Arnaldo Rolon fidgets with the pill box lying open on the kitchen table in his apartment in Spanish Harlem. The box has three compartments for each day of the week: two for the drugs that Rolon takes morning and evening to keep the AIDS virus in check, and one for the tuberculosis medicines that he takes at midday under the eye of public health worker Paul Norero.
"I'm sick and tired of medication," says Rolon, whose elaborate tattoos don't hide the scars on his arms left by past drug use. Norero smiles and listens. Rolon sips a glass of water and begins to swallow the five pills one by one as he talks about his TB.
"I was, like, letting it go for a little while when I started coughing blood. . . . They found it in my chest. I was in the hospital almost six months. They had me locked up in a special room by myself."
Locking someone in a hospital room is sometimes still deemed necessary in 1999 to make sure tuberculosis patients take their medicine. Despite all of medical science's advances, this disease that killed Stone Age hunter-gatherers and Egyptian pharaohs remains one of the world's two deadliest infections. TB kills 1.5 million to 2 million people per year -- almost as many as AIDS. Experts say that toll could increase in the coming years because TB bacteria are evolving dangerous new strains that are increasingly drug-resistant -- especially in cases where doctors prescribe ineffective treatments or where patients fail to take all of their pills.
"If we sit back and allow drug resistance to grow unchecked, we may one day be faced with incurable tuberculosis," said Kenneth Castro, director of the division of tuberculosis elimination at the federal Centers for Disease Control and Prevention.
This could, in effect, return the world to the pre-antibiotic era, setting the stage for a global comeback of the disease.
Smallpox is gone. Polio is going. Diphtheria, measles and cholera are shadows of their former apocalyptic selves, preventable with vaccines or treatable with drugs. It's the end of the 20th century, the moment when the great infectious diseases of the past were supposed to shuffle offstage, making way for the gene therapies, designer drugs and off-the-shelf replacement organs that would conquer heart disease, cancer and Alzheimer's disease during the coming decades, prolonging and enhancing human life.
After all, antibiotics and vaccines -- potent weapons against infections -- have been the crowning achievements of medicine in this century, just as genetic and technological fixes for inherited and chronic illnesses seem likely to be the triumphs of the next. Even AIDS, the new viral plague first recognized less than two decades ago, seems less like a death sentence to many Americans since new drugs widely available in wealthy countries have made long-term survival possible for many patients.
But the microbes that cause AIDS, tuberculosis, malaria and other infectious diseases are not cooperative, stationary targets. They are living organisms, forever evolving to meet new threats to their existence and to exploit changes in their environment. And that environment is us. As we multiply and migrate, cough and take medicines, we are human culture flasks full of bacteria and viruses that are constantly shifting their genetic defenses to survive the weapons we use to fight them.
Survive they have. Despite all of the past century's medical advances, infectious diseases still cause one-fifth of all deaths worldwide, with AIDS and tuberculosis being the biggest killers. The stubborn persistence of TB, a disease that has been curable with drugs for the past half-century, is a testament to the vast distance that lies between finding an effective treatment and delivering it to the people who need it most.
While rich countries pursue ever more costly drugs and medical technologies, people in poor ones continue to die prematurely of diseases that could be cured or prevented with simple and relatively inexpensive treatments. In developing countries, infections are still the major cause of death, and drugs for AIDS, cancer and many other conditions are beyond the means of most citizens. New vaccines such as the ones for hepatitis B and the meningitis-causing bacteria Hemophilus influenzae, which could save millions of lives worldwide, are priced too high for many of the populations that could benefit most. "More than a billion fellow human beings have been left behind in the health revolution," says Gro Harlem Brundtland, director-general of the World Health Organization.
In the case of TB, the yawning health gap between rich and poor could have worldwide consequences. Lacking resources for clinics, laboratories and medicines, governments of many developing countries -- and of some developed ones, such as Russia -- either never established effective programs to treat the disease or let them lapse. Treatment of TB was haphazard and often inadequate, a situation that encourages the emergence of drug-resistant strains of bacteria that can be difficult or impossible to kill. Such a strain can circle the planet in a day and can spread to anyone who breathes the same air as a coughing, infected person. In one recent incident, a woman with drug-resistant TB coughed into the stuffy air of an airline cabin during a transcontinental flight and infected four of her fellow passengers.
The world is growing smaller, but the resurgence of TB could be the event that teaches us just how small it is. "From the point of view of an infectious disease," said Barry Bloom of the Harvard School of Public Health, "there is no place on the planet from which we are removed and no one to whom we are unconnected."
The New York Outbreak
In little more than 100 years, medicine has moved from the discovery in 1882 that tuberculosis was caused by a bacterium to the deciphering, in 1998, of the entire genome for Mycobacterium tuberculosis, the microbe that causes the disease. Researchers discovered the first drugs that killed TB bacteria in the 1940s, and in the decades since, doctors have been able to cure most cases, fueling hope that TB would soon be eradicated.
In the United States, until recently, most people believed the war against tuberculosis had been won. Starting in the 1970s, budget-cutters set about dismantling the nation's TB control programs. But within less than two decades, poverty, a tide of new immigrants, worsening urban crowding, relaxed vigilance by health departments and the AIDS epidemic contributed to a resurgence of the disease.
During the early 1990s, New York City suffered a frightening outbreak of tuberculosis caused by a new strain resistant to all of the standard treatments. By 1992, TB had become more common in central Harlem than in many developing countries -- and in some of the city's hospitals, more than 80 percent of patients infected with the new strains were dying. The resistant microbes spread rapidly in hospitals, homeless shelters, prisons and other places where people lived and worked in close quarters.
City and federal health officials, facing the grim possibility of a return to the pre-antibiotic era, have spent more than $700 million in the last eight years to bring the city's epidemic of drug-resistant tuberculosis under control. They built a state-of-the-art isolation ward at the city jail on Rikers Island. They closed down the biggest homeless shelters. They hired health workers like Norero to track down new cases and to watch TB patients take their medicines, making daily rounds that often included subway stations, bridges, parks and crack houses. They improved city laboratories' capacity to test for antibiotic resistance, and paid for the expensive multidrug regimens required to treat resistant cases of the disease.
The effort appears to have largely worked, and the immediate U.S. crisis has subsided. Yet, even now, some physicians who treat the infection and some scientists who study it wonder whether TB will ever be conquered. The pas de deux danced by the microbe and its human host is more complex and subtle than anyone realized.
In many people, tuberculosis bacteria survive in the lungs for years -- often for a lifetime -- without causing symptoms. But if the infection begins to progress and damage the lungs, a TB sufferer starts to cough, spreading the bacteria to an average of one new person a month. Because the bacteria are particularly adept at evolving resistance to antibiotics, patients must take two to four drugs daily for at least six months to halt the disease's progress. Inadequate or incomplete drug treatment is more dangerous than none at all, because it encourages the development of resistant strains.
Throughout the world, health workers like Norero who watch patients take their daily pills make up the vanguard of the campaign against TB. Such "directly observed treatment, short-course," or DOTS, is highly effective in curing the disease as long as the strain being treated isn't resistant. It is the cornerstone of the WHO's plan for combating tuberculosis.
But wherever TB treatment and control programs are poor, resistant strains continue to appear and spread, including in Russia, Eastern Europe and many other regions. In a study last year, WHO surveyed 35 countries for strains of drug-resistant TB and found them present, to varying degrees, in every one.
Many tuberculosis experts say a strategy that depends on DOTS alone will never suffice to conquer the disease. Beating TB, they say, will require an international effort to find and treat people with drug-resistant infections, as well as the development of better diagnostic tests, new drugs and an improved vaccine.
"The message of WHO should not be that DOTS is the real answer to TB," said Bloom. "It's the best we have . . . but what they haven't emphasized is that what we have is not good enough."
Slow but Steady Survival
In a "hot zone" lab high above the Bronx, half a dozen young scientists swathed in gowns, head covers, masks, rubber gloves and paper booties are playing genetic tricks on TB bacteria. Tuberculosis is highly contagious, so the lab is biosafety level 3 -- equipped with a germ-filtering ventilation system and other safeguards to prevent the microbes from escaping into the outside world.
With their gloves securely taped to their paper sleeves, the researchers dissect freshly killed mice and put the animals' tuberculosis-loaded lungs, spleens and livers into sealed containers. The bacteria growing in the mice's organs are mutants, made deliberately in the lab. The scientists are studying how such mutant strains behave in animals to learn which genes tuberculosis bacteria need to grow and to destroy lungs and other organs.
"This is the first time in the history of the world that we have had independent mutants" of TB, says William Jacobs, a professor of microbiology at Albert Einstein College of Medicine in the Bronx. "We have every gene out there and we don't know which ones are going to be important."
Tuberculosis bacilli evolved from microbes that live in soil, and compared with other disease-causing bacteria, they grow at a glacial pace. Slow, steady growth is part of their survival strategy, but it makes the disease maddeningly difficult to study, diagnose and monitor in the laboratory. It can take as long as 10 weeks, starting with a sample of mucus coughed up by a sick person, to find out whether the patient has TB and is infected with a strain resistant to the most widely used drugs.
At the beginning of New York City's TB outbreak, some patients who were put on standard treatment died before their test results came back showing that they were infected with drug-resistant strains.
Jacobs, who heads the Bronx lab, has devoted much of his career to figuring out what makes TB bacteria tick: which genes they need to infect a host, which ones they need to become resistant to a drug, which ones make a strain more likely to cause severe disease. Such work is key to developing new therapies and a more effective vaccine.
Tuberculosis research is likely to be one of the first fields to benefit from the international effort to decode the human genome, which has spawned projects to decipher the genetic sequences of many other organisms. A laboratory in Cambridge, England, published the complete genetic sequence for one TB strain in 1998, and an American research group at the Institute for Genomic Research in Rockville has almost finished the sequence of a second strain. Now, Jacobs says, when his team isolates and studies a new genetic mutation, "we know exactly where we are on the genome."
Jacobs has developed what he hopes will be a simpler and cheaper way to test TB strains for drug resistance. Dubbed the "Bronx Box," it's a kit holding an array of tubes, each one containing a different antibiotic. The tubes also contain a phage, a virus discovered and modified by Jacobs that can infect TB bacteria and splice a gene for luciferase, the chemical that fireflies use to produce light, into the microbes' DNA.
A sample of the TB bacteria being tested is placed into each tube, and the tubes are enclosed in a dark box containing a square of Polaroid film. If the bacteria are resistant to a drug in one of the tubes, they will grow and make that tube glow, creating a spot on the Polaroid film. The test yields results in as little as 12 days.
These days, Jacobs, who is gradually losing his vision because of an inherited disease, can't always see that faint glow. But his invention may someday make an impact on drug-resistant tuberculosis, both in the United States and in developing countries.
"At the end of the day," Jacobs said, "I'm interested in controlling and eradicating TB. I don't care where that takes me."
The Roles of AIDS and Immigration
In the meantime, the world must depend on the efforts of people such as Norero, who has spent the last two years making daily visits to about a dozen TB patients in tough, drug-infested neighborhoods of Harlem and Washington Heights. The patients on his rounds offer a snapshot of the city's recent history and of the forces that have contributed to TB's comeback.
There's an elderly Jewish man in a tiny apartment who has lived in the Washington Heights neighborhood for decades, and a West African security guard who came to this country 2 1/2 years ago. Several of Norero's patients also have AIDS, which makes people particularly vulnerable to tuberculosis. Others say they were never sick a day until a cough, fever or other symptoms led to the unexpected diagnosis of TB.
In a brick high-rise building with a sweeping view of the East River, Michael Frasier sits dejectedly on a couch, his eyes on the carpet. Frasier, 47, is an emaciated man who answers most questions in monosyllables. He once ran the mail room for a large New York company, but became disabled by AIDS four years ago and more recently developed TB. He spends days with his mother, Thelma Frasier, 72, a forthright woman who has her own perspective on tuberculosis.
"I had TB 47 years ago," Thelma Frasier recalled. "He was only a baby. . . . I stayed in the hospital for more than a year."
Thelma Frasier said she was sent to Sea View Hospital on Staten Island, a sanatorium. Her three small children weren't allowed to visit her. She used to wave to them from the hospital window.
"At that time people were really dying," she said. The first drugs effective against TB had just been discovered; Frasier recalls that doctors gave her streptomycin injections twice a day "for three whole years."
Thelma Frasier's illness was arrested, but it's possible that she transmitted tuberculosis to Michael when he was an infant. It may have lain dormant in his lungs for most of his life, only becoming active when his immune system had been weakened by AIDS. Alternatively, he may have acquired the infection sometime in the last few years.
When New Yorkers such as Frasier are diagnosed with TB, a sample of the bacteria infecting their lungs is often sent downtown to a Manhattan laboratory, where it's chemically processed to produce an image of the bacteria's DNA. The new scientific technique of DNA fingerprinting, often used to track criminals, is proving invaluable for tracking tuberculosis bacteria in communities.
With DNA profiles of TB bacteria from more than 10,000 patients stored on computers in his Manhattan laboratory, Barry Kreiswirth of the Public Health Research Institute is helping health departments in New York City and New Jersey trace patterns of the disease's spread.
"When you look at a place like New York, which is a melting pot, you see these remnants of migration of people," Kreiswirth said. When he investigated recent TB cases in New Jersey, one strain showed up in elderly African American men who had lived in Patterson all their lives, while a different strain prevalent in the Far East was found in recent Asian immigrants.
As people become more mobile, TB control programs can no longer stop at national borders. In 1997, 40 percent of new tuberculosis cases in the United States were in people born in other countries, compared with 22 percent a decade earlier.
Tuberculosis was supposed to have been vanquished in this century. Whether it will be defeated in the next depends on a kind of medical arms race. On one side are scientists, doctors and public health workers, hurrying to track down new cases and to develop better tools for diagnosing and treating the disease; on the other are the hardy TB bacteria with their penchant for evolving new drug-resistant strains. Some observers are hedging their bets.
"The bug has a very clever way of coexisting" with the human species, said Kreiswirth. "It's infected one-third of the [world's] population, yet it still hasn't wiped us out. It's always spy versus spy -- and unfortunately, my perception is, the bug always wins."