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In the spring of 1993, an outbreak of adult human respiratory distress syndrome was recognized among Native Americans in the Four Corners area of the southwestern United States.¹ Soon thereafter, a hantavirus was confirmed as the etiologic agent of this disease, termed hantavirus pulmonary syndrome (HPS).² The virus, a member of the family Bunyaviridae and named Sin Nombre virus (SNV), was shown to be a member of the genus Hantavirus.³ Some implications of these events were published in the JAVMA.⁴

Although essentially all other members of the virus family Bunyaviridae have been shown to be transmitted via arthropods, hantaviruses are known to be transmitted only by rodents.⁵ Moreover, illnesses caused by hantaviruses in Asia and Europe are characterized principally by renal involvement and not by respiratory symptoms. The clinical course of HPS caused by SNV differs substantially from disease resulting from infection with Old World hantaviruses Hantaan, Seoul, Dobrava, and Puumala.

Onset of HPS caused by SNV is characterized by a prodrome including fever, myalgia, and various respiratory symptoms. People with HPS have acute pulmonary edema and shock; pathogenesis of the disease appears to be related to the presence of viral antigens in pulmonary capillaries.⁶ People infected with the virus may have an abrupt onset of acute respiratory distress associated with interstitial pulmonary edema and cardiopulmonary compromise, and die a week or less after onset. Other symptoms reported in the early stages of HPS include headache, abdominal pains, nausea, and vomiting. Other organ systems do not seem to be involved, although mild renal insufficiency has been detected in a few patients (just as pulmonary involvement has been observed in patients infected with hantaviruses known to cause hemorrhage, fever, and renal impairment).

The pathophysiology of HPS may be similar to that of illnesses caused by other hantaviruses, such as hemorrhagic fever with renal syndrome in those infected in Europe and Asia, except, of course, that the principal affected organs are the lungs, not the kidneys. Nonetheless, an antigen of SNV has been detected in tissues from the lung, kidney, heart, liver, and spleen. The cause of death in HPS patients is not clear, but the catastrophic failure of the lungs certainly is central. Capillaries leak profusely, flooding air spaces with fluid; the attendant pH imbalance is the feature immediately preceding death. Severely ill patients have signs of shock. Early recognition and rapid transport to a tertiary care facility is necessary if intervention is to be facilitated. At present, intensive hemodynamic monitoring and supportive care is the only treatment regimen considered effective; antiviral drugs have not been shown to be efficacious. Clearly, it is of critical importance to prevent infections causing such life-threatening illnesses.

Subsequent to the molecular identification of SNV as the etiologic agent of HPS,⁷ molecular epidemiologic studies revealed that the natural host and reservoir of this virus was the deer mouse (Peromyscus maniculatus), the most common mammal in North America.⁸ Notwithstanding the widespread distribution of this rodent, the 1993 cases of HPS were clustered in only the Four Corners states (New Mexico, Colorado, Utah, and Arizona). Further investigations have revealed that only 115 of the 288 HPS cases in the United States until November 30, 2001, have been in the Four Corners area.^a The other cases were detected in 31 states and 4 Canadian provinces (British Columbia, Alberta, Saskatchewan, and Manitoba); there is published evidence for the presence of hantaviral infections in rodents, but not humans in Mexico.

Caucasians comprise 78% of the cases, Native Americans comprise 19%; 60% of HPS patients have been males. The mean age of patients is 37 years, with a range of 10 to 75 years; a mild illness attributed to SNV was detected in a 4 year old. In the 1993 outbreak, the case-fatality rate was 38% and more than 60% of the first recognized patients died. When a newly recognized virus is found to be killing more than half its victims, media reporters and the public in general tend (not unreasonably) to think of the Andromeda Strain. In fact, retrospective epidemiologic studies have shown that SNV has a widespread geographic distribution, being detectable essentially wherever the deer mouse occurs,⁹ and is known to have caused infections since at least 1956 and likely for at least hundreds of years before that.

Realistically, given good nursing practices and availability of results of research investigations, diseases caused by these newly recognized viruses are usually manageable. People infected with the viruses can be treated with some success, and additional cases can be avoided.

Because of the impetus of the 1993 outbreak, a considerable amount of research on hantaviruses has been done in the Americas. Many more HPS cases have been recognized in Central and South America than in North America. Sophisticated molecular detection systems have been developed throughout this hemisphere and, together with similar studies in Asia and Europe, 39 hantaviruses have been recognized.^b Interestingly, each hantavirus is associated with a primary rodent reservoir host, which may be evidence of coadaptation (Appendix).

The geographic distribution of most of the hantaviruses detected in rodents are limited by the geographic distributions of their hosts.¹⁰ Seoul virus, which is associated with rats of the genus Rattus, has been found essentially worldwide in port cities where these rats have invaded. Just as these rats have been stowaways on ships, Seoul virus has accompanied them as internal stowaways. Interestingly, transmission of this virus to humans from laboratory rats, which ostensibly became infected after contact with cohoused or feral wild rats, has been documented on numerous occasions. It is disquieting that an association has been made between antibody to Seoul virus and chronic renal disease in a city in the United States with large populations of rats.¹¹

In all, 11 hantaviruses have been recognized thus far in the United States (Appendix). It can be said with some assurance that many more hantaviruses have yet to be detected. These viruses are neither simple to isolate (in cell cultures or laboratory hosts) nor detect by classic diagnostic means. Elegant polymerase chain reaction assays have been developed, and these can be used to detect the presence of hantaviral RNA and determine the geographic and host origins of many hantaviruses. Many hantaviruses have not been isolated, only detected and molecularly characterized. Noninfectious antigens, expressed using known gene sequences, have been useful in diagnostic assays and for cross comparisons. The viruses identified in the Appendix have names but some may simply be variants of others, so this list should be considered provisional. Signs of illness in rodent hosts of hantaviruses are inapparent and little, if any, evidence of disease has been noticed in them.

What can be made of this confusing mélange of viruses, hosts, and diseases? What are the risk factors for acquiring an infection with one of these viruses? What research results have been useful in identifying epidemiologic characteristics of these viruses? Although other hantaviruses are likely to have similar epidemiologic characteristics and modes of transmission to humans, we confine our discussion to HPS caused by SNV.

Transmission of SNV is believed to be via aerosols containing saliva, urine, or feces from infected deer mice.¹² These rodents can be peridomestic and will invade homes if given the least opportunity. Most people with hantavirus infections acquired their infections through their vocations, although simply living in a rural area might be considered a risk factor. Working in dusty areas, such as barns and attics, renovating mobile homes in rural areas, cleaning (sweeping or wiping dust) long-unoccupied vacation homes, having an air conditioner with a mouse nest inside, exposing rodent nests or excreta while farming or gardening, and camping and participating in other activities that would activate resting dust particles or otherwise expose one to them, may all be risk factors. Nonetheless, prophylactic rodent exclusion measures can be taken.¹³ With singular possible exception of the Andes virus in South America,¹⁴ there is no evidence for person-to-person transmission of hantaviruses.

Long-term studies of SNV and other hantaviruses in the western United States have provided insights to their persistence, transmission, and amplification. Under contract with the national Centers for Diseases Control and Prevention (CDC), groups in Colorado, New Mexico, Arizona, and Montana have been trapping, measuring, sampling, tagging, and releasing rodents at approximately monthly intervals at multiple sites in each state.¹² Mark-release-recapture data have provided insight as to which deer mice become infected and when they become infected. Most deer mice with antibody to SNV are males, suggesting that territoriality or other inherent traits may lead to intraspecific fighting and virus transmission (via infected blood, urine, and saliva).¹⁵ Whereas most male deer mice in Colorado acquired their infections between late summer and late fall, many female deer mice in Colorado became infected from mid-winter to late spring. Deer mouse population density in Colorado was highest in late summer to late fall. This increase occurred irrespective of meteorologic conditions, but the intensity of population increases was dependent on the amount of precipitation, vegetative responses to intense climatic events and, in general, the trophic cascade that is brought about by a constellation of these conditions. Changes in available food sources appear to be robustly impacted by conditions such as the El Niño-Southern Oscillation phenomena, but the totality of the impact may not be seen for as long as 18 to 24 months after the most intense period of the event.¹⁶

Where rodent species diversity was high, the prevalence of SNV infection of deer mice (as determined by the presence of antibody) was low; where rodent species diversity was moderate, the prevalence of infection was moderate; and where rodent species diversity was low, the prevalence was high. This suggests that preservation of intact ecosystems is important, if not critical, in maintaining diverse habitats.¹⁷,^c Transseasonal maintenance of SNV was dependent on the persistence of long-lived infected deer mice that shed virus, whether persistently or intermittently.¹⁸ When drought or other adverse conditions impacted negatively on the ability of such mice to survive, the probability of survival of the virus also appears to have been impacted.

Navigational instincts of deer mice provide them with a sophisticated homing ability. That is, deer mice trapped within their home range (including human residences) and released up to a mile away returned to the sites where they were trapped, and did so within a few hours, returning more quickly when repeatedly trapped and released. We have taken these findings as reason to not live-trap and release deer mice unless invasion by other mice also is prevented.¹⁹ Our studies of dual captures of deer mice and other rodents may provide indication that certain individual rodents, perhaps litter mates, may participate in group-foraging behaviors.²⁰ Genomic studies of these individuals are expected to reveal whether they are associated by chance or by inherited inclination.

Studies in progress include remote sensing of habitats by satellite imaging as a means of determining fitness of sites,²¹ estimates of plant primary productivity, and measurements of available arthropod mass as a food source. We also are investigating the possibility of immunizing wild populations of deer mice against SNV.

Taken together, we expect these and other studies of rodent biology and fluctuating virus prevalences to provide practical information that may make important contributions toward our ability to predict human risk of acquiring HPS. If we are able to predict periods in which increased prevalence of SNV can occur, we may be able to predict human risk of HPS and of other rodent-borne viral diseases, including those caused by arenaviruses.

Given that only rodents have been shown to be natural hosts of hantaviruses in the Americas, veterinarians and others working with small mammals other than rodents likely need not be concerned about acquiring HPS. Studies designed to determine the prevalence of antibody to SNV in domestic cats, dogs, horses, cattle, and coyotes in the southwestern United States revealed that 4 of 145 (2.8%) cats and 4 of 85 (4.7%) dogs had trace antibody reactivity, unconfirmed by other tests. Sera from the other animals was not reactive.²² On the basis of these and other studies, it appears that domestic animals, particularly dogs and cats as well as coyotes, do not have a major role in the maintenance and transmission of SNV. Nonetheless, as cats sometimes take live rodents home, it is possible that such a rodent infected with SNV could serve as asource of SNV for human infections.

For those who must handle rodents, some measure of confidence can be taken from the observation that < 1% of more than 1,000 mammalogists and wildlife biologists who handled thousands of rodents had antibody reactive with SNV and only 1 had disease consistent with HPS.^d Nevertheless, risk of infection increased with the number of Peromyscus that investigators had handled during their careers, and at least 3 wildlife biologists are included in the CDC HPS case registry. Therefore, precautions including the use of gloves, laboratory coats, and even respirators are recommended for those who handle these creatures.²³ There still are many aspects of hantavirus epidemiology that are poorly understood and likely even more that are unrecognized. Thus, the bottom line is that while we need not be alarmed about hantaviruses, we should be careful.

Appendix
Recognized hantaviruses, listed by rodent host subfamily, disease caused, and location first detected

References

1. Hughes JM, Peters CJ, Cohen ML, et al. Hantavirus pulmonary syndrome: an emerging infectious disease. Science 1993;262:850–851.

2. Butler JC, Peters CJ. Hantaviruses and hantavirus pulmonary syndrome. Clin Infect Dis 1994;19:387–394.

3. Ksiazek TG, Peters CJ, Rollin PE, et al. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. Am J Trop Med Hyg 1995;52:117–123.

4. Weigler BJ. Zoonotic hantaviruses: new concerns for the United States. J Am Vet Med Assoc 1995;206:979–986.

5. Lee HW, Calisher C, Schmaljohn C. Manual of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. In: Lee HW, Calisher C, Schmaljohn C, eds. Seoul, Republic of Korea: Asan Institute for Life Sciences, 1999.

6. Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. Am J Pathol 1995;146:552–579.

7. Nichol ST, Spiropoulou CF, Morzunov S, et al. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993;262:914–917.

8. Childs JE, Ksiazek TG, Spiropoulou CF, et al. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. J Infect Dis 1994;169:1271–1280.

9. Mills JN, Ksiazek TG, Ellis BA, et al. Patterns of association with host and habitat: antibody reactive with Sin Nombre virus in small mammals in the major biotic communities of the southwestern United States. Am J Trop Med Hyg 1997;56:273–284.

10. Schmaljohn CS, Hjelle B. Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3:95–104.

11. Glass GE, Childs JE, Watson AJ, et al. Association of chronic renal disease, hypertension, and infection with a rat-borne hantavirus. Arch Virol 1990;(suppl 1):69–80.

12. Mills JN, Ksiazek TG, Peters CJ, et al. Long-term studies of hantavirus reservoir populations in the southwestern United States: a synthesis. Emerg Infect Dis 1999;5:135–142.

13. Glass GE, Johnson JS, Hoddenbach GA, et al. Experimental evaluation of rodent exclusion methods to reduce hantavirus transmission to humans in rural housing. Am J Trop Med Hyg 1997;56:359–364.

14. Padula PJ, Edelstein A, Miguel SDL, et al. Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 1998;241:323–330.

15. Glass GE, Childs JE, Korch GW, et al. Association of intraspecific wounding with hantaviral infection in wild rats (Rattus norvegicus). Epidemiol Infect 1988;101:459–472.

16. Yates TL, Mills JN, Parmenter CA, et al. The ecology and evolutionary history of an emergent disease: hantavirus pulmonary syndrome. Bioscience 2002;52:989–998.

17. Epstein PR. Emerging diseases and ecosystem instability: new threats to public health. Am J Pub Health 1995;85:168–172

18. Calisher CH, Mills JN, Sweeney WP, et al. Do unusual site-specific population dynamics of rodent reservoirs provide clues to the natural history of hantaviruses? J Wildl Dis 2001;37:280–88.

19. Calisher CH, Sweeney WP, Root JJ, et al. Navigational instinct: a reason not to live-trap deer mice in residences. Emerg Infect Dis 1999;5:175–176.

20. Calisher CH, Childs JE, Sweeney WP, et al. Dual captures of Colorado rodents: implications for transmission of hantaviruses. Emerg Infect Dis 2000;6:363–369.

21. Glass GE, Cheek JE, Patz JA, et al. Using remote sensed data to identify areas at risk for hantavirus pulmonary syndrome. Emerg Infect Dis 2000;6:238–247.

22. Malecki TM, Jillson GP, Thilsted JP, et al. Serologic survey for hantavirus infection in domestic animals and coyotes from New Mexico and northeastern Arizona. J Am Vet Med Assoc 1998;212:970–973.

23. Mills JN, Yates TL, Childs JE, et al. Guidelines for working with rodents potentially infected with hantavirus. J Mammalogy 1995;76:716–722.