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Should Individuals Who Are Tuberculin Skin Test Negative and Positive to RD1–IFN- Assay Receive Preventive Therapy?

We thank Girardi and colleagues for their letter and comments on our recent article (1). They have posed a cogent question: how should we manage tuberculin skin test (TST)–negative individuals who are positive by RD1-based IFN- blood tests?

Current European guidelines, of which those published by the U.K. National Institute of Clinical Excellence (NICE) in March 2006 are the first example (2), recommend use of the new blood tests in (1) individuals at risk of latent tuberculosis infection (LTBI) who have tested positive by TST and (2) individuals in whom the TST is unreliable (i.e., those with cellular immune suppression who commonly produce false-negative TST results). In contrast, current U.S. guidelines suggest up-front use of a blood test in all groups (3). Thus, in Europe, if guidelines are followed, TST-negative, IFN- blood test–positive individuals should only be identified among immunosuppressed populations.

In the absence of a gold standard of asymptomatic Mycobacterium tuberculosis infection, it is difficult to ascertain whether a TST-negative, IFN- blood test–positive result represents M. tuberculosis infection. However, the high sensitivity of the ELISpot blood test, and its robustness to cellular immune suppression (4–7), means that people with recent TB contact who have suppressed or immature (i.e., infants) immune systems and test TST-negative but ELISpot-positive are likely to have false-negative TST results and should be considered to be infected. The high risk of progression to TB disease in such individuals requires clinicians to have a low threshold for diagnosis and treatment of LTBI. These attributes of ELISpot were, we presume, the basis for the recommendation by NICE to use blood tests up front in these vulnerable groups. Our recent article exploits the high sensitivity of ELISpot to expand our understanding of the natural history and biology of TB exposure and infection (1). We found indirect evidence that a minority of immunocompetent recent TB contacts who were TST-negative, ELISpot-positive at screening may have a self-resolving infection with M. tuberculosis. If this is the case, they should have no forward risk of progression to TB disease, but long-term follow-up of large numbers of such contacts would be required to confirm this.

It is important to remember that only a small proportion of TST-positive TB contacts progress to active TB (approximately 5% over 2–5 yr) and the majority of TST-positive contacts who receive preventive therapy would not in any case have progressed to TB. Therefore, just as with TST, there will be ELISpot-positive contacts who will benefit from preventive therapy and others who will not. The key determinant of net treatment benefit will be the overall population risk of progression to TB disease in ELISpot-positive contacts, just as with TST. This is why natural history studies with hard clinical outcomes (i.e., development of TB) are urgently required and have been called for by the World Health Organization, NICE, and the Centers for Disease Control and Prevention.

In the meantime, we believe that European guidelines, as first embodied by NICE, represent a sensible compromise regarding deployment of new blood tests, until the prognostic power of these tests in recent TB contacts is elucidated.

Ajit Lalvani, Kerry Millington and Katie Ewer

Tuberculosis Immunology Group, National Heart and Lung Institute, Wright Fleming Institute of Infection & Immunity, Imperial College London, London, United Kingdom

FOOTNOTES

Conflict of Interest Statement: A.L. is the named investigator on several patents related to T-cell diagnosis filed by the University of Oxford. Regulatory approval of ELISpot has been undertaken by Oxford Immunotec, in which A.L. is a shareholder and to which he acts as a scientific advisor. K.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.E. is a named inventor on a patent application relating to the use of the RD-1–based ELISpot assay.

REFERENCES

1. Ewer K, Millington KA, Deeks JJ, Alvarez L, Bryant G, Lalvani A. Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis. Am J Respir Crit Care Med 2006;174:831–839.[Abstract/Free Full Text]
2. National Collaborating Centre for Chronic Conditions. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: Royal College of Physicians; 2006.
3. 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;54(RR-15):49–55.[Medline]
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