Hantavirus

1
Hantavirus

• Loraine Wu
• Howard Zeng
• Yuka Yamaguchi

2
What is Hantavirus?

• 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

3
Old World Hantavirus vs New World Hantavirus

• Found mostly in Europe and Asia
• Carried by rodents
• Causes HFRS
• Targets the kidney
• Mortality rate is lt10-15
• Vaccine exists for these strains

• Discovered in the four corners in America
• Carried by rodents
• Causes HPS
• Targets the lungs
• Mortality rate is 50-60
• Vaccine does not exist for these strains

4
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

5
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

6
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

7
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

8
Meanwhile..

• 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

9
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

10
Mouse genocide

• 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

11
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

12
Hanta virus

• 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

13
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

14
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

15
The CDC

• 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!

16
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

17
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

18

• 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.

19
                                             Fi
gure 2. Towns involved in the 1996 HPS outbreak
in southern Argentina.
20
Hantavirus HFRS

• Hantavirus named according to rodent host/First
  Hantavirus detection

21
Hantavirus HPS
22
Hantavirus HPS
23
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24
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

25
HPS Statistics as of March 28, 2002
26
Topics of Molecular Biology

• Bunyaviridae family
• Structure and properties
• Transcription and replication
• Pathogenesis
• Host and epidemiology
• Transmission

27
Family Bunyaviridae
28
Bunyaviridae Family

• Similarities
• RNA viruses
• Enveloped
• Tri-segmented genome
• Differences
• Hantavirus transmitted through aerosolized rodent
  urine, feces and saliva.
• Others genera transmitted through arthropod
  vectors.

29
23 Well-described Hantaviruses
(Adapted from work by Simmons and Riley)
30
Virus is Rodent-specific
Murinae
Arvicolinae
Sigmodontinae
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32
Physical Properties of Virion

• Spherical or oval-shaped.
• Diameter 80-120 nm.
• Unique grid-like surface pattern -- transmembrane
  glycoproteins.
• Survive 12 hours at 4 ?C, high salt concentration
  and non-physiological pH.
• 1-3 days after drying.

(Image taken from CDC)
33
Viral Genome

• Granular, filamentous interior consists of genome
  and protein structure.
• Single-stranded negative-sense RNA.
• Approximately 13 kb.
• Three segments
• Small (S) 1,700 bases.
• Medium (M) 3,600 bases.
• Large (L) 6,500 bases.

(Original image kindly provided by Dr. Simmons of
U. Missouri)
34
Panhandle Structure

• The 3 and 5 terminal sequences are conservative
  and complementary, forming panhandle structure.
• Believed to be initiation signals for
  transcription and gene expression.

(Images adapted from work by Meyer and Schmaljohn)
35
Protein Products
(Images adapted from work by Jonsson and
Schmaljohn)

• Four proteins products
• S segment ? Nucleocapsid protein.
• Encapsulate vRNA and cRNA.
• Regulate replication and transcription.
• Nucleocapsid protein vRNA Ribonucleocapsids.

36
Protein Products Contd

• M segment ? Glycoproteins, G1 and G2.
• Associated with the lipid membrane.
• Interact with integrin receptors on host cell
  surface.
• Induce neutralizing antibody response in animals.
  
• L segment ? RNA-dependant RNA polymerase (RdRp)
• Associated with the ribonucleocapsids.
• Endonuclease Cleave host mRNA caps, which are
  used to prime transcription from vRNA to mRNA.
• Replicase Generate copies of the genome.
• Helicase Unwind RNA during transcription.

37
Transcription Viral Entry

• Virion binds to a host cells surface receptor.
• Enter the cell through receptor-mediated
  endocytosis.
• Pathogenic hantaviruses use ?3 integrin receptor.
• Non-pathogenic hantaviruses use ?1 integrin
  receptor.
• Virus uncoats in the cytoplasm, and releases the
  three ribonucleocapsids.

38
Transcription and Translation

• Primary transcription
• For all negative-sense RNA virus, an initial
  burst of transcription.
• Viral RNA polymerase transcribes viral RNA into
  mRNA.
• Viral mRNAs are translated into proteins.
• Polymerase and nucleocapsid proteins are
  translated on free ribosomes.
• G1 and G2 proteins are translated on
  membrane-bound ribosomes.

39
Replication

• An uncharacterized signal switches transcription
  to replication.
• Maybe cytoplasmic accumulation of nucleocapsid
  proteins.

(Image provided by Dr. Simmons of Univ. of
Missouri)

• RdRp makes complementary RNA (cRNA).
• cRNA is used as template to make viral RNA
  (vRNA).
• Production of vRNA results in more viral genomes
  for packaging into progeny virions.
• Increases the number of templates for mRNA
  synthesis.

40
Prime and Realign Model

• Question 1 How does hantavirus cap the 5 end of
  its mRNA transcripts?
• Answer Cap snatching.
• Question 2 Where does hantavirus get the primers
  from for transcription?
• Answer Stolen host mRNA caps are used as
  primers.
• Observations
• The 5 end of viral mRNA is heterogeneous.
• 5 UAG triplets (stop codon) are deleted.
• Commonly, there is a terminal G.

41
Prime and Realign Model Contd

• Garcin, et al. proposes that G residue aligns
  with vRNA template to initiate transcription.
• After a few RNAs are added, the mRNA slips back
  to realign with the template.

• Replication has a similar prime and realign
  model.
• When cRNA is made, RdRp cleaves off the terminal
  G base.

42
Virion Assembly

• Nascent vRNA associate with nucleocapsid and
  polymerase proteins upon transcription.
• G1 and G2 are expressed from a single mRNA, and
  are cleaved cotranslationally.
• Virus and proteins assemble in the Golgi
  apparatus.

43
Virion Release and Persistence

• Virions are transported to the cell surface
  within Golgi vesicles.
• Two hantavirus strains, including Sin Nombre
  Virus, bud from cell membranes.
• Infected cells are not lysed.
• Hantavirus infection is persistent in cultured
  cells and in rodents.
• Maintain viral genetic information
• Avoid the rodent immune system

44
The Big Picture
(Image kindly provided by Dr. Simmons of Univ. of
Missouri)
45
Pathogenesis

• In both cell cultures and rodents, hantavirus
  does not cause clinical symptoms, despite the
  presence of large amounts of antibodies.
• In human, the virus causes HFRS and HPS.
• The pathogenesis of HFRS and HPS are incompletely
  understood.
• Lack of animal models for human symptoms.
• The requirement for Biosafety Level 3 or 4
  containment limits the number of laboratories
  that can work on it.

46
?3 Integrins and Pathogenesis

• Observation All pathogenic hantaviruses use ?3
  integrin receptors to infect host cells.
• Experiment When ?3 receptors are blocked by
  integrin-specific antibodies, cells are not
  infected by Sin Nombre Virus (SNV), New York
  Virus (NY-1), Hantaan Virus (HTN) or Seoul Virus
  (SEO).
• Hantavirus pathogenesis is related to the use of
  ?3 integrin receptor.

47
?3 Integrins

• ?3 integrins are critical surface receptors on
  endothelial cells and macrophages in human.
• platelet activation and adhesion
• endothelial cell adherence
• capillary integrity and vascular permeability
• Hantavirus dysregulates normal ?3 functions,
  which are fundamental to pathogenesis.
• HFRS- and HPS-causing hantaviruses have different
  G1 and G2 composition
• Interactions between viral G proteins and ?3
  receptors contribute to pathogenic differences.

48
Immune Response Pathogenesis

• Observation The onset of hantavirus symptoms
  coincide with immune response.
• Autopsy results showed higher than normal numbers
  of interleukin (IL), tumor necrosis factor (TNF),
  interferons (INF), and activated T cells.
• Hantavirus pathogenesis is a result of the host
  inflammatory response to the virus.
• Hantavirus pathogenesis awaits for a suitable
  animal model.
• Hooper, et al. reported Syrian hamsters
  inoculated with Andes Virus strain develop
  compatible HPS symptoms.

49
Rodent Hosts and Epidemiology

• Carried by peri-domestic and wild rodents.
• Each strain of hantavirus is generally associated
  with a single rodent species.
• 100 rodent species have been screened, and 23
  hantaviruses found ? 1/4 of the rodents are
  carriers.
• There are about 2000 species of rodents. 2000 x
  1/4 500 different strains of hantaviruses.
• Not all hantaviruses cause disease, e.g.,
  Prospect Hill virus found in the US.
• HPS-causing rodents in the US belong to the
  Muridae family, Sigmodontinae subfamily.

50
Rodent Hosts in the United States

• Deer mouse (Peromyscus maniculatus).
• Carrier of Sin Nombre strain, primary agent of
  HPS in the US. 250300 cases since discovery.
• gt 50 mortality rate.

51
White-footed Mouse (Peromyscus leucopus)

• Carrier of New York strain.

52
Cotton Rat (Sigmodon hispidus)

• Carrier of Black Creek Canal strain.

53
Rice Rat (Oryzomys palustris)

• Carrier of Bayou strain.
• gt 40 mortality rate.

54
Rodent Transmission
Infected rodent
Virions in excretion (urine, feces, saliva).
Biting, fighting, sexual behavior.
Naive rodent
55
From Rodent to Human

• Breathing contaminated air, touching contaminated
  surface, and bite from infected rodent.

56
Person-to-Person Transmission

• In general, hantavirus is not transmitted among
  human.
• The Andes strain found in the 1995 outbreak in
  Argentina may be an exception.

57
Summary

• Negative-sense RNA virus.
• Family Bunyaviridae. 23 strains so far.
• Simple structure tri-segmented genome 4
  proteins.
• Simple replication and transcription.
• Prime and realign model.
• Pathogenesis is unclear.
• Dysregulate ?3 integrin receptor.
• Immunoresponse.
• Carried by rodents.
• Transmitted through inhalation or contact with
  rodent excretion.

58
Topics

• Clinical Manifestations
• HFRS
• HPS
• Comparison
• Diagnostics
• Treatments
• Vaccines

59
Clinical Manifestations

• Hantavirus is associated with two frequently
  fatal human diseases
• a. Hemorrhagic Fever with Renal Syndrome (HFRS)
  -15 fatality
• b. Nephropathia Epidemica (NE) a mild form of
  HFRS
• Hantavirus Pulmonary Syndrome (HPS)
• -50 fatality

60
Stages of Hemorrhagic Fever with Renal Syndrome
(HFRS)

• After an incubation period of 1 or 2 weeks (4-40
  days)
• 1)Febrile Phase
• 2)Hypotensive Phase
• 3)Oliguric Phase
• 4)Diuretic Phase
• 5)Convalescent Phase

61
HFRS Febrile Phase

• Persists 3-5 days
• Sudden onset of fevers and chills
• Accompanied by headache, severe myalgia, nausea
• Blurred vision, photophobia, pain on ocular
  movement
• Flushing of face, V-area of the neck and back
• petechiae
• Abdominal pain and back pain.
• Vascular leak syndrome thirst, edema,
  hemoconcentration, postural hypotension

www.emedicine.com/emerg/topic887.htmsectionpictu
res
62
HFRS Hypotensive phase

• -Lasts for hours or days
• - Blood pressure decrease, hypovolemia, shock
• -worsening of bleeding manifestations petechiae,
  epistaxis, gastrointestinal and intracranial
  bleeding
• -levels of urea and creatinine in blood rise,
  proteinuria
• - leukocytosis, thrombocytopenia

www.emedicine.com/emerg/topic887.htmsectionpictu
res
33 of all HFRS deaths are linked to multi-organ
hypoperfusion at this stage
63
HFRS Oliguric Phase

• Lasts 3-7 days
• Elevation of blood pressure
• Hypervolemia leading to hypertension
• Urine output decreases (renal dysfunction)
• Blood electrolyte imbalance
• Continuation of hemorrhagic symptoms
• Severe complications cardiac failure pulmonary
  edema, and cerebral bleeding
• 50 of fatalities during this phase

64
HFRS Recovery

• Diuretic Phase
• Lasts a few days to a few weeks
• Clinical recovery begins
• 3-6 liters of urine/ day
• Anorexia, lassitude due to dehydration
• Convalescent Phase
• Lasts 2-3 months
• Progressive improvement in glomerular filtration,
  renal blood flow, and urine concentrating ability

65
Nephropathia Epidemica (NE)

• Puumala strain
• Most common form of HFRS in Europe
• Generally a milder form of HFRS
• Similar sequence of symptoms, but attenuated
• Only 6 of serologically confirmed cases require
  hospitalization

66
Stages of Hantavirus Pulmonary Syndrome (HPS)

• After asymptomatic incubation of 4-30 days
• 1) Febrile Phase
• 2) Cardiopulmonary Phase
• 3) Diuretic Phase
• 4) Convalescent Phase

67
HPS Febrile phase

• Lasts 3-5 days (1-12 days)
• Fever, myalgias, malaise
• Other symptoms headache, dizziness, anorexia,
  nausea, vomiting, and diarrhea.
• Difficult to diagnose as HPS at this stage, since
  the symptoms are similar to many other viral
  prodromes

Image from CDC
68
HPS Cardiopulmonary Phase

• Non-productive cough and tachypnea appear
• Presentation and rapid progression of shock and
  pulmonary edema (4-24h).
• Hypovolemia due to progressive leakage of high
  protein fluid from blood to lung interstitium and
  alveoli
• Myocardial failure
• Hypotension and oliguria
• Death within 24-48 hours due to hypoxia and/or
  circulatory compromise.

69
HPS

• Diuretic Phase
• Rapid clearance of pulmonary edema
• Resolution of fever and shock
• Early sign spontaneous diuresis
• Convalescent Phase (up to 2 months)
• Slow but full recovery
• Short term finding pulmonary dysfunction.
• Decreased small-airways flow and diminished
  diffusing capacity

70
HPS

• Clinical Laboratory Findings
• Thrombocytopenia (decrease in number of
  platelets) this is consistent in almost all
  cases in Americas
• Normal or elevated white cell count on
  presentation of symptoms which increases to high
  values as disease progresses (leukocytosis).
• A left shift and presence of immunoblasts from
  late in febrile phase.
• Hemoconcentration

71
HPS

• Radiologic Findings
• Radiography of chest show progression from slight
  interstitial edema to bilateral alveolar edema

Images from CDC
72
HPS Differential Diagnosis

• During prodromal phase difficult to differentiate
  HPS from other acute febrile conditions.
• Blood picture circulating immunoblasts and
  thrombocytopenia
• Cardiopulmonary phase
• Common cause of diffuse pulmonary edema is silent
  myocardial infarction
• Obtain ECG and echocardiogram
• Bilateral pneumonia with sepsis, adult
  respiratory distress syndrome complicating
  systemic infections, sepsis syndrome complicated
  by disseminated intravascular coagulation or
  alcohol toxicity

73
Similarities between HFRS and HPS

• Febrile illnesses with acute onset
• Generalized vascular involvement (capillary leak,
  vasodilation)
• Common laboratory features thrombocytopenia,
  proteinuria, and leukocytosis with occurrence of
  activated lymphocytes in peripheral blood.
• Theory same pathophysiological events, different
  location.
• The main difference between the two conditions
  seems to be the difference in location of the
  particular vascular beds afflicted.

74
Similarities Post-mortem Analysis

• The lack of histological lesions in both HFRS and
  HPS cases to explain disordered organ function
• Hantaviruses induce altered endothelial function
  without overt cell death

Image from CDC

• Functional derangement of vascular endothelium
• Increased permeability of microvascular beds

75
Similarities Spectrum of Illnesses

• There is no clear delineation the symptoms of
  some HFRS and HPS causing strains overlap
• HFRS cases without apparent renal involvement
• Renal involvement in HPS cases
• HPS associated with Bayou and Black Creek Canal
  viruses display moderate to prominent renal
  involvement.
• HPS associated with SNV without pulmonary
  symptoms
• Pulmonary manifestations in HFRS
• Pulmonary complications recorded in 6 of 828
  patients in 1954 outbreak of HFRS fatal
  complications in 2

76
Etiological Diagnosis

• Serologic
• Detection of circulating immunoglobulins.
• Usually there is a robust immune response by the
  time symptoms are present (24hours within one
  week of infection)
• IgM present 3-6 months after infection
• IgG can be detected for years post infection
• ELISA IgM capture assay, using either SNV,
  Laguna Negra, or Andes antigens depending on
  location
• Broad cross-reactivities
• Western blot assay using recombinant antigens
  and isotype specific conjugates for IgM/IgG
  differentiation
• Indirect Immunofluorence
• Rapid immunoblot strip assay (RIBA) an
  investigational prototype assay to identify serum
  antibody to recombinant proteins and peptides
  specific for different strains of hantavirus

77
Etiological Diagnosis

• Immunohistochemistry can test formalin fixed
  tissues with specific monoclonal and polyclonal
  antibodies
• -retrospective
• RT-PCR Demonstration of hantavirus antigen in
  tissues by immunochemistry
• Use of genus specific primers
• Confirms genotype of the infecting virus
• Exponential production of product that may be
  sequenced for further study

78
Treatment Bad News

• There is NO CURE for HFRS or HPS!!

79
Treatment

• Aggressive supportive care
• Fluid management
• Hemodynamic monitoring
• Ventilatory support
• Peritoneal dialysis
• Pressor agents (blood pressure support)
• Inotropic agents (cardiac support)
• Increases cardiac muscle contractility
• Broad spectrum antibiotic therapy until HPS is
  proven (to cover for differential diagnoses)
• Intravenous ceftriaxone or aminoglycoside
• Doxycycline

80
Experimental TreatmentExtracorporeal Membrane
Oxygenation (ECMO)

• CASE REPORT University of New Mexico Hospital
  (UNMH)
• ECMO as rescue therapy
• - Physicians reviewed hemodynamic and
  oxygenation data from the 14 HPS patients treated
  at UNMH during the 1993 Four Corners outbreak
• - Identified the findings that correlate with
  100 mortality from HPS related cardiopulmonary
  failure
• - Identified three patients with confirmed HPS
  and severe cardiopulmonary failure, with
  predicted 100 mortality to be put on ECMO
• - 2 of 3 survived with good outcome

81
ECMO how does it work?

• Takes over the function of heart and lungs while
  the patient recovers from initial cause of
  pulmonary/cardiac failure

• Three components
• 1)membrane artificial lung that adds oxygen and
  removes carbon dioxide
• 2) roller pump that moves the patients
  deoxygenated blood to the membrane and back into
  the body
• 3) heat exchanger that warms the blood back to
  body temperature

http//biomed.brown.edu/Courses/BI108/BI108_2001_G
roups/ECMO

• Venoarterial ECMO A catheter takes blood from
  a major vein, runs it through the ECMO machine,
  and then replaces the blood, under pressure, to
  arterial circulation.

82
ECMO Why isnt it used?

• Complications of the therapy itself
• Cost tens of thousands to a million dollars per
  patient depending on length of time necessary
• Only specialized tertiary care institutions have
  these units.

83
Experimental Treatmentantiviral agents
(Ribavirin)

• RNA virus mutagen antiviral guanosine analog
• Inhibits hantavirus growth in vitro
• Mechanism is unknown
• Severson et al (2003) hypothesize that ribavirin
  challenges the fidelity of the hantavirus
  polymerase, causing error catastrophe

www. sch-plough.com/prod/prod03_anti.htm

• 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

84
RibavirinHPS

• 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)
• INCONCLUSIVE
• 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

85
Treatment

• Future strategies for treatment
• Target the hantavirus/ß-3 integrin interaction
• Immunologic approach
• Target host inflammatory responses
• In progress work to find inhibitors of TNF-?

86
Vaccines

• 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 gt100,000 participants
  showed that four years after primary vaccination,
  average prevention rates were gt90
• 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

87
Vaccines

• U.S. is now focusing on recombinant DNA
  approaches.
• Investigational vaccinia HTNV vaccine is
  currently offered to laboratory workers at
  USAMRIID.

88
Summary

• 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

89

• 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
• human communities.
• -JA Lednicky Department of Pathology,
  Loyola University Medical Center,

90
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

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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 20th 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

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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 

93
However

• However, there are currently quick and efficient
  diagnostic tests
• Treatments for HFRS available
• Vaccines are against HFRS are also available

94
HPS as a bio-weapon

• Hantavirus causing HPS are classified under
  Biological Agents Category C third priority
• Emerging Pathogens  
• Availability
• Ease of production
• Potential for high morbidity, mortality and major
  public health impact 

95
However 

• 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

96
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

97
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

98
Staying Safe

• 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

99
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.

100
Lowering the risk of contracting HPS
101
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. Its NOT the flu)
• Improving diagnostic techniques
• Making sure that resources for outbreak
  investigations are readily available

102
References

• Simmons, J, Riley, L (2002). Hantaviruses an
  overview, Comparative Medicine 52, 97-110.
• Garcin, D, Lezzi, M, Dobbs, M, Elliott RM,
  Schmaljohn C, Kang CY, Kolakofsky D (1995). The
  5 end of Hantaan virus (Bunyaviridae) RNAs
  suggest a prime-and-realign mechanism for the
  initiation of RNA synthesis. J. Virio 69,
  5754-5762.
• Centers for Disease Control and Prevention
  (2002). Hantavirus Pulmonary Syndrome - United
  States Updated Recommendation for Risk
  Prevention. MMWR 51.
• Schmaljohn, C. Hantaviruses (Bunyaviridae),
  Academic Press, 1999.
• Meyer B, Schmaljohn C (2000). Persistent
  hantavirus infections characteristics and
  mechanisms. Trends in Microbio 8, 61-67.
• National Center for Infectious Diseases.
  Preventing hantavirus disease education video,
  September 1994.
• Zhao X, Hay, J (1997). The epidemiology of
  hantavirus infections. Clinical Microbiology
  Newletter 19, No. 7.
• Crowley, MR., et al (1998). Successful treatment
  of adults with severe Hantavirus pulmonary
  syndrome with extracorporeal membrane
  oxygenation. Critical Care Medicine 26, 409-414.
• Khaiboullina, Svetlana F. and Stephen C. St. Jeor
  (2002). Hantavirus Immunology, Viral Immunology
  15, 609-625.
• Peters, C.J., Gary L. Simpson and H Levy. (1999).
  Spectrum of Hantavirus Infection Hemorrhagic
  Fever with Renal Syndrome and Hantavirus
  Pulmonary Syndrome, Annu. Rev. Med. 50, 531-45.
• Severson, William E., Connie S. Schmaljohn, Ali
  Javadian, and Colleen B. Jonsson (2003).
  Ribavirin causes error catastrophe during hantaan
  virus relication, Journal of Virology 77,
  481-488.
• Peters, Clarence J. Infections Caused by
  Arthropod and Rodent Borne Viruses (2001-2003).
  Harrisons Principles of Internal Medicine.
  McGraw Hill Companies.

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The End

• Thank you!