Arbovirus part 2
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Dr.T.V.Rao MD
Dr.T.V.Rao MD 1
Arboviruses Arthropod-Borne
VirusesPart 2
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Dr.T.V.Rao MD 2
Arthropod-borne VirusesArboviruses belong to three families
1. Togaviruses e.g. EEE, WEE, and VEE
2. Bunyaviruses e.g. Sandfly Fever, Rift Valley Fever, Crimean-Congo Haemorrhagic Fever
3. Flavivirus e.g. Yellow Fever, Dengue, Japanese Encephalitis
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Dr.T.V.Rao MD 3
DENGUE FEVER
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Dr.T.V.Rao MD 4
Arboviruses• The Arbovirus are also called as Arthropod borne viruses, represent an ecological grounding of viruses with complex transmission cycles involving Arthropods
• These viruses have diverse physical and chemical properties and are classified in several virus families.
• Dengue infection is caused by Arbovirus
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Dr.T.V.Rao MD 5
History - Dengue • This disease was first described 1780,
and the virus was isolated by Sabin 1944. Dengue virus infection is the most common arthropod-borne disease worldwide with an increasing incidence in the tropical regions of Asia, Africa, and Central and South America.
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Dr.T.V.Rao MD 6
Over view of Dengue
• With more than one-third of the world’s population living in areas at risk for transmission, dengue infection is a leading cause of illness and death in the tropics and subtropics. As many as 100 million people are infected yearly. Dengue is caused by any one of four related viruses transmitted by mosquitoes
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Dr.T.V.Rao MD 7
Dengue • Dengue is the biggest Arbovirus problem in the
world today with over 2 million cases per year. Dengue is found in SE Asia, Africa and the Caribbean and S America.
• Flavivirus, 4 serotypes, transmitted by Aedes mosquitoes which reside in water-filled containers.
• Human infections arise from a human-mosquitoe-human cycle
• .
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Dr.T.V.Rao MD 8
Current Trends• In the 1980s, DHF began a second
expansion into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of dengue fever in 1994..
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Dr.T.V.Rao MD 9
Distribution of Dengue
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Dr.T.V.Rao MD 10
Dengue Infection and Implications
• Dengue virus (DENV) infects 50 million (WHO) to 100 million (NIH) people annually.. DENV infection can cause dengue fever, dengue haemorrhagic fever, dengue shock syndrome, and death.
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Dr.T.V.Rao MD 11
Dengue Mosquito transmitted Viral Infection
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Dr.T.V.Rao MD 12
What causes Dengue• Dengue (DF) and dengue haemorrhagic
fever (DHF) are caused by one of four closely related, but antigenic ally distinct, virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the genus Flavivirus. Infection with one of these serotypes provides immunity to only that serotype for life,
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Dr.T.V.Rao MD 13
Aedes aegypti – Vector
• Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species. Other species of Aedes can also transmit.
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Dengue Virus – A Flavivirus• Flavivirus are
spherical and 40- 60 mm in diameter.
Genome – Positive sense, single sense RNA,11kb in size
Genome – RNA infectious
Enveloped virus Dr.T.V.Rao MD 14
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Dr.T.V.Rao MD 15
How Mosquitos spread the infection
• The disease starts during the rainy season, when vector Mosquito Aedes aegypti is abundant
• The Aedes breeds in the tropical or semitropical climates in water holding receptacles or in plants close to human dwellings
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Dr.T.V.Rao MD 16
Cycle of Infection Continues
• A female Aedes acquires the infection feeding upon a viremic human.
• After a period of 8 – 14 days mosquitoes are infective and remain infective for life. ( 1- 3 ) months.
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Dr.T.V.Rao MD 17
Pathogenesis
• Presence of existing Dengue antibody, associated with fresh viral infection with new serotype complexes and forms within few days of the second dengue infection.
• Non neutralizing enhancing antibodies promote infection of higher number of Mononuclear cells.
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Dr.T.V.Rao MD 18
Immunology Dengue
• Four serotypes exist distinguished by Molecular basis and Nt tests
• Infection confers life long immunity • But cross protection between serotypes is
of short duration.• Reinfection with different serotype after
primary attack is more dangerous causes Dengue hemorrhagic fever.
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Dr.T.V.Rao MD 19
Clinical Manifestations
• Any or few of the following events can occur.
• Fever,• Severe head ache• Muscle and joint pains• Nausea, vomiting,• Eye pain
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Dr.T.V.Rao MD 20
How Dengue Infection starts and manifests
• Incubation period 4 – 7 days ( 3 – 14 days)• Fever may start with, Malise,chills,head ache• Soon leads to severe back ache, joint pains,
muscular pain, pain in the eye ball.• Temperature may persist for 3 -5 days.• Myalgia may be severe with deep bone pain ( Break bone fever ) characteristic of the
Disease
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Dr.T.V.Rao MD 21
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Dr.T.V.Rao MD 22
Dengue with Rashes
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Dr.T.V.Rao MD 23
Dengue Hemorrhagic Fever
• DHF was first recognized in the 1950s during the dengue epidemics in the Philippines and Thailand. Today emerging DHF cases are causing increased dengue epidemics in the Americas, and in Asia, where all four dengue viruses are endemic, DHF has become a leading cause of hospitalization and death among children in several countries. ( WHO )
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Dr.T.V.Rao MD 24
Dengue Hemorrhagic Fever• Common in children.• In children passively acquired contributed by
the maternal antibodies transferred to the fetus.• In other ( Adults ) the presence of antibodies
due to previous infection with different serotype• Initially presents like classical Dengue infection• But patients condition abruptly worsens, an
important cause of morbidity and mortality in Dengue
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Dr.T.V.Rao MD 25
Basic Understanding of Dengue Hemorrhagic Fever
• Dengue Hemorrhagic Fever is a probable case of dengue and
• hemorrhagic tendency evidenced by one or more of the following:
• Ø Positive tourniquet test• Ø Petechial, ecchymosis or purpura• Ø Bleeding from mucosa (mostly epistaxis or bleeding
from• gums), injection sites or other sites• Ø Haematemesis or melena
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Dr.T.V.Rao MD 26
How to do a Tourniquet test• The tourniquet test is
performed by inflating a blood pressure cuff to a point mid-way between the systolic and diastolic pressures for five minutes. A test is considered positive when 10 or more petechiae per 2.5 cm2 (1 inch) are observed. In DHF, the test usually gives a definite positive result (i.e. >20 petechiae).
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Dr.T.V.Rao MD 27
What Happens in Dengue Hemorrhagic Fever
• Thrombocytopenia (platelets 100,000/cu.mm or less) and Ø Evidence of plasma leakage due to increased capillary permeability manifested by one or more of the following:
• – A >20% rise in hematocrit for age and sex• – A >20% drop in hematocrit following treatment
with• fluids as compared to baseline• – Signs of plasma leakage (pleural effusion, ascites or• hypoproteinaemia).
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Dr.T.V.Rao MD 28
Risk factor for DHF• Important risk
factors for DHF include the strain of the infecting virus, as well as the age, and especially the prior dengue infection history of the patient
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Dr.T.V.Rao MD 29
Dengue Hemorrhagic Syndrome
• Chateresied by shock and hemoconcentration
• Contributed by circumstantial evidence suggests secondary infection with Dengue type 2 following type 1 infection in the past.
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Dr.T.V.Rao MD 30
Dengue hemorraghigic Syndrome
• DHS is caused due to release of, 1 Release of cytokines 2 Vasoactive mediators. 3 Procoagulants
Manifest with disseminated intravascular coagulation
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Dr.T.V.Rao MD 31
DiagnosisIn resource rich establishments
1 Reverse transcriptase polymerase chain reaction methods help rapid identification
2 Isolation of virus is difficult 3 The current favored approach is inoculation
of mosquito cell line with patient serum coupled with nucleic acid assay to identify a recovered virus.
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Dr.T.V.Rao MD 32
Dengue Serology• The serology is limited with cross reactivity of
IgG antibodies to heterologous Flavivirus antigens
• Most commonly used methods are Viral protein specific capture IgM or IgG by
ELISA IgM antibodies develop within few days of
illness Neutralizing anti Haemagglutination inhibiting antibodies
appear within a week after onset of Dengue fever
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Dr.T.V.Rao MD 33
Importance of paired sample testing in Serology
• Testing one sample for serum and reporting a negative test is fallacious
• Analysis of paired acute and convalescent sera to show significant rise in antibody titer is the most reliable evidence of an active dengue infection.
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Newer Diagnostic MethodsRT - PCR
• RT PCR is a highly sensitive tool in Diagnosis, with established high sensitivity in Diagnosis in Puzzles
• Developing world lacks resources to implement and utilize the Scientific advances
Dr.T.V.Rao MD 34
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Dr.T.V.Rao MD 35
Treatment • No Anti viral therapy
available• Symptomatic management
in Majority of cases• Dengue Hemorrhagic fever
to be treated with suitable fluid replacement
• No Vaccine available, difficult in view of four serotypes.
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Dr.T.V.Rao MD 36
Control of Dengue
• Control of Mosquito breeding places.
• Anti mosquito measures • Use of Insecticides. • Screened windows and doors can
reduce exposure to vectors.
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Dr.T.V.Rao MD 37
Epidemiology - Dengue
• Dengue virus are distributed world wide in tropical regions.
• Where the Aedes vectors exist, are endemic areas
• Changing and increasing incidences are associated with rapid urban population growth, over crowding and lax mosquito control measures
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Dr.T.V.Rao MD 38
Viral Hemorrhagic Fevers
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Dr.T.V.Rao MD 39
Viral Haemorrhagic Fevers
• Acute infection:
fever, myalgia, malaise; progression to prostration
• Small vessel involvement:
increased permeability, cellular damage
• Multisystem compromise (varies with pathogen)
• Hemorrhage may be small in volume
(indicates small vessel involvement, thrombocytopenia)
• Poor prognosis associated with:
shock, encephalopathy, extensive hemorrhage
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Dr.T.V.Rao MD 40
Viral Hemorrhagic Fevers
• Diverse group of illnesses caused by RNA viruses from 4 families:– Arenaviridae, Bunyaviridae, Filoviridae, Flaviridae– Differ by geographic occurrence and
vector/reservoir– Share certain clinical and pathogenic features
• Potential for aerosol dissemination, with human infection via respiratory route (except dengue)
• Target organ: vascular bed• Mortality 0.5 - 90%, depending on agent
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Dr.T.V.Rao MD 41
Viral Hemorrhagic Fever viruses
• Filoviruses Ebola Hemorrhagic fever (EHF)Marburg virus
• Arena viruses Lassa fever“New World Arena viruses”
• Bunyaviruses Rift Valley fever (RVF)Crimean Congo Hemorrhagic fever (CCHF)
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Viral Hemorrhagic Fevers
• Category A agents – Filo viruses– Arena viruses
• Category C agents – Hantaviruses– Tick-borne hemorrhagic
fever viruses– Yellow fever
Dr.T.V.Rao MD 42
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Dr.T.V.Rao MD 43
Viral Hemorrhagic Fevers Transmission
• Zoonotic diseases– Rodents and arthropods main reservoir– Humans infected via bite of infected arthropod, inhalation of
rodent excreta, or contact with infected animal carcasses
• Person-to-person transmission possible with several agents– Primarily via blood or bodily fluid exposure– Rare instances of airborne transmission with arenaviruses and
filoviruses
• Rift Valley fever has potential to infect domestic animals following a biological attack
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Dr.T.V.Rao MD 44
Viral Hemorrhagic FeversClinical Presentation
• Clinical manifestations nonspecific, vary by agent
• Incubation period 2-21 days, depending on agent
• Onset typically abrupt with filoviruses, flaviviruses, and Rift Valley fever
• Onset more insidious with arenaviruses
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Dr.T.V.Rao MD 45
Viral Hemorrhagic FeversInitial Symptoms
– High fever– Headache – Malaise – Weakness– Exhaustion
– Dizziness– Muscle aches– Joint pain– Nausea– Non-bloody diarrhea
Prodromal illness lasting < 1 week may include:
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Dr.T.V.Rao MD 46
VHF Surveillance: Clinical Identification of Suspected Cases
• Clinical criteria: – Temperature 101 F(38.3 C) for <3 weeks– Severe illness and no predisposing factors for
hemorrhagic manifestations – 2 or more of the following:
• Hemorrhagic or purple rash• Epistaxis • Hematemesis • Hemoptysis• Blood in stools • Other hemorrhagic symptoms • No established alternative diagnosis
JAMA 2002;287Adapted from WHO
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Dr.T.V.Rao MD 47
Viral Hemorrhagic FeversTreatment
• Supportive care
• Correct coagulopathies as needed
• No antiplatelet drugs or IM injections
• Investigational treatments, available under protocol:
– Ribavirin x 10 days for Arenaviridae and Bunyaviridae
– Convalescent plasma w/in 8d of onset for AHF
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Dr.T.V.Rao MD 48
Viral Hemorrhagic Fevers Management of Exposed Persons
• Medical surveillance for all potentially exposed persons, close contacts, and high-risk contacts (i.e., mucous membrane or percutaneous exposure) x 21 days – Report hemorrhagic symptoms (slide 47) – Record fever 2x/day
• Report temperatures 101F(38.3C) Initiate presumptive ribavirin therapy
• 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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Dr.T.V.Rao MD 49
Viral Hemorrhagic Fevers Infection Control
• Airborne & contact precautions for health care, environmental, and laboratory workers
• Negative pressure room, if available
– 6-12 air changes/hour
– Exhausted outdoors or through HEPA filter
• 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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Dr.T.V.Rao MD 50
Tick Borne Hemorrhagic Fevers
• Kyasanur Forest Disease,• ( Karnataka India )• Like Russian Spring Summer Encephalitis,• Present with Fever, Headache, Conjunctivitis, Myalgia, Severe prostration,
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Dr.T.V.Rao MD 51
Viral Hemorrhagic FeversSummary of Key Points
• A thorough travel and exposure history is key to distinguishing naturally occurring from intentional viral hemorrhagic fever cases.
• Viral hemorrhagic fevers can be transmitted via exposure to blood and bodily fluids.
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Dr.T.V.Rao MD 52
Pathogenesis.• Enters through the bite of Insect vector,• Multiply in RES.• Target the organ CNS Encephalitis, Liver Yellow fever, Capillary endothelium in Hemorrhagic fevers.
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Dr.T.V.Rao MD 53
Rodent Borne Hemorrhagic Fevers,
• Hanta Virus, Produces pulmonary infections in USA
•Belong to Bunya Virus –Hanta Viruses
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Dr.T.V.Rao MD 54
Hanta Viruses,• Human disease Hemorrhagic fever with renal
syndrome• Hanta virus pulmonary syndrome.• Spread by inhalation of Aerosols of Rodent
Excreta,• Renal Involvement and failure• Lead to Hemorrhagic shock, Korea• Spread by Rats carried in ships,
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Dr.T.V.Rao MD 55
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Dr.T.V.Rao MD 56
Laboratory Diagnosis
•Detection of viral nucleic acid,
•Grown in culture lines,•PCR,
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Dr.T.V.Rao MD 57
Filoviruses,African Hemorrhagic Fevers.
• Most important Diseases are• Marburg and Ebola.• The nature of Viruses are 80 nm
Filamentous threads,• Produce Internal and external
Bleeding.
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Dr.T.V.Rao MD 58
Filoviruses. Marburg
• Marburg 1967 African Green Monkey,
• Bat – Rodent – Host Human.• East Africa Monkey – Humans.
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Dr.T.V.Rao MD 59
Filoviruses - Ebola
• Incubation 2-21 days• Carries 80% mortality.• Barrier Nursing Most essential.• ELISA test• Culturing Hazardous.• RT-PCR• Transporting and carrying Primates is
Hazardous
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Dr.T.V.Rao MD 60
1979, 2004
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UgandaUgandaUgandaUgandaUgandaUgandaUgandaUgandaUganda
SudanSudanSudanSudanSudanSudanSudanSudanSudan
Ivory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory Coast
1994
1994, 1996, 1996
1976, 1995
1996*
2000
1976, 1979, 2004
*Doctor returningfrom Gabon
Ebola Outbreaks
Congo2003
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Dr.T.V.Rao MD 61
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Dr.T.V.Rao MD 62
Bunya viruses
• Rift Valley fever• Crimean Congo
hemorrhagic fever
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Rift Valley Fever• Disease of sheep and
cattle
• Humans: Asymptomatic-to-mild
• Rare VHF, encephalitis, retinitis
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Dr.T.V.Rao MD 64
Rift Valley Fever• Mosquito-borne (Aedes spp.)
vertical transmission in mosquitos• Transmission:
– Animal contact (birthing or blood) – Laboratory aerosol
• Mortality 1% overall• Therapy: Ribavirin?• Live-attenuated vaccine (MP-12) undergoing trials
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Dr.T.V.Rao MD 65
Rift Valley Fever: Clinical features
• 3-7 day incubation, 3-5 day duration
• Asymptomatic or mild illness• Fever, myalgia, weakness, weight loss• Photophobia, conjunctivitis
• Encephalitis• <5% hemorrhagic fever• 1-10% vision loss (retinal hemorrhage, vasculitis)
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Dr.T.V.Rao MD 66
CRIMEAN CONGO HEMORRHAGIC FEVER(CCHF)
• Extensive geographic distribution
(Africa, Balkans, and western Asia)• Transmission:
– Tick-borne (Hyalomma spp.) – Contact with animal blood or products– Person-to-person transmission
by contact with infectious body fluids– Laboratory worker transmission
documented
• Mortality 15-40%• Therapy: Ribavirin
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Dr.T.V.Rao MD 67
CCHF: Pathogenesis• Viremia present throughout disease• IFA becomes positive in patients destined to survive days 4-6,
often simultaneously with Viremia• Recovery may be due to CMI or neutralizing antibodies• Patients that die usually still Viremia• Virus grows in macrophages and other cells• DIC often present• Poor prognosis signaled by early elevated AST and clotting
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Dr.T.V.Rao MD 68
CCHF: Clinical features
• 4-12 day incubation after tick exposure• 2-7day incubation after direct contact with infected
fluids• Abrupt onset fever, chills, myalgia, severe headache• Malaise, GI symptoms, anorexia• Leukopenia, thrombocytopenia, hemoconcentration,
proteinuria, elevated AST• Hemorrhages may be profuse (hematomas, ecchymoses)
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Dr.T.V.Rao MD 69
PREVENTION OF CCHF
• DEET repellents for skin• Permethrin repellents for clothing –
(0.5% permethrin should be applied to clothing ONLY)
• Check for and remove ticks at least twice daily. • If a tick attaches, do not injure or rupture the
tick.
Remove ticks by grasping mouthparts at the skin surface using forceps and apply steady traction.
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Dr.T.V.Rao MD 70
Guanarito (Venezuelan Hemorrhagic Fever)
• Venezuela, central plains• Rodent borne (Zygodontomys
brevicauda)• Person-to-person transmission not
documented• Mortality 20-30%• Therapy:Ribavirin(?)
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Dr.T.V.Rao MD 71
South American Hemorrhagic Fevers: Clinical features
• 1-2 week incubation• Gradual onset fever, malaise, myalgias, anorexia• Headache, abdominal pain, nausea, vomiting, orthostasis• Petechiae (axillae, palate), gingival hemorrhage• Neurologic signs (hyporeflexia, tremor, lethargy,
hyperesthesia)• Leukopenia, thrombocytopenia, proteinuria
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Dr.T.V.Rao MD 72
South American Hemorrhagic Fevers: Clinical features
• 70% Recovery in 7-8 days without sequelae, prolonged fatigue and weakness common.
• Severe disease– Severe hemorrhage– Delerium, coma, convulsions– Combined hemorrhagic/neurologic disease
• High mortality
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Dr.T.V.Rao MD 73
• Rule out or treat febrile illnesses:
malaria, rickettsia, leptospirosis, typhoid, dysentery• Early hospitalization
• Distant medical evacuation associated with high mortality
• Cautious sedation and analgesia
• Careful hydration
• Pressors, cardiotonic drugs
• Support of coagulation system
VHF: Supportive therapy
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Dr.T.V.Rao MD 74
Ribavirin
• Guanosine nucleoside analog:
blocks viral replication by inhibiting IMP dehydrogenase
• Licensed for treatment of RSV and HCV• Potential adverse effects:
• Dose dependent reversible anemia• Pancreatitis• Teratogen in rodents
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Dr.T.V.Rao MD 75
• Programme Created by Dr.T.V.Rao MD for Medical Students in the
Developing World• Email