Monday, September 17, 2012

Hantaviruses


This week we will discuss the hantaviruses. These viruses are found in three distinct, yet large, regions of the world: Asia, Europe, and the Americas. Moreover, they produce two distinct clinical syndromes delineated by these same regional geographies, hemorrhagic fever with renal syndrome in the Old World, and hantavirus pulmonary syndrome in the New World. These viruses can be highly virulent and result in high mortality.

The Pathogen. Hantaviruses are in the Bunyaviridae family of viruses. These spheroid viruses are approximately 95 to 110 nanometers in diameter. They are enveloped viruses with negative-sense, single-stranded RNA genomes in three segments. The three segments are classified as large (L), medium (M), and small (S). Each segment has an associated RNA polymerase:


Hantavirus structure (Published in JASN December 1, 2005 vol. 16 no. 12 3669-3679)

The viruses invade host cells by endocytosis and replicate via the ER-Golgi intermediate compartment. Endothelial cells are the primary target host cells for hantavirusesVascular permeability is increased in both pathogenic forms of the disease, and is a key feature of the pathogenesis of these viruses, though hemorrhage and frank renal failure are limited to hemorrhagic fever with renal syndrome (HFRS), while hantavirus pulmonary syndrome (HPS) is characterized by lung involvement.

Hantavirus Life Cycle (Published in Clin. Microbiol. Rev. April 2010 vol. 23 no. 2 412-441)

There are scores of distinct hantavirus species, but the most relevant for human infection are the Hantaan virus of Asia and eastern Europe and the Dobrava virus of southern Europe, which cause HFRS, and the Sin Nombre virus of North America and the Laguna Negra virus and the Andes virus of the Southern Cone of South America, which cause HPS.

The Reservoir. Rodents serve as the natural reservoir for hantaviruses, though the relevant rodent species differ by geography and virus species.

The primary reservoir for the Hantaan virus is Apodemus agrarius, which is commonly known as the Striped Field Mouse:

Apodemus agrarius

This mouse is found from eastern Europe to Japan and is common in both forested and agricultural landscapes, and is, in fact, a common pest to agricultural communities across this very wide geographic region.

The primary reservoir for the Dobrava virus is Apodemus flavicollis, which is commonly known as the Yellow-necked Mouse:

Apodemus flavicollis

This mouse is found in southern Europe in mountainous, forested landscapes.

The primary reservoir for Sin Nombre virus is Peromyscus maniculatus, which is commonly known as the Deer Mouse:

Peromyscus maniculatus

This mouse is found throughout North America and is particularly common in the Mountain West, in forested, or mixed grassland-forested, landscapes.

The primary reservoir for Andes virus, and the many related viruses, is Oligoryzomys longicaudatus, which is commonly known as the long-tailed pygmy rice rat, or colilargo:

Oligoryzomys longicaudatus

This mouse is common in the mountains regions of Argentina and Chile in forested and shrub landscapes. Several other species in the genus Oligoryzomys can also serve as reservoir species for Andes virus.

The Disease. As mentioned above, hantaviruses cause two distinct clinical disease forms: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).

HFRS typically presents with high fever, severe lower back or abdominal pain, and bleeding, petechiae, and disseminated intravascular coagulation. Intestinal problems are common with associated with nausea, vomiting, and diarrhea. Respiratory dysfunction can sometimes present if there is sufficient fluid accumulation in the lungs. Renal dysfunction is the hallmark of HFRS. Hypotension is also common, as is increased heart rhythm and decreased partial pressure of oxygen in the blood. Shock can occur and must be managed accordingly. Macroalbuminuria and renal failure usually present one to two weeks after the onset of initial symptoms. Thrombocytopenia and increased serum creatinine are common laboratory findings. The Hantaan virus and Dobrava virus are the primary species causing most HFRS cases.

HPS typically presents with high fever, myalgia, headache, but bleeding is not common. The intestinal problems described for HFRS can also present in HPS, including nausea, vomiting and diarrhea. Respiratory symptoms are the hallmark of HPS, but generally NOT during the early period of the infection. Leakage of the alveolar capillary beds leads to fluid accumulation in the alveoli and the later cardiopulmonary symptoms, which include elevated heart rate, rapid breathing, and hypoxia. Thrombocytopenia is common, as it is for HFRS, but hemorrhage is not. Continued loss of fluid into the lungs leads to pulmonary edema, which can be identified radiographically:


Cough and shortness of breath are late stage respiratory symptoms that are common to most patients. Metabolic acidosis can also occur in the later stages. While some degree of proteinuria is also common, extensive renal damage is rare.

The Epidemiology and the Landscape. The mode of transmission for hantaviruses is from infected rodents to humans via the airborne route. The virus is shed in the stool, urine, and saliva of the rodent reservoirs. As the excreta dry out, the virus remains viable in dust. If the the dust is disturbed, particularly by human activity in enclosed areas, the virus particles can be inhaled as they are introduced into the air. Hantaviruses are not transmissible from person to person.


There are approximately 100,000 incident cases of HFRS, with between 1% and 15% mortality associated with these cases. Good estimates for HPS incidence and HPS-associated deaths are not available, though the incidence is very low in North America. Nevertheless, the mortality attributable to HPS is generally much higher than that attributable to HFRS. Between 30% and 50% of admitted HPS cases do not survive the disease.

The approximate distribution of concentrated Old World hantaviruses is depicted below in the map by Ho Wang Lee:


Hantaan virus is represented by the shaded areas in northeastern Asia and southeastern Russia, while the shaded areas in southern Europe represent Dobrava virus. The shaded areas in Scandinavia and northwestern Russia represent Puumala virus, which is a less significant cause of human infection. The map above is quite dated, as is obvious from the "U.S.S.R" label. While these approximate areas of concentration are still relevant for today, they are, nevertheless, only approximations and they do only represent the areas of greatest concentration.

The map below published in the journal Emerging Infectious Diseases, gives a much more accurate distribution of the range and concentration of Hantaan virus in China, as well as the primary rodent reservoir, Apodemus agrarius:

Distribution of Hantaan virus in China (Published in: Emerg Infect Dis. 2007 Sep)

The map below depicts the the distribution of New World hantaviruses, with their associated rodent reservoirs in italics.
Distribution of hantaviruses and their reservoir species in the Americas (Published in: Virus Research, Volume 162, Issues 1–2, December 2011, Pages 138-147)

At its simplest, the landscape of hantavirus infections, whether they are located in the eastern or western hemispheres, is comprised of rodent and human habitats wherein their points of intersection can create loci of zoonotic transmission from the rodents to humans. However, it is insufficient to claim that the landscape epidemiology of hantaviruses can simply be reduced to the contact between rodents (largely mice) and humans. There are, in fact, important features of both the physical and social landscape that determine the degree of contact between humans and the relevant rodent reservoirs.

For the most part, hantavirus transmission occurs in rural settings regardless of the geographic region or virus species. Nevertheless, the particular rural spaces that facilitate transmission can be different. For example, Hantaan virus infection in humans most commonly occurs in agrarian communities. This is driven in large part by the reservoir host, the Striped Field Mouse (Apodemus agrarius), which can exploit crop fields, and any human structures therein, as a readily available ecologic niche across a large portion of its range. As such, an agricultural landscape facilitates the potential contact between this particular reservoir species and human farmers sharing a common space. In addition, human Hantaan virus infection tends to occur in areas of mid to high precipitation.

While still a rural infection, Sin Nombre virus, on the other hand, is most common in the arid and semi-arid regions of the mountain west in North America, which only encompasses a part of the wider range of the reservoir host, the Deer Mouse (Peromyscus maniculatus). Nevertheless, perturbations in climate that lead to higher than normal precipitation can cause dramatic changes in the landscape epidemiology of Sin Nombre virus. In 1993 following an El Nino Southern Oscillation (ENSO), higher than normal levels of precipitation led to exceptionally high production of pine nuts in the southwestern range of the Deer Mouse. Pine nuts are a preferred food source for this mouse and this abundance of food following the ENSO subsequently led to a population explosion in the reservoir host mouse. As such, the contact rate between humans and mice increased as the expanding population of the mice brought them into greater contact with humans in rural settings. This led to a large (and first documented) Sin Nombre virus outbreak in the Four Corners region of the American Southwest. People of the Navajo Nation in particular were greatly affected by this outbreak. It is important to note that human hantavirus infection almost always occurs at the intersection between places of human habitation/occupation and the range of the mouse. Sporadic human infection in a wilderness setting outside the context of a human constructed space is extremely rare.

Control and Prevention. Rodent control is the primary strategy to control hantavirus infection in humans. While rare in any context, taking precautions to eliminate safe spaces for mice in the home or other structures of human habitation or occupation will eliminate effective human to mouse contact and thus block transmission of hantaviruses. The image below depicts the many areas within household structures that can be exploited by mice:


It is clear from the picture that a mouse has many opportunities for both food and habitation in and around the home. In order to eliminate safe spaces for mice the following steps can be employed:

Remove all food sources: Food and garbage should always be kept in well-sealed containers that cannot be breached by rodents. In addition, as depicted above, pet food and/or garden fruit and vegetables left unattended outside will often attract rodents.

Household maintenance: Good maintenance both inside and outside the home can be very important in eliminating rodent habitat. On the outside, overgrown plants and shrubs, unattended woodpiles or debris, and unattended outdoor structures can all serve as welcome homes for rodents, and should be be regularly maintained. On the inside, poorly sealed foundations, roofing, vents, and other household structures can provide easy access to the interior of the house and thus provide good mouse habitat. As such, it is very important to maintain good structural integrity of the house to keep the rodents out.

Pest control: Directly controlling rodent populations can be accomplished by keeping pets, especially cats, in the home, or by setting bait and traps. However, it is extremely important to maintain barrier control when disposing of rodent carcasses or when cleaning or setting traps. Rubber gloves, protective goggles, and a respirator should always be used.

Special case: Infrequently used or poorly ventilated spaces: Some structures that are infrequently used or are poorly ventilated, such as vacation homes, cabins, workplaces, or even standard basements/cellars, may have rodents and be contaminated with excreta and saliva. When confronted with the need to clean these kinds of spaces, the same barrier protection described above should be used (i.e. rubber gloves, protective goggles, and a respirator). In addition, it may be prudent to spray the floor with a disinfectant that is capable of lysing the envelopes of viral particles before sweeping and cleaning the space.

16 comments:

  1. It is interesting that there are no clearly effective treatments for hantavirus infection. Currently, Ribavarin, an antiviral drug, has shown efficacy in animal models (mice) and in a clinical trial in China. However with humans, it appears to be imperative that the drug is given early in the course of the disease. There are ongoing trials in the US, Canada, and Chile for antiviral medications such as Ribavarin and methypednisolone. Finally, there has been theoretical speculations regarding the use of human neutralizing antibodies for immunotherapy and the development of prophylaxis or vaccination.

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  2. Replies
    1. Flynn is right; there currently are no apparent treatments or a widely accepted Hantavirus vaccine. A lot of research and development has been conducted, for the past two decades or so, to try to create a Hantavirus vaccine. In the early 90s, South Korea had approved a Hantavirus vaccine and began vaccination campaigns. The results were somewhat promising since there was a decline in the number of HFRS patients, but this could have been due to climate and environmental changes causing a decrease in the number of rodents thereby limiting exposure.

      Here’s an article from 1995 about the US military testing a Hantavirus vaccine:

      http://www.nytimes.com/1995/05/23/science/vaccine-for-hanta-virus-found-safe-in-early-test.html?src=pm

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    2. Flynn, thanks for that information. I was not aware that trials were underway in Canada and Chile for antivirals such as Ribavirin and Methylprednisolone. A bit of an unrelated fact - recently, an epidemic of fungal meningitis (across over 20 states, so far) has been related to common stocks of methylprednisolone from Framingham, MA. Hopefully, the hantavirus researchers are not using any contaminated Framingham methylprednisolone in their research!

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    3. By the way, here's just one article on that epidemic:

      http://www.cbsnews.com/8301-204_162-57526249/meningitis-outbreak-may-affect-more-than-23-states/

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  3. As long as I know, The Hantaviruses that cause Hantavirus Pulmonary Syndrome (HPS in the United States are not known to be transmitted by any types of animals other than certain species of rodents. Dogs and cats are not known to carry Hantavirus; however, they may bring infected rodents into contact with people if they catch such animals and carry them home. Guinea pigs, hamsters, gerbils, and rodents from pet stores are not known to carry Hantavirus. So people have pets at their home should be so careful.

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    1. From the article we are informed the primary carrier of Hantavirus are the striped field mouse and it is not able to be passed from human to human. However recently human to human transmission have been recorded in South America with the Andes Virus. Viruses are passed from rodent to rodent by contact with saliva, urine or feces of infected rodents. Since Hantaviruses are a relatively new viral discovery no treatments are currently available.

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  4. The most recent Hantavirus outbreak in the United States occurred in Yosemite National Park in California several months ago. As a means to control the outbreak, deer mice across the park were being trapped and/or killed. Officials have noticed an increase in the deer mice population, which likely led to the increase in exposure to the virus. In the post it was mentioned that in 1993, following an ENSO, there was an increase in the deer mouse population – I wonder what the reason for the overpopulation of deer mice in Yosemite might be. Also, I’m curious to know how the virus spreads among the rodent population – is it transmitted from mouse to mouse? And would killing/exterminating the infected rodent population severely disrupt the ecosystem?

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    1. Perhaps the reason behind the increased deer mouse population is due to depopulation of the natural predator. Depopulation of the natural predator may be due to habitat destruction. These are just some hypothetical answers, however, it highlights the importance of each species in their ecological niche. Disruptions in the balance and web of relationships between species in an ecosystem can lead to drastic changes (e.g. hantavirus outbreak). Therefore, I believe that exterminating the rodent population will have deleterious consequences. Perhaps the hantavirus can utilize other species as reservoirs. Extermination of the deer mouse population may push the hantavirus to occupy other reservoirs that we do not know, which may make prevention of hantavirus human infection more difficult.

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  5. The deer mice population can fluctuate depending on several factors such as food supply, the number of predators present and the weather/other environmental factors. One theory is that when there are a lot of humans present (in an ideal camping season) they scare away many animal predators that would normally prey on this population. Since these mice can breed at all times of the year and the offspring mature and become sexually active rapidly this will translates into an exponential reproductive rate.

    Another theory; if the fall has had a lot of flooding (wet weather conditions) many of spring liters die. But, if there is a dry season then these liters mature and once again this population will increase significantly.

    So.. this population can fluctuate greatly at different times of the year, from year to year and from place to place.

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  6. The virus can be transmitted between the rodent population just as it can be transmitted from rodent to human populations.

    The fact that they can reproduce so quickly counteracts the possible negative consequences on the ecosystem, caused by killing some of them when necessary.

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  7. Hantavirus is forever with us in this world. It is unlikely to ever be eradicated because of its reservoir in deer mouse, however, keeping the virus out of humans is plausible by the proposed control and prevention measures. It is quite remarkable that the virion remains infective on fomites for long periods of time when bunyaviruses are enveloped viruses (which are generally considered less stable). Is there any rational behind this stability?

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  8. I'm really interested by this specific strain of Hantavirus found in Isla Vista, CA, which happens to be my old college town. I wonder if it found specifically only in Isla Vista and not elsewhere in Santa Barbara County, which is very agricultural, or maybe the landscape of this specific hantavirus strain is more built around crowding and probably less than hygienic conditions. This article also mentions how Sin Nombre hantavirus has been linked to El Nino and with the predicted El Nino for this upcoming winter, I wonder if we are expecting an increase in hantavirus cases along with it.

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  9. There are people who love camping and hiking. It is their favorite time spend with their family or friends. But there are viruses like Hantavirus which causes serious disease in people. We know that deer mouses carry this virus and shed it through their feces and urine. I am curious how can you prevent getting this virus which can be swept along with the dust by the wind and
    carried at the long distances and land on any surface. In my opinion you can get this virus everywhere because it is carried by the wind. Also, I am curious if are there any future vaccinations on their way for this type of virus especially for people who camp and hike frequently.

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  10. This was a great article! Both HFRS and HPS seem like terrible diseases, however the latter has a morlaity rate about 3 times that of the former. People who are on anticoagulants may be at a greater risk of hemorrhaging, especially if they are suffering from HFRS.
    Although the article demonstrated to a great extent the particular climate and social setting (Rural vs Urban) the Hanta virus reservoirs thrive in, I am curious as to the effects of other social factors in the spread of these diseases. For instance, I would hypothesize that the socioeconomic status of a community in a certain area plays a key role in the spread of Hanta virus. It is possible that lower income families may have a harder time sealing up leaks in their homes, which would lead to the entry and infestation of infected rodents and consequently the spread of Hanta virus. Even if other individuals in the community did manage to properly secure their homes, those who were not able to secure their homes would provide breeding grounds for mice causing a population increase. Increase in the mice population would mean a higher risk of developing Hanta virus diseases for the entire community.

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  11. This is a very interesting article! It's very interesting that Hantaviruses cause two very distinct clinical syndromes: one affecting the renal system (HFRS) and the other affecting the respiratory system (HPS). Given the severe health consequences of the two syndromes, I assume that prompt diagnosis and symptomatic treatment are of the utmost importance. However, I think that it is very difficult to diagnose either of the two syndromes because the symptoms are mostly non-specific. For example, the article says that someone with HFRS may have high fever, severe low back pain, severe abdominal pain, bleeding, and petechiae (tiny bruises). The person may also have GI disturbances like nausea, vomiting, and diarrhea. On the other hand, someone with HPS may also have high fever as well as the GI symptoms, but there are no bleeding and no bruises. Instead, the person may experience severe shortness of breath due to fluid buildup in the lungs. Both syndromes exhibit nonspecific signs and symptoms that don't point directly to Hantavirus infections. For example, Ebola, as we learned in class, can present with internal bleeding, fevers, GI symptoms. So clinicians must have a high index of suspicion. This may be augmented by the patient's recent travel history and the landscape in which he/she was in prior to infection.

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