One Year Later, The Hantavirus Investigation Continues

on the hantavirus--a mysterious microbe that last year caused the sudden deaths of more than a dozen men and women in the southwest United States. Part 1, presented in the July 11, 1994, edition of The Scientist (page 14), described the effective cooperation among scientists to identify the microorganism. This article provides an account of how the research community is following up on hantavirus studies and what the prospects are for future paths of investigation. Last year's sudden and alarming spread of a deadly microorganism known as hantavirus in the Four Corners region of the United States--where Utah, Arizona, Colorado, and New Mexico meet--precipitated what some observers regard as an unprecedentedly successful collaboration among scientists from a wide variety of disciplines and organizations. The pernicious strain of this rodent-borne virus, which has caused at least 45 deaths in the U.S. so far, was unknown to science until last May. But, because of a fortuitous combination of factors, say researchers, the hantavirus and its carrier--the deer mouse (Peromyscus maniculatus)--were accurately identified in less than one month. Independent observers of the unfolding investigation, as well as those most intimately involved, cite three main reasons for the swift success in pegging the hantavirus as the cause of more than a dozen deaths in the spring of 1993: the development of modern molecular techniques such as the polymerase chain reaction; an existing library of viral genetic information at the Department of Defense; and the swift action taken by medical investigators at the start of the outbreak. In an effort to curtail more deaths, scientists' attention has now turned to developing coherent and effective health- education schemes to decrease human contact with rodents. Basic research on the pathology of the disease and the ecology of the deer mouse also continues. The investigators' inquiries are reaching well beyond the American Southwest to locate new hantavirus cases and strains. As of mid-May this year, 73 cases have been reported in 18 states, up from 53 cases reported at the end of 1993 (see map). Researchers say they are all too aware of the growing threat of new microorganisms worldwide, including the hantaviruses. "The IOM [Institute of Medicine] report on emerging infections [J. Lederberg, R.E. Shope, S.C. Oaks, Jr., eds., Emerging Infections: Microbial Threats to Health in the United States, Washington, D.C., IOM, National Academy Press, 1992] did finger hantavirus as a potential culprit, but along with dozens of other prospects that unhappily remain as candidates for grave future troubles. And it is far from clear what the future significance of hantavirus will be, given the prevalence of the Peromyscus mouse reservoir," warns Joshua Lederberg, University Professor at Rockefeller University in New York. In order to understand the hantavirus and its carrier, scientists from a wide variety of disciplines--such as virology, mammalogy, and public health--and from many types of organizations are now sharing their findings with the scientific community in a spate of recently published papers (see list on page 17). In conjunction with the Centers for Disease Control and Prevention (CDC) in Atlanta, groups such as the Indian Health Service (IHS) and state health departments located in the Four Corners region, the University of New Mexico in Albuquerque, the Navajo Nation, and the Office of the Medical Investigator (OMI) in Albuquerque are continuing this work in a multidisciplinary, coordinated research effort. According to Pat McConnon, chief of operations and management for the Hantavirus Task Force--an interdisciplinary group of CDC epidemiologists, laboratory technicians, and public health experts --Congress appropriated about $6 million in emergency funds in August 1993, utilized to devise and implement a plan to halt the spread of the virus. Two months later, CDC received another $5.9 million in operating funds for fiscal year 1994, says McConnon. This sum funds a variety of projects, including: $1.7 million to the Four Corners state health departments for ongoing clinical, health education, and rodent studies; $1.7 million to CDC for testing human and rodent tissue samples for the presence of hantavirus (McCon-non says that from June 1993 through May 1994, more than 50,000 samples of blood and tissue from humans and rodents were submitted to CDC for analysis); $400,000 to CDC for training 34 state health departments to perform the tests that identify the hantavirus in human tissue; $650,000 to IHS for developing prevention and education programs and conducting rodent studies; and $200,000 to other government entities, such as the Navy and the U.S. Park Service, for helping with rodent-control schemes. Scientists involved in the hantavirus investigation say an important part of their work has been to formulate a coherent agenda for research and prevention efforts. CDC's Hantavirus Task Force is the group that coordinates these activities, explains McConnon. For example, it approves the protocol for rodent surveys and is responsible for the hantavirus surveillance program--a nationwide mechanism for collating information on new cases of hantavirus infection. Citing a need for a broad range of expertise on the task force, its chairman, CDC epidemiologist C.J. Peters, says, "One of the reasons to have a task force was to get additional talent in [from CDC's nationwide offices]. Another was to try to find a way to make ends meet so that we could get the job done. We had to essentially put together a policy for rodent-borne viral diseases in this country where none had existed before--and quickly." After the initial outbreak, the task force looked at policies that had been used in Europe and Asia to combat other hantaviruses, but none of those were helpful, says Peters. "So we borrowed from common sense about what mammalogists knew about the nature of the deer mouse and what other people had tried in other countries," he says. "One of our jobs this year will be to find out if the [prevention] measures we recommended are really doing any good." A medical mystery surrounding the illness caused by the hantavirus--called hantavirus pulmonary syndrome--is why it attacks the lungs primarily. Other hantaviruses native to Asia and Europe affect the kidneys. To understand the disease's pathology, clinicians analyze the tissues of autopsied patients. "We did autopsies here in New Mexico until [about] July 19 [1993]. Then there was a long hiatus until this spring when we did a few more," says Kurt Nolte, a medical investigator with OMI. Using an electron microscope, Nolte and colleagues have found the hantavirus in endothelial cells of many human tissue types, including the lungs. "The million-dollar question is: `If it's in the endothelial cells throughout the body, why do capillaries in the lung leak, and not anywhere ' " asks Nolte. The cause of death in people infected with hantavirus is a suffocating flooding of the lungs with fluid from surrounding capillaries. So, says Nolte, looking for the difference in leakiness in lung capillaries compared with other types of capillaries is one of his office's major areas of investigation. J.S. Duchin et al., "Hantavirus pulmonary syndrome: A clinical description of 17 patients with a newly recognized disease," New England Journal of Medicine, 330(14):949-55, 1994. H. Feldmann et al., "Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome," Virus Research, 30:351-67, 1993. J. Lederberg, R.E. Shope, S.C. Oaks, Jr., eds., Emerging Infections: Microbial Threats to Health in the United States, Washington, D.C., Institute of Medicine, National Academy Press, 1992. S.T. Nichol et al., "Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness," Science, 262:914-17, 1993. C.F. Spiropoulou et al., "Genome structure and variability of a virus causing hantavirus pulmonary syndrome," Virology, 200:715-23, 1994. R.P. Wenzel, "A new hantavirus infection in North America," NEJM, 330(14):1004-5, 1994. Understanding the symptoms of the hantavirus is only part of the story, say investigators. Working on another aspect of the hantavirus puzzle is a small army of mammalogists and field biologists from state, federal, and university departments. They say they hope to gain a better understanding of the population fluctuations of the deer mouse and, therefore, prevalence of the hantavirus in nature from year to year. Terry Yates, curator of mammals at the University of New Mexico's Museum of Southwestern Biology, is one of the principal investigators on a multi-agency-sponsored survey of rodent populations in the Four Corners region. He says that this collaborative endeavor among state agencies, universities, CDC, and IHS has two components. The first part is looking at how widespread the hantavirus is in wild populations of mice. "We need to know where the virus is and isn't, how widely distributed it is across different [mouse] species, and if there is any difference in distribution [in mouse populations] due to altitude or latitude," Yates says. For example, he says, researchers might ask: "Do deer mice that live on mountaintops have it as well as those that live in the deserts?" The second component--a long-term monitoring project of mouse populations known to carry the hantavirus--began this month. "My crew [and others] will go out once a month and sample the rodents, put them to sleep--very gently--and take a small blood sample from them. Then they will revive them and release them exactly where they came from. Then we'll analyze that blood sample for presence or absence of hantavirus," Yates says. At the same time, field biologists will measure the plants and animals deer mice depend on, in addition to climatic conditions, to find a possible connection between the prevalence of infection in mice and ecological factors. With this information, Yates says, he will be able to ask the question "Can we predict in advance when the rodent population will increase?"--thereby enabling public health authorities to warn people that a bad hantavirus year might be imminent. Mammalogist Robert R. Parmenter, also at the University of New Mexico, was called in by CDC after last spring's initial outbreak to help with the first rodent studies. His group is continuing to sample rodents in the Southwest, noting that the population levels were low this spring in central New Mexico, compared with last spring, when above-average rainfall produced an abundant food supply. This contributed to a mouse population explosion that, scientists speculate, triggered the epidemic there. Yates adds: "We also have the world's largest collection of mammals here [at the museum], so we are looking back through time to see how far back we can trace this virus." While Yates is working on proj-ects that deal with hantavirus outbreaks of the past and future, Pat Bohan-- director of the division of environmental health services for the Navajo-area IHS office in Window Rock, Ariz.--is busy trying to stem the number of current hantavirus cases. Bohan's office designs and distributes educational materials whose main message is how to avoid contact with all rodents. Getting the word out takes many forms, says Bohan. IHS, along with CDC and others, have developed brochures aimed at children and adults. They have also produced slide sets and a video for a variety of audiences, among other items. "We have a broad range of materials to hopefully appeal to a broad range of people. We're trying to flood the area with information," says Bohan. Ben Muneta, an epidemiologist with IHS in Albuquerque, grew up in the area where the outbreak first occurred. He was called in to help design culturally sensitive educational materials and to act as a liaison between the Navajo Nation and the medical community. His and others' suggestions led to the production of two versions of the IHS educational video--one in English and another in a Navajo language. "I believe we've been as successful as anyone can be under the circumstances," says Bohan, referring to the remoteness of the Four Corners region. "I think we're doing a phenomenal job in getting the educational materials developed and [distributed] as quickly as we have." Rima F. Khabbaz, a CDC medical epidemiologist, became involved last August when she was asked to organize the national hantavirus surveillance program. Khabbaz works with state health department officials and private physicians; her responsibilities include standardizing the definition of the hantavirus pulmonary syndrome and streamlining the process of reporting new cases to CDC. "The process is well under way," says Khabbaz, referring to her program's work in the last 11 months. For example, she says, in early June, CDC sent the antigen to test for the presence of hantavirus in human tissue to several state health labs, so they can start to do their own analyses. Other CDC epidemiologists are looking just as carefully for new strains of hantavirus as they are for new cases. "We have at least three unique hantaviruses in the U.S.," says molecular virologist Stuart Nichol, head of the molecular biology section of CDC's special pathogens branch. "The first is the Muerto Canyon type [the name given to the hantavirus strain first found in the Four Corners region], which is basically throughout the entire country. A virus has also been detected in Florida, which is tentatively being called Black Creek Canal virus, which is associated with cotton rats," Nichol says. He adds that a third type was found in Louisiana, with an as-yet-unidentified rodent host. "I think we're going to find a lot more [strains] as we take a really in-depth look across the country at more rodents," predicts Nichols. "One of the things I like about this story," says Peters, "is that it makes us all look good. We were prepared and we had some luck in this thing moving along."

One Year Later, The Hantavirus Investigation Continues

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Karen Kreeger

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July 1994

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