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A More Reliable Test For Latent TB - ScienceDaily

Two new interferon-gamma blood test assays to detect latent tuberculosis infection (LTBI) showed customers were exposed to a supermarket employee in Holland who had smear-positive tuberculosis, while traditional tuberculin skin tests (TST) did not, according to a large contact study.

Ailko Bossink, M.D., Ph.D., of the Department of Pulmonology at Diakonessenhuis Utrecht in The Netherlands, and eight associates recruited 785 supermarket customers who had not received BCG vaccine against tuberculosis, the immunizing agent prepared from Calmette-Guéren bacillus. TST results are not accurate in those vaccinated with BCG.

All individuals in the study cohort were recruited from over 20,000 customers who had shopped at the supermarket for more than 10 months. Many had numerous contacts with the infected employee, who had been contagious since February 2004. The large-scale contact investigation began in January 2005.

"One-third of the world's population is believed to harbor latent TB infection, or LTBI," said Dr. Bossink. "Approximately 5 to 15 percent of immunocompetent persons with LTBI will develop TB disease. In countries with a low-incidence of TB, the tracing and targeted treatment of individuals with LTBI constitutes the major pillar of TB control. "

For the study, researchers selected 469 customers randomly on the day that their TST was administered and 316 with a TST result of more than 0 mm.

TSTs are based on a skin reaction to injection, scratching or puncturing the skin with a purified protein derivative of tuberculosis bacterium. Swelling and redness indicate a positive result.

In the new blood tests, two interferon-gamma release assays (IGRAs) measure response to an antigen highly specific for Mycobacterium tuberculosis. One of the blood tests, QuantiFERON-TB Gold, has received approval from the U.S. Food and Drug Administration for use in the United States. The other has been approved for use in Europe.

"Among the 785 study participants, TST results were associated with age, whereas positive interferon-gamma blood test assay results were significantly associated with cumulative shopping time," said Dr. Bossink. "TST results were not associated with any measure of exposure to the index case in the supermarket."

The researchers noted that positive TST responses largely reflected delayed type hypersensitivity due to remote infection with M. Tuberculosis acquired before the source case at the supermarket became infectious.Among the 759 shoppers who had valid results from both interferon-gamma blood assay, slightly over 80 percent (608) were concordant negative with both blood tests, while 72 were concordant positive and 79 were discordant. Overall agreement between the two tests was 89.6 percent.

"Although the interferon-gamma blood tests are now considered more specific and show a better correlation with exposure than TST, it has not been demonstrated whether they provide a valid basis for therapeutic decisions regarding treatment," said Dr. Bossink. "The risk of TB disease in the presence of a positive test result had not been established."

"Notably, positive interferon-gamma blood assays were observed in a significant proportion of recently exposed contacts with a negative TST result," he added. "The clinical significance of this finding merits further study if the blood tests are to replace the TST and be used for therapeutic decisions."

In an editorial on the research in the same issue of the journal, Madhukar Pai, M.D., Ph.D., and Dick Menzies, M.D., M.Sc., of McGill University in Montreal, Canada, wrote:

"The key question is whether the two new IGRAs are better than the TST in predicting the development of TB disease, and thus identifying persons who will benefit most from latent TB infection (LTBI) therapy. There is abundant evidence, from numerous large-scale cohorts and randomized trials, regarding the prognosis of untreated persons with positive TST results; this remains the greatest advantage of the TST."

"What is urgently needed is similar longitudinal studies of cohorts who have been tested with IGRA (ideally both IGRAs) and the TST," they continued. "However, in almost all low-incidence, high-income countries, it would be ethically impossible not to treat persons with evidence of LTBI. Moreover, in high-incidence countries, where treatment of LTBI is not the current standard of care, it would seem unethical to test for a condition without plans to offer appropriate treatment."

"However, this should not be a problem. Almost everyone would agree that individuals with concordant positive TST and IGRA are likely to have LTBI and they will never inform the question as to which test predicts active TB better. Thus, such patients can and should be managed appropriately. However, individuals with discordant results (TST+/IGRA- or vice versa) will be informative regarding the risk of development of active disease without treatment. In addition, because the clinical interpretation, and therefore management is unclear for persons with such discordant results, equipoise exists. Therefore, close observation without treatment is reasonable and ethical."

Reference:  Second issue for March 2007 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

New Tuberculosis Blood Test Is Useful Tool, If Used With Care

The newly introduced Interferon-Y release assays (IGRA) is a new group of blood tests that offer many operational advantages over the conventional tuberculin skin tests (TST) -- particularly in the diagnosis of latent tuberculosis (TB).

An editorial published in Respirology by Wiley-Blackwell discusses the role of IGRA in the diagnosis of TB and brings attention to the potential caveats in the application of these new tests.

"IGRA offers many advantages over TST, such as completion of tests in one visit, availability of results within 24 hours, absence of inter and intra-divergence, ability to detect potential immonu-depression and the avoidance of the booster phenomenon. However, their current cost and the need for delivery of fresh blood limits the feasibility of large-scale application in most TB-endemic areas," said author Professor Chi Chiu Leung of the Tuberculosis and Chest Service, Department of Health, Hong Kong.

TB is an ancient disease that remains a major killer in many parts of the world. It is estimated that one out of ten infected immuno-competent individuals will develop the clinical disease in his or her lifetime.

The ultimate purpose of screening for TB infection is to prevent the onset of the disease. Unfortunately, none of the existing tests for TB infection can distinguish between latent infection and active disease.

"While it is generally difficult to interpret a positive test in TB-endemic areas, IGRA may still play an important adjunctive role for the diagnosis of active TB in children. The new tools offer significant advantages over TST, especially in setting with widespread BCG vaccinations after infancy or revaccinations." said Professor Leung.

He added, "With the various intrinsic limitations present in IGRA, added care should be exercised in the application and interpretation of the new tools. Further studies are required to provide definitive answers and allow these new tools to be applied more effectively."

This paper is published in the January 2009 issue of Respirology (Vol. 14, Issue 2).

TST Test Fails To Accurately Diagnose TB In HIV+ Pregnant Women

A new study finds that the most commonly used test for tuberculosis fails to accurately diagnose TB in up to 50 percent of pregnant women who are HIV+. The research published early online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine is believed to be the first study to compare the accuracy of two TB tests - the Quantiferon Gold In Tube® blood test and the more commonly used TST or tuberculin skin test - in this population. The study "Quantitative IFN-?, IL-2 Response and Latent Tuberculosis Test Discordance in HIV-infected Pregnant Women" is also the first study to examine pregnancy's effect on the body's response to TB. 'Over-reliance on TST test means that we are failing to detect and treat a potentially life-threatening infection in tens of millions of high-risk women.' The researchers' aim in this study was two-fold:

(1) to assess the accuracy of TB tests in diagnosing a highly contagious and world-wide public health scourge in patients who are doubly at risk and

(2) to find a method to identify which women carrying latent TB infection are most likely to develop active TB. In latent TB the individual is infected but does not show any symptoms.

Some individuals with latent TB go on to develop active TB --the form of the disease that causes symptoms in the carrier and transmission to others. While a healthy, functioning immune system can keep the infection in check, pregnancy and HIV infection, which compromise the immune system, increase the chances of developing active TB. Therefore, there is a critical need to improve diagnosis.

"The World Health Organization and many governments endorse the TST because it is a cheap and ubiquitous test," said lead study author Jyoti Mathad, MD, MSc, Instructor of Medicine in the Center for Global Health at Weill Cornell Medical College. "However, our over-reliance on this single test means that we are failing to detect and treat a potentially life-threatening infection in tens of millions of high-risk women. We found that QGIT positivity was almost three times higher than the more widely used TST at every time point tested," noted the authors.

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Dr. Mathad and her colleagues enrolled 252 women who were in their second or third trimester and receiving care at a public teaching hospital in India. The women received TB testing at enrollment during pregnancy or at delivery. An additional 39 women participated in a longitudinal study to assess how the TB tests were affected by changes in different stages of pregnancy. They were tested at delivery and three months postpartum. The researchers also collected blood samples to assess for levels of infection-fighting proteins.

"Our blood data suggests that pregnant women produce lower levels of the immune chemicals that many TB diagnostics look for. This finding has implications beyond diagnostics," said Dr. Mathad. "For example, not all pregnant women lose immune control of TB infection. But, currently we have no way of predicting which women are most likely to get sick from the disease. Our findings about these immune chemicals provide a starting point for developing a test that will tell us who in this already high-risk population is at greatest risk of disease and death and is in most need of treatment." She added that this insight about indicators of risk would also benefit other high-risk groups such as the elderly, young children and all people who are HIV positive.

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In terms of the broader significance of their findings, the researchers would welcome a greater effort to include pregnant women in future medical studies. "Pregnant women have been excluded from all 40 trials of new TB drugs that are ongoing today," said Dr. Mathad. "Some of the caution is justified, but, oftentimes, it is simply the path of least resistance. This habit - and habit is all that it is in many cases- exacts a toll on women worldwide. Pregnant women often get stuck taking longer regimens of outdated drugs due to a lack of research."

Source-Eurekalert

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