# 1993 Four Corners hantavirus outbreak

The 1993 Four Corners hantavirus outbreak was an outbreak of hantavirus disease in the Four Corners region of the US states of Arizona, Colorado, and New Mexico. The outbreak marked the discovery of hantaviruses in the Western Hemisphere that could cause disease and revealed the existence of a novel type of disease caused by hantaviruses: hantavirus pulmonary syndrome (HPS). Hantaviruses that cause disease in humans are native to rodents and, prior to the outbreak, were known to exist primarily in Asia and Europe, but previously were only associated with a different disease called hemorrhagic fever with renal syndrome (HFRS).
The outbreak was discovered in May 1993 after a young Navajo couple died within days of each other due to sudden respiratory failure. Medical investigators quickly found other cases with the same symptoms: an initial phase of fever, muscle pain, and variable respiratory symptoms such as coughing, followed by sudden respiratory distress. A thorough investigation into the cause of the outbreak discovered a new hantavirus as the agent responsible, Sin Nombre virus, and identified its natural reservoir as the eastern deer mouse (Peromyscus maniculatus). A report by the Hantavirus Study Group was later released in April 1994 that described in detail the newly named disease hantavirus pulmonary syndrome.
After the discovery of the outbreak in May, the outbreak continued to worsen in June and reached a peak in July. The number of new cases then sharply declined. During the peak of the outbreak from May to August, 23 cases were confirmed in the Four Corners region, most of which resulted in death. Intravenous administration of the antiviral drug ribavirin was tested experimentally during the outbreak, and a toll-free telephone hotline was set up to provide information about the outbreak and receive reports of suspected cases. By the end of the year, 48 cases had been confirmed nationwide, 27 of which, 56%, resulted in death. During the outbreak, indigenous people in the Four Corners region experienced significant prejudice and discrimination since most cases in the area were among the Navajo.
The 1991–1992 El Niño indirectly caused the outbreak by producing a warmer-than-usual winter and increased rainfall in the spring. This increased the amount of vegetation available for rodents for food and shelter, which led to a 10-fold increase in the rodent population in the Four Corners region in one year. With a much larger rodent population, interactions between humans and rodents became more likely to happen. According to Navajo oral tradition, outbreaks occurred in 1918, 1933, and 1934, all of which were preceded by the same environmental conditions that occurred prior to the 1993 outbreak. A similar increase in cases occurred in 1998.
Since the 1993 outbreak, other hantaviruses that cause HPS have been found throughout the Americas. Sin Nombre virus remains the most common cause of HPS in North America. Although the disease was feared by many to be contagious during the 1993 outbreak, human-to-human transmission of Sin Nombre virus has never been observed. Infection remains rare—about 10–50 cases of HPS occur each year in the US, most in spring and early summer and mainly in western states. Infections usually occur at home or in the workplace when inhaling aerosols that contain rodent excretions. While treatment has improved, HPS still has a case fatality rate of around 40%. No vaccines exist to protect against Sin Nombre virus infection, so important means of prevention include avoiding or minimizing contact with rodents and safely cleaning up after them.

## Background

The Four Corners region is the name given to the area where the borders of the US states of Arizona (AZ), Colorado (CO), New Mexico (NM), and Utah (UT) all meet each other. Most of the area belongs to semi-autonomous Native American nations. The largest is the Navajo Nation, followed by the Hopi, Ute, and Zuni. The area is part of the Colorado Plateau and is characterized by arid, rolling plains with sedimentary rocky features such as mesas, buttes, and canyons. The region is mostly rural: Farmington, New Mexico, the largest city in the region, has a population of around 44,000, and the Navajo Nation, which takes up a large portion of the region, has a population of around 165,000 (2020), with a population density of around 6 people per square mile (2.32 people per square km).
Hantaviruses are a family of viruses that constitute the family Hantaviridae. Hantaviruses known to cause disease in humans are native to rodents and assigned to the genus Orthohantavirus. Each species of hantavirus is transmitted usually by one rodent species. Prior to the 1993 Four Corners outbreak, Old World hantaviruses were known to cause hemorrhagic fever with renal syndrome (HFRS) and a milder form of it called nephropathia epidemica, which had mainly been observed in Asia and Europe. In the Americas, New World hantaviruses that had been identified were not known to infect or cause illness in humans. The 1993 outbreak marked the first time that a disease caused by New World hantaviruses was identified.

## Initial cases

On the morning of Friday, May 14, 1993, a 19-year-old Navajo man was riding in the back of a car with his family from Crownpoint, NM to Gallup, NM when he became severely short of breath. They stopped their car at a convenience store in Thoreau, NM, about 30 miles (42.28 km) east of Gallup, and contacted emergency services. By the time help had arrived, he had already collapsed due to respiratory failure. An ambulance crew performed CPR on him as he was taken to the Gallup Indian Medical Center, where he was diagnosed with fluid buildup in the lungs (pulmonary edema). Even with emergency treatment, though, he died in the emergency department. The man had previously visited an outpatient clinic a few days prior due to fever, headache, cough, and muscle pain, which were treated symptomatically. The death of the young man, a competitive marathon runner, due to sudden respiratory failure confused medical staff.
Because the man's death was highly unusual, it was required to be reported to the New Mexico Office of the Medical Investigator (OMI). The only officer on duty that day was investigator Richard Malone. He had previously investigated a similar death of a 30-year-old Navajo woman a few weeks earlier, in April, at the same medical facility in Gallup. The woman's death, tentatively labeled acute respiratory distress syndrome (ARDS), was investigated in postmortem examination by University of New Mexico pathologist Patricia McFeeley. The woman's lungs were twice as heavy as usual and filled with the clear, yellowish liquid of blood plasma. Tests came back negative for all known diseases that could have caused her death. Malone contacted McFeeley, who was on duty that Friday morning, and she agreed to perform an autopsy on the man once permission was obtained from the man's family because of how similar the two cases were.
Continuing to investigate the cause of the disease, Malone spoke to the parents of the deceased man. They told him that their son collapsed when they were on their way to the funeral of their son's 21-year-old fiancée, the mother of his infant child. She had died just five days earlier, on May 9, at a clinic in Crownpoint with the same symptoms as her fiancé. Since Crownpoint is in the Navajo reservation, the clinic there was not required to report her death to the New Mexico OMI. Furthermore, due to her history of asthma, her death initially was not considered as alarming as her fiancé's death. After contacting McFeeley again and updating her on the situation, Malone convinced the families of the deceased to have the couple's bodies examined in autopsy. McFeeley then reported a possible outbreak of an unknown and deadly respiratory illness to the state health department in Santa Fe that Friday afternoon and prepared for autopsy. The autopsies of the couple, conducted by McFeeley, showed only severe pulmonary edema with no explanation for the cause of illness.

## The investigation expands

Malone then contacted Bruce Tempest, the then medical director at Gallup Indian Medical Center. Tempest recalled having spoken to two physicians who had cared for young, previously healthy tribal members who died suddenly from an unknown respiratory illness. Malone and Tempest agreed that the situation required further action, so they started looking for more cases. Tempest was aware of the three recent cases in New Mexico as well as a case from the previous November in Arizona. Upon contacting Arizona health officials, they informed him of a recent case, so on May 17 Malone and Tempest notified the NM Department of Health of their concerns. State officials notified the Centers for Disease Control and Prevention (CDC) on May 18, and on May 24 they sent a letter describing the illness and situation to clinicians in the Four Corners states and asked for any similar cases to be reported to them immediately, which was effective in identifying several more potential cases.
After learning of the situation, the press reported on May 27 that an unexplained illness was killing tribe members in the Four Corners region, which caused panic in the public. Navajo and Hopi people were ostracized from the rest of society, and politicians were pressured to act. On May 28, NM state officials contacted the CDC to ask for assistance. Within hours, a team of investigators was assembled. Jay Butler, an epidemiologist at the Epidemic Intelligence Service (EIS) at the CDC, was made the leader of the investigative team, and he was assisted by two EIS officers, Ronald Moolenar and Jeffrey Duchin. Less than 24 hours later, the group arrived at the campus of the University of New Mexico and were joined by other professionals to form a team that included people from the CDC, the state health departments of NM, CO, and UT, the Indian Health Service, the Navajo Nation, and the University of New Mexico.
In a meeting that took place from May 29 to May 31, the task force agreed to evaluate any patient in the area from January 1, 1993 onward who had imaging that showed evidence of unexplained excess substances in both lungs (bilateral infiltrate) with low levels of oxygen in the blood (hypoxemia) as well as any case with unexplained pulmonary edema. More than 30 suspected cases were found and various causes were considered. Plague, tularemia, and anthrax, among other diseases, were eliminated from consideration due to lack of evidence. The team considered the disease outbreak to be caused by either a new, aggressive form of influenza, an environmental toxin, or a previously unrecognized pathogen.

## Hantavirus suspected

On Tuesday, June 1, fifteen members of the investigative team began on-site reviews of medical records. They interviewed patient families and control families, inspected homes and workplaces, and obtained IgM antibody samples from suspected cases. After testing at a local laboratory continually yielded no positive results, samples were flown to the CDC in Atlanta, Georgia for immediate analysis. By Friday, June 4, scientists of the Special Pathogens Branch of the CDC had tested IgM antibodies from nine patients with 25 different virus samples. Antibodies from every patient showed reactivity to three species of hantavirus and none of the other 22 viruses: Hantaan virus, Puumala virus, and Seoul virus. The samples were then shown to be reactive to Prospect Hill virus, a hantavirus that was known to infect voles in Maryland but which had never been associated with human disease or even isolated from human tissue.
Some members of the team had experience with and knowledge of HFRS, known to be caused by hantaviruses mainly in Asia and Europe. The disease, transmitted to humans from rodents, is characterized by a significant increase in the vascular permeability of endothelial cells, mainly in the kidneys, with massive loss of intravascular fluid into the extravascular space in the renal cortex, the renal medulla, and the space behind the lining of the abdomen. The loss of fluid is so severe that the density of blood cells in blood increases due to the loss of liquid, a condition called hemoconcentration. Hemoconcentration was observed in several cases and, combined with the CDC's findings, a hantavirus was suspected of causing the outbreak.
According to pulmonologist Charles J. Van Hook, suspecting a hantavirus required a substantial leap of thought at the time. Identified hantaviruses in the Western Hemisphere were only known to infect rodents, and no instances of human disease had been described. There were also no known hemorrhagic fevers endemic to North America, and none of the victims had traveled abroad or come into contact with foreigners before falling ill. Furthermore, the disease had little renal involvement—in all cases, the main organs affected were the lungs. Nonetheless, an unknown hantavirus that specifically infected pulmonary capillary endothelial cells was suspected by some members of the investigative team. Acting on the information gathered so far, the CDC dispatched a rat trapping team to New Mexico on June 7, which proceeded to capture around 1,700 rodents from June to mid-August at patient and control sites. The most commonly captured species was the eastern deer mouse (Peromyscus maniculatus).

## A new viral disease

At the same time as the rodent trapping operation, scientists at the CDC's Special Pathogens Branch worked to identify the new hantavirus. On June 10, reverse transcription polymerase chain reaction (RT-PCR) was used to obtain a DNA sequence 139 nucleotides in length from one segment of the virus's genome from samples taken from the 21-year-old woman who died on May 9. Additionally, hantaviral antigens were identified in the endothelium of the pulmonary capillary bed and in other tissues by the CDC's Viral Pathology Laboratory. On June 16, the same team identified an identical viral base pair sequence and prevalence of hantavirus antibody in eastern deer mouse specimens captured on site, which conclusively identified the virus and its natural reservoir. By late June, testing had shown that about 30% of trapped eastern deer mice and a small number of other rodents had been infected with the hantavirus. Late in the summer of 1993, researchers confirmed that human-to-human transmission of the virus does not occur.
Due to difficulties in culturing the virus, it wasn't until November 1993 that the virus was cultured independently by teams at the CDC in Atlanta, using tissue from a deer mouse trapped near the home of a patient in New Mexico, and the US Army Medical Research Institute of Infectious Diseases at Fort Detrick in Frederick, Maryland, using samples taken from tissue of a New Mexico patient and a mouse trapped in California. Initially, the CDC proposed to name the virus the Muerto Canyon virus after a location in the Navajo reservation, as it is customary to name hantaviruses after where they are discovered. The Navajo, however, strongly opposed any further association with the virus because of the prejudice against them it had caused, and the proposed name was problematic given the location's connection to a past Spanish atrocity, so the Navajo Nation Council voted unanimously to request the CDC to find an alternative name. After successful pushback from the Navajo, the CDC named the virus Sin Nombre virus, Spanish for the virus with no name.
The Hantavirus Study Group, formed to study the clinical course of the disease, published their findings in the April 7, 1994 edition of The New England Journal of Medicine, in which they described the newly named disease hantavirus pulmonary syndrome. They found eighteen people who had either serologic or PCR evidence of infection, most of them young adults. Physical examination of these people showed fever, rapid and shallow breathing (tachypnea), an abnormally fast heart rate (tachycardia), and low blood pressure (hypotension). Severe pulmonary edema occurred in almost all cases. Other symptoms included low oxygen levels in the blood (hypoxemia), higher than normal white blood cell count in the blood (leukocytosis), hemoconcentration, abnormally low platelet levels in the blood (thrombocytopenia), and increased time needed for the liver to produce prothrombin and for blood to clot.

## Response

Early on, doctors and nurses who treated patients at IHS medical centers wore surgical gowns and masks to reduce the chance of contracting the disease. Fifty Navajo medicine men met on June 1 in Window Rock, Arizona to discuss the outbreak and told people to be wary of deer mice and prairie dogs. Navajo elders knew that mice that entered the home put people at risk of infection when they come into contact with the feces or urine of the rodent, so they recommended burning contaminated clothing and protecting food from being accessed by rodents. In early June, health officials advised residents not to clean places that may have rodent wastes since doing so could stir up aerosols that contain the virus. During the outbreak, Navajo medicine men performed blessings and purification ceremonies where victims had died.
The antiviral drug ribavirin was made available for treatment on June 4 and intravenous ribavirin stocks were provided to health care facilities in the Four Corners region. Intravenous administration of ribavirin had shown some effectiveness in treating severe infections of Hantaan virus, another hantavirus, when provided early during illness, so it was tested experimentally on suspected cases during the outbreak. A toll-free telephone hotline was opened by the government from June 3 to December 31 to provide updated information about unexplained respiratory illness and to receive calls about suspected hantavirus cases throughout the country. The CDC considered removing the possibility of infection by trapping and poisoning deer mice, but this has been rejected as infeasible given the large geographic area and undesirable since mice are an important part of the ecosystem.

## Course of outbreak

In the weeks following the discovery of the outbreak, a dozen more cases occurred, mostly among the Navajo. The death rate remained high, even for those who made it to the hospital more quickly than the early victims. In one case, a person felt fine in the morning but was dead by the end of the day. By late May, the outbreak became more alarming. Two family members of the deceased couple had fallen ill with respiratory illness. On May 22, a medical technician who had assisted McFeeley in the autopsy room became ill with fever and muscle aches, which worried health workers due to the technician's close contact with potentially contaminated tissues. The outbreak continued to worsen in June and reached a peak in July, declining sharply thereafter. From May to August, 23 cases of hantavirus had been confirmed in the Four Corners region. Nationwide, 30 cases had been confirmed, 20 of which resulted in death. By October, 60 cases of hantaviral disease had been reported nationwide, about half in the Four Corners region. The rest were from California, Texas, Louisiana, Idaho, Nevada, the Dakotas, and Montana. Around 40 of these cases had been confirmed by laboratory, with 25 deaths.
Through December 31, 48 cases were confirmed nationwide, with 27 deaths (56%). Death rates were similar across age, sex, and race. Most of the infected were male and, in the Four Corners region, all cases either lived in rural areas or visited rural areas prior to falling ill. Of the 33 cases to occur in AZ, CO, and NM in 1993, 25 occurred during the height of the outbreak from April to July, and of those 33 people, 19 died (58%). Symptoms of affected persons during the outbreak started with an early phase of fever, muscle pain, and variable respiratory symptoms such as coughing, followed by sudden respiratory distress. Other early symptoms reported were headache and gastrointestinal symptoms including abdominal pain, nausea, and vomiting. Hemoconcentration and thrombocytopenia were reported in most cases. In all reviewed cases, bilateral pulmonary infiltrates developed within two days of hospitalization; during hospitalization, fever, hypoxia, and hypotension occurred.
HPS cases in the US in 1993 :
| $_0$ | $_0$ | $_2$ | $_5$ | $_6$ | $_{10}$ | $_{12}$ | $_3$ | $_2$ | $_6$ | $_1$ | $_1$ |
| Jan | Feb | Mar | Apr | May | Jun | Jul | Aug | Sep | Oct | Nov | Dec |
* Lived
* Died

## Societal effects

National media flooded the local community with reporters and took pictures of funerals, printed deceased people's names, and tried to interview victims' families without respecting the traditional four-day mourning period in Navajo culture. Sometimes, the media incorrectly reported the names of victims and communities. Media coverage often led to a negative portrayal of Navajo culture and association of the disease with the Four Corners region, and various names for the disease entered public discourse, such as Navajo Flu, Navajo Illness, and Four Corners Illness. Residents began posting anti-media signs, and resentment became so severe that some people refused to cooperate with medical investigators, who also failed to respect mourning practices as they continuously asked for information about recent deaths. Within a month of the outbreak's discovery, it became clear that the disease was not restricted to the Navajo or the Four Corners region. The popular press by that point, however, had moved on to other news and left the Navajo with the stigma that they created.
Before the disease's transmission method was confirmed, there was widespread fear that the disease was contagious. This contributed to discrimination and racism against the Navajo. For example, some restaurants refused to serve Navajo people, while in others staff wore gloves when serving them or threw away their used plates instead of re-using them. The high case fatality rate of the disease only intensified people's fears despite the lack of evidence for human-to-human transmission. Local restaurants saw a significant decline in business, many people stopped going to the movies, and very few people attended the annual Gallup Inter-Tribal Ceremonial that was held that summer. Many people canceled vacations to the area, and revenue from tourism declined. Some people wore surgical masks when leaving the house. In general, though, people in the area went outside less frequently during the outbreak.
Peterson Zah, the president of the Navajo Nation at the time, was a vocal critic of the sensationalist news coverage of the outbreak and the stigmatization of the Navajo. He said: "The story of Hanta Virus is a perfect example of an intercultural setting and the friction that lies just beneath the surface, and which explodes when unknowing outsiders trample on age-old customs. Deaths and the unknown nature of the illness served only to reinforce stereotypes ... [and] the view of Indians as second-class citizens was further supported." During the outbreak, Zah appealed to the media to respect the privacy of people who lost family members. Once the disease's connection to rodents was made, many people viewed the Navajo as dirty. Some members of the Navajo Nation expressed skepticism toward the government's explanation, instead blaming the outbreak on toxic waste, while others speculated that the disease was brought to the reservation by tourists or that it had escaped from Fort Wingate, located 20 miles (32.19 km) south of the Navajo reservation, which the US Army had been in the process of closing prior to the outbreak.

## Before the outbreak

A question for the scientific community at the time was why the outbreak occurred. A group of biologists at the University of New Mexico who were studying the deer mouse population in the Four Corners region during that time period noticed that the deer mouse population experienced a 10-fold increase in population from May 1992 to May 1993. Working with environmental scientists, the biologists demonstrated that the conditions of the 1991–1992 El Niño caused a relatively warm 1992–1993 winter and rainy 1993 spring. The area had previously been experiencing drought for a few years, but with increased snow melt and rainfall came a relative abundance of springtime vegetation in the area. This provided more shelter and food for local animals, which led to rapid growth in the deer mouse population, which in turn increased the number of interactions between humans and deer mice. The species of deer mouse that carries Sin Nombre virus, in particular, is more likely to enter human dwellings than other deer mice species.
According to the Navajo creation myth, mice are considered to inhabit the nocturnal and outdoors world and humans the daytime and indoor world. The two should not come into contact or sickness and death may occur. Furthermore, it is said that when mice enter a house and find an unclean environment with food laying about, they become angry at the mess and may strike down someone in the household, usually a young, healthy family member. Navajo oral tradition spoke of past outbreaks in 1918, 1933, and 1934, which they attributed to excess caused by "disharmony". Every year that the disease struck had excess rain and snowfall, which led to increased rodent food supply and consequently greater rodent populations and more human-rodent interactions.
Biologists believe that people probably had died from hantavirus infection before the outbreak but that their cause of death was unknown at the time. Additionally, genetic analysis of Sin Nombre virus has indicated that it has existed in its natural reservoir since long before the outbreak. Recollecting on patients Tempest had treated in the years prior to the outbreak, he said: "I will never be able to know for sure but I believe they were also Hantavirus victims." Serum samples collected in 1991 and 1992 as part of the Navajo Health and Nutrition Survey were tested and showed that three out of 270 had antibodies to hantavirus, indicative of past infection. By examining tissue samples of people who died to unexplained ARDS, the case of a 38-year-old man who died in Utah in 1959 became the earliest confirmed case of HPS.

## Aftermath

Following the outbreak, the medical community nationwide was asked to report HPS-like illnesses with unexplained causes. Other hantaviruses responsible for HPS were subsequently found in the US, including Bayou virus, Black Creek Canal virus, and New York virus. HPS has since been discovered not just in the US, but also in Canada, Argentina, Brazil, Chile, Paraguay, and Uruguay. Just like in 1993, high precipitation following a severe El Niño in 1998 led to an increase in hantavirus cases in affected areas. Based on environmental models of El Niño oscillations, it is possible to predict where future increases in hantavirus cases will occur. Winter severity and cone crop productivity especially are predictive of the following year's deer mouse population—harsher winters result in a smaller deer mouse population and by extension fewer HPS cases while warmer temperatures entail greater HPS incidence.
Sin Nombre virus remains the most common cause of HPS in North America. In its natural reservoir, it causes a chronic and asymptomatic infection. Sin Nombre virus is primarily associated with one species of deer mouse, and other hantaviruses discovered in North America follow the same pattern, each with their own natural reservoir. In the US, most HPS cases occur in rural areas in western states and almost all infections are contracted at home or in the workplace by inhaling aerosols that contain rodent excretions. Around 850 cases of HPS in 39 states were recorded from 1993 to 2023. About 10–50 cases occur each year in the US, most in spring and early summer. Human-to-human transmission of Sin Nombre virus has never been observed, not even among health care workers exposed to infected people.
Infection is rare but still carries a high case fatality rate of around 40%. Treatment has improved since the outbreak through means such as preemptively preparing anyone suspected of hantavirus infection for extracorporeal membrane oxygenation (ECMO) upon hospital arrival. Experimental testing of ribavirin during the outbreak did not show a significant benefit to its use, and research has since shown that it is ineffective if administered after the early stage of disease, so the CDC does not recommend ribavirin as a treatment for HPS. No vaccines exist to protect against Sin Nombre virus infection, so important means of prevention include avoiding or minimizing contact with rodents, preventing them from entering one's home, keeping one's home clear of food that may attract them, and safely cleaning up after them.