viral

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VIRAL HAEMORRHAGIC FEVER

• Dr Ngemera Johannes A
• MD(HKMU) Mmed Int. Med. (MUHAS)
• March 15th, 2023

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VHFs - Overview

• Introduction
• Epidemiology
• Causes
• Transmission
• Pathogenesis
• Clinical Presentation
• Laboratory diagnosis
• Management
• Dengue Fever
• Ebola

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Viral Hemorrhagic Fevers (VHFs) - Introduction

• Diverse group of illnesses caused by RNA viruses
  belonging to the families
• Arenaviridae
• Bunyaviridae
• Filoviridae and
• Flaviridae.
• Affects multiple organ systems in the body
• Damages Vascular system
• Impair bodys ability to regulate itself
• Many cause severe and life-threatening disease.
• Differ by geographic occurrence and
  vector/reservoir

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Epidemiology

• Survival depend on an animal or insect host (the
  natural reservoir)
• Geographically restricted to areas where their
  host species live
• Naturally reside in an animal reservoir host or
  arthropod vector
• Rodents and arthropods main reservoirs for
  viruses causing VHFs.
• Ticks and mosquitoes vectors for some VHFs
• Ebola and Marburg unknown host factors
• Humans - not the natural reservoir but are
  infected via contact with infected hosts or
  arthropod vectors

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Epidemiology

• Incubation period
• Typical 5-10 days
• Range 2- 21 days

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Causes of VHFs

• Arenaviridae
• Lassa fever
• New World hemorrhagic fever
• Flaviviridae
• Yellow fever
• Omsk hemorrhagic fever,
• Kyasanur Forest disease
• DENGUE

• Filoviridae
• EBOLA
• Marburg viruses
• Bunyaviridae
• Rift Valley fever,
• Crimean-Congo fever
• agents of hemorrhagic fever with renal syndrome

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Family Disease Vector in Nature Geographic Distribution
Filoviridae Ebola Unknown Africa
Marburg Unknown Africa
Arenaviridae Lassa Hemorrhagic Fever Rodent West Africa
New World hemorrhagic fever Rodent West Africa
Bunyaviridae Crimean-Congo hemorrhagic fever Tick Africa, Asia, Eastern Europe, Middle East
Rift Valley fever Mosquito Africa, Saudi Arabia, Yemen
Hemorrhagic Fever with renal syndrome Rodent Asia, Europe
Flaviviridae Dengue Mosquito Africa, Asia
Yellow fever Mosquito Africa, Tropical America
Omsk hemorrhagic fever Tick Central Asia
Kyasanur Forest disease Tick India
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Transmission

• Potential for aerosol dissemination via
  respiratory route (except dengue and yellow
  fever)
• Exposure of body excretions (urine, fecal matter,
  saliva) from infected reservoir hosts or vectors,
  e.g. rodents
• From animals to humans direct contact
• Person to person
• e.g. Ebola, Marburg, Lassa and Crimean-Congo
  hemorrhagic fever
• Vector bite
• Mosquito bite ? Yellow fever, Dengue

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Pathogenesis

• Viruses enter the bloodstream through various
  mechanisms
• Mosquito or tick bite
• inhalation
• mucous membrane exposure
• parenteral exposure
• Cause disease during the period of viremia.
• The infectious dose is low (1 to 10 organisms)

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Pathogenesis

• Endothelial infection may occur and may be
  limited or widespread, depending on the virus.
• Hemorrhagic manifestations occur as a result of
• Thrombocytopenia or
• Severe Platelet dysfunction
• Endothelial dysfunction.

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Pathogenesis

• ?? vascular permeability is common and may result
  in
• Periorbital edema and
• hemoconcentration
• Vascular dysregulation also often occurs,
  manifested by flushing of the face and chest.
• Extensive lymphoid necrosis
• Spleen, thymus, and lymph nodes

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Pathogenesis

• marked cytopathic effect (highly destructive to
  the cells they infect).
• Ebola, Marburg, yellow fever, and Rift Valley
  fever viruses
• infection to monocyte-derived dendritic cells
• Ebola and Lassa viruses
• Dendritic cells exposed to these viruses
• do not up-regulate,
• fail to secrete pro-inflammatory or
  immunoregulatory cytokines, and
• do not effectively stimulate T cells

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Pathogenesis

• Disseminated intravascular coagulation (DIC)
• Ebola virus infection
• Marburg, Rift Valley fever, and Crimean-Congo
  hemorrhagic fever
• triggered by immune-mediated mechanisms
• Suppression of the host antiviral response
• play a critical role in pathogenesis of Ebola
  virus infection
• Lymphocyte depletion through apoptosis
• play a role in suppression of the immune response
  

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Clinical Presentation

• Non-specific
• Varies depending on the infecting agent
• Incubation period is 2-21 days, depending on
  infecting agent
• Onset typically abrupt with filoviruses,
  flaviviruses, and Rift Valley fever
• Onset more insidious with arenaviruses

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Clinical Presentation - Initial Symptoms

• Prodromal illness lasting lt 1 week may include
• High fever
• Headache
• Generalized body weakness (Malaise)
• Dizziness
• Muscle and Joints pain
• Nausea
• Non-bloody diarrhea
• DDx?

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Clinical Presentation - Signs

• Flushing, conjunctival injection (red eye)
• Pharyngitis
• Skin Rash
• Edema
• Hypotension
• Shock
• Mucous membrane bleeding

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Diagnosis of VHF

• based on three components
• History of exposure - Symptoms
• Detailed clinical assessment - Signs
• Laboratory investigations Confirm Diagnosis

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Laboratory Investigations

• FBP
• Leukopenia is suggestive, but WBC may be normal
  or elevated
• Thrombocytopenia is typical, but sometimes mild
  or absent
• Hematocrit normal or increased early
• Liver function Test
• AST (SGOT) typically elevated prognostic value
• Bilirubin may be elevated
• Prothrombin/APTT usually prolonged
• Fibrinogen elevated, normal, or decreased
• Renal Function Test
• BUN/Creatinine related to circulatory status
• Proteinuria

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Specific diagnoses of VHFs agents

• Blood samples for detecting
• specific antibodies
• viral antigens (ELISA)
• viral nucleic acid - reverse transcriptase
  polymerase chain reaction (RT-PCR)
• virus isolation Culture and Sensitivity

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Differential Diagnosis of VHF

• Bacterial
• Typhoid fever
• Meningoccemia,
• Rickettsioses,
• Leptospirosis
• Protozoal
• Falciparum malaria
• Other
• Vasculitis
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome

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Treatment of VHFs

• Supportive care
• Hydration, electrolytes balance, feeding
• Pain and anxiety management
• for multi organ dysfunctions and hemorrhagic
  events
• vasoactive drugs,
• haemodialysis,
• mechanical ventilation,
• Platelets and/or RBCs transfusion.
• Ribavirin
• inhibit Viral replication
• should be started as soon as a case of VHF is
  suspected
• 30 mg/kg IV Stat, then 16 mg/kg IV 6hourly for 4
  days, followed by 8 mg/kg 8hourly for 510 days

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Management of Exposed Persons

• Medical surveillance for all potentially exposed
  persons, close contacts, and high-risk contacts
  for 21days
• mucous membrane or percutaneous exposure
• Report hemorrhagic symptoms
• Record fever 2x/day
• Percutaneous/mucocutaneous exposure to blood or
  body fluids of infected
• Wash thoroughly with soap and water,
• Irrigate mucous membranes with water or saline

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Management of Exposed Persons

• Only licensed vaccine
• Yellow Fever
• Investigational vaccines AHF, RV, HV
• Possible use of Ribavirin to high-risk contacts
  of CCHF and LF patients

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Infection Control

• Airborne contact precautions for
• Health care
• Environmental and
• Laboratory workers
• Personal protective equipment
• Double gloves
• Impermeable gowns, leg and shoe coverings
• Face shields and eye protection
• N-95 mask or PAPR

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Infection Control

• Laboratory samples handling
• Prompt burial or cremation of deceased with
  minimal handling
• Autopsies performed only by trained personnel
  with PPE

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DENGUE FEVER
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DENGUE FEVER

• Mosquito-borne viral disease
• widespread throughout the tropics
• Dengue virus is transmitted by female mosquitoes
  mainly of the species
• Aedes aegypti and,
• to a lesser extent, Aedes albopictus.
• Aedes mosquito also transmits
• Chikungunya,
• Yellow fever and
• Zika infection.

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Dengue Virus

• Four distinct, but closely related, serotypes
• DEN-1, DEN-2, DEN-3 and DEN-4
• Recovery from infection by one provides lifelong
  immunity against that particular serotype.
• However, cross-immunity to the other serotypes
  after recovery is only partial and temporary.
• Subsequent infections by other serotypes increase
  the risk of developing severe dengue.

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Dengue Virus Infection
Symptomatic
Asymptomatic
Undifferentiated fever
Classical Dengue fever (DF)
Dengue Haemorrhagic fever (DHF)
Without Haemorrhage
With Haemorrhage
No Shock
Dengue Shock syndrome (DSS)
Increase in Severity and mortality
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Clinical presentation

• Based on severity
• Classical dengue fever
• Dengue hemorrhagic fever (DHF)
• Dengue shock syndrome (DSS)
• Note
• Dengue Shock Syndrome is actually a severe form
  of Dengue hemorrhagic Fever

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Classical Dengue fever

• Break bone fever
• Acute febrile viral disease frequently presenting
  with
• Headache retroorbital headache
• Bone or joints pain
• Muscular pain
• Skin rashes and
• Leukopenia

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Dengue hemorrhagic fever

• Fever or recent history of acute fever
• Hemorrhagic manifestations
• Thrombocytopenia (Platelets lt 100,00/mm3)
• Evidence of leaky capillaries
• ? Hematocrit ( 20 over the baseline)
• ? Serum albumin
• Pleura or other effusions

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Grades of Dengue hemorrhagic fever

• Grade 1
• Fever and non specific constitutional symptoms
• Positive tourniquet test only hemorrhagic
  manifestation
• Grade 2
• Grade 1 spontaneous bleeding
• Grade 3
• Signs of circulatory failure - Rapid weak pulse,
  Hypotension and cold/clammy skin
• Grade 4
• Profound Shock ? Undetectable Pulse and BP

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Danger signs of Dengue hemorrhagic fever

• Abdominal pain intense and sustained
• Persistent vomiting
• Abrupt change from fever to hypothermia with
  sweating and prostration
• Restlessness of somnolence
• Note
• All of these are signs of impending shock ?
  patient needs close observation and fluids

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Dengue hemorrhagic fever

• Hemorrhagic manifestation
• Skin hemorrhage
• Petechieae, purpura, ecchymoses
• Scleral injection
• Gingival bleeding
• Nasal bleeding
• Gastrointestinal bleeding
• Hematemesis, melena, hematochezia
• Haematuria
• Increased menstrual flow

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Dengue shock syndrome

• Four criteria of Dengue haemorrhagic fever
• Fever or recent history of acute fever
• Haemorrhagic manifestations
• Thrombocytopenia (Platelets lt 100,00/mm3)
• Evidence of leaky capillaries
• ? Hematocrit ( 20 over the baseline)
• ? Serum albumin
• Pleura or other effusions
• PLUS
• Evidence of circulatory failure(Shock)
• Rapid weak pulse
• Hypotension
• Cold clammy skin and altered mental status

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Differential Diagnosis of Dengue fever

• Malaria
• Other Viral Hemorrhagic fever
• Ebola virus
• Yellow fever
• Chikungunya virus
• Zika virus infection

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Laboratory Investigations

• IgG or IgM antibody titers of dengue virus
• Dengue virus antigen
• Dengue NSI test
• Other investigations
• FBP Thrombocytopenia, Leucopenia
• RFT Creatinine (eGFR), Urea
• LFT AST, ALT
• Coagulation profiles
• Stool for Occult Blood GI Bleeding

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Dengue NSI Rapid test
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Treatment

• No specific antiviral treatment
• Supportive care
• Analgesics Paracetamol Avoid NSAIDs and
  Steroids
• Fluid replacement 0.9NaCl or Ringers Lactate
• Blood Transfusion
• Platelets and fresh frozen plasma to control
  Bleeding
• Close monitoring
• Vital signs, Urine Output
• Serial Lab Investigations

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Prevention and Control

• Mosquito control
• Infected person
• Vaccination (Four serotyptes)

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EBOLA HEMORRHAGIC FEVER
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Ebola Hemorrhagic Fever

• Key facts
• The Ebola virus causes severe viral haemorrhagic
  fever (VHF) outbreaks in humans.
• Viral haemorrhagic fever outbreaks have
  a case fatality rate of up to 90.
• Ebola haemorrhagic fever outbreaks occur
  primarily in remote villages in Central and West
  Africa, near tropical rainforests

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Reservoir and transmission to humans

• Researchers believe that
• Ebola virus is animal-borne
• Bats are the most likely reservoir
• Bats infect chimpanzees, gorillas, forest
  antelopes, porcupines
• Humans handle and eat bush meat (bats,
  chimpanzees, gorillas)
• Infected human passes infection from person to
  person
• Ebola is not a new disease discovered 1976
• Outbreaks have appeared sporadically in Africa.

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Transmission

• Intimate contact
• Infected Human
• Cadaver
• Wild animals
• Nosocomial transmission
• Re-use of needles and syringes
• Exposure to infectious tissues, excretions, and
  hospital wastes
• Aerosol transmission
• Primates
• Reservoir is UNKNOWN
• Fruit Bats considered to be the natural host.

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• EHF Risk Factors
• Direct physical contact
• Body fluids
• No contact no disease

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EBOLA Outbreaks in Africa
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Pathogenesis

• Mode of Entry
• Mucosal surfaces
• Breaks, and abrasions in the skin
• Parenteral
• Target cells and tissues - supports viral
  replication
• Monocytes, Macrophages and dendritic cells
• Endothelial cells,
• Fibroblasts,
• Hepatocytes,
• Adrenal cortical cells, and
• several types of epithelial cells

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Pathogenesis

• Viral dissemination
• Via monocytes, macrophages, and dendritic cells
  to regional lymph nodes, probably through the
  lymphatic system, and
• Through bloodstream to the liver and spleen

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Clinical Presentation

• Initial symptoms are nonspecific, may include
• fever
• chills
• Muscle and joints pain and
• malaise
• can progress to develop gastrointestinal
  symptoms
• severe watery diarrhea
• nausea
• vomiting
• abdominal pain

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Clinical Presentation

• Other symptoms
• chest pain
• shortness of breath
• headache or confusion
• conjunctival injection
• hiccups
• seizures and
• cerebral edema

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Clinical Presentation

• Bleeding can manifest later as
• petechiae,
• ecchymosis/ bruising, or
• oozing.
• Frank hemorrhage less common.
• Some develop diffuse erythematous maculopapular
  rash that can desquamate.

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Clinical Presentation

• Most common symptoms reported during current
  outbreak
• fever (87)
• fatigue (76)
• vomiting (68)
• diarrhea (66)
• loss of appetite (65)
• Patients with fatal disease
• develop more severe clinical signs early during
  infection and
• die between days 6 - 16 of complications (mean of
  7.5 days).
• In non-fatal cases, patients may have fever for
  several days and improve, around day 6.
• The case fatality proportion in West Africa is
  about 71

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Diagnosis of Ebola

• Diagnosing Ebola can be difficult at first since
  early symptoms, such as fever, are nonspecific to
  Ebola infection.
• However, if a person has the early symptoms and
  has had contact with Ebola they should be
  isolated and public health professionals
  notified.
• Samples from the patient can then be collected
  and tested to confirm infection.

Source Centers for Disease Control and
Prevention http//www.cdc.gov/vhf/ebola/diagnosis/
index.html
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Diagnosis of Ebola
Timeline of Infection Diagnostic tests available
Within a few days after symptoms begin - ELISA testing - IgM ELISA - Polymerase chain reaction (PCR) - Virus isolation
Later in disease course or after recovery - IgM and IgG antibodies
Retrospectively in deceased patients - Immunohistochemistry testing - PCR - Virus isolation
Centers for Disease Control and Prevention
ttp//www.cdc.gov/vhf/ebola/diagnosis/index.html
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Laboratory investigations

• FBC
• Liver Function Test
• Renal Function test
• Enzyme-Linked Immuno Sorbent Assay (ELISA)
• Antigen detection tests
• virus isolation by cell culture

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Treatment of Ebola

• No approved treatments available
• Supportive care of complications
• Hypovolemia
• Electrolyte abnormalities
• Hematologic abnormalities
• Refractory shock
• hypoxia
• Hemorrhage
• DIC
• septic shock
• multi-organ failure

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Treatment of Ebola

• Recommended care includes
• Volume repletion
• maintenance of blood pressure (with vasopressors
  if needed)
• maintenance of oxygenation
• pain control
• nutritional support
• treating secondary bacterial infections
• Treat pre-existing comorbidities

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Treatment of Ebola

• Among patients from West Africa, large volumes of
  intravenous fluids have often been required to
  correct dehydration due to diarrhea and vomiting.
• Several investigational therapeutics for Ebola
  virus disease are in development.
• There are no approved vaccines available for EVD.
  
• Several investigational Ebola vaccines are in
  development, and Phase I trials are underway for
  some vaccine candidates.

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Ebola Prevention and Control
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YELLOW FEVER

• Caused by yellow fever virus (Flavivirus)
• Transmitted predominantly by Aedes mosquitoes
• Endemic in equatorial Africa and South America
• Estimated 200,000 cases and 30,000 deaths
  annually
• Overall case-fatality rate in Africa 23

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YELLOW FEVER

• The virus is endemic in 45 tropical countries in
  Africa and Latin America
• Combined population of over 900 million people
• In Africa, an estimated 508 million people in 33
  countries

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Transmission
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YF Virus Transmission Cycles in Africa
Urban
Intermediate/ Savannah
Jungle/Sylvatic
Aedes aegypti
Aedes africanus spp. Haemagogus spp. Sabethes
spp.
Semi-domestic Aedes spp.
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Role of humans in yellow fever transmission

• Incubation period of 2-6 days
• Human become viremic capable of infecting
  mosquitoes
• Shortly before onset of fever and for the first
  35 days of illness
• Virus has been found in the blood up to 17 days
  after illness onset
• The extrinsic incubation period in Ae. aegypti is
  912 days
• Once infected, mosquitoes remain so for life

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TIMELINE OF YELLOW FEVER TRANSMISSION
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YF Clinical Presentation
Death 1-2
Detected by surveillance
Fever Jaundice Hemorrhage 2-3
Fever 9-10
Not detected by surveillance
Asymptomatic 85
Incubation period of 2-6 days
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Diagnostic Testing for Yellow Fever

• Laboratory diagnosis usually accomplished by
  testing of serum for antibodies
• ELISA on serum samples to detect YF-specific IgM
  and IgG antibodies
• Confirmatory (plaque reduction neutralization
  testing, PRNT) testing is needed due to
  cross-reactive flaviviral antibodies (e.g.,
  dengue, WNV)
• Acute samples often positive for virus by viral
  isolation or viral RNA detection through RT-PCR
• Post-mortem samples should be obtained
• Frozen viral isolation and RNA detection
• Fixed IHC staining

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YF Treatment, Prevention and Control

• Treatment
• No specific anti-viral treatment
• Supportive therapy
• Prevention and Control
• Vaccination
• Mosquito control

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Personal Protection Measures

• Vaccination
• Use insect repellant on exposed skin
• DEET
• Picaridin
• Oil of lemon eucalyptus
• IR3535
• Wear long sleeves, long pants, hats, socks

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Immunity to Yellow Fever

• Natural disease provides life-long immunity
• Sporadic disease occurrence and deadly nature
  does not allow for high levels of immunity
• Most areas have no previous immunity and minimal
  cross protective immunity to YF
• Yellow fever 17D Vaccine
• Live attenuated viral vaccine
• Given every 10 years

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Yellow Fever Vaccine Requirements

• Most endemic countries require proof of
  vaccination for all travelers coming from other
  endemic areas
• Certain countries with the vectors but without
  the disease require proof of vaccination for all
  travelers from endemic areas

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Indications for YF Vaccine

• For persons 9 months of age
• Planning travel to or residence in an endemic
  area
• Planning travel to a country with an entry
  requirement
• Needs to be given 10 days prior to arrival in
  endemic area
• Revaccination at 10 year intervals

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International Health Regulations 2005

• Allow countries to require proof of YF
  vaccination
• for entry
• Goal is to prevent importation and indigenous
  transmission of YF virus
• Proof of vaccination must be documented on
  International Certificate of Vaccination or
  Prophylaxis (ICVP)
• YF vaccine is only vaccine currently required
  under International Health Regulations
• Traveler without proof of vaccination can be
  detained for 6 days (incubation period)

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Reference

• WHO Global Strategy for dengue prevention and
  control 2012-2020, Chapter 2
• Bronze MS, Shepherd SM Dengue. Medscape Updated
  Dec 12,2018
• Standard Treatment Guidelines National
  Essential Medicines List 5Th ED, December 2017
• Centers for Disease Control and Prevention.
  http//www.cdc.gov/vhf/ebola/hcp/clinician-informa
  tion-us-healthcare-settings.html