dm01.jpg (12405 bytes)Tuberculosis thrives again, just a plane ride away
So recently after the events of September 11th, the illustration for this month’s Disease Management section seems eerily prescient. Airplanes can be a powerful vector of airborne infectious disease, and we wanted to depict that public health threat in a world where physical borders are no longer effective barriers.

Unfortunately, the message about the dangers of angry intruders, capable of wreaking havoc inside this country, has been all-too-aptly demonstrated recently. There may even be similarities in how we should confront the two. In this section, we discuss some of the options for fighting back on the infectious disease front, but I’ll leave the other to the policy experts in Washington, D.C.

— Coleen Curran

While the rate of tuberculosis (TB) is exploding in other countries, its incidence in the United States is it at record low levels. So why are public health officials here still not sleeping soundly at night?

Three reasons. It’s a small world with a lot of big planes; TB is caused by an airborne bacteria; and it’s growing resistance to our first- and second-line antibiotics is downright frightening.

Despite the record drop of U.S. TB cases, recorded at just 16,377 in 2000, the deadly infectious disease grows stronger overseas due to new antibiotic-resistant strains and the many more people living with compromised immune systems. TB is now among the world’s top three infectious diseases, right behind malaria and AIDS. It infects about two billion people — one-third of the world’s population — and annually kills an estimated 2 million, mostly in developing countries. Researchers believe 70 million people will die of TB between now and 2020.

“If not controlled, the rise of TB will have a major effect on all countries,” says Nanibhushan Dattagupta, Ph.D., president and co-founder of Applied Gene Technologies in San Diego. “No human being will be isolated from this infection because we travel so much.” To protect the United States, the Centers for Disease Control and the World Health Organization have asked the United States to focus on lowering the world’s TB rate, most prevalent in Africa, Asia, Eastern Europe and Central America.

Heeding the call this summer, Congress introduced a Stop Tuberculosis Now Act, which would amend the Foreign Assistance Act of 1961 by making TB control a national priority and authorize a spending increase for international efforts to curtail the disease. “It will be impossible to control tuberculosis in the U.S. until we control it worldwide,” said Hawaii Sen. Daniel Inouye. Hawaii routinely has among the highest TB rates in the U.S. because of its gateway location for immigrants. “Virtually every international airport in the U.S. therefore is a port of entry for carriers of tuberculosis,” he says.

TB, called “arguably the most successful pathogen on the planet” by William Jacobs, a researcher at Albert Einstein College of Medicine in New York, is caused by one smart bacterium. At the turn of the 20th Century, nearly everyone who developed the disease died from it. Patient isolation in sanitariums came into vogue. At one point, TB was the leading cause of death in the United States.

The discovery of powerful antibiotics in the 1940s helped stem the tide of TB deaths and promised to eliminate the disease. But the TB vaccine, Bacille Calmette-Guerin (BCG), developed 80 years ago, turned out to be no match for the powerful, mutating Mycobacterium tuberculosis that causes the disease. “BCG vaccine is unable to protect the way it could protect us 30 years ago,” says C. Nagaraja Sridhar, Ph.D., vice president and co-founder of Applied Gene Technologies. “It survives long after the vaccine dies. It somehow camouflaged itself from the BCG vaccine.” It can lurk dormant in the body for decades. With the emergence of AIDS in the 1980s, stronger more drug-resistant strains of TB made a worldwide comeback. HIV-positive patients infected with the airborne bacterium are 800 times more vulnerable to developing TB, according to the San Francisco TB Clinic.

The 3,000 or so droplets released by a single cough from a TB-infected person makes it easy for the airborne bacteria to invade new victims. A normal human immune system usually kills the M. tuberculosis and only 5 to 10 percent of those infected develop TB. In those with a weakened immune system, it colonizes in the lungs. Symptoms include persistent cough, weight loss, fevers, night sweats and fatigue or weakness. It also triggers an overactive immune response, which is not fully understood, causing damage to the lungs, respiratory failure and death.

Antibiotics to treat TB are fairly inexpensive, but they must be taken for up to six months. Unfortunately, many patients discontinue their medication when symptoms disappear. This allows the bacterium to survive. To combat this, a new TB protocol, DOTS, (Directly Observed Treatment, Short Course) was developed. It involves clinicians directly observing patients taking their medications and finishing treatment. The drugs cost from $10 to $15. The strategy has improved cure rates by up to 50 percent and has reduced drug resistance. But only one-fourth of the world’s active TB patients are now treated using the DOTS method. The Stop Tuberculosis Now Act would increase foreign aid to this program up to $200 million by next year.

The genome sequencing of M. tuberculosis in 1998 revealed 4,000 genes and reinvigorated TB research. “There is a lot of hope because of the genome sequencing,” Sridhar says. The sequencing inspired pursuits for stronger vaccines along with faster, cheaper diagnostic tests and better drug therapies.

The TB problem is exacerbated by the cost of diagnosis, says Dattagupta of Applied Gene Technologies, which is developing a fast, cheap and easy TB test. “In developing countries, diagnosis still costs more than the antibiotics to treat TB. The majority, 80 percent of cases, can be cured very easily. The six-month therapy costs about $11. The diagnosis costs more than that.” Without an early diagnosis, the patient has a very good chance of infecting others, Dattagupta says. With early diagnosis, patients can be cautioned and treated. Time is of the essence with the new strains of TB, which can take just months to kill. Some countries, too poor to pay for diagnostic tests, treat only the symptoms. “That is dangerous,” Sridhar says. “There are severe side effects. TB in newborns is very bad. Side effects of treatment can kill a baby.”

Applied Gene Technologies is a year away from marketing a diagnostic test that requires no electricity to run, a tremendous benefit in developing countries. The company is using its proprietary platform, Tessera Array Technology (TAT), to develop nucleic acid probe tests for infectious diseases and cancer. A sample of sputum is analyzed with a TAT assay to diagnose TB, and results are reported within an hour.

Gen-Probe, also in San Diego, developed the first test of its kind to diagnose TB in one day. The test is marketed to industrialized nations such as Germany, which is seeing its TB rate escalate due to immigration. Vivian Jonas, marketing manager at Gen-Probe, helped develop the test using Transcription Mediated Amplification done in a clinical lab.

“The benefit: In a single shift a result can be reported out the same day or the next day, to minimize spread,” Jonas says. Prior to the Gen-Probe test, TB was diagnosed with a culture, which can take two to eight weeks; an X-ray; or a smear for acid-fast bacillus, the most commonly used test outside the U.S. “It’s very quick, but it’s not specific,” she adds.

The market for new TB drugs, vaccines and diagnostic tests is not lucrative because most patients are poor. The Gen-Probe test, on the market since 1995, is sold to clinical labs in Europe, Japan, the United States and Canada. “It’s too expensive to be used in third-world markets,” Jonas says.

Despite the bleak statistics, there’s reason to believe that the torrent of AIDS and TB deaths in the 1980s has caused industrialized countries to take notice of the worldwide problem. Private grant programs and governmental-sponsored research are reportedly on the increase.

“The global epidemic of TB threatens all peoples, including Americans,” says Sen. Inouye, the lead sponsor of the Stop Tuberculosis Now Act. “We can no longer remain complacent. We must make every effort to stop this disease.”

Lori Tighe is a freelance writer based in Timonium, Md.