Of mice and men: Hantavirus infections represent a global problem

Issue: August 2017

ByThomas M Yuill, PhD

ByDonald Kaye, MD, MACP

In May 1993, a “new” disease appeared in a physically fit young Navajo man living in the Four Corners area where Colorado, New Mexico, Arizona and Utah join. Suffering from shortness of breath, he was rushed to a hospital in New Mexico and soon died. This pulmonary insufficiency was later termed hantavirus pulmonary syndrome, or HPS. At that time, a review of medical records indicated that the man’s fiancee had similar symptoms and died the week before. These two deaths led the New Mexico Office of the Medical Investigator to review medical records of patients in the area who had died of acute respiratory failure. Five cases involving young, previously healthy individuals were found. Follow-up investigations found additional cases in the Four Corners area. Investigators conducted field studies to identify hosts of the virus, including sampling rodents living in and around homes of individuals who had died. Evidence of hantavirus infection was found mainly in the deer mouse (Peromyscus maniculatus). The virus was isolated by the CDC’s Viral Special Pathogens Branch and designated Sin Nombre virus, or SNV.

The deer mouse is among the most widely distributed mammals in North America, ranging from Western Canada and the United States down through Central Mexico. Field studies by several investigators provided additional evidence for the role of the deer mouse as the reservoir host. Interestingly, the deer mouse population was high at the time of the occurrence of these first cases. This was also an El Niño year (El Niño southern oscillation; ENSO), accompanied by high rainfall. Later studies in the 1991-1992 ENSO event and another in 1997-1998 showed that the increased precipitation in the Southwestern U.S. was accompanied by an increase in vegetation growth, providing more available food for these rodents. This caused a sharp increase in the rodent population, with greater risk of SNV exposure for people living in close contact with them. Of interest, an oral history provided by Native American healers in the Four Corners area describes clusters of similar deaths over three climatic cycles with related ecological changes in the 20th century.

A series of additional field studies showed that SNV was present in foci of deer mouse populations from Canada to the Southwestern U.S. However, the deer mouse populations and the prevalence of SNV in the rodents varied over time and space. The virus establishes persistent infections in the mice and is shed in saliva, feces and urine. Male mice have higher prevalence than females due to transmission from fighting. The presence of virus in a contaminated environment turns out be an important factor in human exposure, as well.

Sporadic human cases of SNV infection continue to this day. The CDC reports that from the time of the first Four Corners cases to Jan. 6, 2016, there have been 659 HPS cases in the U.S., with an additional 31 cases identified retrospectively from medical records. The mean age of these patients was 38 years (range, 5-84 years), and 63% were male. The case fatality rate was 36%.

Human cases result from inhalation of aerosolized particles contaminated by SNV and other hantaviruses. A dramatic cluster of cases occurred in Yosemite National park during the summer of 2012. The affected individuals were staying in the “signature” tent cabins in the Curry Village of the park. Deer mice were nesting inside the double walls of the tent cabins. Ten people were infected, three of whom died. Eight of these infected individuals were from California, one from Pennsylvania and one from West Virginia. The two cases from the Eastern U.S. illustrate that a person can develop the disease far from the site of infection and underscore the need to take good travel histories.

The CDC describes symptoms as initially, “very nonspecific ... with a relatively short febrile prodrome lasting 3 to 5 days. In addition to fever and myalgias, early symptoms include headache, chills, dizziness, nonproductive cough, nausea, vomiting and other gastrointestinal symptoms. Malaise, diarrhea and lightheadedness are reported by approximately half of all patients, with less frequent reports of arthralgias, back pain and abdominal pain. Patients may report shortness of breath (respiratory rate usually 26 to 30 times per minute). Typical findings on initial presentation include fever, tachypnea and tachycardia. The physical examination is usually otherwise normal.

“Within 24 hours of initial evaluation, most patients develop some degree of hypotension and progressive evidence of pulmonary edema and hypoxia, usually requiring mechanical ventilation. The patients with fatal infections appear to have severe myocardial depression, which can progress to sinus bradycardia with subsequent electromechanical dissociation, ventricular tachycardia or fibrillation.

“Hemodynamic compromise occurs a median of 5 days after symptom onset — usually dramatically within the first day of hospitalization ... overt hemorrhage occurs rarely in HPS, although hemorrhage is occasionally seen in association with disseminated intravascular coagulation. In contrast to septic shock, HPS patients have a low cardiac output with a raised systemic vascular resistance ... Poor prognostic indicators include a plasma lactate of greater than 4 mmol/L or a cardiac index of less than 2.2 L/min/m2. Whilst pulmonary edema and pleural effusions are common, multiorgan dysfunction syndrome is rarely seen. However, HPS patients sometimes have mildly impaired renal function. Survivors frequently become polyuric during convalescence and improve almost as rapidly as they decompensated ... Atypical clinical presentations with prominent renal insufficiency have also been reported.”

There is no specific treatment or cure for HPS. Supplementary oxygen may be required, and in some cases, extracorporeal membrane oxygenation has been used. IV ribavirin is probably not effective once HPS has developed.

Because there is no commercially available vaccine for SNV, infection by this and other rodent-borne hantaviruses is prevented by avoiding exposure to rodent-contaminated environments. In the North American temperate zone, this is particularly important when cleaning up outbuildings and cabins that have been closed for the winter. The CDC and most state and provincial health agencies provide recommendations for avoidance of exposure to SNV that are relevant to most hantaviruses around the world:

Eliminate or minimize contact with rodents in the house, workplace or campsite.
Seal up holes and gaps in houses and other structures to prevent rodent entry.
Trap rodents in and around the house to decrease rodent populations.
Eliminate available food sources for rodents.
Ventilate rodent-infested closed areas for 3 or more hours before entry.
Avoid raising dust when sweeping wet surfaces with a bleach solution.
Keep food and garbage in rodent-proof sealed containers.
Keep outside cooking areas and surfaces clean.
Keep bird feeders away from houses and other buildings, and clean up spilled bird seed.
Keep garbage compost containers at least 30 m distant from houses and other buildings.
Keep grain and animal food in sealed containers, and remove uneaten food daily.
Remove rodent nesting sites including trash, wood piles and old equipment from around the house and other buildings.
Keep grass well-cut and eliminate weeds from around houses and other buildings.

An interesting observation has been recorded in which hantavirus infection may have been acquired in Washington State from an automobile cabin air system. Apparently, these systems can become infested with deer mice and there is potential for aerosolization of the virus.

SNV is not the only hantavirus in the Americas that can cause sporadic cases of HPS. Other hantaviruses in North America that have caused HPS and their rodent hosts include: Monongahela (Peromyscus maniculatus), New York (P. leucopus), Bayou (Oryzomys palustris) and Black Creek Canal (Sigmodon hispidus) viruses.

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In Latin America, the hantaviruses of greatest public health significance are Andes virus and Choclo virus. Andes virus occurs in Argentina and Chile and causes tens of human HPS cases each year. The case fatality is around 35%. The long-tailed pygmy rice rat (Oligoryzomys longicaudatus) is the reservoir host. The population of this rodent undergoes considerable increases in areas when its important food supply — colihue cane (Chusquea culeou) — blooms and releases seeds. An increase in cases of Andes virus HPS follows increases in the populations of its rodent host. Andes virus is unique among the hantaviruses in that direct person-to-person transmission can occur. However, this mechanism of transmission is very infrequent and occurs only when there is very close interpersonal contact, usually among family members. Nevertheless, epidemiological surveillance teams usually monitor family members of patients to determine if person-to-person transmission has occurred. In addition to Andes virus, there are 12 other hantaviruses in South America that have caused sporadic cases of HPS. There are doubtless others that remain to be discovered. Ten of the 12 have rodent hosts and the remaining two probably do as well.

Closeup view of a deer mouse (Peromyscus maniculatus) peering out from inside a bird house.

Choclo virus causes a few cases of HPS each year in the Azuero Peninsula of Panama. The croplands and food sources of the area, such as stored grain, attract the rodent host of Choclo virus — the Costa Rican pygmy rice rat (Oligoryzomys fulvescens). The virus is not as virulent for humans as Andes virus or SNV, and the case fatality rate is lower.

Hantaviruses are also found in Asia and Europe, and several are significant causes of human disease and death. These viruses cause hemorrhagic fever with renal syndrome (HFRS). However, there may be noncardiogenic HPS-like lung involvement before any kidney involvement, as well as considerable clinical overlap between HPS and HFRS. More than 15,000 HFRS cases are estimated to occur yearly worldwide, more than half of them in China. One of these, Seoul virus (SEOV), although first isolated in Asia, is now widely found around the world. Its main host is the brown rat (Rattus norvegicus), which has resulted in the virus’ wide distribution geographically through movement of these rodents via international maritime shipping. SEOV has also been found in laboratory and pet rats, and it has also been isolated from R. losea and Niviventer confuscianus in China.

Perhaps the best known Asian hantavirus is Hantaan virus, the cause of Korean hemorrhagic fever and severe HFRS. Korean hemorrhagic fever initially had a case fatality rate of 10%, which was reduced to 1% because of more effective supportive treatment. The reservoir host of Hantaan virus is the striped field mouse, Apodemus agrarius. Hantaan virus occurs from Korea, China and far Eastern Russia to the Balkans.

In Europe, of the four recognized hantaviruses that cause HFRS, two — Dobrava-Belgrade virus (DOBV) and Puumala virus (PUUV), are of particular public health importance. DOBV is distributed widely in Europe and eastward into Russia. The main reservoir host is the yellow-necked mouse, Apodemus flavicollis. DOBV HFRS can vary from mild to relatively severe. Besides renal involvement, cardiac, pulmonary, ocular and hormonal disorders are common during the acute stage of PUUV and DOBV infection. About 16% to 48% of hospitalized DOBV-infected patients require dialysis and prolonged intensive care.

Puumala virus occurs in Scandinavia, Europe, the Balkans and Russia. The HFRS from PUUV infections, also termed nephropathia epidemica, is usually very mild. About 5% of hospitalized PUUV-infected patients require dialysis and prolonged intensive care. The widely distributed rodent host is the bank vole, Myodes glareolus.

Thus, hantavirus infection is a worldwide problem but with different syndromes in different geographical locations. Infection in humans is dependent on exposure to the varying rodent populations that are the natural hosts of the different hantaviruses. The hantavirus story is not over. New hantaviruses are being discovered and not all of them in rodent hosts. Many of these hantaviruses, as well as previously described ones, are not known to cause human disease. Yet.

References:
CDC. Hantavirus Pulmonary Syndrome (HPS). https://www.cdc.gov/hantavirus/hps/index.html. Accessed July 13, 2017.
CDC. Hemorrhagic Fever with Renal Syndrome (HFRS). https://www.cdc.gov/hantavirus/hfrs/index.html. Accessed July 13, 2017.
CDC. HPS in the United States. https://www.cdc.gov/hantavirus/surveillance/index.html. Accessed July 13, 2017.
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Jonsson CB, et al. Clin Microbiol Rev. 2010;doi: 10.1128/CMR.00062-09.
ProMedMail. Hantavirus - Americas (21): USA (Washington) automobile air system suspected. Archive number: 20170315.4901561. http://www.promedmail.org. Accessed July 13, 2017.
Razuri H, et al. Emerg Infect Dis. 2014;doi:10.3201/eid2002.131418.
Vaheri A, et al. Rev Med Virol. 2013;doi:10.1002/rmv.1722.
Yuill T, et al. Hantaviruses. In: Yamada A, et al, eds. Confronting Emerging Zoonoses: A One Health Paradigm. Japan: Springer Japan; 2014; 45-76

For more information:
Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society of Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Thomas M. Yuill, PhD, is a ProMED virus diseases moderator and professor emeritus, department of pathobiological sciences and department of forest and wildlife ecology, University of Wisconsin-Madison.

Disclosures: Kaye and Yuill report no relevant financial disclosures.