THE WAR BETWEEN MAN AND MICROBE

In The Coming Plague, Laurie Garrett investigates the global epidemic of infectious diseases. Far from being beaten, they are emerging in new and more virulent forms. In our first extract, she tracks a deadly virus that hit America two years ago

LONG-DISTANCE runner Merrill Bahe was on his way to his girlfriend's funeral on 14 May 1993, when he found himself gasping for air. Suddenly, and quite dramatically, he was overcome with fever, headache and respiratory distress. In the presence of his grief-stricken relatives, Bahe gulped desperately for air in their car, en route south to Gallup, New Mexico. Minutes later the 19-year-old Navajo athlete was dead.

His 24-year-old girlfriend had died in a small Indian Health Service clinic 60 miles away from Gallup a few days earlier, after an identical bout of sudden respiratory illness. And within the week, her brother and his girlfriend, also young, athletic Navajos who lived near Bahe, fell mysteriously ill; the young woman died.

Word of the sudden deaths spread across the Navajo Nation of 175,000 people living in an area of 17 million acres spanning four states: Arizona, New Mexico, Colorado and Utah. Because the borders of the four states meet in the area, the region is called Four Corners. The locale for many John Wayne Westerns, Four Corners is surrounded by massive tracts of sparsely populated sandstone landscape that plunge into majestic canyons and arch upward forming dramatic ridges and peaks. It is a place where people speak of "big sky" as they gaze across the psychedelically coloured desert to the wide horizon.

The doctor who pronounced Bahe dead on arrival at the emergency room of the Indian Health Centre in Gallup was internist Bruce Tempest. He was struck by Bahe's youth and athleticism, and recalled discussing a similar case over the phone with an IHS colleague at another Navajo clinic. When he discovered that the other case was Bahe's fiancee, Tempest realised this might not be a routine case of unexplained illness and set in motion what was to lead to a national epidemic investigation.

The Navajo IHS was unique in that its clinics were spread out over an area so vast that some physicians never had an opportunity to meet one another. But they were in constant telecommunication, and IHS physicians known for their particular expertise receive dozens of calls a day from other doctors working in American Indian clinics from Colorado all the way down to Window Rock, Arizona, hundreds of miles to the south. Tempest, who had worked in the area for the IHS since 1967, was known for his unique problem-solving ability in confusing situations. As a result, he already had on his desk in Gallup the medical files on a Navajo woman who had died mysteriously in a distant clinic five month earlier, of an apparently similar acute respiratory distress, and he had served as a telephone adviser on a couple of other puzzling pulmonary cases during the spring.

Now he got on the phone and rang all those attending physicians, asking for details on the earlier respiratory death cases. "So by the end of the day, Friday [14 May], I was able to compile a list of five healthy young people who had died of acute respiratory distress syndrome," Tempest later said.

He also rang the New Mexico Department of Health and IHS epidemiologist, Dr Jim Cheek. The state set its laboratories in motion, testing the autopsy samples and reviewing medical charts, looking for evidence of the respiratory diseases that had haunted the Navajos for decades: bubonic plague, Hemophilus influ-enza, viral pneumonia and influenza.

The obvious and immediate autopsy finding was that the lungs of Bahe and his girlfriend were so severely fluid-filled that they weighed twice as much as would normally be expected for young adults of their sizes.

Isolated cases of the bubonic form of the plague had occurred sporadically among the Navajos for decades, carried by prairie dogs [burrowing rodents]. Since the early 1970s, health officials in the state had maintained a strong and vigilant plague-surveillance programme, quickly spotting the occasional case. Far less common was pneumonic plague, in which bacteria grew in the victims' lungs and could be spread through the air from one person to another. New Mexico has an extraordinary plague laboratory - possibly the best in the world - which has seen enough cases over the years to be able to diagnose rapidly and stop an outbreak. On the basis of their symptoms, state officials therefore hypothesised that Bahe and his girlfriend had died of pneumonic plague.

But that wasn't what the laboratory concluded. No plague bacteria could be found in the victims' blood or tissue samples.

Next, Cheek suspected a toxic chemical might be the cause. A computer search turned up several possibilities, but "the one that fit the bill perfectly", Cheek said, was phosgene. Used during World War I by the Germans, phosgene could cause symptoms of Acute Respiratory Distress Syndrome, or ARDS, over 24 hours after exposure. A sister compound, phosphene, was also known to cause ARDS but produced more rapid symptoms. Although largely banned in the United States, Cheek discovered that phosphene was still legally used to kill prairie dogs, which that year had been particularly pernicious. "Aha! We have something here," he exclaimed. "Somebody has been doing some prairie dog eradication."

But his enthusiasm was soon dampened by an investigative visit to the Bahe dwelling, a trailer. He found no sign of phosphene containers, chemical spray apparatus or residual chemicals. In fact, he found nothing out of the ordinary in the empty trailer, except, perhaps, an unusual amount of mouse faeces scattered here and there. Cheek assumed that the rodents had invaded the trailer after it was abandoned by the ailing humans.

By 20 May, Cheek had a list of 10 suspected cases, all from the Four Corners area, and he was stumped. The 35-year-old physician had been in the New Mexico area for only seven months, and he was running out of ideas. So, having spent the previous two years working in the epidemiology department of the Centre for Diseases Control (see panel overleaf), he called the agency's top expert on epidemics and his old friend, Rob Breimen.

"I wondered if it might be some kind of mycoplasma [bacteria], because they're so hard to culture in the laboratory. I thought maybe that's why we weren't finding anything," Cheek later said.

Breimen, who had been involved in previous investigations of equally puzzling outbreaks (including the identification of Legionnaires' Disease at a Bicentennial gathering in a Philadelphia hotel), was intrigued. The next day he shared the curious list of 10 suspect ARDS cases with a few CDC colleagues, all of whom agreed that there was something awfully odd about such sudden deaths among healthy young people. A week later the Indian Health Service and the state of New Mexico formally requested CDC assistance in solving the Four Corners mystery. Now the vaguely interesting puzzle was a matter of official urgency.

IN NAVAJO culture it is taboo to speak of the dead or utter their names for several days after their demise. But by now the local press had got wind of the story and reporters were crawling all over the Navajo Nation asking questions about the lives and deaths of Merrill Bahe and the other known ARDS victims. Matters worsened when an Arizona newspaper published details about one patient, drawing extensively from the deceased's medical chart.

"The obvious conclusion people drew was that the paper got it from us," IHS physician Bruce Tempest said. "Here we were trying desperately to protect patient confidentiality, and the public trust was eroding. We were getting it from both sides, being accused of giving the press confidential information on the one hand, and charged with some conspiratorial cover- up on the other."

The situation reached boiling point when some officials and media referred to the mysterious ailment as "Navajo flu" or "Navajo disease", ignoring the fact that non-Navajos were also falling ill, and marking the American Indians with what the Navajos considered a grossly unfair stigma. By the first week of June the situation was out of control, as anti-Indian racism mixed with fears of disease. Non-Navajos stayed away from Indian-owned businesses, schoolchildren from the Navajo Nation were denied a planned field trip to California, waitresses reportedly wore rubber gloves when serving Navajo customers, and there were rumours of tourists driving across the Navajo mesas wearing surgical masks.

There were also reports of health investigators and journalists being run off the Navajo Nation at gunpoint by angry residents, and Jim Cheek feared that the entire disease investigation might collapse. Cheek, a Cherokee Indian, sympathised with the Navajos and worked with the IHS area director, Dr John Hubbard, to relieve the tensions. They made their case at a meeting of the Tribal Council. Tribal president Peterson Zah promised full cooperation, and Hubbard vowed there would be no further violations of tribal sensitivities.

What followed was an investigation unprecedented in its integration of community members into every aspect of the inquiry. Tribal medicine men and elders were respectfully consulted, and they provided the investigators with two vital clues: the pinon nut harvest was unusually large that spring, as was the mouse population. Not since the great epidemics of 1918 and 1936, the elders said, had pinon, mouse and disease conditions all been so high. The elders' insights steered the investigators toward searching for a link between the ailments and mice.

By then the field team included more than a hundred scientists, physicians and animal trappers, all scouring the Four Corners area. And in the high security labs at CDC in Atlanta the disease detectives were getting close.

During the pre-dawn hours of Thursday, 3 June, antibodies against a family of viruses called hantaviruses cross-reacted in test tubes with blood from the patients. Furthermore, patient blood carefully injected into laboratory mice showed even stronger antibody reaction to hantavirus reagents. That proved that the agent was infectious and that the virus could reproduce and multiply inside mice. Identifying the exact strain of hantavirus responsible for the outbreak, however, would require infected wild animals - the microbes' reservoirs. Only in these would virus levels be sufficient to make isolation and full identification possible.

At a staff meeting that day CJ Peters, head of the CDC's pathogens branch, told his colleagues who were about to head out to Four Corners that the culprit was probably a hantavirus, and he wanted them to send back plenty of wild rodent samples. Applause and disbelief followed. While the staff praised the lab's speedy solution of the cause of the epidemic, some were dubious: all known hantaviruses caused kidney problems, none produced respiratory distress. Those familiar with hantavirus history were sceptical that the virus - first noted in Korea - could have found its way to a landlocked, remote region of North America.

HANTAVIRUSES first came to world attention during the Korean War. Between 1951 and 1954, over 2,500 GIs and an unknown number of Korean soldiers fell ill with a mysterious disease that caused fevers, fatigue and kidney failure: 121 GIs died. US Army researchers fairly quickly figured out that the disease was caused by a virus that was normally carried by field mice. It took over 20 years, however, for scientists to successfully isolate the virus - which they called Korean Hantaan - from the lungs of infected Apodemus agrarius mice.

When the army scientists involved in the early research into the hantaviruses heard about the preliminary conclusions of the Four Corners investigations, they were excited and intrigued. James LeDuc, a microbiologist, and his colleague from Johns Hopkins University, Jamie Childs, had been the first to apply polymerase chain reactions (PCR) - the genetic "fingerprinting" of cells - to the diagnosis and study of hantaviruses. LeDuc and Childs developed PCR techniques for hantaviral searches in 1991, identifying the precise DNA sequence in the virus, which in 1993 were of great help to CJ Peters's Special Pathogens Laboratory at the CDC.

By early June 1993, less than a month after Merrill Bahe's death, the second wave of CDC field investigators headed out to Four Corners. 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. Teaming up with Navajo trappers and health workers, they went out to every site where people had become ill and set hundreds of animal traps, heavier ones that could handle animals as large as raccoons and skunks, and smaller aluminium traps for mice, prairie dogs and the like.

When the traps were collected nearly half them contained all sorts of creatures, from mice and prairie dogs to rats and 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, commonly known as a deer mouse.

In initial blood antibody tests the 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 PCR techniques for diagnosing these infections were now in use, only the deer mice were found to be commonly carrying the virus.

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 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 unrecognised hantavirus".

THE P maniculatus were not 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 throughout the United States and northern Mexico. Only the Deep South states of the US seemed to be excluded from the deer mouse's natural territory. P. maniculatus were, in other words, ubiquitous North American field rodents.

And it wasn't long before evidence of the virus was being identified all over the country. A woman seemed to have died of the mysterious ARDS a thousand miles away from Four Corners, in east Texas. There were suspected outbreaks in California, Nevada, Oregon, Louisiana, Arizona, Utah and Idaho. By summer's end scientists suspected that more strains of hantaviruses remained to be uncovered in North America, and that 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. The Four Corners outbreak prompted scientists to rethink diseases once labelled 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 Middle-sex 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 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.

German physicians from the University of Wurzburg reported that a surge in European hantavirus cases occurred during the spring of 1993, leading to haemorrhagic fever with kidney complications. They noted that rodent control efforts had slowed since German unification, and wondered if the surge in the German rat population could have been prevented. Similar surges in infection were noted in Bel-gium, France and the Netherlands in 1993.

"These rodents and their viruses have been here for millennia," one of the scientists involved in the Four Corners investigation concluded. "There may have originally been a common ancestor virus infecting a single rodent species which mutated and spread to other rodents over time. But these viruses have almost certainly been among us for centuries.

"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 recognised 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 recognised the virus among us?" the scientist 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.

SUCCESSFUL isolation of the Four Corners 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. An experimental vaccine existed for the Korean virus, 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 collective scientific enterprise identified the cause of the mysterious disease and swiftly brought the epidemic to a halt. 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 candour and collectivity, rather than the secrecy, backbiting, rivalry and mutual contempt that had characterised many other scientific pursuits of emerging microbes.

The novel discovery - one that is sure to permanently change the course of microbe and epidemic research - was the role of molecular biology and, in particular, polymerase chain reactions. Just as police work was forever changed by the discovery that all human beings have unique fingerprints that can be "lifted" from 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.

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.

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 means Valley of Death. !

NEXT WEEK: Moving and mutating microbes