Hunting for the Hidden Killers

By WALTER ISAACSON

They could not afford to jump to conclusions--any conclusions. Their only hope was to be grindingly, interminably thorough. Otherwise, they could pursue a course of investigation for hours or days, only to find it ended nowhere.

--The Andromeda Strain by Michael Crichton

The enemy is always time--an agonizing reminder of the suffering that can result from staying one step behind an elusive killer. At the outset of each new inquiry, they may not even know the description of their quarry, but its power is often all too evident. Along with old-fashioned legwork and intuitive insights, the specialists use the latest in scientific technology to compile and compare clues about nature's threatening puzzles. Such is the work, such is the mission, such are the stakes for America's disease detectives, whose special calling it is to track invisible killers, to identify mysterious illnesses that erupt from nowhere to menace life and health. Today an elite cadre of these experts--pathologists and epidemiologists, assisted by a larger army of lab technicians and doctors--are coordinating their skills in an effort to conquer a new threat: Acquired Immune Deficiency Syndrome, the confounding killer known as AIDS.

As of last week, there were 1,641 victims of AIDS, including 644 deaths, since it was first identified as a disease in the U.S. two years ago. Each month an average of 165 new cases is reported. The largest concentration of victims is in New York City (732 cases, 284 deaths). San Francisco has the next largest outbreak (160 cases, 54 deaths), followed by Los Angeles (100 cases, 40 deaths). AIDS is spreading, albeit slowly, to other nations; 122 cases have been reported in 17 countries.

AIDS attacks its victims by knocking out the immune system, thus leaving them defenseless against a host of "opportunistic" infections. A rare form of cancer or pneumonia becomes a deadly invader, but so does a fungus or a common virus. Thus far, there is no cure for AIDS and its source remains unknown. "We've looked at a lot of suspects," says Dr. Anthony Fauci of the National Institutes of Health (NIH), "but we have not come up with enough grounds for an indictment."

Asking questions. Hunting for clues. Testing theories. Hitting blind alleys. Asking more questions. The assault on the mystery of AIDS is a prime example of how disease detection works. The foundation has been laid by epidemiologists who have carefully analyzed the spread of the disease. So far, 75.9% of the victims in the U.S. have been active homosexual men, 16% intravenous drug users, 5% immigrants from Haiti, and 1% hemophiliacs. Only 96 victims so far are not known to be members of one of these risk groups. More than 90% of the victims are males between the ages of 20 and 49; young people account for just 1.3%. One cause for concern is that the incubation period of AIDS may be anywhere from six months to three years, and many people may have the disease without knowing it.

The outbreak of an epidemic* can provoke a primal panic by raising the specter of a rampant "Andromeda strain." Indeed, perhaps the most severe side effect of AIDS has been the largely unwarranted hysteria that has accompanied the syndrome (see following story). In order to allay fears that AIDS is widely contagious, Secretary of Health and Human Services Margaret Heckler last week visited the Warren Magnuson Clinical Center in Bethesda, Md., where she shook hands with AIDS victims and sat at their bedsides. Said Heckler: "What's just as bad as the disease is the fear of the disease. The fear has become irrational." Explains Dr. James Curran, head of the AIDS task force at Atlanta's Centers for Disease Control (CDC): "For a person not in a known risk group, the risk is not only minimal but likely to remain minimal. It apparently is not spread through routine contact or through respiration, like the flu." Indeed, none of the hundreds of health-care workers who have treated patients have been infected by AIDS.

Nevertheless, Heckler stressed to the patients that "AIDS is our No. 1 health concern and the epidemic is our No. 1 priority." Her department, which includes CDC and NIH, is spending $14 million on AIDS research this year and requesting $12 million more. Some gay activists have charged that the Reagan Administration is neglecting AIDS because it primarily affects homosexuals. (In fact, the money allocated to AIDS research so far is greater than the $20 million spent over eight years on toxic shock syndrome and Legionnaire's disease.) Heckler's department also publishes a biweekly bulletin reporting the findings of researchers; next week it will start operating a toll-free hotline (800-342-AIDS) to answer questions about the syndrome.

American health officials once dreamed of eliminating infectious diseases, at least in the U.S. That Faustian ambition has been foiled by the mobility of American society, the influx of tourists and immigrants (illegal as well as legal), changes in technology that create new, inviting environments for organisms and, most notably, by casual intimacies encouraged by the sexual revolution. As many as 20 million Americans may now suffer from genital herpes, an incurable but nonfatal disease. In addition, an estimated 1 million new cases of gonorrhea and 100,000 of syphillis are reported each year. "What may be different these days is the number of persons who can be exposed in a short period," says Dr. William Foege, 47, director of the CDC. "The average AIDS victim has had 60 different sexual partners in the past twelve months."

The struggle to conquer such epidemics, and the fear they spread, is the work of a special breed. They are spiritual descendants of Dr. John Snow (1813-58), who tracked the incidence of cholera during the London epidemic of 1831 and stemmed further devastation by shutting down one of the city's water pumps. In the past few decades, his followers have significantly improved the quality of life. In much of the world they have virtually eliminated the threat of such onetime plagues as polio, smallpox, cholera and diphtheria.

Those medical-mystery solvers include general practitioners and specialists who become involved in a particular case because it affects their patients. Others can be found among the nation's state and local public health officers. Researchers at the NIH supply scientific support. Coordinating this network, and indeed serving as the FBI of disease detection and the Interpol for medical sleuths around the globe, are the 4,030 workers at the CDC. The vanguard of this organization is the center's Epidemic Intelligence Service (EIS), which sends out its corps of 120 young, bright and determined investigators around the U.S. and the world. "We see the CDC people as our sort of big brother," says Nevada Health Official Dr. Otto Ravenholt.

The CDC complex near Atlanta belies its importance. Its headquarters are located in a squat suburban brick building, graced in front by a bust of Hygeia, the Greek goddess of health. Some sections are housed in wooden barracks around a former Army hospital. The agency, then known as Malaria Control in War Areas (MCWA), was created in 1942 to find ways to protect U.S. soldiers against malaria. The organization has since taken part in the successful campaign against polio (by pioneering the use of the Salk vaccine), and lessened the threat of rabies (by showing it could be carried by bats). The CDC also conducted nationwide childhood immunization programs for measles, mumps and rubella. Says Director Foege: "Today 5,000 children are running around who would be in their graves if it weren't for these programs."

For all its successes, the CDC has had to fight for funds--including money to set up EIS in 1951--by stressing the national security benefits of the center. In 1981, the White House considered cutting the CDC budget by 23%; Richard Schweiker, who was then HHS Secretary, successfully fought to protect its funds. With the current concern about AIDS, the CDC seems secure for the present; its 1983 budget is $261 million, less than 1% of the amount spent for Medicare and Medicaid.

Each year the CDC accepts 60 or so people involved in health care for a two-year tour of duty with the EIS. "We look for the bright, somewhat aggressive independent thinker," says Dr. Lyle Conrad, head of the division's field service officers. About half are based in Atlanta; the rest are assigned to public health departments around the country, with which the CDC works closely. All are on call 24 hours a day, ready to go wherever a disease breaks out, be it food poisoning or a case of primary pneumonic plague that appeared in 1980 in California (all 185 people who were exposed to the victim were inoculated six hours after the disease was confirmed). After completing their two years, EIS graduates are given a prized emblem of their craft: a key chain with a tiny metal keg of Watney's Red Barrel Beer, served at the John Snow Pub on the site of the infamous water pump in London.

In addition to the 1,000 requests for help that come from state and local agencies each year, the CDC undertakes about 50 projects overseas. Recent examples: tackling a polio epidemic in Indonesia meningitis in Upper Volta, malaria in Zanzibar, toxic reaction to polluted cooking oil in Spain and observing an immunization program against childhood diseases in China. Dr. Bess Miller, 35, was exhausted from working on the AIDS epidemic last year when the phone at home rang one evening. "My first thought was that they wanted to send me somewhere," she recalls. They did. Soon she was in the Israeli-occupied West Bank investigating a mysterious malady afflicting young Palestinian schoolgirls. Miller and Israeli health officials concluded that the problem was caused by a wave of hysteria; it soon disappeared.

CDC's most sophisticated facility is its Maximum Containment Laboratory, which handles highly lethal diseases that have no known antidotes. Workers, all of whom are volunteers, must punch in a code to open the outer shell of the lab; after a trip through a chemical-shower chamber, they must provide another personal number to gain access to the pressurized inner sanctum. There the scientists wear seamless blue space suits, equipped with their own air filtration systems, to work with some of the world's most lethal microbes, including those that cause Lassa fever and Ebola virus, two maladies that produce severe internal bleeding and are native to Africa. There have been no fatalities in the lab. When a worker is exposed to a disease, he is flown to the Army's Medical Research Institute of Infectious Diseases in Frederick, Md.

Other CDC experts work with Immigration and Naturalization Service officials to prevent exotic diseases from entering the country. Laboratory Director Joseph McCormick, who studied Lassa fever in Sierra Leone, sped to the Atlanta airport in a four-wheel-drive vehicle during a snowstorm last January to pick up a mysteriously ailing passenger from Nigeria. The man was placed in an isolation room until it was certain he was not suffering from one of the deadly viruses.

The case that made the CDC known to the public at large remains a classic in the annals of medical detective work. In July 1976, Pennsylvania chapters of the American Legion held a rollicking convention at Philadelphia's Bellevue Stratford Hotel. In the next few days, eleven Pennsylvanians died, apparently of pneumonia; a Legion officer alerted health authorities that the victims all had attended the convention. A phone call was made to Atlanta for help. Late that night, Dr. Theodore Tsai, an EIS officer, arrived in the state health office, carrying a cooler, to collect blood samples and respiratory secretions. He was the first of 32 CDC officials who worked on the case.

With a malady of unknown cause, the first step is to decide how to define it. "We wanted the definition to be broad enough to include most cases, but not so broad that it would include everybody with a cold," Tsai recalls. Six EIS agents fanned out across the state, questioning other suspected victims. Where did they eat and drink? Were the windows open in their hotel rooms? What events did they attend? A more detailed survey went out to all 4,400 Legionnaires who had attended the convention, and 3,500 were returned within three days. Other agents followed up stray leads, like a call from a magician who admitted lighting a sparkler at the hotel. Back in Atlanta, clinicians noticed the high white blood cell counts in specimens from the victims, and began to search for bacteria under their microscopes.

At first CDC experts suspected an attack of swine flu, which health officials had been fearing that year. But the evidence did not support that hypothesis. Some who had merely walked past the hotel contracted the disease. Yet it was noncontagious: no one caught it from the original 182 victims, 29 of whom died. Nor were any bacteria found. "The picture slowly evolved that we didn't know what we were dealing with," Tsai remembers.

The outbreak vanished as quickly as it began, but researchers at CDC, including Microbiologist Joseph McCade, 43, continued to examine the specimens taken from the victims. Five months after the convention, he took another look at some red sausage-shaped bacteria and concluded that they were the culprits. They had festered in the water of the hotel's cooling tower and had been carried through the air as the water evaporated. The antibiotic Erythromycin proved effective in treating the disease, and many similar cooling towers across the country are now chlorinated to guard against another outbreak.

Another famed mystery was solved primarily by the epidemiologists rather than the lab scientists. In January 1980, doctors in Wisconsin and Minnesota noticed that an unusual number of young women were suddenly developing high temperatures and low blood pressure, with potentially fatal results; out of the 55 patients in the CDC's initial study, seven had died by the end of May. Dr. Kathryn Shands of EIS led the CDC investigation, developing a clear definition for what soon became known as toxic shock syndrome and recording in detail all the cases.

A staphylococcus bacterium was clearly the cause of the outbreak, but the medical question was "Why?" Through further epidemiological studies, the medical sleuths found that most of the new cases under investigation involved menstruating women who had been using tampons. A majority had used Procter & Gamble's Rely tampons, a new superabsorbent brand, which may have provided an environment that encouraged bacterial growth. After the product was removed from the market, the number of reported toxic shock cases dropped sharply.

One of the few blemishes on the CDC's record involves an epidemic that never happened. In 1976, swine flu broke out at Fort Dix, N.J., killing one soldier. Health officials worried about the similarity of the virus to one that had caused the deadly 1918 influenza pandemic that killed more than 500,000 Americans. At President Gerald Ford's urging, a $100 million program was rushed into being to immunize people across the country. Not only did no epidemic break out, but 100 or so people came down with a syndrome, apparently connected to the vaccines, that caused partial paralysis. Ninety million unused doses were left over. Officials say that the swine flu debacle was one reason why the Carter Administration decided not to reappoint Dr. David Sencer, who was then the CDC director and is now Commissioner of the New York City Board of Health. Sencer was replaced by Foege, an articulate career public health official from Washington who led the worldwide crusade to eliminate smallpox.

Sometimes serendipity plays a role in discovering a new approach to a familiar disease. Last summer a 42-year-old drug addict, unable to talk, bent over and hardly able to move, was brought to the Santa Clara Valley Medical Center. His symptoms were similiar to those of patients afflicted with Parkinson's disease, which usually affects the elderly. Dr. William Langston speculated that the cause might be something in the heroin that the victim used. The doctor and his team were able to track down others who had used the same batch of the drug and found similar reactions. Through a chance conversation with another doctor, help from police, and tips resulting from a newspaper story, Langston uncovered other cases and obtained samples of the bad drug.

Several months later Langston read an article in a medical journal about a chemist who had killed himself after contracting Parkinson's-like symptoms from a dose of artificial heroin. From a report analyzing the dead chemist's brain, Langston found that the heroin involved contained an additive similar to the one in the bad batch of heroin he had been studying. The mysterious ingredient, a chemical known as MPTP, had moved from the blood into the brain and damaged the same area affected by Parkinson's disease. No other substance is known to do that. Last April Dr. Irwin Kopin of the National Institute of Mental Health, co-author of the journal article, announced that he had used MPTP to induce Parkinsonism in rhesus monkeys. The work of these two men suggests that the previously unexplained symptoms of Parkinson's might result from exposure to MPTP, and thus that the disease itself may be caused by environmental factors.

Nothing in the history of disease detection compares in size or intensity with the chase now under way to solve the mystery of AIDS. It began in early 1981, when Dr. Michael Gottlieb of U.C.L.A. told Los Angeles health officials that he had five patients, all of them active homosexuals, who were suffering from an unusual and deadly form of pneumonia, pneumocystis carinii. More alarming still, their immune systems seemed to have broken down. Gottlieb and an EIS agent based in Los Angeles reported the grim news in CDC's weekly publication. Almost simultaneously, Dr. Alvin Friedman-Kien of New York University noted that several of his homosexual patients had the same weakened immune systems and were suffering from Kaposi's sarcoma, a rare cancer of the skin usually seen only in older men. Later that summer Dr. Harold Jaffe of CDC, while attending a conference in California, was told of an additional case of a young homosexual suffering from Kaposi's.

"We were struck by how strange this was," recalls Jaffe. A group of medical detectives at the CDC was organized into an AIDS task force under the direction of Dr. Curran, a venereal disease specialist. They quickly uncovered 50 cases around the country that fit the definition of what the CDC officially dubbed AIDS. Initially it seemed that the culprit might be amyl nitrate or butyl nitrate, often known as "Rush" or "poppers," which are inhalants that provide a short-lasting high. But a study comparing homosexuals with AIDS to disease-free gays showed little correlation with use of the drug. The 20-page questionnaire disclosed, however, that AIDS victims tended to be sexually promiscuous. In addition, some were the passive partners in anal intercourse.

Then came another clue: reports of drug abusers, most of them heterosexual, coming down with AIDS. This added credence to the theory that a virus or some other infectious agent, transmitted by dirty needles as well as by sexual contact, might be the cause. This conjecture was supported by evidence that sexual partners of drug users, and even a few children of those with the disease, had contracted what seemed to be AIDS. So had a few hemophiliacs and blood-transfusion recipients. One baby in San Francisco with symptoms of AIDS, it was discovered, had been given blood from a donor who turned out to have the disease.

The strongest evidence that an infectious agent was on the loose came from what has been called the Los Angeles cluster. Interviewing victims, investigators began compiling the names of their sex partners. Three different men, none of whom knew each other, each mentioned the same man in New York City; he turned out to be an AIDS victim. Since then, 40 cases in ten cities have been linked to one another by sexual relationships.

The next clue was confusing. Immigrants from Haiti turned up with AIDS. Not only was this puzzling--many claimed they were neither homosexuals nor drug users--but the discovery raised special problems for the epidemiologists. Homosexuality is scorned in Haiti, and the victims were reluctant to talk about their sexual habits. The language barrier also played a role; it was hard for investigators to describe in Creole--the everyday patois of Haiti--the homosexual acts in question, particularly since the same word applies to both homosexuality and transvestism. Many of the immigrants were in the U.S. illegally, and thus understandably reluctant to talk to Government agents about anything.

The Haitian connection is still puzzling. The disease apparently broke out on the impoverished Caribbean isle in 1981, at about the same time as it did in the U.S. Some experts suspect that AIDS is caused by a newly introduced viral agent from Africa, where Kaposi's is common, and may have been transmitted by Haitians who once worked in Zaire. Port-au-Prince has many popular gay bars, and the disease could have been brought back to the U.S. by visiting Americans--or taken to Haiti by Americans in the first place. Recent investigations suggest that the disease is probably transmitted in Haiti, much as it is in the U.S., by homosexual activity or by dirty needles, and that Haitians have no more propensity for the disease than victims in the U.S.

As the search and speculation went on, researchers in U.S. labs added their own clues: the blood of AIDS victims has an imbalance among the cells that help govern the production of antibodies. A normal immune system has twice as many helper Tcells, which stimulate the making of antibodies, as it does suppressor Tcells, which keep antibody production under control. In an AIDS victim, the ratio may be reversed. Often there are fewer cells of both types.

Based on what is known so far, two theories have emerged. One is that AIDS is caused by a specific agent, most probably a virus. "The infectious-agent hypothesis is much stronger than it was months ago," says Curran, reflecting the prevailing opinion at CDC. NIH Researcher Fauci, who staunchly believes that the culprit is a virus, has been collecting helper T-cells from AIDS victims to look for bits of viruses within their genetic codes. So far, however, this and other complex methods of detecting viruses have yielded nothing conclusive. Suspicion focuses on two viruses: one is a member of the herpes family called CMV; the other, called human T-cell leukemia virus, or HTLV, is linked to leukemia and lymphoma.

The other theory is that the immune system of AIDS victims is simply overpowered by the assault of a variety of infections. Both drug users and active homosexuals are continually bombarded by a gallery of illnesses. Repeated exposure to the herpes virus, or to sperm entering the blood after anal intercourse, can lead to elevated levels of suppressor Tcells. The immune system eventually is so badly altered that, as one researcher puts it, "the whole thing explodes." Other experts combine the two theories, speculating that a new virus may indeed be involved, but that it only takes hold when a combination of factors affects the potential victim, such as an imbalanced immune system or certain genetic characteristics.

Whatever theory may prove to be correct, the research has provided inspiration for fresh studies by epidemiologists. The levels of Tcells, the presence of HTLV and CMV viruses, and the swelling of lymph glands are regarded as possible "markers" that indicate the early stages of AIDS. At the New York Blood Center, Dr. Cladd Stevens and Friedman-Kien are examining the blood of homosexuals who do not have AIDS to see what factor might be unique to those who do develop the syndrome. By chance they have thousands of samples of blood, 1,500 of them from homosexuals now being studied, which were collected in 1979 for an unrelated hepatitis-B project. To date, 18 men in the survey have developed AIDS.

No cure is in sight. But the research already has benefited some patients. New knowledge about the immune system has inspired doctors to be more careful when treating Kaposi's to use therapies that do not lead to further suppression of the immune system. Fauci of NIH has conducted a bone marrow transplant that bolsters a patient's immune system. Along with many other researchers, he is testing the effects on AIDS patients of new forms of interferon, a component of the human immune system that can now be reproduced by genetic engineering.

Despite the concern about the death and suffering of its victims, and despite the lack of any solution so far, health officials are optimistic that science will eventually conquer AIDS. "We've beaten other diseases, and we're determined to beat this one too," says HHS Secretary Heckler.

Heckler's opinion, which is shared by many medical detectives, is rooted in a century of victories over diseases whose ravages once shaped the course of history. Only a few decades ago, fear of a polio outbreak could empty schools; victims in iron lungs would be put on exhibit in small towns to raise money for the March of Dimes. All that is history now.

Optimism about AIDS is bolstered by new weapons being added to the medical arsenal. Interferon holds the promise of retarding the growth of cancerous cells. Potentially as powerful is a process that creates new cells called hybridomas. Cells that build antibodies against specific diseases are fused with tumor cells to make hybrids, which have the durability of tumors and the power to create antibodies. These cells may eventually be used to develop vaccines that will protect humans against new diseases and can help the body fight certain cancers.

Nevertheless, optimism is tempered by knowledge that the struggle against disease never ends. Of the deadly African Ebola virus, Foege says: "What keeps it from spreading here? I don't know." Thus research work on Ebola at Atlanta's Maximum Containment Lab goes on. Another potential threat is a subviral particle that combines with the hepatitis-B virus to cause more severe infections and liver cancer. Discovered in 1977, this so-called Delta agent is starting to show up in high-risk groups, including some of the same ones who develop AIDS. Even the victory over smallpox permits no complacency. In its place, a disease called monkeypox has erupted in Africa. "It's probably a disease that's been around a long time but has been masked by smallpox," Foege says. "Once you get rid of one disease, a new one becomes visible."

Then there are the scourges that have always been with us, the Legionnaire's bacteria that suddenly find an environment in which to flourish anew momentarily, or the influenza virus that undergoes minor mutations to spring forth with renewed vigor. Indeed, of all the potential disease agents looming on the horizon, it is the familiar flu virus that worries Foege the most. "I fully anticipate that possibly in our lifetime we will see another flu strain that is as deadly as 1918. We have not figured out good ways to counter that." The same holds for the most common of bacteria and viruses, like the staphylococcus, which are adept at evolving into new forms.

"Just a few years ago, in an excess of hubris, I predicted we were nearly finished with the problem of infection," Dr. Lewis Thomas, noted biologist and prize-winning author (The Lives of a Cell), observed recently. "I take it back." Through the heroic struggle of medical sleuths, most diseases faced today can be controlled, as some day AIDS will be. But microbes, which have existed on this planet far longer than man, show no signs of being unconditionally conquered. Amid the billions that exist harmoniously around us, there will always be some that become unexpectedly disruptive, mysteriously virulent. Said Thomas: "There is a lot more research to be done, not just about AIDS but into infectious diseases in general. We have not run out of adversaries, nor is it likely we will do so for a long time to come." Thus the disease detectives must keep pounding the pavement, peering through microscopes, asking their questions.

--By Walter Isaacson.

Reported by Joseph N. Boyce/Atlanta and Peter Stoler/Washington, with other bureaus

* The classic definition of an epidemic is an outbreak of disease affecting 1% of the population. But most doctors now agree on a newer criterion and declare an epidemic whenever the incidence of a disease rises above its normal "background level," or rate of natural occurrence.

With reporting by Joseph N. Boyce, Peter Stoler This file is automatically generated by a robot program, so viewer discretion is required.