Stalking The Deadly Hantavirus: A Study In Teamwork

Editor's Note: This is the first part of a two-part series on hantavirus, the mysterious and lethal microorganism whose sudden appearance in the southwestern United States last year led to the deaths of more than a dozen people and sparked a flurry of activity in the research community. The following article recounts the swift and effective response to the frightening microbe by scientists of various disciplines. The second part of the series, to appear in the July 25 issue, discusses researchers' ongoing efforts to forestall further outbreaks of hantavirus-related infections. A lethal killer, untimely death, and hardworking detectives- -all of these were ingredients in the mystery surrounding last year's sudden outbreak of a deadly strain of hantavirus new to science and North America. But more intriguing, say researchers, is the other hantavirus story--the galvanization of seemingly disparate lines of research to solve, in a matter of weeks, one of the United States' most deadly epidemiological enigmas. Between May and June of last year, physicians and public health specialists confirmed that 13 people--several of them members of the Navajo Nation--had died of a mysterious disease characterized by flu-like symptoms that quickly deteriorated into a dangerous form of adult respiratory distress syndrome. No one had ever seen this pathology before--but, thanks to the sharp investigative work of a dedicated group of researchers, the culprit was correctly identified as a unique type of rodent-borne hantavirus in less than one month. "The discovery of a hantavirus infection with pulmonary syndrome is one of the success stories of the integration of medical care, public-health oversight, and molecular diagnostic technologies," says Joshua Lederberg, University Professor at Rockefeller University in New York. "That such an outbreak was [quickly] detected on the Navajo territory is at least partly a reflection of a governmental structure for health care, and prompt communications among the medical officers of that health service," he says, referring to the broad-based team of scientists from government agencies and research institutes. These researchers worked together to identify the cause of the outbreak and, thereby, alert the medical community about its existence and educate people about how to avoid it. THE LIFE AND TIMES OF THE HANTAVIRUSES Researchers stress that the microbe that is causing the most recent hantavirus outbreak is by no means isolated to the United States; rather, it comes from a family of viruses with a long history and a worldwide distribution. Various strains of hantaviruses have been found in Russia, Manchuria, Scandinavia, Lapland, and Korea. And hantavirus- like diseases were first recorded in China as early as 960 A.D. The Muerto Canyon, or Death Canyon, virus--the eerily appropriate name for the hantavirus isolated from the American Southwest in 1993--is a unique type of hantavirus. It causes lethal, flu-like symptoms, with about 60 percent mortality in cases reported so far. These are collectively known as the hantavirus pulmonary syndrome because the lungs are the primary target of infection. The first hantavirus strain was isolated in 1976 and named after a South Korean river--the Hantaan. This strain has a much lower mortality associated with it--1 percent to 15 percent. Its suite of symptoms is called hemorrhagic fever with renal syndrome because the major organ it affects is the kidney. In the 1950s, during the Korean War, thousands of United Nations troops contracted Korean hemorrhagic fever. This outbreak was eventually linked to a hantavirus and is responsible for U.S. Department of Defense (DoD) involvement in research on hantaviruses as well as for hantaviruses' adaptation to tissue culture and their eventual characterization and inclusion in DoD's library of viral genetic information. --K.Y.K. The scientists involved study a variety of subjects, including the fluctuations of rodent populations in the American Southwest, exotic diseases in U.S. troops stationed abroad, and viral genetics. Their work is sponsored by organizations at many levels and in many settings, such as the Centers for Disease Control and Prevention (CDC) in Atlanta, the Indian Health Service (IHS) in Rockville, Md., the University of New Mexico in Albuquerque, the Navajo Nation, the New Mexico State Department of Health in Santa Fe, and the Office of the Medical Investigator (OMI) in Albuquerque. In May 1993, all of these groups came together in the Four Corners region--where Utah, Arizona, Colorado, and New Mexico meet and where the virus was first found--to investigate the growing epidemic. Although this new hantavirus has not been eradicated--dozens of cases have subsequently been reported since the end of 1993-- researchers, nevertheless, marvel at the astounding collaboration because of both the coordination of communications and the speed with which the exact identification of the viral strain was achieved. Scientists also attribute the success of the hantavirus team to work already being conducted by the U.S. Department of Defense (DoD), namely the Army. For decades, Army researchers have been identifying and cataloging pathogens-- including hantaviruses found outside the U.S. (see accompanying story)--that afflict service personnel. "I think one of the things that was extremely important was that we had an infrastructure present that was familiar with hantaviruses, even though they're not U.S. pathogens," says C.J. Peters, chief of the special pathogens branch at CDC, of the DoD research. But, according to Peters, that's only part of the story of the science behind the investigation. "If the front end wasn't there, we wouldn't have brought other things to bear. PCR [polymerase chain reaction] was extremely important in clinching the case and identifying the new hantavirus, and absolutely basic in going around the country to find additional hantaviruses," he says. "Science was at a point where connections [were able to be made]. If we didn't have PCR, we maybe couldn't have done this," says Richard Wenzel, an infectious disease specialist at the University of Iowa College of Medicine, Iowa City, who wrote an op-ed piece about the hantavirus outbreak for the New England Journal of Medicine (R.P. Wenzel, 330[14]:1004-5, 1994). The account of events leading to the positive identification of the epidemic reads almost like the coverage of a relay race, with each runner--or in this case scientist--handing off the baton to the next in line. Two New Mexico state agencies played a crucial part in catalyzing the initial diagnosis. On May 14, 1993, a young man en route to his fiancee's funeral was brought into the Gallup Medical Center--a rural hospital run by IHS--where he died shortly thereafter of unknown causes, although he had developed flu-like symptoms a few days earlier. Richard Malone, an OMI deputy field investigator--and one of the "real heroes" of the hantavirus story, according to Kurt Nolte, a medical investigator for the state of New Mexico-- responded quickly to a call from the Gallup Medical Center on May 14. As a result, autopsies were performed on the young man and his fiancee--who had died of similar symptoms five days earlier--by OMI pathologist Patricia McFeeley that same evening. She was struck by the remarkable similarity between the two cases and an autopsy she had performed one month earlier, says Nolte, prompting OMI to notify the New Mexico health department about a possible epidemic in the making. Three days later--on May 17--Bruce Tempest, chief of medicine at the Gallup Medical Center also alerted the New Mexico health department about five cases (including the same young couple autopsied by McFeeley) who mysteriously died of respiratory failure. "This fellow came in and died in our emergency room," says Tempest. "I had been called earlier in the week about his fiancee, who had died at another hospital. I didn't know what to make of her. Then he came in and it took on a lot more importance." Piecing together this information with three earlier cases from the center and other hospitals, Tempest says, "I began to realize that these all fit a pattern." At the time, he says, a perplexing common characteristic was that the victims were all young and healthy, and that their deaths came swiftly and painfully. Researchers now know that the median age of victims of this hantavirus is 33 years, according to CDC officials. Flu-like symptoms--fever, chills, and muscle pains--are the first clinical signs of infection. But it is acute respiratory failure--when the lungs drown in fluid from the circulatory sys- tem--that causes death in nearly two-thirds of the cases. Tempest explains that these symptoms--called the hantavirus pulmonary syndrome--come on very quickly, over a matter of days, compared to other respiratory illnesses. News of these early cases quickly made its way to CDC via C. Mack Sewell, state epidemiologist for the New Mexico health department. "We called CDC on May 18, not to invite them in at that point, but basically to see if they were getting reports of unusual deaths," he says. The next day Sewell's office called neighboring health departments in the Four Corners region to see if they also had reports of mysterious deaths originating with flu-like symptoms. "By May 24, it was clear we had to alert the medical community," he says. That same day, "Dear Dr." letters--a general query describing the illness's symptoms and asking if similar cases had been seen--were mailed to state health departments across in the country. By late May, the CDC special pathogens branch was brought in because of its highly safe equipment and facilities, and special expertise for dealing with microbes that pose a dangerous threat to public health. Researchers attribute the quick turnaround in identifying the hantavirus to a number of factors, namely PCR and DoD's existing library of viral genetic information. HANTAVIRUS VIDEO Less than nine months after the initial hantavirus cases were reported, the Centers for Disease Control and Prevention (CDC) in Atlanta--along with the Indian Health Service in Rockville, Md., the Navajo Nation, the New Mexico Office of the Medical Investigator, the New Mexico State Department of Health, and the University of New Mexico in Albuquerque--produced an educational videotape entitled "A New Hantavirus" for distribution to health professionals. The free video covers details on the outbreak, its clinical description, laboratory diagnosis, treatment, surveillance, and prevention. The 57-minute video and its companion booklet may be copied for educational purposes. For more information, contact Ethleen Lloyd, CDC, 1600 Clifton Road, N.E., Mail Stop A-26, Atlanta, Ga. 30333Phone: (404) 639-1510 Fax: (404) 639-1509 --K.Y.K. Says Lederberg: "There is perhaps no precedent for the speed with which this new syndrome was related to previous cases of hantavirus with renal syndrome. All of this was enabled by the very sophisticated use of PCR and other diagnostic DNA technologies, and a background of research information on what, until then, was recorded as an obscure virus." Specimens from the New Mexico state health department were first sent to the CDC flu branch by May 28, where pathologist Sherif Zaki studied them, says Thomas Ksiazek, chief of the immunodiagnostic section of the CDC special pathogens branch. "Then, because the mortality was so high, [the samples] came to special pathogens," says Ksiazek. "We tested against a whole bunch of our favorite viruses and several of the hantaviruses gave us hits. Since that's one of the viruses that we work with, it flowed very naturally that we continued to [lead] the investigation," says CDC's Peters. Ksiazek and colleague Pierre Rollin, head of the athogenesis section of the special pathogens branch, used enzyme-linked immunosorbent assays--previously developed by the Army--to run tests on microbes that cause viral hemorrhagic fevers. The hantavirus group gave a positive result on June 2. After identifying the hantavirus antibodies, Stuart Nichol, chief of the molecular biology section at the special pathogens branch, started to work on a finer identification, using PCR. "We started quickly in designing the PCR primers- -probes to sort of go on a genetic fishing expedition--to see whether we could actually fish out information from [the hantavirus] tissues." He and colleagues unequivocally identified it not only as a hantavirus, but also as a new hantavirus. That was on June 4. Because all other known hantaviruses were isolated from rodents, CDC epidemiologists James Childs and John Krebs were dispatched to New Mexico to trap rodents from households where people had become ill. By June 14, "the loop was closed," says Ksiazek--30 percent of the deer mice sent back to CDC for analysis matched the tests already done on humans. This confirmed that the deer mouse, Peromyscus maniculatus, was the carrier of the hantavirus strain found in the Southwest. "The [DNA] sequence that we detected in the rodents was exactly the same as what we detected in humans," says Nichol. In mid-June, Robert Parmenter, a mammologist from the University of New Mexico who studies rodent population dynamics, was drawn into the picture. He was contacted because epidemiologists on the case were looking for climatological and ecological reasons why the outbreak just happened to occur in the spring of 1993. Parmenter explains that in 1992, an atmospheric and oceanic condition off the Pacific coast of America--known as El Nino--produced a very wet spring in the Southwest. Rodent populations exploded, presumably because of an increased food supply, which built up during the rainy growing season. "When we collected rodents in the spring of 1993 the populations were still very high, and this coincided with the time when everyone is out cleaning garages and sheds, breathing the dust where [rodent] feces are found," says Parmenter, referring to a likely path of mouse-to-human transmission. "One of the fascinating elements about this story is that it was sitting right there all the time," says Peters. "I mean, the earliest case that we've found retrospectively is from 1978, but I'm sure that it was here at some level for a very long time, and it's been completely missed in a supposedly technologically advanced country."

Stalking The Deadly Hantavirus: A Study In Teamwork

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