Hantaviruses belong to the bunyaviridae family of viruses.
Hantavirus leads to diseases such as HPS (Hantavirus Pulmonary Syndrome) and HFRS (Hemorrhagic Fever and Renal Syndrome)
There are many different strains of Hantaviruses, but only a few strains of Hantavirus actually lead to disease
Old World Hantavirus vs New World Hantavirus
Found mostly in Europe and Asia
Carried by rodents
Targets the kidney
Mortality rate is <10-15%
Vaccine exists for these strains
Discovered in the “four corners in America
Carried by rodents
Targets the lungs
Mortality rate is 50-60%
Vaccine does not exist for these strains
The History of Hantavirus
In 960 AD, Chinese medical records document a possible outbreak of HFRS
About 1000 years later (1913) Russian clinical records from eastern Siberia also document the symptoms of a mysterious disease, which is highly suspected to have been HFRS
Virus of Wars?
An outbreak of “Field nephritis” occurred in both German and Allied troops during WWI in Flanders, Belgium
During WWII, Field nephritis makes another appearance.
During the Japanese invasion of Manchuria in 1934, Hantavirus also made an appearance
Throughout the war, focal outbreaks of HFRS occurred
From the initial encounter with HFRS, Japanese physicians immediately began a full study of the disease
Those smart Japanese doctors…
By 1940, the Japanese had a comprehensive clinico-pathological description of the disease
The disease had incubation period was estimated to be about 2-3 weeks
Mortality rates were found to be around 10%
Is it the mouse?
In 1944, Japanese physicians and scientists begin testing on human subjects
Tissues from wild mice A. agrarius and from mites were injected into “volunteers” to induce the disease.
From these studies the Japanese physicians deduced that the mice and the mites were possible carriers of the disease causing virus
Soviet scientists were also hard at work
Annual outbreaks of HFRS (aka Tula fever) were seen in the Amur River Valley of Russia beginning in 1932
Soviets also performed tests on human subjects to discover the natural reservoir for this disease
They deduced that 3 species of mites were incapable of transmitting the disease to humans
It IS the mouse
In 1939, an incident occurred that incriminated field mice more clearly
Workers in 2 different camps, 4 km apart were engaged in earth moving labor
31 workers in one camp and those living around that camp fell ill with HFRS
Only 1 other worker from the other camp fell ill
Rodent contact was documented to be the highest in the camp with the infected workers
In Sept 1961, rodents ( Clethnommys glareolus and C rustlius) were sent from Kirov county in Russia to Moscow as part of a tick borne encephalitis test
On October 18, the first worker fell ill
By Nov 1, 20/23 of the workers had contracted the disease!
44/94 casual visitors contracted HFRS
All the mice were sacrificed on Nov 2, and the last case of HFRS was documented on Nov 29
5 of the workers who had previously contracted HFRS did not contract the disease because of acquired immunity
Fortunately, there were no fatalities
Hantavirus strikes again
America met HFRS in 1951 during the Korean War
By 1954, over 3,000 UN soldiers had been clinically diagnosed with this disease, which had been given the name Korean Hemorrhagic fever
The Japanese literature was quickly translated to gain a better understanding of this illness
The mortality rate for these soldiers was 7%
After the coded serum sample from convalescent HFRS patients in the Soviet Union were studied in 1978, scientists finally made the crucial connection between field nephritis, KHF and Tula fever.
Hantavirus is named for the Hantaan River which flows through the endemic region in Korea. (this is where the prototype strain was found)
At this point, scientist were able to isolate and propagate the virus
In 1983, the World Health Organization finally adopted the name HFRS to describe all the previous outbreaks of Hantavirus
Hantavirus in America
In April, 1993 a young healthy Navajo woman in the “four corners” dies of an acute respiratory disease
The fiancée of the dead woman also dies on his way to her funeral
The “blood vessels in his lungs had spurt blood and had caused him to drown in his own blood”
The mysterious illness
An Indian Health physician began to notice an outbreak of an unexplained illness that caused death among normal healthy young adults
After calling his colleagues, he discovered that 10 people had already died of a similar respiratory disease
Autopsies did not reveal any sign of viral pneumonia, influenza or any other common disease that attacked the lungs
Although this disease was not specific to the Navajo people, to the media, the disease became known as the “Navajo disease”
When the number of cases doubled to about 20 victims, the CDC was called in
In May 1993, the CDC was called in to investigate the case.
The CDC, using immunofluorescent techniques and their virus library, was able to positively identify this new virus as a relative of the hantavirus strains that were found on the Eurasian continent
However, scientists were skeptical for 3 reasons
The only hantaviruses known were on the Eurasian continent
The diseases caused by the Eurasian hantavirus strain did not cause respiratory failure
The new virus in the “four corners” appeared to be 5 times as lethal as the strain in Europe!
Those smart Navajo elders….
The CDC also spoke to some of the Navajo elders
The elders noted that because of the increase in rainfall that year, the pinon crop as well as the mice population had thrived that year
According to oral tradition, in 1918 and 1932, a similar outbreak had occurred, and mice were always seen as the carriers of disease
This information helped incriminate the mouse as a reservoir and also helped positively identify the virus as a Hantavirus
Human to human transmission?
In 1996, there was an outbreak of HPS in Southern Argentina
18 incidents of HPS were discovered within a period of 3 months
Among the 18, 5 of the patients were physicians
The mouse/rat population was low in 1996, thus further suggesting that person to person transmission was very probable in this incident
The pattern of transmission for Andes strain does not follow that of any other hantavirus
Figure 1. Transmission tree for HPS cases in southern Argentina, September-December 1996, indicating dates of onset of symptoms, survivor status, and proposed lines of transmission. Lines of transmission are hypothetical since many of the patients had contact with multiple HPS patients. Bold lines denote husband and wife. The two sporadic cases, U and R, are not shown.
Figure 2. Towns involved in the 1996 HPS outbreak in southern Argentina.
Hantavirus named according to rodent host/First Hantavirus detection
Tracking HPS in the United States (1993 till 2001)
As of April 2001, 283 hantavirus cases have been confirmed in 31 states
Mean age of those contracting the disease was 37, Range: 10-70
Mortality rate: 50%
Incidents of HPS date back to 1959 and 1978 although it was unidentified at the time
The most popular vectors include the deer mouse and cotton rat
HPS Statistics as of March 28, 2002 Mean= 37 [10 - 75] N Male Female 335 (100%) 203 (61%) 132 (39%) White 255 (76%) American Indian 71 (21%) Black Asian 3 ( 1%) Hispanic 43 (13%) Dead 126 (38%) Age (years)
Topics of Molecular Biology
Structure and properties
Transcription and replication
Host and epidemiology
Hantavirus transmitted through aerosolized rodent urine, feces and saliva.
Others genera transmitted through arthropod vectors.
23 Well-described Hantaviruses (Adapted from work by Simmons and Riley)
Old World Virus
Old World Virus
New World Virus
Virus is Rodent-specific Murinae Arvicolinae Sigmodontinae Virus Strain Rodent Host Apodemus agrarius Apodemus flavicollis Rattus norvegicus Bandicota indicus Peromyscus maniculatus Sigmodon hispidus Microtus pennsylvanicus Clethrionomys glareolus Sin Nombre Black Creek Canal Bayou Prospect Hill Puumala Hantaan Dobrava Seoul Thailand Oryzomys palustris New York Peromyscus leucopus
Severson et al (2003) hypothesize that ribavirin challenges the fidelity of the hantavirus polymerase, causing error catastrophe
Effective in treating HFRS if administered 5 days after onset of disease.
-Lessens renal failure
-Decreases bleeding manifestations
-Decreases overall mortality
Not proven effective in HPS
Open label protocol treating 30 patients with HPS with IV ribavirin (June 4, 1993 to September 1, 1994), comparing outcome to 34 untreated HPS patients :
Treated: mortality rate of 47% (14/30)
Untreated: mortality rate of 50% (17/34)
Most enrolled were ill in the early phase of the epidemic or presented in nonepidemic areas where diagnosis may have been delayed.
Treatment with ribavirin may have come too late.
Currently in progress : an NIH sponsored double-blinded placebo controlled trial of intravenous ribavirin for presumed HPS:
Designed to treat patients in the earliest stage of illness before the onset of shock.
And so we await the results…
Future strategies for treatment
Target the hantavirus/ β -3 integrin interaction
Target host inflammatory responses
In progress: work to find inhibitors of TNF-
No hantavirus vaccines are currently approved for common use in the U.S.
Inactivated virus vaccines in Asia
Cell culture derived vaccines in China
Vaccination trial with >100,000 participants showed that four years after primary vaccination, average prevention rates were >90%
Formalin inactivated rodent brain derived vaccines for HFRS (from SEOV and HTNV infections).
Example: Hantavax, commercially produced in South Korea
Seroconversion of 97% one month after second vaccination
Safe, only minor side effects
U.S. is now focusing on recombinant DNA approaches.
Investigational vaccinia HTNV vaccine is currently offered to laboratory workers at USAMRIID.
HFRS: febrile illness with acute renal dysfuntion
HPS: febrile illness with acute pulmonary dysfunction.
Both characterized by vascular leakage.
Treatment is mainly supportive
Inactivated virus vaccines are available for HFRS in Asia
There are no vaccines for HPS
“ Based on current human population growth and
development trends, hantavirus diseases will become
more common in the near future unless public health
measures are taken to curtail or eliminate rodents from
-JA Lednicky Department of Pathology, Loyola University Medical Center,
Hantavirus as a bioweapon?
In more recent years, it has been more common for outbreak investigators to consider the possibility of a terrorist event when they investigate the cause of an outbreak
The 1993 outbreak of Hantavirus in the Four Corners represented an incident in which a bio-terrorist attack was suspected
Throughout the investigation there were rumors that a biological agent had been released as an act of genocide against the Navajo people
Speculation of Hantavirus use?
The outbreak in Korea in 1950 is suspected to have been caused by bioterrorist attack
In 1995, an outbreak in Bosnia infected over 250 people (outbreak)
Because this virus has made an appearance at almost every major war of the 20 th century, it has definitely been suspected to have been used as a biological weapon
However, it is unknown whether this occurs mainly because of increased exposure during wartime or a disruption in the ecosystem resulting in an increase in the mouse population
HFRS as a bio-weapon
HFRS is categorized as a Biological Agents Category A: High priority
Easily disseminated or transmitted person to person
High mortality - major P.H. impact
Cause public panic, social disruption
Special action for P.H. preparedness
However, there are currently quick and efficient diagnostic tests
Treatments for HFRS available
Vaccines are against HFRS are also available
HPS as a bio-weapon
Hantavirus causing HPS are classified under Biological Agents Category C: third priority
Ease of production
Potential for high morbidity, mortality and major public health impact
SNV is highly lethal in its aerosolized form (four corners incident)
Certain forms (the Andes virus) are suspected of being able to transmit through human contact
There are no vaccines
Natural immunity to HPS is low
Mice populate the entire United States
Can pose a worldwide threat because it is carried by all types of rodent
If hantavirus were to be used…
The hantavirus can only exist 1-3 days outside of the host because of its weak lipid envelope
However, the symptoms will take anywhere from 4-40 days to show, thus delaying the impact of the weapon release
This may cause secondary and tertiary waves of illness, especially if a strain that has properties that allow for human-human transmission
The good news
The Hantavirus can be destroyed with a simple detergent
The disease itself is considered rare, as the virus is not very infectious except under certain circumstances (like an attack!)
The detection methods are improving, thus allowing physicians and other health personnel to catch the disease at an earlier time, thus increasing the chances of full recovery
As usual, PREVENTION is the BEST method
Even if Hantavirus is not used as a bioterrorist method, because of the nature of the rodent reservoir, everyone is potentially at risk
Furthermore, education would help prevent or contain an outbreak or an attack
Keep away from…
occupying rodent-infested vacant cabins or other dwellings;
cleaning barns or other outbuildings;
disturbing rodent infested areas while hiking or camping;
planting or harvesting fields,
living in or visiting areas where there has been an increase in rodents.
Lowering the risk of contracting HPS
Preventing the spread of a possible bio-terrorist attack or outbreak
Maintaining surveillance systems for emerging diseases allows possible infectious diseases to be detected quickly and efficiently
If the weapon is transmissible from person to person, there may only be a short window of opportunity to identify the organism and prevent further spread before a second wave of illness strikes
Training emergency personnel and more experienced in addressing the cases of unexplained illness (ie. It’s NOT the flu)
Improving diagnostic techniques
Making sure that resources for outbreak investigations are readily available
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