26 July 2007
Use of Gamma-interferon assays in low- and medium-prevalence countries in Europe: a consensus statement of a Wolfheze Workshop organised by KNCV/EuroTB, Vilnius Sept 2006
F. Drobniewski (firstname.lastname@example.org)1,2, F Cobelens3,4, J-P Zellweger5 on behalf of the KNCV/EuroTB Workshop
1. Mycobacterium Reference Unit and, Health Protection Agency (HPA), London, United Kingdom
2. Clinical TB and HIV Group, Institute of Cell and Molecular Sciences, Barts The London School of Medicine, Queen Mary College, University of London, London, United Kingdom
3. KNCV Tuberculosis Foundation, The Hague, The Netherlands
4. Academic Medical Center , Center for Infection and Immunity Amsterdam, Amsterdam, The Netherlands
5. Department of ambulatory care and community medicine, University of Lausanne, Switzerland
Interferon gamma release assays (IGRA) offer an alternative to tuberculin skin testing (TST or Mantoux) for the diagnosis of tuberculosis (TB) latent infection (LTBI) or as an additional diagnostic method for active TB [recently reviewed in 1-5].
Two detailed sets of guidelines, one from the Centers for Disease Control, United States (CDC)  and the other from the United Kingdom National Institute for Clinical Excellence,  have been generated on the appropriate use of novel IGRAs for the diagnosis of LTBI and active TB. In the formulation of these guidelines, two commercial systems were considered, the T Spot (Oxford Immunotec, UK) and Quantiferon Gold (Cellestis, Australia).
Public health specialists involved in TB control, mainly in European countries with low and intermediate incidence of TB, met in Vilnius, Lithuania, in September 2006, to consider the use of IGRA assays against the background of those two guidelines and the increasing demand for the use of these assays. The group did not feel that it was necessary to write their own guidelines but rather to emphasise the main points of agreement with the published guidelines.
This statement represents a consensus of the group. As the field is rapidly evolving, the group felt that this guidance should be kept under regular review as new data becomes available.
For the diagnosis of latent TB infection
There was consensus on the value of the use of these tests for the diagnosis of LTBI as described in the two guidelines [6,7] based on the following agreed points:
- Although there is no clear gold standard for LTBI, IGRA, in published contact tracing incidents, reflect the degree of exposure to infectious cases more accurately than does TST. This suggests that IGRAs are more specific than TST. Discordant results between IGRAs and TST, however, cannot be completely explained by the notion that IGRAs are more specific with regard to cross-reaction with non-tuberculous mycobacterial (NTM) infections or with the Bacille Calmette Guerin (BCG) vaccine.
- Both commercial systems probably perform well for LTBI detection in immunocompetent individuals.
- Studies of IGRA sensitivity suggest they are at least as sensitive as TST in TB patients but may be less sensitive than TST for detecting LTBI in immunocompetent individuals.
- Theoretically, a combination of TST (with its high sensitivity) followed by IGRAs (with their greatest specificity) should be an optimal approach for contact tracing in incidents where there is a known index or source case. Clearly this advantage is negated where the patient does not return for reading of the TST. In those cases, the single-visit IGRA would be more advantageous.
- Although it is reasonable to assume that a positive IGRA is as predictive of later active TB as a positive TST, there is no evidence so far to suggest a higher or lower degree of predictability (see future work).
- IGRAs are of value for diagnosing/excluding LTBI in children or HIV-positive (or other immuncompromised) individuals, including those about to receive anti-tumour necrosis factor or other immunomodulating therapy.
- IGRAs are of value in any situation requiring serial TST testing, e.g. occupational health-related screening/exposure.
The group felt that further work was needed in the following areas:
- In low and intermediate incidence environments, longitudinal studies are needed to establish the real probability of a positive IGRA predicting future active TB. This is challenging but this should not delay the use of these tests in general.
- It is not clear that IGRAs and TST are measuring the same pool of immunological effector cells and further analysis of the underlying immunology is required.
- Test reproducibility should be addressed in studies of serial examinations of infected individuals. Apparent reversion of positive infection is known to occur in a small number of individuals but the meaning of this reversion is unclear.
- Similarly, there is a need to define the comparative sensitivity of TST and IGRA assays in different populations.
- IGRAs are of some value in diagnosing active TB but should NOT replace appropriate microbiological and molecular investigation. IGRAs have no benefit in known pulmonary TB cases with bacteriological/molecular confirmation.
- Studies have shown a variable but generally high sensitivity (75-97%) of IGRA. The sensitivity may be slightly reduced by active disease, as TST is reduced by anergy in severe disease.
- The specificity is very high (90-100%, where there is no evidence of previous active TB). IGRAs do not cross-react with BCG but cross-react with a small number of non-tuberculous mycobacteria.
- IGRAs would have the greatest potential benefit in the diagnosis of TB in cases that are difficult to diagnose, such as children, immunocompromised patients such as HIV-positive individuals, and in cases of extra-pulmonary TB (especially TB meningitis).
- There is evidence for the usefulness of IGRAs to diagnose active TB in children and HIV-positive individuals, but little for diagnosing extra-pulmonary TB at this time.
- Overall, both tests perform similarly but the T spot may be more sensitive in HIV-positive and severely immunocompromised individuals and has fewer indeterminate results. However, this may be due to the current cut-offs used for these tests (see future work). Conversely, the Quantiferon assay is easier to perform and is less time-sensitive.
The group felt that further work was needed in the following areas:
- More carefully designed head to head studies are needed in general, particularly for groups that are hard to diagnose (children, HIV-positive and other immunocompromised individuals, and those with extra-pulmonary TB, particularly TB meningitis).
- Analysis of cut-offs used in both assays and consideration of different cut-offs for different patient groups is needed.
- The reproducibility of the test should be addressed by a series of repeated or sequential examinations of patients and exposed persons.
There is a place for IGRAs in the diagnosis of both latent infection and active TB; their use should be carefully considered in relation to the likely value to the individual and to the public good.
- Pai M, Riley LW, Colford JM, Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis. 2004;4(12):761-76.
- 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 Mar 6;146(5):340-54.
- 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 Infect Dis. 2007 Jun;7(6):428-38.
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- Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, Drobniewski F, Lalvani A. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess. 2007 Jan;11(3):1-196.
- Mazurek GH, Jereb J, LoBue P, Iademarco MF, Metchock B, Vernon A. Guidelines for Using the QuantiFERON-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States. MMWR Recomm Rep. 2005 Dec 16;54(RR-15):49-55. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm
- Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. Clinical Guideline 33, National Institute for Clinical Excellence, London 2006.
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