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Microsoft PowerPoint - 14. HFV I

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					   Hemorrhagic fever viruses
•Arenaviruses: ambisense RNA, segmented 2

•Filoviruses: enveloped, (-)ssRNA

•Bunyaviruses: enveloped, segmented 3, (-)
 and ambi-RNA

•Flaviviruses: enveloped, (+)ssRNA




    Viral Hemorrhagic Fevers
• Viral hemorrhagic fevers (VHFs) refer to a group of
  illnesses that are caused by several distinct families of
  viruses.
• In general, the term "viral hemorrhagic fever" is used to
  describe a severe multisystem syndrome (multisystem
  in that multiple organ systems in the body are affected).
• Characteristically, the overall vascular system is
  damaged, and the body's ability to regulate itself is
  impaired.
• These symptoms are often accompanied by
  hemorrhage (bleeding); however, the bleeding is itself
  rarely life-threatening.
• While some types of hemorrhagic fever viruses can
  cause relatively mild illnesses, many of these viruses
  cause severe, life-threatening disease.




       Viral Hemorrhagic Fever:
           Clinical Definition
•Acute infection that begins with fever, myalgia
 (肌肉痛), malaise (身體不適) and progresses to
 prostration (衰竭).
•Evidence of vascular dysregulation and
 increased vascular permeability
•Multisystem involvement
•Hemorrhage indicates extent of small vessel
 involvement but not necessarily large in volume
•Shock, encephalopathy (腦病), extensive
 hemorrhage
•poor prognosis




                                                              1
VIRAL HEMORRHAGIC FEVERS:
         1993-1996
• 1993 Rift Valley Fever epidemic in Egypt
• 1993 Bolivian HF first case since 1975
• 1993 HPS Discovery
• 1994 HPS New viruses found
• 1994 Bolivian HF Family epidemic
• 1994 Sabia virus Laboratory infection, US
• 1994 Lassa fever Case imported Lagos
• 1994 CCHF UAE epidemic stockyards
• 1994 Ebola virus New subtype in Ivory Coast
• 1994-5, Ebola virus , Gabon , Zaire strain
• 1995 Ebola virus Epidemic in Zaire
• 1996, Ebola virus , Gabon , Zaire strain




VIRAL HEMORRHAGIC FEVERS:
         1996- 2005
•1998-2000, Marburg HF, Democratic Republic
 of Congo (DRC).
•2000-2001, Ebola Sudan strain, Uganda
•2001, Crimean-Congo HF, Kosovo
•2001-2002, Ebola Zaire strain, Gabon
•2002, Ebola Zaire strain, DRC
•2004, Ebola Sudan strain, Sudan
•2004-2005, Marburg HF, Angola
•2005, Ebola, (Republic of ) Congo




                   Treatment
•Patients receive supportive therapy, but
 generally speaking, there is no other treatment
 or established cure for VHFs.
•Ribavirin, an anti-viral drug, has been effective
 in treating some individuals with Lassa fever or
 HFRS (by Hantavirus).
•Treatment with convalescent-phase plasma has
 been used with success in some patients with
 Argentine hemorrhagic fever.




                                                     2
                 Control of HFV I
•With the exception of yellow fever and Argentine
 hemorrhagic fever, for which vaccines have
 been developed, no vaccines exist that can
 protect against these diseases.
•Therefore, prevention efforts must concentrate
 on avoiding contact with host species.
•If prevention methods fail and a case of VHF
 does occur, efforts should focus on preventing
 further transmission from person to person, if the
 virus can be transmitted in this way.




                 Control of HFV II
•Because many of the hosts that carry hemorrhagic
 fever viruses are rodents, disease prevention
 efforts include
    #controlling rodent populations;
    #discouraging rodents from entering or living in
 homes or workplaces;
    #encouraging safe cleanup of rodent nests and
 droppings.
•For hemorrhagic fever viruses spread by arthropod
 vectors, prevention efforts often focus on
 community-wide insect and arthropod control. In
 addition, people are encouraged to use insect
 repellant, proper clothing, bednets, window screens,
 and other insect barriers to avoid being bitten.




               Control of HFV III
 • For those hemorrhagic fever viruses that can be
   transmitted from one person to another, avoiding close
   physical contact with infected people and their body
   fluids is the most important way of controlling the spread
   of disease.
 • Barrier nursing or infection control techniques include
   isolating infected individuals and wearing protective
   clothing.
 • Other infection control recommendations include proper
   use, disinfection, and disposal of instruments and
   equipment used in treating or caring for patients with
   VHF, such as needles and thermometers.




                                                                3
                     TRENDS IN VIRAL HEMORRHAGIC FEVER CONTROL

    Trends           SURVEILLANCE/PREDICTION
                     •Remote Sensing (RVF/Hantaan)
      in             •
                     Rapid Automated ELISA for Vector Infection (RVF, CCHF)


     VHF             •
                     Rapid Automated ELISA for IgG/IgM antibodies in sentinels (RVF,
                     CCHF)


    control          •Detection Methods for fixed tissues (RVF, CCHF,
                     Ebola/ Marburg, Yellow Fever, Dengue)

                     PREVENTION
                     •Ecological Strategies (RVF)
                     •New Vaccine Candidates
                           •
                           Argentine HF (conventional, live attenuated)
                           • Vally Fever (mutagenized, MP-12)
                           Rift
                     THERAPY
                     •Early diagnosis (Lassa, RVF, CCHF, Hantaan, Ebola/Marburg,
                     Yellow Fever)
                     •Ribavirin Therapy (RVF, CCHF, Hantaan)
                     UNMET RESEARCH NEEDS
                     •
                     Ways to control Lassa Fever, Hantaan
                     •
                     Understand filovirus reservoir
                     •
                     Role of Hantaan in chronic disease




      Common Features in HFV
• They are all RNA viruses, and all are covered, or enveloped, in a
  fatty (lipid) coating.
• Their survival is dependent on an animal or insect host, called the
  natural reservoir.
• The viruses are geographically restricted to the areas where their
  host species live.
• Humans are not the natural reservoir for any of these viruses.
  Humans are infected when they come into contact with infected
  hosts. However, with some viruses, after the accidental transmission
  from the host, humans can transmit the virus to one another.
• Human cases or outbreaks of hemorrhagic fevers caused by these
  viruses occur sporadically and irregularly. The occurrence of
  outbreaks cannot be easily predicted.
• With a few noteworthy exceptions, there is no cure or established
  drug treatment for VHFs.




       Hosts and Vectors of HFV
• Viruses associated with most VHFs are zoonotic. This means that
  these viruses naturally reside in an animal reservoir host or arthropod
  vector.
• They are totally dependent on their hosts for replication and overall
  survival.
• For the most part, rodents and arthropods are the main reservoirs for
  viruses causing VHFs.
• For example, the multimammate rat, cotton rat, deer mouse, house
  mouse, and other field rodents.

● Arthropod ticks and mosquitoes serve as
vectors for some of the illnesses. However,
the hosts of some viruses remain unknown --
Ebola and Marburg viruses are well-known
examples.




                                                                                       4
  Factors in the Emergence of HFV

 •Microbial evolution: mutation, recombination,
  transfer
 •Environment: weather, land use, water
 •Social: economic, warfare, population,
  urbanization
 •Health care: antibiotics, immunosuppression,
  devices
 •Food: production and distribution
 •Behavior: sex, drugs, travel, child care
 •Public health infrastructure




                            Hemorrhagic Fevers and Their Virus Families
                            ARENAVIRUS
                                           Old World   Lassa Fever (Africa)      Lassa Virus
Hemorrhagic                                American

   Fever                                               Argentine HF
                                                       Bolivian HF
                                                                                 Junin Virus
                                                                                 Machupo Virus

  Viruses                                              Venezuaelan HF            Guanarito Virus
                                                       Brazilian HF              Sabia Virus
                            BUNYAVIRIDAE
                                                       Rift Valley Fever         Phelobovirus
                                                       Crimean Congo HF          Nairovirus
                                                       HF with Renal
                                                                                 Hantavirus
                                                       Syndrome
                                                       Hantavirus Pulmonary
                                                       Syndrome
                            FILOVIRUS
                                                       Marburg HF
                                                       Ebola HF
                            FLAVIVIRUS
                                                       Yellow Fever
                                                       Dengue HF
                                                       KFD and Omsk HF




   Risk of HFV to the Traveler
               Disease             I.P. in days        Case Infection         Case Fatality


        Lassa fever                 5-16                 <10%                  15%


        South American HF           7-14                 >50%                  10 -15 %


        Rift Valley fever           2-5                   1%                   50%


        Crimean - Congo             3-12                  20-100%              15-30 %
        HF
        Hemorrhagic fever           9-35                  4-80%                5-15%
        with renal syndrome
        HPS                         7-30                 >80%                  40-50%


        Ebola and Marburg           3-16                 >75%                  25-90 %


        Yellow Fever                3-6                   80-95%               20 %


        Dengue HF                   3-15                  0.007-1%             1%-20%
        Kyasanur Forest             3-8                   variable             0.5-10 %
        HF Omsk HF




                                                                                                   5
                       HFV Genome
                            (-)sense




                        Arenaviruses
Ex: Lassa Fever Virus
Nature Host (Reservoir): Vertebrate
Vector: rodents
Genome: ambisense RNA, segmented 2




    Transmission of Arenaviruses




-contact with the excretions or materials contaminated with the excretions of an
infected rodent.
  -Some arenaviruses, such as Lassa and Machupo viruses, are associated with
secondary person-to-person and nosocomial (health-care setting) transmission.
This is due to direct contact with the blood or other excretions, containing virus
particles, of infected individuals.
   -Airborne transmission has also been reported         From CDC,US fact sheet




                                                                                     6
             Lassa Fever Virus




                                              Lassa Virion EM




Arenaviruses Pathogenic in Humans




                 Filoviruses

• Ex: Ebola virus                              Ebola
• Reservoir: unknown,
• Vector: unknown,
 the virus can be replicated in some
  species of bats…
• Transmission: zoonotic                        Marburg
 Once a human is infected, however,
  person-to-person transmission is the
  means by which further infections occur.
  It can transmit by close personal contact
  between an infected individual or their
  body fluids, and another person.




                                                                7
                        Modes of Infection of Ebola




             Chronology and geographic
        distribution of Ebola virus outbreaks




                                                                                              Till 1995




              Known Cases and Outbreaks of
               Marburg Hemorrhagic Fever
Year(s)            Country          Apparent or              Reported no. of        Reported no. (%) of                     Situation
                                                    Outbreaks               Fever, in Chronological Order
          Known Cases and print (54 KB/2 pages) of Marburg Hemorrhagicdeaths among cases
                 Download PDF version formatted for
          Marburg Hemorrhagic Fever >          suspected origin human cases
          May 6, 2005
1967        Germany and          Uganda                  32                      7 (21)                       Simultaneous outbreaks occurred in
                                                                                                              laboratory workers handling African green
            Yugoslavia
                                                                                                              monkeys imported from Uganda.

1975        Johannes-            Zimbabwe                3                       1 (33)                       A man with a recent travel history to
                                                                                                              Zimbabwe was admitted to hospital in
            burg, South Africa
                                                                                                              South Africa. Infection spread from the
                                                                                                              man to his traveling companion and a
                                                                                                              nurse at the hospital. The man died, but
                                                                                                              both women were given vigorous
                                                                                                              supportive treatment and eventually
                                                                                                              recovered.

1980        Kenya                Kenya                   2                       1 (50)                       Recent travel history included a visit to
                                                                                                              Kitum Cave in Kenya's Mount Elgon
                                                                                                              National Park. Despite specialized care in
                                                                                                              Nairobi, the male patient died. A doctor
                                                                                                              who attempted resuscitation developed
                                                                                                              symptoms 9 days later but recovered.

1987        Kenya                Kenya                   1                       1 (100)                      A 15-year-old Danish boy was hospitalized
                                                                                                              with a 3-day history of headache, malaise,
                                                                                                              fever, and vomiting. Nine days prior to
                                                                                                              symptom onset, he had visited Kitum Cave
                                                                                                              in Mount Elgon National Park. Despite
                                                                                                              aggressive supportive therapy, the patient
                                                                                                              died on the 11th day of illness. No further
                                                                                                              cases were detected.

1998-       Democratic           Durba, DRC              154                     128 (83)                     Most cases occurred in young male
                                                                                                              workers at a gold mine in Durba, in the
2000        Republic of
                                                                                                              north-eastern part of the country, which
            Congo (DRC)                                                                                       proved to be the epicentre of the outbreak.
                                                                                                              Cases were subsequently detected in the
                                                                                                              neighboring village of Watsa.

2004-       Angola               Uige Province, Angola   313 as of May 6, 2005   280 (89) as of May 6, 2005   Outbreak believed to have begun in Uige
                                                                                                              Province in October 2004. Most cases
2005
                                                                                                              detected in other provinces have been
                                                                                                              linked directly to the outbreak in Uige.
                                                                                                              International assistance, coordinated by
                                                                                                              WHO, is currently organizing to help
                                                                                                              contain this outbreak. For updated case
                                                                                                              numbers, please see the WHO Web site.




                                                                                                                                                            8
           Ecologic and Geographic
        Distribution of Filovirus Disease




(A) Known occurrence points of filovirus hemorrhagic fevers (HFs) identified by virus species.
(B) Geographic projection of ecologic niche model based on all known filovirus disease occurrences in Africa.
(C) Geographic projection of ecologic niche model based on all known Ebola HF occurrences (i.e.,
eliminating Marburg HF occurrences). (D) Geographic projection of ecologic niche model based on all known
occurrences of Marburg HF (i.e., eliminating Ebola HF occurrences).




Projection of Ecologic and Geographic
   Distribution of Filovirus Disease

                                                     Potential Environments in Asia




                                                    (A) Projection of model for Marburg HF occurrences to
                                                        southeastern Asia.
                                                    (B) Projection of model for all filovirus disease
                                                        occurrences to southeastern Asia (the projection of
                                                        models for Ebola HF occurrences is identical to this
                                                        map). US CDC 2004




                                    Bunyavirus
 •Ex: Hantavirus; Crimean-Congo
  haemorrhagic fever (CCFV)
 •Reservoir: vertebrates (plants for
  tospovirus)
 •Vector: arthropod, (rodents for
  Hantavirus)
 •Transmission: arthropod bites,
  rodent secretion contact for
  Hantavirus




                                                                                                                9
  Bunyavirus Genomes
  (Hantavirus)
  enveloped,
  segmented 3,
  (-) and ambi-RNA




          Replication of Bunyavirus




   Geogrphic Distribution of CCHF




Crimean-Congo hemorrhagic fever virus, Nairovirus genus, family Bunyaviridae




                                                                               10
    Distribution of Hanta Virus




Finding the New World Hantavirus
•Identified in the United States in 1993
 (New Mexico and Nevada), and
•retrospectively diagnosed for an incident in
 1987 (Utah),
•During the 1997-98 El Niño, rodent
 populations grew dramatically in January
 and February of 1998, followed by a 3-
 year-long increase in the cases of HPS.




  Hantavirus Prevalence in US




                                                11
              Question
•What is the vector?
•Which kind of mouse?
•How to transmit?




Distribution of the Deer-mouse and
                 HPS




   Transmission of Hantavirus




                                     12
         HPS Cases




  New World Hantaviruses




Target End-Organs of Bunyavirus




                                  13
      Transmission of Hantavirus




                           Flavivirus
•Ex: yellow fever virus,                                Yellow fever virus
 JEV, Dengue V…
•Reservoir: vertebrates
•Vector: arthropods
•Transmission:
 arthropod bites




             Flavivirus Distribution



                                       Tickborne Encephalitis Virus, TBEV




West Nile Virus in Red; JEV in Green




                                                                             14
         What Can We Do to Help?
• Counter Strategies:
  developing containment, treatment, and vaccine
  strategies for these diseases
• Rapid Diagnosis:
  developing immunologic and molecular tools for more
  rapid disease diagnosis
• Understand the Transmission and Pathogenesis:
  studying how the viruses are transmitted and exactly
  how the disease affects the body (pathogenesis)
• Viral Ecology:
  understanding the ecology of these viruses and their
  hosts in order to offer preventive public health advice for
  avoiding infection




     Arenaviridae Recent Findings
• DNA Vaccine Induces Immunological Protection.                                   Virology. 25 April

   2005; 335(1): 87-98

• RNAi Inhibits Multiplication of Lymphocytic
  Choriomeningitis Virus. Virology. Sept 2005; 79(17): 11071-11081
• Receptor Binding Characteristics Highly Conserved
  Among Arenaviruses. Virology. May 2005; 79(10): 5979-5987
• Human-to-Human Transmission of LCMV via Organ
  Transplantation. (Massachusetts, Rhode Island 2005). Morbidity and Mortality Weekly Report.
   June 3, 2005; 54(21):537-539.

• Junin Arenavirus Preferentially Binds to and is Released
  From Apical Plasma Membrane. Journal of General Virology. May 2005; 86(5):
   1475-1479.




          Arbovirus Detection Strips




                                                                                                       15

				
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