"We need every tool we can in our armory against tuberculosis, and as this test enters clinical practice, this offers a real hope to conquer this disease," researcher Ajit Lalvani, an infectious disease physician, told United Press International.
Archaeological evidence from the spines of Egyptian mummies reveals the germ has ravaged humanity for at least 5,000 years. The father of medicine, the Greek Hippocrates, noted that TB was the most widespread disease of his time. Among the famous tuberculosis has killed over the years are George Orwell, Eleanor Roosevelt, Franz Kafka and Anton Chekhov.
The pale skin and red lips brought on by tuberculosis were later romanticized in Puccini's La Boheme and other 19th century works of art, as well as with accounts of the legendary gunslinger Doc Holliday of the Wild West -- where the gambler's appearance stood in sharp counterpoint to his devil-may-care attitude. At the time of the famous shoot out at the OK Corral involving Holliday, one out of seven reported deaths was caused by tuberculosis. The germ killed more people in history than the Black Death or leprosy with 1 billion dead worldwide in the last two centuries alone.
In the middle of World War II, scientists finally introduced a medicine powerful enough to rescue tuberculosis victims, the antibiotic streptomycin. In successive decades more drugs have been brought into service against the disease but a staggering 2 billion people -- a third of the world population -- are still infected with the airborne infection. While many harbor the germ Mycobacterium tuberculosis without symptoms, each year 8 million people worldwide develop active TB, with the bacterium killing someone once every 15 seconds.
One of the challenges in the eradication of the disease is eliminating the dormant reserves of the germ lurking in the unsuspecting populace. The drugs for killing tuberculosis when it's dormant work very well, Lalvani explained, but the problem is identifying who really has it.
"When it's dormant, the person who has it is indistinguishable from normal people," Lalvani said. Doctors also don't want to just give such drugs indiscriminately in an attempt to prevent any outbreaks, because they can damage the liver and even have lethal side effects.
The main roadblock to hunting dormant TB down is the existing skin test, "the oldest diagnostic test still in use in clinical medicine. It's inaccurate and cumbersome, but nobody's been able to develop a better one until now," Lalvani said.
This 100-year-old test involves sticking a crude extract of some 200 proteins from dead tuberculosis bacteria into the skin. If a person were already infected with tuberculosis, his or her immune system would recognize traces of the intruder and react. Three to seven days after getting this exam with the "tuberculin" extract, patients are supposed to return to the physician, where they have their pricked skin measured for a bump with a ruler.
The problem is tuberculin can also raise a skin bump if a person was vaccinated against tuberculosis with Bacillus Calmette-Guerin, or BCG, named after the French scientists who developed it from weakened cow tuberculosis. "In these 200 proteins, that mixture is widely shared between the TB bacterium and the BCG vaccine. That means if you have the BCG vaccine like most of the world, you may well come up falsely positive," Lalvani said.
Lalvani and his team developed an experimental new blood test for tuberculosis in 1998. In findings appearing April 5 in the medical journal The Lancet, when the researchers employed it against the largest tuberculosis outbreak in Britain since World War II, they found the test was significantly more accurate at detecting hidden TB than the old skin-prick test. Moreover, it can be automated so "you can get a result the next morning," he explained. "It's a 100-year upgrade."
"It's not like you take a ruler and measure the size of a bump on the skin. Give four doctors and four nurses a ruler, and they all come up with different results. And then people have to come back and have it read. Some 30 to 50 percent never do. These are healthy and busy men and women who don't want to leave work," Lalvani said.
Conventional diagnostic tests for diseases look for antibodies, the proteins the body releases to flag potential intruders. "In TB infection, you only have a very feeble antibody response, so feeble that you could not test for it," Lalvani said.
While dormant TB bacteria can hide inside white blood cells lining the lungs, where it can incubate for up to 40 years, they still make proteins, which find their way to the surface of the white blood cells. Immune defenders found in the bloodstream called T cells recognize these proteins, and serve as the crux for the new test named ELISPOT, or enzyme-linked immunospot, the first T-cell based diagnostic test in clinical medicine.
Medical specialists administering the exam take a sample of blood and put it into a dish coated with antibodies and containing a solution of two tuberculosis-specific proteins. If the patient has tuberculosis, the T cells in his or her blood will react to the proteins and pump out a defensive compound called interferon gamma. The antibodies lining the dish are specific to interferon gamma and latch onto it. The blood is then washed off leaving the interferon gamma. Another solution containing a different set of interferon-gamma-specific antibodies is added. This second group of antibodies, linked to a dark blue dye, latches onto the first set of antibodies marking them with color.
"You can literally see the footprints of TB-specific T cells if there are any," Lalvani said.
The researchers used their novel test alongside the old tuberculin exam in Leicestershire, Britain, in February 2001, when 1,128 students were screened for TB after one student developed full-blown tuberculosis. "It was an absolutely huge outbreak. It accounted for over a quarter of all pediatric tuberculosis in the U.K. that year. About a third of the school was infected," Lalvani said.
Children who spent more time near the student with active TB, such as those in the same class, were significantly more likely to test positive with ELISPOT than with the skin test. ELISPOT also did not register any false positives with vaccinated students.
"The results are very interesting. It is very sound work and convincing evidence," pulmonologist John Murray, professor emeritus at the University of California at San Francisco, said from Paris. "The place we have to go from here is not in Leicestershire, but in the developing countries of the world, where BCG has been very widely used."
Lalvani added that investigators should follow people tested with ELISPOT over the long term to see if they develop active TB. In addition, the research team wants to see if ELISPOT works well with those with weak immune systems, such as organ transplant recipients and newborns. Of especial importance, Murray noted, was testing it with HIV-infected patients.
"HIV is the probably the most important driving force behind the resurgence of TB in the world," Murray said. As the immune system-crippling virus spreads in developing countries, "the likelihood of getting TB goes up six to 10 times if you're HIV positive."
Lalvani is already collaborating with scientists in South Africa, Zambia, India, Turkey, Italy, and the U.S. National Institute of Health and elsewhere to work with ELISPOT. "We are using it," added tuberculosis expert Peter Barnes, the director of the Center for Pulmonary and Infectious Disease Control at the University of Texas Health Center at Tyler.
(Reported by Charles Choi, UPI Science News, in New York.)
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