Viral Hemorrhagic Fever

Transcription

1 Viral Hemorrhagic Fever

2 Overview Organism History Epidemiology Transmission Disease in Humans Disease in Animals Prevention and Control

3 What is Viral Hemorrhagic Fever? Severe multisystem syndrome Diffuse Damage to overall vascular system Symptoms often accompanied by hemorrhage Rarely life threatening in itself Includes conjunctivitis, petechia, echymosis Relatively high mortality

4 Quick Overview: Who are they? VHFs are: Enveloped Lipid-encapsulated Single-strand RNA Zoonotic (animal-borne) Geographically restricted by host Persistent in nature (rodents, bats, mosquitoes, ticks, livestock, monkeys, and primates) Survival dependent on an animal or insect host, for the natural reservoir

5 Quick Overview: Who are they? Arenaviridae Lassa Fever Argentine HF (Junin) Bolivian HF (Machupo) Brazilian HF (Sabia) Venezuelan HF (Guanarito) Bunyaviridae Rift Valley Fever (RVF) Crimean Congo HF (CCHF) Hantavirus (Hemorrhagic Fever with Renal Syndrome (HFRS)) Hantavirus Pulmonary Syndrome (HPS) Filoviridae Marburg Ebola Flaviviridae Yellow Fever Dengue Fever Omsk HF Kyasanur Forest Disease

6 Quick Overview: How do we get infected? Rodents & Arthropods, both reservoir & vector Bites of infected mosquito or tick Inhalation of rodent excreta Infected animal product exposure Person-to-Person Blood/body fluid exposure Airborne potential for some arenaviridae, filoviridae

7 Arenaviridae Junin virus Machupo virus Guanarito virus Lassa virus Sabia virus

8 Arenaviridae History First isolated in : Junin virus - Argentina First to cause hemorrhagic fever Argentine hemorrhagic fever 1963: Machupo virus Bolivia Bolivian hemorrhagic fever Guanarito (Venezuela) Sabia (Brazil) 1969: Lassa virus Nigeria Lassa fever

9 Arenavirus Structure Single-stranded, bi-segmented RNA genome Large segment (7200nt), small one (3500nt) Lipid envelope with 8-10nm club-shaped projections

10 Arenaviridae Transmission Virus transmission and amplification occurs in rodents Shed virus through urine, feces, and other excreta Human infection Contact with excreta Contaminated materials Aerosol transmission Person-to-person transmission

11 Arenaviridae in Humans Incubation period days Fever and malaise 2 4 days Hemorrhagic stage Hemorrhage, leukopenia, thrombocytopenia Neurologic signs

12 Arenaviridae: Lassa Fever First seen in Lassa, Nigeria in Now in all countries of West Africa 5-14% of all hospitalized febrile illness Rodent-borne (Mastomys natalensis) Interpersonal transmission Direct Contact Sex Breast Feeding

13 Lassa Fever Virus Background Discovered in 1969 when two missionary nurses died in Lassa, Nigeria, W. Africa It expands to Guinea, Liberia, Sierra Leone 100 to 300 thousand cases per year with approx. 5,000 deaths

14 Lassa Fever Distinguishing Features Gradual onset Retro-sternal pain Exudative pharyngitis Hearing loss in 25% may be persistent Spontaneous abortion Mortality 1-3% overall (up to 50% in epidemics) Therapy: Ribavirin

15 Bunyaviridae Rift Valley Fever virus Crimean-Congo Hemorrhagic Fever virus Hantavirus L-segment codes for an L- protein (the RNA dependent RNA polymerase); M segment codes for two surface glycoproteins G1 and G2 which form the envelope spikes; S segment codes for an N- protein (nucleocapsid protein).

16 Rift Valley Fever (RVF) Bunyaviridae Crimean-Congo Hemorrhagic Fever (CCHF) Hantavirus Old World: Hemorrhagic fever with renal syndrome (HFRS) New World: Hantavirus pulmonary syndrome (HPS) 5 genera with over 350 viruses

17 Bunyaviridae Transmission Arthropod vector Exception Hantaviruses RVF Aedes mosquito CCHF Ixodid tick Hantavirus Rodents Less common Aerosol Exposure to infected animal tissue

18 Bunyaviridae Transmission to humans Arthropod vector (RVF, CCHF) Contact with animal blood or products of infected livestock Rodents (Hantavirus) Laboratory aerosol Person-to-person transmission with CCHF

19 Rift Valley Fever Predominantly a disease of sheep and cattle 1930: First identified in an infected newborn lamb in Egypt In livestock: ~100% abortion 90% mortality in young 5-60% mortality in adults

20 Rift Valley Fever Asymptomatic or mild illness in humans Distinguishing Characteristics Hemorrhagic complications rare (<5%) Vision loss (retinal hemorrhage, vasculitis) in 1-10% Overall mortality 1% Therapy: Ribavirin?

21 Crimean-Congo Hemorrhagic Fever Distinguishing features Abrupt onset Most humans infected will develop hemorrhagic fever Profuse hemorrhage Mortality 15-40% Therapy: Ribavirin

22 Bunyaviridae: Crimean-Congo HF Transmission to humans: Ixodid, Hyalomma spp. ticks Contact with animal blood/products Person-to-person Laboratory aerosols Extensive geographical distribution

23 Bunyaviridae: Hantaviruses Transmission to humans: Exposure to rodent saliva and excreta Inhalation Bites Ingestion in contaminated food/water (?) Person-to-person (Andes virus in Argentina)

24 Hemorrhagic Fever with Renal Syndrome (HFRS) Distinguishing Features Insidious onset Intense headaches, Blurred vision kidney failure (causing severe fluid overload) Mortality: 1-15%

25 RVF Bunyaviridae Humans Incubation period 2-5 days 0.5% - Hemorrhagic Fever CCHF Incubation period 3-7 days Hemorrhagic Fever days following clinical signs Hantavirus Incubation period 7 21 days HPS and HFRS

26 Filoviridae Ebola Ebola-Zaire Ebola-Sudan Ebola-Ivory Coast Ebola-Bundibugyo (Ebola-Reston) Marburg Ebola Marburg

27 Filoviridae History 1967: Marburg, Frankfurt, Belgrade European laboratory workers 1976: Ebola virus Ebola Zaire Ebola Sudan 1989 and 1992: Ebola Reston USA and Italy Imported macaques from Philippines 1994: Ebola Côte d'ivoire

28 Filoviridae Transmission Reservoir is UNKNOWN Bats implicated with Marburg Intimate contact Nosicomial transmission Reuse of needles and syringes Exposure to infectious tissues, excretions, and hospital wastes Aerosol transmission Primates

29 Filoviridae: Ebola Rapidly fatal febrile hemorrhagic illness Transmission: bats implicated as reservoir Person-to-person Nosocomial Five subtypes Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast, Ebola-Bundibugyo, Ebola-Reston Ebola-Reston imported to US, but only causes illness in non-human primates Human-infectious subtypes found only in Africa

30 Filoviridae: Ebola Distinguishing features: Acute onset Weight loss/protration 25-90% case-fatality

31 Filoviridae: Marburg Transmission: Animal host unknown Person-to-person infected animal blood/fluid exposure Indigenous to Africa Uganda Western Kenya Zimbabwe Democratic Republic of Congo Angola

32 Filoviridae: Marburg Distinguising features Sudden onset Chest pain Maculopapular rash on trunk Pancreatitis Jaundice 21-90% mortality

33 Filoviridae Humans Most severe hemorrhagic fever Incubation period: 4 10 days Abrupt onset Fever, chills, malaise, and myalgia Hemorrhage and DIC Death around day 7 11 Painful recovery

34 Flaviviridae Dengue virus Yellow Fever virus Omsk Hemorrhagic Fever virus Kyassnur Forest Disease virus

35 Flaviviridae History 1648 : Yellow Fever described 17 th 20 th century Yellow Fever and Dengue outbreaks 1927: Yellow Fever virus isolated 1943: Dengue virus isolated 1947 Omsk Hemorrhagic Fever virus isolated 1957: Kyasanur Forest virus isolated

36 Flaviviridae Transmission Arthropod vector Yellow Fever and Dengue viruses Aedes aegypti Sylvatic cycle Urban cycle Kasanur Forest Virus Ixodid tick Omsk Hemorrhagic Fever virus Muskrat urine, feces, or blood

37 Flaviviridae Epidemiology Yellow Fever Virus Africa and Americas Case fatality rate varies Dengue Virus Asia, Africa, Australia, and Americas Case fatality rate 1-10% Kyasanur Forest virus India Case fatality rate 3 5% Omsk Hemorrhagic Fever virus Europe Case fatlity rate 0.5 3%

38 Flaviviridae Humans Yellow Fever Incubation period 3 6 days Short remission Dengue Hemorrhagic Fever Incubation period 2 5 days Infection with different serotype Kyasanur Forest Disease Omsk Hemorrhagic Fever Lasting sequela

39 Yellow Fever Distinguishing features Biphasic infection Common hepatic involvement & jaundice Mortality: 15-50%

40 Flaviviridae: Dengue Dengue Fever (DF) /Fatality: <1% Dengue Hemorrhagic Fever (DHF)/ Fatality: 5-6% Dengue Shock Syndrome (DSS) /Fatality 12-44% Four distinct serotypes DEN-1, DEN-2, DEN-3, DEN-4 Distinguishing Features Sudden onset Eye pain Rash Complications/sequelae uncommon Illness less severe in younger children

41 Omsk Hemorrhagic Fever Distinguishing Features Acute Onset Biphasic infection Complications Hearing loss Hair loss Psycho-behavioral difficulties Mortality: 0.5 3%

42 Flaviviridae: Kyanasur Forest Distribution: limited to Karnataka State, India Distinguishing Features Acute onset Biphasic Case-fatality: 3-5% ( cases annually)

43 Symptoms/Signs vary with the type of VHF

44 Common Pathophysiology Small vessel involvement Increased vascular permeability Multiple cytokine activation Cellular damage Abnormal vascular regulation: Early -> mild hypotension Severe/Advanced -> Shock Viremia Macrophage involvement Inadequate/delayed immune response

45 Common Pathophysiology Multisystem Involvement Hematopoietic Neurologic Pulmonary Hepatic (Ebola, Marburg, RVF, CCHF, Yellow Fever) Renal (Hantavirus) Hemorrhagic complications Hepatic damage Consumptive coagulopathy Primary marrow injury to megakaryocytes

46 Common Clinical Features: Early/Prodromal Symptoms Fever Myalgia Malaise Fatigue/weakness Headache Dizziness Arthralgia Nausea Non-bloody diarrhea

47 Common Clinical Features: Progressive Signs Conjunctivitis Facial & thoracic flushing Pharyngitis Exanthems Periorbital edema Pulmonary edema Hemorrhage Subconjunctival hemorrhage Ecchymosis Petechiae But the hemorrhage itself is rarely lifethreatening.

48 Symptoms Incubation period of 6-21 days 80% of human infections are asyptomatic Onset is slow: fever, weakness, & malaise Few days: headache, pharyngitis, muscle pain, retrostinal & abdominal pain, nausea, vomiting, conjunctivitis, diarrhea, cough, & proteinuria Severe cases: facial swelling, lung cavity fluid, hemorrhaging, hyopotension, Neurological problems: tremors, encephalitis, hair loss, gait disturbance, deafness 95% death rate among pregnant women & spontaneous abortion

49 Common Clinical Features: Severe/End-stage Multisystem compromise Profuse bleeding Consumptive coagulopathy/dic Encephalopathy Shock Death

50 Clinical Symptoms More severe Bleeding under skin Petechiae, echymoses, conjunctivitis Bleeding in internal organs Bleeding from orifices Blood loss rarely cause of death

51 Major antiviral cells in early phrase Plasmcytoid DC2 1.A major IFNα producer after viral infection 2. Toll-like receptor -3 < 2 days after viral infection 1. Cytolysis by perforin-granzyme 2. IFN γ: protect uninfected cells and activate macrophages 3. Mediate ADCC IFNγ 1. Phagocytosis of virus and virus-infected cells 2. Kill virus-infected cells 3. Produce antiviral molecules: TNFα, NO, IFNα

52 Adaptive (specific) immune response to viral infection IFNγ IFNα and IFNβ Neighboring uninfected cells Protection Killing

53 Innate & Adaptive Immunity Timeline Cambridge University Immunology Lectures (www)

54 Complete Blood Count Lab studies Leucopenia, leucocytosis, thrombocytopenia, hemoconcentration, DIC Liver enzymes Alb Proteinuria universal Serological tests Ab not detected acute phase; Direct examination blood/tissues for viral Ag enzyme immunoassay. Immunohistochemical staining liver tissue Virus isolation in cell culture RT-PCR sequencing of virus Electron microscopy specific and sensitive

55 Treatment Supportive care: Fluid and electrolyte management Hemodynamic monitoring Ventilation and/or dialysis support Steroids for adrenal crisis Anticoagulants, IM injections, Treat secondary bacterial infections

56 Treatment Manage severe bleeding complications Cryoprecipitate (concentrated clotting factors) Platelets Fresh Frozen Plasma Heparin for DIC Ribavirin in vitro activity vs. Lassa fever New World Hemorrhagic fevers Rift Valley Fever No evidence to support use in Filovirus or Flavivirus infections

57 Prevention and Control

58 Prevention Nosocomial: Complete equipment sterilization & protective clothing House to house rodent trapping Better food storage & hygiene Cautious handling of rodent if used as food source If human case occurs Decrease person-to-person transmission Isolation of infected individuals

59 Prevention and Control Avoid contact with host species Rodents Control rodent populations Discourage rodents from entering or living in human populations Safe clean up of rodent nests and droppings Insects Use insect repellents Proper clothing and bed nets Window screens and other barriers to insects

60 Vaccination Argentine and Bolivian HF PASSIVE IMMUNIZATION Treat with convalescent serum containing neutralizing antibody or immune globulin Yellow Fever ACTIVE IMMUNIZATION Travelers to Africa and South America Experimental vaccines under study Argentine HF, Rift Valley Fever, Hantavirus and Dengue HF

61 VHF Personal Protective Equipment Airborne and Contact isolation for patients with respiratory symptoms N-95 or PAPR mask Negative pressure isolation Gloves Gown Fitted eye protection and shoe covers if going to be exposed to splash body fluids Droplet and Contact isolation for patients without respiratory symptoms Surgical mask Gloves Gown Fitted eye protection and shoe covers if going to be exposed to splash body fluids Environmental surfaces Cleaned with hospital approved disinfectant Linen incinerated, autoclaved, double-bagged for wash

62 Why do VHFs make good Bioweapons? Disseminate through aerosols Low infectious dose High morbidity and mortality Cause fear and panic in the public No effective vaccine Available and can be produced in large quantity Research on weaponization has been conducted