The Killers All Around

They can strike anywhere, anytime. On a cruise ship, in the corner restaurant, in the grass just outside the back door. And anyone can be a carrier: the stranger coughing in the next seat on the bus, the college classmate from a far-off place, even the sweetheart who seems perfect in every way. For wherever we go and whatever we do, we are accosted by invaders from an unseen world. Protozoans, bacteria, viruses -- a whole menagerie of microscopic pests constantly assaults every part of our body, looking for a way inside. Many are harmless or easy to fight off. Others -- as we are now so often reminded -- are merciless killers.

Humanity once had the hubris to think it could control or even conquer all these microbes. But anyone who reads today's headlines knows how vain that hope turned out to be. New scourges are emerging -- AIDS is not the only one -- and older diseases like tuberculosis are rapidly evolving into forms that are resistant to antibiotics, the main weapon in the doctor's arsenal. The danger is greatest, of course, in the underdeveloped world, where epidemics of cholera, dysentery and malaria are spawned by war, poverty, overcrowding and poor sanitation. But the microbial world knows no boundaries. For all the vaunted power of modern medicine, deadly infections are a growing threat to everyone, everywhere. Hardly a week goes by without reports of outbreaks in the U.S. and other developed nations. Some of the latest examples:

-- A Royal Caribbean cruise ship on a trip to Baja California returned early to Los Angeles last week after more than 400 passengers came down with an unidentified intestinal ailment. It may have been the reason one elderly man died. And just a few weeks ago, 1,200 disgruntled passengers were evacuated from the ocean liner Horizon in Bermuda because of the threat of Legionnaires' disease. Among customers on previous Horizon voyages this summer, there have been 11 confirmed cases of the potentially fatal pneumonia-like illness and 24 suspected cases. At least one victim died.

-- A Yale School of Medicine researcher is recovering from a rare and potentially lethal disease called Sabia virus. Before 1990, the illness was unknown to medicine. Then a woman in the town of Sabia, Brazil, died from a mysterious virus that had evidently been circulating in local rodents for years before making an assault on humans. Brazilian doctors sent samples to Yale, and a month ago the scientist became infected when he accidentally broke a container holding the virus. Health officials point out that it is not easily passed between humans, but some 80 people who came into contact with the man have been under observation.

-- More than 850 people have come down with cholera in southern Russia, and officials fear the disease could erupt into an epidemic. Cholera outbreaks were rare in that part of the world before the breakup of the Soviet Union, but collapsing health services and worsening sanitary conditions have fostered the disease. Shortages of vaccines, meanwhile, have led to an upsurge in diphtheria in Russia, and health experts have encountered cases of typhoid, hepatitis, anthrax and salmonella in neighboring Ukraine.

-- The notorious flare-up in Gloucestershire, England, of what the press dubbed flesh-eating bacteria alerted people to the dangers of streptococcus-A infections. The common bacteria that cause strep throat generally produce no lasting harm if properly treated, but certain virulent strains can turn lethal. Strep-A infections claim thousands of lives each year in the U.S. and Europe alone.

-- Newspaper accounts publicized a startling flare-up of tuberculosis that was first detected last year at a high school in Westminster, California, a middle-class suburb of Los Angeles. The disease was apparently brought in by a 16-year-old Vietnamese immigrant who contracted it in her native country. Nearly 400 young people, or 30% of the school's students, have tested positive for the infection, and at least 12 have a variety of the TB bacterium that is resistant to standard antibiotic treatment. One student has lost part of her lung.

-- The New England Journal of Medicine reported that the children of Cincinnati suffered an epidemic of pertussis (whooping cough) last year. There were 352 cases (none fatal), compared with 542 cases in the 13 years from 1979 to 1992. The alarming part was that most of the children had been properly vaccinated, suggesting that an unusually hardy strain of the pertussis bacterium might be emerging. Another disturbing statistic: there were more than 6,500 cases nationwide, the largest number in more than 26 years.

-- In many parts of the U.S., especially the Northeast, people are already leery of strolling in wooded areas for fear of encountering ticks carrying Lyme disease, a potentially chronic, arthritis-like condition. Now the Journal of the American Medical Association has reported on another tick-borne disease, which struck 25 people in Wisconsin and Minnesota, killing two. It is caused by a new variety of the Ehrlichia bacterium, which was first detected in humans in 1954. Doctors are concerned because life-threatening Ehrlichia infections may be misdiagnosed as Lyme disease or even a bad cold.

A generation ago, no one had ever heard of Lyme or Legionnaires' disease, much less AIDS. Back in the 1970s, medical researchers were even boasting that humanity's victory against infectious disease was just a matter of time. The polio virus had been tamed by the Salk and Sabin vaccines; the smallpox virus was virtually gone; the parasite that causes malaria was in retreat; once deadly illnesses, including diphtheria, pertussis and tetanus, seemed like quaint reminders of a bygone era, like Model T Fords or silent movies.

The first widespread use of antibiotics in the years following World War II had transformed the most terrifying diseases known to humanity -- tuberculosis, syphilis, pneumonia, bacterial meningitis and even bubonic plague -- into mere inconveniences that if caught in time could be cured with pills or shots. Like many who went through medical school in the 1960s, Dr. Bernard Fields, a Harvard microbiologist, remembers being told, "Don't bother going into infectious diseases." It was a declining specialty, his mentors advised -- better to concentrate on real problems like cancer and heart disease.

The advent of AIDS demolished that thinking. The sight of tens of thousands of young people wasting away from a virus that no one had known about and no one knew how to fight was a sobering experience -- especially when drugs proved powerless to stop the virus and efforts to develop a vaccine proved extraordinarily difficult. Faced with AIDS, and with an ever increasing number of antibiotic-resistant bacteria, doctors were forced to admit that the medical profession was actually retreating in the battle against germs.

The question ceased to be, When will infectious diseases be wiped out? and became, Where will the next deadly new plague appear? Scientists are keeping a nervous watch on such lethal agents as the Marburg and Ebola viruses in Africa and the Junin, Machupo and Sabia viruses in South America. And there are uncountable threats that haven't even been named: a virus known only as "X" emerged from the rain forest in southern Sudan last year, killed thousands and disappeared. No one knows when it might arise again.

A U.S. Army lab in Frederick, Maryland, faced a terrifying situation in 1989 when imported monkeys started dying from a strain of the Ebola virus. After destroying 500 monkeys and quarantining the lab and everyone in it, officials found that this particular strain was harmless to humans. But the episode was dramatic enough to inspire an article in the New Yorker magazine -- now expanded into a soon-to-be released book called The Hot Zone -- and work on two competing movies (one of which seems to have collapsed before production).

The Ebola affair and the emergence of AIDS illustrate how modern travel and global commerce can quickly spread disease. Germs once confined to certain regions may now pick up rides to all parts of the world. For example, the cholera plague that is currently sweeping Latin America arrived in the ballast tanks of a ship that brought tainted water from Asia. And the New England Journal of Medicine has reported two cases of malaria in New Jersey that were transmitted by local mosquitoes. The mosquitoes were probably infected when they bit human malaria victims who had immigrated from Latin America or Asia. Writes author Laurie Garrett in a book to be published next month called The Coming Plague: "aids does not stand alone; it may well be just the first of the modern, large-scale epidemics of infectious disease."

The latest bulletins from the germ front come on top of a long series of horror stories. For years now people have been reading about -- and suffering from -- all sorts of new and resurgent diseases. As if AIDS were not enough to worry about, there was a rise in other sexually transmitted infections, including herpes, syphilis and gonorrhea. People heard about the victims who died in the Northwest from eating undercooked Jack in the Box hamburgers tainted with a hazardous strain of E. coli bacteria. They were told to cook their chicken thoroughly to avoid food poisoning from salmonella bacteria. And last year they saw how the rare hantavirus, once unknown in the U.S., emerged from mice to kill 30 people in as many as 20 states.

All this bad news is undoubtedly having a cumulative impact on the human psyche. The age of antibiotics is giving way to an age of anxiety about disease. It's getting harder to enjoy a meal, make love or even take a walk in the woods without a bit of fear in the back of the mind. No wonder people pay an unreasonable amount of attention when tabloids trumpet headlines about "flesh-eating bacteria." And no wonder Stephen King's The Stand, a TV mini-series based on his novel about a "superflu" that ravages the world's population, earned some of the year's highest ratings.

The odds of contracting a life-threatening infectious disease are still very low -- at least in the developed world. But the threats are real and frightening enough to spur medical researchers to redouble efforts to learn more about how the many kinds of microbes cause disease -- and how they can be kept at bay.

MICROORGANISMS

It is tempting to think of the tiny pathogens that produce such diseases as malaria, dysentery, TB, cholera, staph and strep as malevolent little beasts, out to destroy higher forms of life. In fact, all they're trying to do is survive and reproduce, just as we are. Human suffering and death are merely unfortunate by-products.

Plasmodium, a protozoan responsible for malaria, flourishes in the human body, growing inside red blood cells until the cells burst. And without enough red cells to carry oxygen through the body, humans become anemic and can die from renal failure or convulsions. Bacteria, which are considerably smaller than protozoans, generally do their damage indirectly, producing toxins that stimulate the body to mount an immune response. Ideally the immune cells kill the bacteria. But if the bacteria get out of control, their poisons can either kill cells or generate a huge immune reaction that is itself toxic.

In an illness like tuberculosis, the immune system kills the body's own cells in the localized areas where TB germs have taken hold, including the lungs or the bones. With staph or strep, the sheer volume of disease-fighting immune cells can overload blood vessels, ripping tiny tears in the vessel linings; toxins can also damage the vessels directly. Plasma begins to leak out of the bloodstream; blood pressure drops, organs fail, and the body falls into a state of shock. In cholera, bacterial toxins attack intestinal cells, triggering diarrhea, catastrophic dehydration and death.

Before the coming of penicillin and other antibiotics, bacterial diseases simply ran their courses. Either the immune system fought them off and the patient survived or the battle was lost. But antibiotics changed the contest radically: they selectively killed bacteria without harming the body's cells. For the first time, potentially lethal infections could be stopped before they got a foothold.

Unfortunately, as Columbia University's Dr. Harold Neu observed in the journal Science, "bacteria are cleverer than men." Just as they have adapted to nearly every environmental niche on the planet, they have now begun adjusting to a world laced with antibiotics. It didn't take long. Just a year or two after penicillin went into widespread use, the first resistant strain of staph appeared. As other antibiotics came along, microbes found ways to resist them as well, through changes in genetic makeup. In some cases, for example, the bacteria gained the ability to manufacture an enzyme that destroys the antibiotic.

By now nearly every disease organism known to medicine has become resistant to at least one antibiotic, and several are immune to more than one. One of the most alarming things about the cholera epidemic that has killed as many as 50,000 people in Rwandan refugee camps is that it involves a strain of bacterium that can't be treated with standard antibiotics. Relief agencies had to scramble for the right medicines, which gave the disease a head start in its lethal rampage.

Tuberculosis, too, has learned how to outwit the doctors. TB is an unusually tough microbe, so the standard therapy calls for several antibiotics, given together over six months. The length and complexity of the treatment have kept underdeveloped nations from making much progress against even ordinary TB. But now several strains have emerged in the U.S. and other developed countries that can't be treated with common antibiotics.

Even such seemingly prosaic but once deadly infections as staph and strep have become much harder to treat as they've acquired resistance to many standard antibiotics. Both microbes are commonly transmitted from patient to patient in the cleanest of hospitals, and they are usually cured routinely. But one strain of hospital-dwelling staph can now be treated with only a single antibiotic -- and public health officials have no doubt that the germ will soon become impervious to that one too. Hospitals could become very dangerous places to go -- and even more so if strep also develops universal resistance.

One of medicine's worst nightmares is the development of a drug-resistant strain of severe invasive strep A, the infamous flesh-eating bacteria. What appears to make this variant of strep such a quick and vicious killer is that the bacterium itself is infected with a virus, which spurs the germ to produce especially powerful toxins. (It was severe, invasive strep A that killed Muppeteer Jim Henson in 1990.) If strep A is on the rise, as some believe, it will be dosed with antibiotics, and may well become resistant to some or all of the drugs.

Microbes' extraordinary ability to adapt, observes Harvard microbiologist Fields, "is a fact of life. It's written into evolution." Indeed, the end run that many organisms are making around modern antibiotics is a textbook case of Darwin's theory in action (anti-evolutionists, take note). In its simplest form, the theory states that new traits will spontaneously appear in individual members of a given species -- in modern terms, mutations will arise in the organisms' genetic material. Usually the traits will be either useless or debilitating, but once in a while they'll confer a survival advantage, allowing the individual to live longer and bear more offspring. Over time, the new survival trait -- camouflage stripes on a zebra, antibiotic resistance in a bacterium -- will become more and more common in the population until it's universal.

The big difference between animals and bacteria is that a new generation comes along every few years in large beasts -- but as often as every 20 minutes in microbes. That speeds up the evolutionary process considerably. Germs have a second advantage as well: they're a lot more promiscuous than people are. Even though bacteria can reproduce asexually by splitting in two, they often link up with other microbes of the same species or even a different species. In those cases, the bacteria often swap bits of genetic material (their DNA) before reproducing.

They have many other ways of picking up genes as well. The DNA can come from viruses, which have acquired it while infecting other microbes. Some types of pneumococcus, which causes a form of pneumonia, even indulge in a microbial version of necrophilia by soaking up DNA that spills out of dead or dying bacteria. This versatility means bacteria can acquire useful traits without having to wait for mutations in the immediate family.

The process is even faster with antibiotic resistance than it is for other traits because the drugs wipe out the resistant bacterium's competition. Microbes that would ordinarily have to fight their fellows for space and nourishment suddenly find the way clear to multiply. Says Dr. George Curlin of the National Institute of Allergy and Infectious Diseases: "The more you use antibiotics, the more rapidly Mother Nature adapts to them."

Human behavior just makes the situation worse. Patients frequently stop taking antibiotics when their symptoms go away but before an infection is entirely cleared up. That suppresses susceptible microbes but allows partially resistant ones to flourish. People with viral infections sometimes demand antibiotics, even though the drugs are useless against viruses. This, too, weeds out whatever susceptible bacteria are lurking in their bodies and promotes the growth of their hardier brethren. In many countries, antibiotics are available over the counter, which lets patients diagnose and dose themselves, often inappropriately. And high-tech farmers have learned that mixing low doses of antibiotics into cattle feed makes the animals grow larger. (Reason: energy they would otherwise put into fighting infections goes | into gaining weight instead.) Bacteria in the cattle become resistant to the drugs, and when people drink milk or eat meat, this immunity may be transferred to human bacteria.

Because microbial infections keep finding ways to outsmart antibiotics, doctors are convinced that vaccines are a better way to combat bacterial disease. A vaccine is usually made from a harmless fragment of microbe that trains the body's immune system to recognize and fight the real thing. Each person's immune system is chemically different from everyone else's, so it's very difficult for a bacterium to develop a shield that offers universal protection. Diphtheria and tetanus can be prevented by vaccines if they are used properly. A vaccine against the pneumococcus bacterium has recently come out of the lab as well, and scientists expect to test one that targets streptococcus A within a year.

VIRUSES

Unlike bacteria and protozoans, which are full-fledged living cells, capable of taking in nourishment and reproducing on their own, viruses are only half alive at best. They consist of little more than a shell of protein and a bit of genetic material (DNA or its chemical cousin RNA), which contains instructions for making more viruses -- but no machinery to do the job. In order to reproduce, a virus has to invade a cell, co-opting the cell's own DNA to create a virus factory. The cell -- in an animal, a plant or even a bacterium -- can be physically destroyed by the viruses it is now helplessly producing. Or it may die as the accumulation of viruses interferes with its ability to take in food.

It is by killing individual cells in the body's all-important immune system that the AIDS virus wreaks its terrible havoc. The virus itself isn't deadly, but it leaves the body defenseless against all sorts of diseases that are. Other viruses, like Ebola, kill immune cells too, but very quickly; the dead cells form massive, deadly blood clots. Still others, hantavirus, for example, trigger a powerful reaction in which immune cells attack both the invading virus and the host's healthy cells.

Unlike bacteria and protozoans, viruses are tough to fight once an infection starts. Most things that will kill a virus will also harm its host cells; thus there are only a few antiviral drugs in existence. Medicine's great weapon against viruses has always been the preventive vaccine. Starting with smallpox in the late 1700s, diseases including rabies, polio, measles and influenza were all tamed by immunization. $

But new viruses keep arising to challenge the vaccine makers. They may have gone undetected for centuries, inhabiting animal populations that have no contact with mankind. If people eventually encounter the animals -- by settling a new part of the rain forest, for example -- the virus can have the opportunity to infect a different sort of host.

Scientists believe Ebola virus made just that kind of jump, from monkeys into humans; so did other African viruses such as Marburg and the mysterious X that broke out in Sudan. And many more are likely to emerge. "In the Brazilian rain forest," says Dr. Robert Shope, a Yale epidemiologist, "we know of at least 50 different viruses that have the capacity of making people sick. There are probably hundreds more that we haven't found yet."

Viruses like Ebola and X are scary, but they're too deadly to be much of a threat to the world. Their victims don't have much of a chance to infect others before dying. In contrast, HIV, the AIDS virus -- which may have come from African primates as early as the 1950s -- is a more subtle killing machine, and thus more of an evolutionary success. An infected person will typically carry HIV for years before symptoms appear. Thus, even though HIV doesn't move easily from one human to another, it has many chances to try. Since the first cases were reported in the late 1970s, HIV has spread around the world to kill perhaps a million people and infect an estimated 17 million.

It isn't just new viruses that have doctors worried. Perhaps the most ominous prospect of all is a virulent strain of influenza. Even garden-variety flu can be deadly to the very old, the very young and those with weak immune systems. But every so often, a highly lethal strain emerges -- usually from domesticated swine in Asia. Unlike hiv, flu moves through the air and is highly contagious. The last killer strain showed up in 1918 and claimed 20 million lives -- more than all the combat deaths in World War I. And that was before global air travel; the next outbreak could be even more devastating.

Vaccines should, in theory, work just as well for new varieties of disease as they do for old ones. In practice, they often don't. An HIV vaccine has proved difficult to develop because the virus is prone to rapid mutations. These don't affect its deadliness but do change its chemistry enough to keep the immune system from recognizing the pathogen.

Creating a vaccine for each strain of flu isn't exactly simple either. "First," says Yale's Shope, "we have to discover something new is happening. Then we have to find a manufacturer willing to make a vaccine. Then the experts have to meet and decide what goes into the vaccine. Then the factory has to find enough hens' eggs in which to grow the vaccine. There are just a lot of logistical concerns."

People are partly to blame for letting new viruses enter human populations. Says Dr. Peter Jahrling, senior research scientist at the U.S. Army Medical Research Institute of Infectious Diseases: "If you're a monkey imported from the Philippines, your first stop when you hit this country is a quarantine facility. If you're a free-ranging adult human being, you just go through the metal detector and you're on your way."

Sometimes environmental changes help microbes move from animals to humans. Lyme disease, a bacterial infection, was largely confined to deer and wild mice until people began converting farmland into wooded suburbs -- which provided equally good habitats for the animals and the bacteria-infested ticks they carry and also brought them into contact with large numbers of people. The mice that transmit the hantavirus often take refuge in farmers' fields, barns and even homes. Air-conditioning ducts create a perfect breeding ground for Legionnaires' disease bacteria. Irrigation ditches and piles of discarded tires are ideal nesting spots for the Aedes aegypti mosquito, carrier of dengue and yellow fevers; imported used tires have already brought the Asian tiger mosquito, also a carrier of dengue, into the U.S.

Clearly there is no way to prevent human exposure to microbes. But the risks can be reduced. To minimize bacterial resistance, for example, doctors can be stingier with antibiotics. "We've been careless," says Dr. Robert Daum, a University of Chicago pediatrician. "Every childhood fever does not require antibiotics." Nor does a healthy farm animal.

Most important is increased vigilance by public-health authorities. The faster a new microbe can be identified and its transmission slowed, the less likely a small outbreak will turn into an epidemic. Unfortunately, the trend has been in the other direction. "Even in the U.S.," says Thomson Prentice of the World Health Organization in Geneva, "disease-monitoring expertise has been lost, either through cost-cutting or reduced diligence. If some of the edge has been lost in the U.S., just imagine how poorer countries have reacted."

American health officials are convinced that their information-gathering network must be strengthened. That has begun to happen under a new program that will, among other things, increase the surveillance of new microbes and educate both health workers and the public about how to deal with emerging diseases.

An all-out effort to monitor diseases, vaccinate susceptible groups, improve health conditions around the world, develop new drugs and get information to the public would be enormously expensive. But the price of doing nothing may be measured in millions of lost lives. Doctors are still hopeful but no longer overconfident. "I do believe that we're intelligent enough to keep ahead of things," says epidemiologist Shope. Nonetheless, neither he nor any of his colleagues will ever again be foolish enough to declare victory in the war against the microbes.

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CREDIT: Source: World Health Organization, Harvard School of Public Health, 1990 figures CAPTION: The World's Deadliest Scourges