By Sharon Kingman

BioWorld International Correspondent

LONDON ¿ A simple new blood test that accurately and rapidly detects people with latent tuberculosis infection could help to eliminate this disease from industrialized countries, the researchers who developed it predict.

The University of Oxford, in Oxford, UK, will shortly be spinning out a new company to manufacture and market the test, which is protected by several international patents.

Ajit Lalvani, clinical lecturer in infectious diseases in the Nuffield Department of Medicine at the university, told BioWorld International, ¿This new test is very sensitive and highly specific. All the evidence to date points to it being much more accurate than the existing skin test. It could make a huge difference to clinicians who will receive much more accurate results, which will allow them to say for certain whether someone is infected or not.¿

The test makes it possible, for the first time, to distinguish between people who have been vaccinated with BCG but are uninfected, and those with latent infection.

Lalvani is the lead author of a paper in the Lancet that reports on a clinical evaluation of the test, titled, ¿Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells.¿ The work was carried out with colleagues in Oxford and other centers in the UK.

In developed countries, where the prevalence of tuberculosis is low, the key strategy for controlling the disease is to identify and treat those who have recently become infected. This is difficult because not all infected people go on to develop symptoms and signs of the disease. A person who has recently acquired the infection by contact with someone who has tuberculosis has a 10 percent risk of developing active tuberculosis during his or her lifetime, and 5 percent of this risk occurs during the first two years. So a healthy person who acquires the infection has a 1-in-20 chance of developing active disease in the first two years. Those who do are likely to go on to infect others.

If people with latent infection can be identified and treated early, the chain of infection can be broken. Unfortunately, conclusive identification is difficult. The only test available to date, known as the tuberculin skin test (TST), was invented 100 years ago. It involves injecting a crude mixture of 200 different tuberculosis proteins into the skin and measuring the size of the inflammatory response three to seven days later.

Lalvani explained, ¿These 200 proteins are shared between Mycobacterium tuberculosis, the BCG vaccine and a range of nonharmful environmental Mycobacteria that people are commonly exposed to. So it is not a very specific test and often gives false-positive results in BCG-vaccinated people.¿

Earlier this year, Lalvani and colleagues reported in the American Journal of Respiratory and Critical Care Medicine that they had developed a method of detecting cells that were responding to a protein found only in M. tuberculosis, called ESAT-6. In someone who has encountered M. tuberculosis, T cells will be present that, when presented with ESAT-6, respond by producing the cytokine interferon-gamma. The new test detects these cells, using the method known as the ex vivo enzyme-linked immunospot, or ELISPOT.

The data presented in that paper showed that the test was positive in 45 (96 percent) of 47 people known to have tuberculosis and in 22 of 26 people suspected of having latent infection because they were household contacts of someone with tuberculosis and had a positive skin test. Lalvani added, however, that the four people who tested negative may have represented uninfected people with false-positive skin tests.

To prove conclusively that the ELISPOT test was a more efficient way of detecting latent infection than the skin test, a study with a different design would be needed, since there is no gold standard test of latent tuberculosis infection. ¿A key factor,¿ Lalvani said, ¿in determining whether you get infected when exposed to an infectious case is the amount of time spent sharing room air with that person. So we went to a contact tracing clinic and identified a series of 50 people with varying, well-defined levels of exposure to tuberculosis.¿ These patients were assigned into four categories of exposure: heavy, moderate, mild and none.

Lalvani and his colleagues then postulated that their assay should be more closely correlated with the level of exposure to tuberculosis than the skin test. Their results show that their hypothesis was correct: the ESAT-6 ELISPOT assay results were significantly more strongly correlated with intensity of exposure to tuberculosis than were TST results. In contrast to the skin test, ELISPOT results were independent of BCG vaccination status.

The researchers are now awaiting results of studies involving more than 2,000 people in the UK, South Africa and India. Lalvani said the test would be of most use to countries with a low prevalence of tuberculosis, where stopping the chain of infection by detecting latent infection is a cornerstone of tuberculosis control.

The group has recently simplified the test to allow it to be used in hospital diagnostic laboratories.

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