The Coming Plague

by Laurie Garrett

  “It doesn’t match,” he said, garnering support from most of the physicians in the room. Those in the meeting who were familiar with hantavirus history were skeptical that the virus—first noted in Korea—could have found its way to a landlocked, remote region of North America.

  Peters told the group that his molecular biology team was working on a detailed genetic analysis of the Four Corners virus, and he suspected it might turn out to be something new.

  “Look, we know there are different types of hantas out there [in the world],” he said. “So let’s not rule things out, or in. Finding antibodies isn’t enough. We know that.”

  Hantaviruses first came to world attention during the Korean War.4 Between 1951 and 1954, more than 2,500 GIs and an unknown number of Korean soldiers fell ill to a mysterious disease that caused fevers, weakness, fatigue, and kidney failure: 121 GIs died of the ailment.5 U.S. Army researchers fairly quickly figured out that the disease was caused by a virus that was normally carried by field mice.

  But it took over twenty years for scientists to successfully isolate the virus—dubbed Korean Hantaan—from the lungs of infected Apodemus agrarius mice. Dr. Karl Johnson, then with the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID) at Fort Detrick, collaborated with Dr. Ho Wang Lee of Korea University Medical School in Seoul to discover the virus, using electron microscopes to spot the round microbes that were neatly stacked in rows along the epithelial lining of Apodemus lungs.6

  The natural territory of A. agrarius included large parts of Japan, Korea, northeastern China, and southeastern and central Russia. In South Korea between 1955 and 1977, over 9,000 cases of Hantaan were documented; 6.5 percent were fatal. Far more cases were suspected, but were thought to have escaped diagnosis because of their similarity to milder, common ailments, such as influenza.

  During the 1970s eleven other forms of hantaviruses were discovered in Eastern Europe and Asia, all linked to usually mild kidney diseases with fatality rates ranging from 10 down to 0.1 percent of all infected people. The viruses were always carried by some type of wild rodent, and people came in contact with the microbes through skin exposure or inhalation of infected animal feces or urine.

  In 1977 Belgian researcher Guido van der Gröen, having maintained his interest in hemorrhagic viruses since the Ebola investigation in Zaire, discovered in his laboratory at the Institute of Tropical Diseases in Antwerp hantavirus-induced mild cases of muscle pain, hypertension, and kidney dysfunction among residents of his city. The apparently urban viral strain was very similar to one previously discovered in Sweden,7 called Puumala virus, carried by voles (Clethrionomys glareolus) that inhabited riverbanks. Between 1977 and 1986 van der Gröen identified seventy-six cases of Antwerp-type hantaviral disease in Belgium and France, and tried to warn local physicians that many hanta cases were undoubtedly going undiagnosed because they were confused with occupational back problems, flu, and other minor ailments.8

  Johnson and Lee, intrigued by van der Gröen’s urban hanta findings, tested rats in downtown Seoul, finding that the two most common species in the world—Rattus rattus and Rattus norvegicus—carried a form of virus only slightly different from the Korean Hantaan strain. They were convinced that the rat infections were relatively recent, having occurred sometime around the Korean War when aerial bombing campaigns drove the A. agrarius field mice out of their natural habitats into urban areas, where they got into turf battles with the rats and probably passed the virus on to the larger rodents in biting and clawing fights.

  Since Korea was rapidly becoming one of America’s biggest trading partners, Johnson wondered whether infected Seoul rats might have found their way into the cargo holds of Korean ships and then escaped into U.S. harbor cities. In 1982, at Johnson’s urging, Fort Detrick and CDC scientists combed the harbor areas of Baltimore, Houston, Philadelphia, San Pedro, and New Orleans looking for rats. Everywhere the Army scientists looked, Seoul virus turned up in both black R. rattus and their brown cousins, R. norvegicus.

  That year, 1982, Lee teamed up with NIH Nobel laureate Carleton Gajdusek to test common North American voles for hantaviruses. They scoured Gajdusek’s property in Frederick, Maryland, capturing local rodents. And the scientists found a new strain of hantavirus—dubbed Prospect Hill virus after the site of its discovery—and showed that it was carried by two vole species, Microtus pennsylvanicus and M. californicus. Between them, these voles spanned territory encompassing most of North America.

  One of the U.S. Army scientists most intrigued by evidence of hantaviruses in North American rodents was a tall, lean microbiologist named James LeDuc. During the early 1980s LeDuc reasoned that somebody in the United States must suffer Hantaan illness if the virus was infecting domestic rats, so he teamed up with other Army scientists and Jamie Childs, then at Johns Hopkins Medical School, to search for evidence of hanta disease in Baltimore. First, they carefully tested the local rats, discovering to their amazement that virtually every rat over two years of age was infected with a hanta virus. The team then tested 1,788 adults admitted either to Johns Hopkins or a Baltimore sexually transmitted disease clinic in 1986; four were infected with the Korean Hantaan virus. Because the individuals hadn’t traveled outside the United States, LeDuc and Childs concluded that they had acquired their infections from local rats.9

  That led LeDuc and Childs to consider focusing their research on people who suffered symptoms that could be produced by hantaviruses. They knew that the viruses could cause chronic kidney disease in Korea and parts of Europe, so they tested the blood of 1,766 people who were undergoing proteinuria blood chemistry analysis at Johns Hopkins, as well as 254 kidney dialysis patients. They discovered that 6.5 percent of the dialysis patients who were suffering hypertensive kidney disease had serum that reacted with Seoul hantavirus antibodies, indicating that they had been infected.10

  LeDuc and Childs also found that common Baltimore house mice—Mus musculus—carried the Seoul virus.

  In August 1986 a Mexican immigrant working in the town of Leakey, Texas, died of internal hemorrhaging and kidney failure. Scientists from the NIH suspected a hantavirus was responsible, and trapped rodents found in areas known to have been frequented by the deceased individual. They discovered that local house mice—again M. musculus—were infected with another type of hantavirus, which they designated Leakey virus.11

  By 1992, LeDuc was convinced that hantaviruses of various types were prevalent in rodents throughout North America, and strongly believed that they were responsible for the higher rates of hypertension and kidney disease seen among America’s inner-city poor, particularly African-Americans. 12 Furthermore, he feared that the problems might be worsening, as rat infestation of American inner-city areas increased. Between 1989 and 1991, for example, citizen complaints about rat infestation increased 33 percent in Baltimore and rodent control staff over the same period declined by 50 percent. All the lost staff had been funded under a federal program which was severely slashed by the Bush administration. Similarly, New York City took significant cuts in rodent control funds between 1989 and 1994, during which federal and local funding plummeted from $10.3 million to $5.2 million. Federal funding completely evaporated by 1992, prompting the New York City Health Commissioner, Dr. Margaret Hamburg, to formally express grave concern to the CDC that hantaviruses and other rodent-borne disease agents might get out of control in America’s largest metropolis. Despite the commissioner’s warnings, the newly elected mayor of New York City, Rudolph Giuliani, slashed the city’s rodent control budget by a further 50 percent in early 1994.

  Budget cuts in 1991–92 at the U.S. Department of Defense forced closure of most Army medical research programs; Childs, Peters, and Ksiazek went to the CDC and LeDuc ended up working at the World Health Organization headquarters in Geneva. Army hantavirus research slowed radically, le
aving only the fortunately prolific molecular biology labs of Dr. Connie Schmaljohn and Peter Jahrling at Fort Detrick to carry the load.

  The moment Peters and his CDC laboratory staff had hints of hantaviruses in the Four Corners outbreak, Childs and LeDuc were excited and intrigued. LeDuc was in daily telephone communication with his former Army colleagues, providing insight and gathering information to pass on to interested WHO scientists.

  Childs and LeDuc were the first scientists to apply polymerase chain reactions, or PCR, to the diagnosis and study of hantaviruses. LeDuc and Childs developed PCR techniques for hantaviral searches in 1991,13 and Peters’s Special Pathogens Laboratory would benefit enormously from that legacy in 1993. As the second wave of CDC field investigators, led by Breimen and McDade, headed out to Four Corners over the first June weekend, Peters, Ksiazek, and PCR expert Stuart Nichol eagerly anticipated receipt of rodent samples, upon which they intended to perform PCR analysis to identify which species of hantavirus was causing the Southwest outbreak.

  Breimen was skeptical of the hanta connection, though he did note that all earlier animal studies of various hantaviruses found high concentrations of the viruses in rodent lungs. One LeDuc/Childs study even indicated that lung tissue was the only site from which viruses could easily be extracted over the full course of a mouse infection.

  During their first forty-eight hours in Albuquerque, Breimen and Chapman hammered out a standard description of the disease, setting out the criteria for designating a suspected ARDS case as a possible hantavirus infection. And they created the questionnaires to be used by Navajo and CDC field investigators making door-to-door surveys on the outbreak.

  No sooner had Chapman completed those tasks, sleeping no more than four hours in two days, than she was asked to assess the utility of ribavirin as a treatment for the mystery disease. LeDuc and his colleagues had tested the antiviral drug on Hantaan patients in China in 1987, finding that it decreased the likelihood of dying if ribavirin was taken within the first three days of the disease. After that time, it wasn’t clear whether or not the drug was beneficial.14

  For physicians in the Four Corners area it was a desperate matter to find something—even a drug of dubious value—to give their ailing patients. Short of ribavirin, all the doctors could offer was good hospital management and TLC. And the mortality rate from the virus was very high, appearing to exceed 70 percent.

  By June 7 the CDC had confirmed twenty-four cases of the strange sickness, twelve lethal, all occurring in the Four Corners area.

  The most important clue the investigators had was the CDC lab’s hints of hantaviruses, which, based on the history of such viruses, pointed to rodent disease carriers. Childs, Chapman, and CDC ecologist John Krebs were among the three dozen investigators who, teamed with Navajo trappers and health workers, went out to every site where people had become ill and set hundreds of rodent traps. They had two types of spring-action traps; one, a heavy steel case, could handle animals as large as raccoons and skunks, while the smaller aluminum traps were designed for mice, prairie dogs, and the like.

  The crews had to be careful, avoiding exposure not only to the mystery virus but also to bubonic plague. Despite a temperature of over 100 degrees, they wore respirator masks, goggles, paper body suits, double-layered latex gloves, and disposable booties over their shoes. These precautions might protect them against airborne bits of hanta-contaminated dust, but Chapman was much more worried about getting bitten by a plague-carrying flea that might crawl under her protective garments to reach her vulnerable skin. She slathered generous layers of insect repellent on her skin as well, knowing that she wouldn’t be able to swat pests when she was wearing the gloves and body suit.

  When an inhabited trap was opened, scientists always stood upwind of the animal and carefully placed a plastic bag containing anesthetic over the door of the trap. As the animal fell into the bag, it quickly went unconscious. Later the scientists would withdraw blood and tissue samples, place them on dry ice, and ship the materials back to Peters’s P3/P4 laboratory for analysis.

  It seemed that the Navajo elders and Robert Parmenter’s scientific team were both right about the huge piñon harvest and a very large rodent population. After five years of severe drought, the Four Corners area had record snowfalls during the 1992–93 winter season, followed by an extraordinarily moist spring. Even in June the scientists could still see greenery in the desert and piñon trees standing flush with nutted cones.

  With the abundant vegetation came apparently unprecedented rodent populations.

  Nearly half the traps contained all sorts of creatures, from mice and prairie dogs to fat rats and smelly skunks, but by far the most common were Peromyscus maniculatus, a brown, big-eared mouse with white belly and tail and huge, black eyes sunk into the skull. Because of its brownand-white coloring, P. maniculatus was called a deer mouse.

  In initial blood antibody tests the CDC investigators found evidence of hanta infection in the deer mice, as well as two other Peromyscus species, two types of chipmunks, common house mice, and Neotoma albigula pack rats.

  In the lab, however, where CDC scientists had just perfected the use of PCR techniques for diagnosing these infections, only the deer mice were found to be commonly carrying the virus. With time the CDC lab would confirm by PCR the presence of the virus in a third of the first 770 P. maniculatus caught in the Four Corners area, as well as in 19.7 percent of P. truei (of 314 tested) and 6.9 percent of P. boylii mice (of 59 tested).

  The P. maniculatus were not mice restricted to habitats in Four Corners; on the contrary, these deer mice could be found all over Canada, as far north as the Arctic Circle, and, to the south, throughout the United States and northern Mexico. Only the Deep South states of the United States seemed to be excluded from the deer mouse’s natural territory. P. maniculatus were, in other words, ubiquitous North American field rodents.

  Knowing that, Breimen and McDade wondered how long it might be before mysterious ARDS cases turned up in other states.

  By the end of the first week in June, Peters’s lab already had suspicions, based on PCR analysis, that the virus infecting both people and Peromyscus in Four Corners was yet another newly discovered hanta strain. By mid-June they were sure: the Four Corners virus was, as they wrote in the CDC weekly publication, “a previously unrecognized hantavirus.”15

  If the virus was genetically different from previously identified hantas, its ability to produce acute respiratory symptoms, as opposed to the kidney problems caused by all other hantaviruses, became less questionable. The CDC lab spent the rest of June, July, and August comparing bits of the genetic sequences of the Four Corners virus with the eleven other known hantaviruses, discovering to their amazement that the new virus cross-reacted most strongly with Prospect Hill, the strain found in Maryland voles that had never been associated with human disease.

  “That surprised us,” Ksiazek said, “because here you had human mortality rates of seventy or eighty percent in Four Corners, and no disease of any kind with Prospect Hill.”

  The PCR analysis eventually revealed some significant differences in the genetic sequences of the two viral strains, yet Prospect Hill remained Four Corners’ closest known relative.16

  By mid-July the CDC lab had received over 10,000 animal and human samples for analysis; by late August that number was approaching 20,000. In addition to the tremendous burden of simply storing and labeling all those samples, Peters and Ksiazek felt they should pull out of their Atlanta freezers archived rodent samples collected during previous years around Four Corners for plague studies. They wanted to use the archive material to answer two key questions: (1) Is there an epidemic of the virus this year among the rodents or are the animals always carrying the virus at about the same frequency of infection? (2) Has this sudden apparent set of infections been the result of the virus’s mutating recently from a benign Prospect Hill-lik
e form to a new type capable of causing ARDS?

  The latter question had some purely circumstantial evidence behind it. Hantaviruses were of a class of viruses whose genetic material was stored in the form of three discrete pieces of RNA. Other segmented RNA viruses, such as influenza, were known to mutate frequently because during viral replication the copying of these big pieces of RNA was often a sloppy business. One RNA piece might cross over another, mixing up their genes. Extraneous bits of RNA in the cell the virus infected might get picked up and incorporated into the virus’s genetic blueprint. The result for many segmented RNA viruses was a sort of natural crapshoot, with each viral replication event carrying some odds of mutation.

  But by August the CDC lab was far too overwhelmed to consider an immediate foray through the archives. The questions would have to remain unanswered for the time being.

  Meanwhile, a woman seemed to have died of the mysterious ARDS a thousand miles away from Four Corners, in East Texas. The epidemic had expanded. In a matter of hours, Dr. Ali Khan, having just completed two years of postmedical training as a CDC Epidemic Intelligence Officer, was wandering around the East Texas town of Lufkin, working with state investigators to ensure that all clues at the death site were properly collected and none was overlooked.

  The victim, a youthful grandmother, had lived in a fairly elegant, neat house located in a rural area not far from the Louisiana border. No rodents were in or around her house, but Khan discovered telltale mouse feces in a back shed the woman used for putting up fruits and vegetables. Her husband said that she spent hours out there, canning all sorts of produce.

  The autopsy revealed that she had suffered a classic case of ARDS of unknown etiology, and Khan had her tissue and blood samples sent to C. J. Peters’s lab, where Four Corners virus infection was confirmed by PCR.