuberculosis Committee:

• Alberta Health and Wellness, Disease Control and Prevention Branch
• Division of Tuberculosis Control, British Columbia Centre for Disease Control
• Manitoba Tuberculosis Control Program
• New Brunswick Department of Health
• 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
• Public Health Division, Medical Group Section, 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, Québec
• 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 Program Evaluation and Research Unit, University of Alberta
• Chairs of Aboriginal Scientific TB, Immigration, Metropolitan TB Issues and Surveillance Subcommittees of the Canadian Tuberculosis Committee
• Tuberculosis Prevention and Control, Public Health Agency of Canada

References

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