Canada Communicable Disease Report

Volume 34 • ACS-6
October 2008

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

PDF Version
13 Pages - 160 KB

Updated Recommendations on Interferon Gamma Release Assays for Latent Tuberculosis Infection

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 March 2008. With more research results related to interferon gamma release assays being published all the time, the fi eld 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 latent tuberculosis infection (LTBI) 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-cellbased 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, UK).

“Interferon Gamma Release Assays for Latent Tuberculosis Infection” was published in Canada Communicable Disease Report (CCDR) as an Advisory Committee Statement (ACS) of the Canadian Tuberculosis Committee (CTC)⁽¹⁾. This was the first official recommendation from Canadian tuberculosis authorities on IGRAs, based on scientifi c literature published up to October 2006. The recommendations have been incorporated into the recently published 6th edition of the Canadian Tuberculosis Standards (2007)⁽²⁾.

Since the publication of the ACS, a large number of IGRA studies have been published. In November 2007, an Expert Work Group was constituted to prepare this first 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⁽³⁾ and an updated version of this meta-analysis published in 2008⁽⁴⁾. 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, several focused subgroup literature reviews were done, synthesizing the relevant English language literature published up to 1 March 2008. These focused reviews covered the following subgroups/areas:

Sensitivity and specificity of IGRAs (with active TB as the surrogate reference standard);
IGRA performance in immunocompromised populations;
IGRA performance in contacts and outbreak investigations;
IGRA performance in healthcare workers;
IGRA performance in children (< 18 years of age); and
IGRA performance in serial testing and predictive value of IGRAs.

The key findings of these reviews are briefly summarized below. Evidence tables and supporting data from the updated subgroup literature reviews are available at http://www. mcgill.ca/recru/documents/.

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 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 decisionmaking 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

IGRAs and TST cannot distinguish between LTBI and active TB.
Both IGRAs have very high specificity (93% to 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 precommercial 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% to 90%, with QFT showing lower sensitivity (~75% to 80%) than T-SPOT.TB (~90%).
Head to head comparisons among patients with active TB suggest that T-SPOT.TB is more sensitive than QFT and TST.
Sensitivity of TST is variable, but on average ~75% to 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 fairly high (~70% to 100%) in immunocompetent individuals (at least comparable to QFT).
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 are 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 viceversa) and the biological basis for such discordance is unknown. Concordance levels seem to vary when IGRA and TST cut-off points are changed.

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 (< 18 years of age)

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 IFN-γ levels are just above the cut-off point and when baseline results are discordant (i.e. TST-/IGRA+); reversion rates low when baseline IFN-γ levels are high and when baseline results are concordantly positive (TST+/IGRA+).
Prognosis of conversions and reversions are unknown.
Only three studies exist on the predictive value of IGRAs, with small numbers of active TB cases. The results of these studies are not consistent.

Revised recommendations

Based on the updated reviews and expert opinion, the Expert Work Group made several recommendations. These are summarized in 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 2007]	Updated recommendation	What has changed and why?
1	Diagnosis of active TB in adults with suspected TB disease	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 Tuberculosis Standards and the International Standards for Tuberculosis Care, and use sputum smear microscopy and culture to investigate patients with suspected active TB.	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.	The previous recommendation is now sub-divided into separate adult and children (< 18 years of age) sections. The recommendation for adults remains unchanged. For children, please see below, #2.
2	Diagnosis of active TB in children (< 18 years of age) 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 defi nitive microbiologic 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.	This new recommendation allows the use of IGRAs as a supplementary diagnostic aid in children with suspected TB disease.
3	Adult and childhood contacts of a case of active infectious tuberculosis	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. 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.	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 or increased risk factors for progression to active disease if infected. 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 on or before the day when the TST is read.	This recommendation is largely unchanged, but the scope has been expanded to cover adults as well as children. Because of the practical diffi culties in drawing blood for IGRAs before or on the same day as placing the TST, the third point has been changed to allow for more time. This is based on the fact that there is no strong evidence that tuberculin skin testing will impact the results of IGRAs within a short period.
4	‘Low risk’ adults and children (< 18 years of age) with a positive TST result	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.	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.	This recommendation is largely unchanged, but the scope has been expanded to cover children as well as adults.
5	Immunocompromised adults and children (< 18 years of age)	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. 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.	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. 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. 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-GIT 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.	This recommendation is largely unchanged, but the scope has been expanded to cover adults as well as children. Also, a note has been added that the T-SPOT.TB test may be more sensitive and therefore helpful in immunocompromised populations.
6	Diagnosis of LTBI in children (< 18 years of age)	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	-	This separate recommendation for children is no longer necessary, because all the other recommendations now apply to both adults and children, with the exception of the use of IGRAs for active TB (where IGRAs can be used in children but not in adults).
7	Routine immigrant screening	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.	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 travelers (adults and children) with risk factors for reactivation of LTBI (these risk groups are listed below). For these persons, recommendations 1, 2, 3 and 5 apply. Immigrants who should receive targeted screening: HIV infection transplantation (related to immunosuppressant therapy) silicosis 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 < 15 years of age who have lived in a country with high TB incidence and have immigrated within the past 2 years persons ≥ 15 years of age 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.	This recommendation is largely unchanged, but the scope has been expanded to cover adults as well as children (< 18 years of age). Also, for targeted screening, recommendations 1, 2, 3 and 5 apply. High TB incidence countries have a rate of sputum smear-positive pulmonary TB (3 years average), as estimated by the World Health Organization, of 15 per 100,000 or greater. See www.publichealth.gc.ca/tuberculosis for international tuberculosis incidence rates.
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.	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 factors 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.	No change, but it has been clarified that IGRAs may be used as a confirmatory test if a false-positive TST is suspected in a low-risk healthcare worker or prison staff /employee or inmate. In such persons, IGRAs may be used for post-exposure screening. See Canadian Tuberculosis Standards, Chapter 4, Table 2, for a list of high and increased risk factors for progression of LTBI to active disease.
9	Population (or communitybased) 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.	This new recommendation addresses the use of IGRAs in prevalence surveys.

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 postive	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⁽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⁽¹⁾. Since the publication of that statement, a large number of IGRA studies have been published. Based on updated literature reviews and expert opinion (as of March 2008), revised recommendations on IGRAs are presented in this updated statement. Overall, the revised recommendations are more liberal than the first, and recommend wider use of IGRAs in routine clinical practice, in both adults and children.

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^(3-5). Emerging data suggest that IGRAs appear to have dynamic characteristics that increase the likelihood of conversions and reversions over time⁽⁶⁾. At present, there is no consensus on the interpretation of IGRA conversions and reversions. Data are 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.

Statement of Disclosure of Interests

Dr. Michael Gardam performed two investigator-driven 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
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 and 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, 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 Prevention and Control, Public Health Agency of Canada

References

Canadian Tuberculosis Committee. Interferon gamma release assays for latent tuberculosis infection. An Advisory Committee Statement (ACS). CCDR 2007;33(ACS-10):1-18.
Public Health Agency of Canada and Canadian Lung Association. Canadian Tuberculosis Standards, 6th edition. 2007.
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.
Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An update. Ann Intern Med 2008;149(3):177-84.
Pai M, Dheda K, Cunningham J et al. T-cell assays for the diagnosis of latent tuberculosis infection: Moving the research agenda forward. Lancet Infect Dis 2007;7(6):428-38.
Pai M, O’Brien R. Serial testing for tuberculosis: Can we make sense of T-cell assay conversions and reversions? PLoS Med 2007;4(6):e208.

*Members: Dr. R. Long (Chair); Dr. A. Al-Azem, Ms. L. Alvarado, Ms. C. Case, Dr. E. Ellis (Executive Secretary), Dr. K. Elwood, Ms. T. Garrahan, Ms. C. Hemsley, Dr. V. Hoeppner, Dr. Frances Jamieson, Ms. E. McQuade, Dr. H. Morrison, Dr. P. Orr, Ms. E. Randell, Dr. P. Rivest, Dr. G. Samuel, Dr. L. Scott, Dr. H. Ward, Dr. W. Wobeser, Ms. J. Wolfe, Ms. M. Yetman and Dr. L. Yuan.

† This statement was prepared by Dr. Madhukar Pai (lead author and chair of the Expert Work Group), and the following Expert Work Group members (in alphabetical order): Drs Michael Gardam, David Haldane, Ian Kitai, Dennis Kunimoto, Richard Long, Dick Menzies, Muhammad Morshed, Heather Ward and Wendy Wobeser. Research assistance was provided by Alice Anne Zwerling.

Members of the Infectious Diseases and Immunization Committee of the Canadian Paediatric Society have reviewed and agree with this statement.

Page details

Date modified:: 2008-10-14

Language selection

Search