Over the next four weeks Khan was constantly on airplanes, flying into suspected ARDS-hanta outbreaks in California, Nevada, Oregon, Louisiana, Arizona, Utah, and Idaho. His second case involved a fifty-one-year-old woman who “lived in smack-of-the-middle-of-nowhere Nevada,†as Khan later described it. She survived acute ARDS, thanks to what Khan insisted was “brilliant medical care by her rural doctors.†According to the woman, all spring and summer her pet cat kept dragging rodents into the house. Her area of Nevada had unusual rainfall, and most of the locals felt the rodent population was just about out of control.
Khan’s third hantavirus victim wasn’t as lucky; a resident of a remote area straddling the California-Nevada border, she died of hanta-ARDS. Khan’s team found infected mice around her property.
The fourth Khan case involved a twenty-nine-year-old ranch hand who worked the range along the northern California coast. He, too, died of acute ARDS.
An Oregon physician alerted the CDC to the possibility that one of his patients, a sixteen-year-old boy, had died mysteriously of ARDS a year earlier and might have been a hantavirus victim. By the end of August the CDC’s lab had confirmed that hantaviruses were in the dead boy’s body.
A particularly emotional case for Khan involved a fellow scientist: a promising twenty-seven-year-old female graduate student, Jeanne Messier, who was conducting ecology research in an isolated part of the California Sierras. Ailing, Messier made her way down to a small medical clinic in Mammoth Lake, California, on July 31, and was immediately airlifted to a hospital in Reno. She died shortly after arrival. Scientists found her Sierras cabin overrun by mice.
The U.S. Congress took notice of these events, and the eight senators representing the Four Corners states pushed through legislation during the dog days of July that allocated $6 million in emergency funds to assist the state and federal investigation; $2.6 million went to the CDC. Some members of Congress remarked that such an allocation might not have been necessary if DOD budget cutters hadn’t gutted the Army’s hanta program two years earlier.17
In August, New Mexico authorities requested additional laboratory assistance from USAMRIID scientists, and Peter Jahrling and Connie Schmaljohn began separate efforts to isolate the strange new hantaviruses that were seemingly cropping up all over the United States. Soon the Army researchers were in a competition—later a rivalry—with their CDC colleagues. They discovered the virus in the body of an eight-year-old Mississippi girl who died of an ailment whose symptoms didn’t match the CDC definition of hanta-ARDS that Breimen and Chapman had written three months earlier. The CDC refused to add the Mississippi case to its growing list of Four Corners virus victims.
“The CDC is claiming it did not meet their case criteria,†Jahrling would later say with some bitterness. “They cannot refute, however, our evidence that we have a replicating hantavirus from that case, in cell culture.â€
In early June, another alert rural physician spotted what would prove to be one of the most puzzling hanta cases, this one occurring in Louisiana. A fifty-eight-year-old bridge inspector had died of sudden ARDS, and rural physicians called Khan in late July. While the Louisiana doctors frankly doubted the case could be another example of Four Corners disease, they had read the CDC’s bulletins and thought Khan should know that the symptoms matched.
Khan was dubious. The Peromyscus mouse didn’t inhabit Louisiana, and the area was over 200 miles away from the East Texas site of Khan’s first investigation. All doubt vanished, however, when Khan saw the patient’s medical records and Peters’s lab group confirmed that the blood samples were antibody-positive for hanta infection. The victim’s farmhouse was neat as a pin—no signs of rodent infestation. But the victim’s co-workers told Khan that they ran into rats and mice every day as they crawled around culverts and ditches to inspect western Louisiana’s bridges.
When the lab did PCR analysis on the Louisiana man’s virus, the mystery deepened: it didn’t match with the Four Corners strain or any other known hantavirus. Fellow bridge workers hadn’t seen the distinctive white-bellied deer mice around their work site, but they had encountered plenty of the big brown Rattus norvegicus—the same rat species LeDuc discovered years earlier carrying Seoul-strain hanta in Baltimore.
Ksiazek was one of the few CDC scientists who weren’t surprised by the discovery.
“These viruses are all pretty close to one another, as viruses go. And all these rodents have common ancestors. The genetically closest viruses are carried by close-relative rodents. Personally, I think this is an indication of co-evolution of rodents and their passenger viruses,†Ksiazek said.
By summer’s end Ksiazek suspected that more strains of hantaviruses remained to be uncovered in North America, and many hundreds of cases of ARDS, kidney disease, and hypertension in the United States every year would turn out to have been caused by these rodent viruses. While only forty-two cases of hanta-ARDS were confirmed by the CDC as of October 29, Ksiazek was convinced that they represented the tiny tip of a vast disease iceberg. Retrospective analysis showed that the earliest identifiable case occurred in July 1991. Since then, patients had ranged in age from twelve to sixty-nine years, and 62 percent had died. Half the victims were American Indians: presumably due to lifestyle, not genetic, factors.18
Throughout history, rats and mice have taken advantage of human movements to gain access to new ecologies around the world. The arrival of R. rattus and its cousins in the Americas is undoubtedly recent, probably having occurred less than 500 years ago when rodent stowaways made their way to American soil from the boats of European explorers and slave traders. And they may have been on the European continent for only some 1,200 to 1,500 years prior to that, having stowed away on traders’ ships and caravans from the Middle East and the Far East.19
Given how recently, on a scale of evolutionary time, these rodents have spread around the world, it should come as no surprise that they carry viruses which, whether found on the Volga steppes or in the deserts of Arizona, bear remarkable resemblances. And if the origins of these hantaviruses can be traced back to the earliest periods of mouse and rat evolution, it would seem logical to assume that careful inspection of Rattus, Peromyscus, and Mus cousins all over the world would reveal still more hanta strains.
The Four Corners outbreak prompted scientists to rethink diseases once labeled as “unknown etiology†and consider the possibility that millions of people worldwide may needlessly suffer ailments and death caused by the rodent-carried viruses.
Kidney expert Dr. Guy Neild of Middlesex Hospital in London was moved to ask during the Four Corners investigation whether the long-mysterious “trench nephritis†that claimed the lives of hundreds of soldiers hunkered down in trenches during the American Civil War and World War I may not have been due to hantaviruses carried by co-entrenched rats or mice.20
German physicians from the University of Würzburg reported that a surge in European hantavirus cases occurred during the spring of 1993, leading to hemorrhagic fever with kidney complications. They noted that rodent control efforts had slowed a bit since German unification, and wondered whether the surge in the German rat population could have been prevented. 21 German records indicated that a first, fairly small hantavirus epidemic surfaced in that country during mid-1990, causing no fatalities, but 88 confirmed renal illnesses. A second German hantavirus epidemic ran its course from September 1992 to October 1993: some 183 illnesses, no deaths. Researchers were certain that the outbreaks were the result of local surges in the rodent and vole populations, and that illnesses in the 1993 outbreak were more severe. They were also certain that hanta cases were underreported by German physicians.22
Similar surges in Puumala infection were noted in France, Belgium, and the Netherlands in 1993.23
Though the Four Corners type of respiratory h
antavirus had never been seen in Russia, classic kidney disease-producing forms were seen between 1985 and 1992 in twenty-three regions of the country, afflicting 68,796 people. The ailments were caused by more than seventy different hantavirus strains that were carried by sixty-three different species of birds and small mammals, including all common rodents.
“These rodents and their viruses have been here for millennia,†McDade concluded. “There may have originally been a common ancestor virus infecting a single rodent species, which may have mutated and spread to other rodents over time. But these viruses have almost certainly been among us for centuries.â€
McDade paused, examined his hands for a moment, and added, “I often wonder with Legionnaires’ Disease, if there had not been an association with a particular hotel, a drama, if you will. If there had just continued to be sporadic, scattered, inexplicable pneumonia deaths, would we have ever recognized Legionnaires’ as a distinct disease?
“And I now wonder the same thing about Four Corners. If there hadn’t been that one cluster of four cases among healthy Navajos, would we have ever recognized the virus among us?†McDade asked, noting that there were many other diseases for which no clear cause is known.
“We should continue to allow for the possibility that they are all due to infectious agents,†he said.24
Inside the CDC’s P4 laboratory Dr. Luanne Elliott was toiling around the clock during the summer and fall of 1993 trying to find a way to grow the Louisiana and Four Corners viruses in test tubes. For four months the slow-growing viruses stubbornly resisted her expert efforts. In the last week of September she finally succeeded in experimentally infecting laboratory mice, and a month later was able to cultivate live virus.
At USAMRIID similar efforts to grow the Four Corners virus in the laboratory, isolate it, and further elaborate its genetic makeup were underway. The two federal laboratories raced to complete the jobs first, eventually reaching a dead heat with both groups declaring victory at the annual meeting of the American Society of Tropical Medicine and Hygiene in Atlanta on November 3, 1993, and at a University of New Mexico hantavirus conference on November 20. Jahrling succeeded in growing virus that came from a New Mexico patient, and University of New Mexico collaborator Kurt Nolte made electron microscope photographs of the Four Corners virus budding from the membranes of monkey cells.25
At the same time, Schmaljohn succeeded in growing Four Corners virus that was extracted from a deer mouse trapped near the California mountain cabin of hantavirus victim Jeanne Messier. As was the case with Jahrling’s isolate, the Schmaljohn virus grew on monkey Vero cells.
And the CDC team isolated the virus from a New Mexico deer mouse, also successfully growing the microbe on monkey cells.
Unfortunately, each group jostled for credit as “the first,†and considerable tensions existed between the CDC and USAMRIID. Eventually they agreed to simultaneous publication of their work, sharing credit for the isolation and identification of the Four Corners virus.
Successful isolation of the virus opened up the next obvious phases of the effort: development of a vaccine and an easy screening test that could be used in rural medical clinics. Schmaljohn’s team had already developed an experimental vaccine for the Seoul virus,26 so there were reasonable grounds for optimism that a similar Four Corners vaccine could be created quickly.
Perhaps more important than an eventual vaccine or diagnostic test was the actual process whereby the collective scientific enterprise identified the cause of the mysterious disease and swiftly brought the epidemic to a halt. Though there were unfortunate tensions between the CDC and USAMRIID, and Navajos felt the sting of discrimination, the overall effort was noteworthy as a demonstration of two old principles of epidemic investigation and as an illustration of an exciting new principle.
The old, but often overlooked principles were simple. All “new†diseases must first be noticed by someone who has the insight and courage to sound an alarm and set in motion a thorough investigation. And once in place, investigations are best conducted in an atmosphere of candor and collectivity, rather than the secrecy, backbiting, rivalry, and mutual contempt that had unfortunately characterized many other scientific pursuits of emerging microbes.
The novel discovery—one that is sure to permanently change the course of emerging microbe and epidemic research—was the utility of molecular biology and, in particular, PCR. Just as police work was forever changed by the discovery that all human beings have unique fingerprints that can be “lifted†from weapons and other objects found at the scene of a crime, so PCR provided a revolutionary tool that, for the first time, put the laboratory scientists in the driver’s seat in an epidemic investigation. Before the CDC animal catchers even set foot in the Four Corners area, Stuart Nichol had been able to use USAMRIID genetic primers for various hantaviruses to rapidly screen human samples shipped to Atlanta by the New Mexico authorities. That would have been impossible twelve years earlier, when the AIDS virus made its appearance.
The hantavirus investigation of 1993 proved that things could be done right, that humanity could comprehend and control the microbes, if there was the political and scientific will.
At the beginning of 1994, the CDC reported that a total of fifty-five hantavirus ARDS cases had been confirmed in sixteen of the United States. Thirty-two of the infected individuals had died. And one of the newly confirmed cases occurred in Florida—an area that was definitely bereft of P. maniculatus deer mice.27 Days later the CDC and the states of Rhode Island and New York announced the death of David Rosenberg, a twenty-year-old student at the Rhode Island School of Design in Providence. Though Rosenberg died of ARDS in a Providence hospital, he had spent the weeks prior to taking ill with his parents on Long Island, and making a student film in his father’s abandoned warehouse in Queens. Investigations revealed that one worker in the Rosenberg family electrical supplies factory, located near the warehouse, had developed antibodies to hantaviruses, and Rosenberg was infected with a virus that closely resembled the Four Corners strain. No infected animals were retrieved, but investigations were hampered by an unusually harsh winter that brought seventeen major snowstorms in New York, driving rodents into hiding.28
In January 1994 the strange new microbe was officially named Muerto Canyon, after the valley inside the Navajo Nation in which the Four Corners virus first appeared.
Muerto Canyon—Valley of Death.
16
Nature and Homo sapiens
SEAL PLAGUE, CHOLERA, GLOBAL WARMING, BIODIVERSITY, AND THE MICROBIAL SOUP
It is hard to gain historical perspective on an event that is completely unlike any other we have seen before.
—Al Gore, Earth in the Balance, 1992
That humanity had grossly underestimated the microbes was no longer, as the world approached the twenty-first century, a matter of doubt. The microbes were winning. The debate centered not on whether Homo sapiens was increasingly challenged by microscopic competitors for domination of the planet; rather, arguments among scientists focused on the whys, hows, and whens of an acknowledged threat.
It was the virologists, and one exceptional bacteriologist, who started the debate in 1989, but they were quickly joined by scientists and physicians representing fields as diverse as entomology, pediatric infectious disease, marine mammal biology, atmospheric chemistry, and nucleic genetics. Separated by enormous linguistic and perceptual gulfs, the researchers sought a common language and lens through which they could collectively analyze and interpret microbial events.
There had never really been a discipline of medical microbial ecology, though some exceptional scientists had, over the years, tried to frame disease and environmental issues in a manner that embraced the full range of events at the microscopic level. It was far less difficult to study ecology at the level of human interaction—the plainly visible.
; There were certainly lessons to be drawn from the study of classical ecology and environmental science. Experts in those fields had, by the 1980s, declared that a crisis was afoot spanning virtually all tiers of earth’s macroenvironment, from the naked mole rats that foraged beneath the earth to the planet’s protective ozone layer. The extraordinary, rapid growth of the Homo sapiens population, coupled with its voracious appetite for planetary dominance and resource consumption, had put every measurable biological and chemical system on earth in a state of imbalance.
Extinctions, toxic chemicals, greater background levels of nuclear and ionizing radiation, ultraviolet-light penetration of the atmosphere, global warming, wholesale devastations of ecospheres—these were the changes of which ecologists spoke as the world approached the twenty-first century. With nearly 6 billion human beings already crowded onto a planet in 1994 that had been occupied by fewer than 1.5 billion a century earlier, something had to give. That “something†was Nature—all observable biological systems other than Homo sapiens and their domesticated fellow animals. So rapid and seemingly unchallenged was human population growth, the World Bank predicted that nearly three times more Homo sapiens, on the order of 11 to 14.5 billion, would be crowded onto the planet’s surface by 2050. Some high-end United Nations estimates forecast that more than 9 billion human beings would be crammed together on earth as early as 2025.
The United Nations Population Fund spoke of an “optimistic†forecast in which the planet’s Homo sapiens population “stabilized†at 9 billion by the middle of the twenty-first century.1 But it was hard to imagine what kind of stability—or, more likely, instability—the world would then face, particularly given that the bulk of that human population growth would be in the poorest nations on earth. By the 1990s it was already obvious that the countries that were experiencing the most radical population growths were also those confronting the most rapid environmental degradations and worst scales of human suffering. 2
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