Position Statement on Interferon-γ Release Immunoassays in the Detection of Latent Tuberculosis Infection

This document endorsed by the National Tuberculosis Advisory Committee is a general guide to appropriate practice, to be followed in the detection of latent tuberculosis infection.

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Endorsed by the National Tuberculosis Advisory Committee
Published by the Australian Government Department of Health and Ageing
September 2009

Detection and treatment of latent tuberculosis infection (LTBI) is considered to be an increasingly important element of tuberculosis (TB) control efforts in Australia and other low incidence countries. In vitro T-cell based interferon-y release immunoassays (IGRAs) are marketed as a substitute for the tuberculin skin test (TST) for the detection of LTBI. The specificity of these immunoassays has been optimised by utilising pooled synthetic antigens, such as early secretory protein 6 [ESAT-6] and culture filtrate protein 10 [CFP-10], from the Mycobacterium tuberculosis-specific region of difference 1 (RD1) region and has been recently reviewed (Pai et al, 2004; Menzies et al, 2007).

Data suggest that IGRAs using these antigens are more specific than TST, having less cross-reactivity with previous BCG immunisation or exposure to non-tuberculous mycobacteria, potentially offering distinct advantages for the detection of LTBI. However, the assessment of the sensitivity of IGRAs for diagnosing LTBI in differing environments and countries is complicated by the lack of a gold standard for diagnosing LTBI, the varied methodology across studies in the performance of TST and the interpretation of TST reactions, and the limited long-term follow-up of those subjects tested with IGRAs compared with the historical data available on those populations tested with TST. There is also limited data on the use of these immunoassays in certain sub-populations such as immunocompromised patients, children, and populations from TB-endemic countries, although such data on these populations are emerging for one or both of the two commercial IGRA in vitro tests currently available. Additionally, long-term follow-up studies are underway and will help clarify issues relating to the performance characteristics of IGRAs. As such information is carefully reviewed, the performance characteristics and clinical interpretation of these immunoassays will become better defined. Furthermore, NTAC feels that the performance, utility and cost effectiveness of IGRAs remain to be defined under Australasian TB program conditions. Finally, populations most in need of access to accurate diagnosis and potential treatment of LTBI are often in remote and other community centres distant from laboratory services, or are the groups for which the IGRA tests are currently assessed to be least reliable, ie, children and the immunosuppressed (although for the latter group, TST is also unreliable). Until many of these issues are clarified, NTAC believes that the performance and interpretation of IGRA tests should be left to clinicians who are skilled in the diagnosis of both active TB disease and LTBI.
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Both NTAC and state-based TB services encourage further clinical and economic evaluation of IGRAs. NTAC considers that the role of IGRAs in diagnosing LTBI will be better defined by:

ongoing comparative studies of TST and interferon-γ assays undertaken by staff specially trained in the standardised application of the TST, where results can be compared as both continuous and dichotomous variables to assess suitable positive/negative cut-off scores, as well as to further investigate sensitivity, specificity and discordant results;
sequential testing of IGRAs on various patient groups to characterise and quantify conversion and reversion reactions;
further research on the use of IGRAs in children; Top of page
independent cost-benefit analysis on the use of IGRAs using states’ and territories’ preferred protocols of investigating LTBI in Australia. Such analysis is needed to investigate the relative economic outcomes of changing from TST to immunoassays taking into account the structure of TB services and program delivery in Australia; and
comparison of alternative IGRAs to determine differences between the assays.

NTAC suggests the research and rollout questions summarised in the December 2005 Morbidity and Mortality Weekly Report (Mazurek et al, 2005) paper from the United States Centers for Disease Control and Prevention and review article by Pai (Pai et al, 2007) could act as a basis for future investigations.

In summary, NTAC makes the following recommendations:

currently TST remains the preferred method of screening for LTBI pending further evaluation of IGRAs;
TST and IGRAs have no place in the initial investigation of active TB disease;
state-based TB services should be encouraged to participate in the evaluation of the role of IGRAs for the investigation of LTBI;
IGRAs should only be carried out by clinicians experienced in the diagnosis and management of TB; and
IGRAs may be used as a supplementary test in individualised clinical assessment, except in children under 2 years of age, for LTBI where increased specificity is valuable in reducing the confounding effect from prior BCG vaccination or prior exposure to non-tuberculous mycobacteria.

In making these recommendations, NTAC recognises that IGRAs are a test for a disease with a delayed onset where the “gold standard” comparator test (ie, TST) is imperfect. The NTAC position statement and recommendations will be under ongoing review and will be revised as new peer-reviewed published data becomes available. NTAC is committed to ongoing monitoring of new diagnostic tests that may be of value in TB control.

References

Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? International journal of Tuberculosis and Lung Disease, 2006;10(11):1192–1204.

Lighter J., Rigaud M., Eduardo R., Peng C-H., Pollack H. Latent tuberculosis diagnosis in children using the QuantiFERON-TB Gold In-Tube assay. Pediatrics 123:30, 2009

Menzies D, Pai M, Comstock G. Meta analysis: New tests for the diagnosis of latent tuberculosis infection: Areas of uncertainty and recommendations for research. Annals of Internal Medicine, 2007;146(5): 340-354,W81-W88.

Mazurek GH, Jereb J, LoBue P, Iardemarco MF, Metchock B, Vernon A. Guidelines for using the QuantiFERON-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States. Morbidity and Mortality Weekly Report, 2005;54(RR15):49-55.

Oxlade O, Schwartzman K, Menzies D. Interferon-gamma release assays and TB screening in high-income countries: a cost-effectiveness analysis. The International Journal of Tuberculosis and Lung Disease, 2007;11(1):16-26.
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Pai M, Dheda K, Cunningham J, Scano F, O’Brien R. T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward. Lancet Infectious Diseases, 2007;7: 428-438

Pai M, Kalantra S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part I Latent tuberculosis. Expert Review of Molecular Diagnostics, 2006; 6(3): 423-432.

Pai M, Riley LW, Colford JM. Interferon-y assays in the immunodiagnosis of tuberculosis: a systematic review. The Lancet Infectious Diseases, 2004;4:761–776.

Pai M., Zwerling A., Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 149: 1, 2008

The National Collaborating Centre for Chronic Conditions (UK). Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006.

Yew W.W., Leung C.C. Update in tuberculosis 2007. Am J Respir Crit Care Med 177: 479, 2008

Endorsed by the National Tuberculosis Advisory Committee 25 June 2009. Endorsed by the Communicable Disease Network Australia 24 July 2009. Endorsed by the Australian Health Protection Committee 28 August 2009. This statement supersedes all previous such statements.

Some members of the Committee declared receipt of limited funding assistance from Oxford Immunotec, Cellestis Limited and CSL Limited to support research and attendance at a conference.

Disclaimer

This document is a general guide to appropriate practice, to be followed subject to the health professional’s judgement and the patient’s preference in each individual case. This document is designed to provide information to assist decision-making and is based on the best evidence available at the time of publication.

While every care has been taken in preparing this document, the membership of the National Tuberculosis Advisory Committee (‘NTAC’), the Communicable Diseases Network Australia (‘CDNA’), the Australian Health Protection Committee (‘AHPC’) and the Commonwealth of Australia (‘the Commonwealth’), as represented by the Department of Health and Ageing, do not warrant, expressly or impliedly, or assume any legal liability or responsibility for, the accuracy, completeness, or usefulness of any information or process contained in this publication.

The NTAC, CDNA, AHPC and the Commonwealth expressly disclaim all and any liability to any person, in respect of anything and of the consequences of anything, done or omitted to be done, by any such person in reliance, whether whole or partial, upon the whole or any part of the contents of this publication.