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Hantavirus pulmonary syndrome in the Four Corners
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In the spring of 1993, a young American Indian couple died in northwest New Mexico. Concerned that the couple may have died from plague, which is present in that region of the United States, authorities requested autopsies.
The autopsy results were negative for plague. But soon, similar reports of various unexplained respiratory illnesses and additional deaths began to pour in from other parts of the Four Corners region. (The Four Corners region is where the borders of Arizona, Colorado, New Mexico and Utah meet.)
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By the end of July, acute hantavirus infection was confirmed in 18 people in the Four Corners region; 14 of these patients died. An additional 28 people from the region were under investigation for hantavirus, 10 of whom died. The outbreak was sudden and continued for several months.
Outside the region, 55 people were reported with unexplained, acute respiratory distress syndrome. By October 1994, mortality was slightly more than 50% in the 94 patients reported.
Investigation begins
New Mexico’s state health department alerted the CDC in early July 1993 and public health teams from around the state and nation sprang into action to investigate and manage the outbreak. The public grew increasingly alarmed as press coverage escalated.
“It was pretty scary at the time, because although we knew it was not taking off like pandemic influenza, we weren’t sure when it was going to stop,” said C. Mack Sewell, DrPH. As New Mexico’s state epidemiologist – a position he still holds today – Sewell was concerned about how many people would be affected.
“We sent ‘Dear Doctor’ letters to all physicians in the state; we thought it was a viral illness,” Sewell said.
One major concern was whether this virus was communicable, which would greatly increase the effect of the outbreak. Investigations of transmission among health care workers and household members of victims ensued.
“It was a very stressful time, but good science was done, and lots of work and great cooperation led to a successful investigation,” Sewell said. “Public health and epidemiology converged to solve a problem.”
A break in the case
“We didn’t know it was mice right away,” Sewell said. “We were not accustomed to dealing with hantavirus, but for reasons that are not completely clear, it clustered and caused an outbreak.”
A break in the case came when CDC scientists ran acute and convalescent blood specimens collected from people affected by the virus against known hantaviruses around the world.
“When they got the cross-reaction at the lab, within three weeks we had knowledge that it was a hantavirus that had never been seen or documented in the United States before,” Sewell said.
Although experts knew hantavirus is rodent-borne and the virus is contracted through exposure to mouse saliva or excreta, concern arose because not all species of the genus Hantavirus cause similar diseases in victims. In the United States, Peromyscus maniculatus, the deer mouse, is the most common vector associated with hantavirus.
Case control studies were launched, which included trapping mice in affected and nonaffected households to prove exposure to mice as a known risk factor.
Public service announcements and brochures for mouse proofing homes were quickly published and distributed. Mouse proofing homes is the only way to reduce hantavirus risk, since trying to trap millions of wild mice would be futile.
“The problem with mouse proofing is that it is hard to do in houses that are in bad shape, as many are in this area,” Sewell said.
Substandard and transient housing are common in the affected area, which included American Indian hogans (homes made of logs and mud which have several holes). Hogans are particularly difficult to mouse proof. Some homes visited by scientists were infested with mice.
“Hantavirus is, in many ways, a disease of poverty because it disproportionally affects those living in substandard housing,” Sewell said. “Mouse proofing these homes can be done, but it takes a lot of time, materials and effort.”
Race against the clock
While the outbreak continued, laboratories were given the task of improving diagnostics and testing for hantavirus.
“At the time, it could take three weeks to get tests back. By then, the person would be dead,” said Brian L. Hjelle, MD, professor in the department of pathology at the University of New Mexico School of Medicine. Hjelle and his laboratory team were asked to devise the rapid test.
“We were trying to beat the autumn season because it was predicted that it was going to be as active as it was in the spring,” Hjelle said.
The prediction was made through an epidemiology curve based on Southeast Asian and European models. The Four Corners outbreak eventually did not follow the model. The region follows a summer peak pattern whereas other parts of the world have peaks in autumn.
After two and a half months of constant laboratory work, Hjelle and his team devised the rapid test for hantavirus. The new test produced results within one day.
“It was an emergency and a crisis situation; we had a pressing practical issue, so we devoted ourselves to it,” Hjelle said. “At the time, no one knew if you could transmit the virus person-to-person, and there was no way to tell if you had it until three weeks later.”
People were concerned because some family members of patients were sick whereas others seemed well, Hjelle said. The team used molecular cloning from 10 human samples and reverse-transcription polymerase chain reaction to identify pieces of the viral genome to link the hantavirus. Each time they identified the sequence, they tried to get corresponding proteins to analyze serum reactions.
“We basically locked ourselves in the lab and worked 17 hours a day for two and a half months to clone as many pieces of the viral genome as we could,” Hjelle said.
Hjelle attributed the scientific work done on the hantavirus outbreak of 1993-1994 to quicker response in later outbreaks.
“We learned a lot about how to do things from this investigation. Our pace was fast, but it was even faster with the SARS investigation,” Hjelle said.
Among lessons learned were how to devote more resources to infectious disease and the need for biosafety laboratories, which have increased in number in the past 15 years.
Hjelle still works with hantaviruses today. His laboratory has developed the only outdoor field level laboratory for mice, which his laboratory uses to study hantavirus.
The University of New Mexico is also one of the only universities that has an extracorporeal membrane oxygenation machine for the treatment of hantavirus patients. The university proximity to the epicenter of hantavirus outbreaks justified the cost of the expensive equipment and the expertise required for operation, Hjelle said.
Hantavirus victims die because their hearts shut down. The ECMO, similar to a heart–lung machine, is usually used for term infants with pulmonary hypertension and is the only treatment for hantavirus. The treatment provides both cardiac and respiratory support to patients whose lungs and hearts are not functioning.
Weather and detection
Hantaviruses, like other zoonotic diseases, are cyclical in nature. By the end of the summer of 1993, the number of cases declined. Hantavirus in the United States usually occurs in spring, summer and autumn. In winter, it is less common because mice hibernate.
El Niño does have some effect on hantavirus cycles, but the reasons are yet unclear. Heavy rainfalls are not predictors, Hjelle said.
“Some of the assumptions made earlier on never turned out to be so simple,” Hjelle said. “With this virus, an outbreak could definitely happen again with the right conditions in place, especially since practices regarding mice haven’t changed drastically and we still have a lot of makeshift housing.”
Historically, hantavirus has been a problem for many years. There was an outbreak among soldiers living in tents overrun with mice during the Korean War in 1951.
“They didn’t realize what was making them sick, but 3,000 U.N. troops contracted it, and 300 died,” Hjelle said. “It was a different type of hantavirus than in the Four Corners, but it still wasn’t detected for another 25 years.”
In 2006, the CDC reported 438 cases of hantavirus pulmonary syndrome from 30 states since the recognition of the virus in 1993. Thirty-five percent of the total cases were fatal.
A disease of poverty
Cases still occur but have not reached the magnitude of the Four Corners hantavirus outbreak. Mortality remains at about 35%. Economic and housing standards in the most prevalent areas have not changed, and no vaccines are in development.
“There is no funding behind it because it is a disease that disproportionately affects the poor,” Hjelle said. Experts said they believe hantavirus will always be considered an “orphan” disease, and no vaccines or treatment for mass distribution will be available.
“One of the problems with this disease is that it does not affect wealthy people, so we aren’t going to get a lot of funding attention,” Hjelle said. – by Kirsten H. Ellis
For more information:
- Ward C, Callister TB, Hayes H, et al. Hantavirus disease – Southwestern United States, 1993. MMWR Morb Mortal Wkly Rep. 1993;42:570-572.
- Additional information about the CDC’s Epidemic Intelligence Service is available online at www.cdc.gov/eis.