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

We read with interest the recent pulmonary perspective by Luca Richeldi about the use of blood tests for the diagnosis of tuberculosis infection (1). Richeldi reviews the evidence suggesting that tests based on in vitro release of IFN- in response to Mycobacterium tuberculosis region of difference 1 (RD1)-antigens, in particular those based on the enzyme-linked immunospot (ELISpot) technique, may be more sensitive than the tuberculin skin test (TST) for the diagnosis of tuberculosis infection. He also argues that routine use of these tests may result in short-term increased costs due to more diagnosis of and treatment for tuberculosis infection. In our opinion, if the preliminary evidence on ELISpot sensitivity is confirmed, other issues, besides that of costs, need also to be addressed before replacing TST in screening programs for latent tuberculosis with more sensitive blood tests.

Lord and coworkers recently analyzed the level of evidence needed to accept a new diagnostic test in routine practice (2). These authors argue that when a new test is more sensitive than an old one, the extra cases detected by the new test may represent a different spectrum of disease compared with those detected by the old test. Thus, the information about the effect of treatment of cases diagnosed by the old test may not necessarily apply to extra cases detected by the new test. The recent paper by Ewer and coworkers (3) suggests that new blood tests for tuberculosis infection may indeed produce a shift in the spectrum of infection detected. These authors identified 14 students who were TST-negative and ELISpot-positive among contacts in a school tuberculosis outbreak. None of them received preventive therapy, and seven became ELISpot-negative during follow-up. In contrast, no change in ELISpot response was observed in the ELISpot-positive, but untreated TST-positive staff. The authors suggested that individuals who were ELISpot-positive only may have been infected with a lower dose of M. tuberculosis, insufficient to induce a cutaneous response to PPD.

Available data on the benefit of treatment of latent tuberculosis infection are based on trials using TST-positive individuals (4). It remains to be demonstrated that a similar benefit could be found in TST-negative individuals who are positive to IFN- tests. Before routine administration of preventive therapy to these individuals is implemented, more natural history data, and ideally a clinical trial comparing the incidence of tuberculosis among those who are treated and those who are not, are needed.

Enrico Girardi, Delia Goletti and Giuseppe Ippolito

Istituto Nazionale per le Malattie Infettive, "L. Spallanzani" –IRCCS, Rome, Italy

FOOTNOTES

Conflict of Interest Statement: E.G. is the named inventor on a patent related to T-cell–based diagnosis of tuberculosis filed by the National Institute of Infectious Diseases "L. Spallanzani," Rome, Italy. D.G. is the named inventor on a patent related to T-cell–based diagnosis of tuberculosis filed by the National Institute of Infectious Diseases "L. Spallanzani," Rome, Italy. G.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Richeldi R. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2006;174:736–742.[Abstract/Free Full Text]
2. Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med 2006;144:850–855.[Abstract/Free Full Text]
3. 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]
4. Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Systematic Rev 1999;CD001363.[CrossRef][Medline]

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