hemorrhagic fevers
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By abhinay sharma bhugooMl-610
23.10.11
Viral Hemorrhagic Fevers Viral hemorrhagic fevers 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.
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.
Atlanta, Georgia: Electron Micrograph: Ebola virus causing African Hemorrhagic Fever. (Courtesy of the National Archives, 82-424)
Hosts and VectorsViruses 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.
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.
OverviewOrganismHistoryEpidemiologyTransmissionDisease in HumansDisease in AnimalsPrevention and Control
Viral Hemorrhagic FeverViruses of four distinct families
ArenavirusesFilovirusesBunyaviruses Flaviviruses
RNA viruses Enveloped in lipid coating
Arenaviridae Bunyaviridae Filoviridae Flaviviridae
Junin Crimean- Congo H.F.
Ebola Kyasanur Forest Disease
Machupo Hantavirus Marburg Omsk H.F.
Sabia Rift Valley fever
Yellow Fever
Guanarito Dengue
Lassa
Hemorrhagic Fever Viruses (2)Hemorrhagic Fever Viruses (2)JAMA, 2002; 287:2391
Asia Balkans, Europe, Eurasia
RodentHemorrhagic Fever with Renal Syndrome
Africa, Saudi Arabia, Yemen
MosquitoRift Valley Fever
Africa, central Asia, eastern Europe, Middle East
TickCrimean-Congo Hemorrhagic
Fever
Bunyaviridae
Geographic Distribution
Vector in Nature
DiseaseFamily
Hemorrhagic Fever Viruses (3)Hemorrhagic Fever Viruses (3)JAMA, 2002; 287:2391
IndiaTickKyasanur Forrest Disease
Central AsiaTickOmsk Hemorrhagic Fever
Africa, Tropical Americas
MosquitoYellow Fever
Asia, Africa, Pacific, Americas
MosquitoDengue Fever, Dengue hemorrhagic fever, Dengue shock syndrome
Flaviviridae
Geographic Distribution
Vector in Nature
DiseaseFamily
Junin virusMachupo virus
Guanarito virusLassa virusSabia virus
Arenaviridae History
First isolated in 19331958: Junin virus - Argentina
First to cause hemorrhagic feverArgentine hemorrhagic fever
1963: Machupo virus – BoliviaBolivian hemorrhagic fever
1969: Lassa virus – NigeriaLassa fever
Arenaviridae TransmissionVirus transmission and amplification occurs
in rodentsShed virus through urine, feces, and other
excretaHuman infection
Contact with excretaContaminated materialsAerosol transmission
Person-to-person transmission
Arenaviridae EpidemiologyAfrica
LassaSouth America
Junin, Machupo, Guanarito, and SabiaContact with rodent excreta Case fatality: 5 – 35% Explosive nosocomial outbreaks with Lassa
and Machupo
Arenaviridae in Humans
Incubation period10–14 days
Fever and malaise2–4 days
Hemorrhagic stageHemorrhage, leukopenia, thrombocytopeniaNeurologic signs
Rift Valley Fever virusCrimean-Congo Hemorrhagic
Fever virusHantavirus
Bunyaviridae History 1930: Rift Valley Fever – Egypt
Epizootic in sheep1940s: CCHF - Crimean peninsula
Hemorrhagic fever in agricultural workers1951: Hantavirus – Korea
Hemorrhagic fever in UN troops5 genera with over 350 viruses
Bunyaviridae Transmission
Arthropod vectorException – Hantaviruses
RVF – Aedes mosquito CCHF – Ixodid tickHantavirus – RodentsLess common
AerosolExposure to infected animal tissue
Bunyaviridae Epidemiology
RVF - Africa and Arabian Peninsula1% case fatality rate
CCHF - Africa, Eastern Europe, Asia30% case fatality rate
Hantavirus - North and South America, Eastern Europe, and Eastern Asia1-50% case fatality rate
Bunyaviridae HumansRVF
Incubation period – 2-5 days0.5% - Hemorrhagic Fever
CCHF Incubation period – 3-7 daysHemorrhagic Fever - 3–6 days
following clinical signs
Hantavirus Incubation period – 7–21 daysHPS and HFRS
Bunyaviridae Animals
RVFAbortion – 100%Mortality rate
>90% in young5-60% in older animals
CCHFUnapparent infection in livestock
HantavirusesUnapparent infection in rodents
Overview in time
1930’s: virus isolated Kenya
1950-1951: outbreak in Kenya
1977-1978: outbreak in Egypt
1987: outbreak in Senegal
1997-1998: outbreak in KenyaLargest reported89.000 human cases-
478 deaths2000-2001: outbreak in
Saudi Arabia and Yemen
Signs and symptomsIncubation period: 2-6 days
Flu like symptoms Fever, headache, myalgia, nausea, vomiting Recovery 4-7 days
Severe Symptoms Retinopathy (0.5-2%) Hemorrhagic fever (<1%) Encephalitis (<1%)
Overall mortality 1%
Distribution of Rift Valley Fever in Africa. Blue, countries with endemic disease and substantial outbreaks of RVF; green, countries known to have some cases, periodic isolation of virus, or serologic evidence of RVF.
What is hemorrhagic fever with renal syndrome?
Hemorrhagic fever with renal failure syndrome (HFRS) occurs mainly in Europe and Asia and is characterized by fever and renal failure associated with hemorrhagic manifestations.
caused by an airborne contact with secretions from rodent hosts infected with the group of viruses belonging to the genus Hantavirus of the family Bunyaviridae.
In Europe, hemorrhagic fever with renal failure syndrome is caused by 3 hantaviruses: Puumala virus (PUUV), carried by the bank vole (Myodes glareolus); Dobrava virus (DOBV), carried by the mouse (Apodemus flavicollis); and Saaremaa virus (SAAV), carried by the striped field mouse (Apodemus agrarius).
History Hemorrhagic fever with renal failure syndrome was
initially recognized between 1913 and 1930 by Soviet scientists,
The disease came to the attention of the Western world in 1950, when the North American soldiers serving with the United Nations forces in Korea developed a febrile illness associated with shock, hemorrhage, and renal failure.
In 1993, in the southwestern United States, an outbreak of respiratory illness caused by the Sin Nombre virus, which belongs to the genus Hantavirus, occurred and was described as the Hantavirus pulmonary syndrome (HPS).
pathogenesisThe pathogenesis is largely unknown, but
findings from several studies have suggested that immune mechanisms play an important role.
Damage to the vascular endothelium, capillary dilatation, and leakage are clinically significant features of the disease.
How do humans get HFRS?
Hantaviruses are carried and transmitted by rodents. after exposure to aerosolized urine, droppings, or saliva of
infected rodents or after exposure to dust from their nests. Transmission may also occur when infected urine or these
other materials are directly introduced into broken skin or onto the mucous membranes of the eyes, nose, or mouth
Transmission from one human to another may occur, but is extremely rare.
Which rodents carry the hantaviruses that cause HFRS in humans?
Rodents are the natural reservoir for hantavirusesstriped field mouse (Apodemus agrarius), the
reservoir for both the Saaremaa and Hantaan virus;
the brown or Norway rat (Rattus norvegicus), the reservoir for Seoul virus;
the bank vole (Clethrionomys glareolus), the reservoir for Puumala virus;
and the yellow-necked field mouse (Apodemus flavicollis), which carries Dobrava virus.
What are the symptoms of HFRS?
The clinical features in hemorrhagic fever with renal failure syndrome (HFRS) consist of a triad of fever, hemorrhage, and renal insufficiency.
Other common symptoms during the initial phase of the illness include headache, myalgia, abdominal and back pain, nausea, vomiting, and diarrhea.
The disease may range from mild to severe. Subclinical infections are especially common in children.
The average incubation period varies from 4-42 days. The disease is characterized by fever, hemorrhagic manifestations, and (if severe) hypovolemic shock.
The disease has 5 progressive stages: febrile, hypotensive, oliguric, diuretic, and convalescent.
Individual patients can completely skip stages.
Febrile phase: Symptoms include fever, chills, sweaty palms, diarrhea, malaise, headaches, nausea, abdominal and back pain, respiratory problems such as the ones common in the influenza virus, as well as gastro-intestinal problems. These symptoms normally occur for three to seven days and arise about two to three weeks after exposure.[8]
Hypotensive phase: This occurs when the blood platelet levels drop and symptoms can lead to tachycardia and hypoxemia. This phase can last for 2 days.
Oliguric phase: This phase lasts for three to seven days and is characterised by the onset of renal failure and proteinuria occurs.
Diuretic phase: This is characterized by diuresis of three to six litres per day, which can last for a couple of days up to weeks.
Convalescent phase: This is normally when recovery occurs and symptoms begin to improve.
How is HFRS treated?Supportive therapy is the mainstay of care for
patients with hantavirus infections. Care includes careful management of the
patient’s fluid (hydration) and electrolyte (e.g., sodium, potassium, chloride) levels, maintenance of correct oxygen and blood pressure levels, and appropriate treatment of any secondary infections. Dialysis may be required to correct severe fluid overload. Intravenous ribavirinhas been shown to decrease illness and death associated with HFRS if used very early in the disease.
Is HFRS ever fatal?Depending upon which virus is causing the HFRS,
death occurs in less than 1% to as many as 15% of patients. Fatality ranges from 5-15% for HFRS caused by Hantaan virus, and it is less than 1% for disease caused by Puumala virus.
How is HFRS prevented?Rodent control is the primary strategy for
preventing hantavirus infections.
Marburg virusEbola virus
Filoviridae History1967: Marburg virus
European laboratory workers1976: Ebola virus
Ebola ZaireEbola Sudan
1989 and 1992: Ebola RestonUSA and ItalyImported macaques from Philippines
1994: Ebola Côte d'Ivoire
Epidemic Outbreaks of Marburg
Out breaks occured in Kenya, South Africa, Democratic Republic of Congo.
Recent outbreak in Angola in 2005
Filoviridae Transmission
Reservoir is UNKNOWNBats implicated with Marburg
Intimate contactNosicomial transmission
Reuse of needles and syringesExposure to infectious tissues, excretions, and
hospital wastesAerosol transmission
Primates
Filoviridae Epidemiology
Marburg – AfricaCase fatality – 23-33%
Ebola - Sudan, Zaire and Côte d'Ivoire – AfricaCase fatality – 53-88%
Ebola – Reston – PhilippinesPattern of disease is UNKOWN
Spread of InfectionsTransmission appears to be associated
with contamination of Blood, Blood stained body fluids or tissues.
Nosocomial spread is common mode of spread, Doctors and Nurses at risk when attending the patients.
Transmission by sexual intercourse has been on record from a case of man infecting his wife 83 days after initial infection.
Pathology and PathogenesisThe viruses belong to group of FilovirusesThe viruses have tropism for Cells of macrophage system Dendritic cells Interstitial fibroblasts Endothelial cells
Virus infect several OrgansHigh titer of viruses are found in Liver Spleen, Lungs Kidneys Blood Other Body fluids
Filoviridae Humans
Most severe hemorrhagic feverIncubation period: 4–10 daysAbrupt onset
Fever, chills, malaise, and myalgiaHemorrhage and DICDeath around day 7–11Painful recovery
Filoviridae Animals
Hemorrhagic feverSame clinical course
as humansEbola Reston
High primate mortality - ~82%
Dengue virusYellow Fever virus
Omsk Hemorrhagic Fever virusKyassnur Forest Disease virus
Flaviviridae History1648 : Yellow Fever described17th–20th century
Yellow Fever and Dengue outbreaks1927: Yellow Fever virus isolated1943: Dengue virus isolated1947
Omsk Hemorrhagic Fever virus isolated1957: Kyasanur Forest virus isolated
Flaviviridae TransmissionArthropod vectorYellow Fever and Dengue viruses
Aedes aegyptiSylvatic cycleUrban cycle
Kasanur Forest VirusIxodid tick
Omsk Hemorrhagic Fever virusMuskrat urine, feces, or blood
Flaviviridae EpidemiologyYellow Fever Virus – Africa and
AmericasCase fatality rate – varies
Dengue Virus – Asia, Africa, Australia, and AmericasCase fatality rate – 1-10%
Kyasanur Forest virus – IndiaCase fatality rate – 3–5%
Omsk Hemorrhagic Fever virus – EuropeCase fatlity rate – 0.5–3%
Flaviviridae HumansYellow Fever
Incubation period – 3–6 daysShort remission
Dengue Hemorrhagic FeverIncubation period – 2–5 daysInfection with different serotype
Kyasanur Forest DiseaseOmsk Hemorrhagic Fever
Lasting sequela
Flaviviridae Animals
Yellow Fever virusNon-human primates – varying clinical signs
Dengue virusNon-human primates – No symptoms
Kyasanur Forest Disease VirusLivestock – No symptoms
Omsk Hemorrhagic Fever VirusRodents – No symptoms
Epidemiology of HFVs
IncubationTypical 5-10 daysRange 2-16 days (except
Hantavirus: 9-35 days)
Modes of Infection
Transmission to Humans
AerosolsDesiccated rodent excreta: Arenaviruses,
hantavirusesGenerated by field mice caught in
agricultural machinery: New World arenaviruses
Generated during slaughter of infected livestock: CCHF, RVF
Contaminated food/waterArenavirus (Lassa)
Transmission to Humans
Arthropod vectors:Mosquitoes
Bunyavirus: RVF Flaviviruses: Dengue, Yellow fever
Ticks Bunyavirus: CCHF Flaviviruses: Kyanasur Forest Disease,
Omsk HFHematophagous flies:
Bunyaviruses: RVF
Infectious Period
Viruses have been found in seminal fluid of patients or sexually transmitted as follows:Ebola – 82-101 days after symptom
onsetMarburg – 83 daysLassa – 90 daysJunin – 7-22 daysLassa fever virus – in urine of patients 32
days after symptom onset
EntryMucous membrane, needle stickInhaled
Viremia and spread to liver, spleen, lungs
Mucosal shedding preceded by fever Incubation period 2 days-3 weeksCoagulation system defects
Hemorrhage, fibrin depositionVascular endothelium disruption
Loss of integrity of vascular endotheliumEdema
Filoviruses, Rift Valley fever, and flaviviruses : characterized by an abrupt onset
Arenaviruses – more insidious onsetEarly signs typically include
Fever, hypotension, relative bradycardia, tachypnea, conjunctivitis, and pharyngitis
Cutaneous flushing or a skin rashPetechiae, mucous membrane and conjunctival
hemorrhage Hematuria, hematemesis, and melenaDIC and circulatory shockCNS dysfunction
Hemorrhagic fever symptom
Maculopapular RashMarburg Disease
(Source: JAMA; 287:2397)
Erythematous RashBolivian Hemorrhagic Fever
(Source: JAMA; 287:2397)
Ocular Manifestation Bolivian Hemorrhagic Fever
(Source: JAMA; 287:2397)
Clinical Characteristics of Hemorrhagic Fever VirusesVirus Distinctive Clinical Features Mortality,
%
Ebola High fever, severe prostration, A diffuse maculopapular rash by day 5, bleeding and DIC common
50-90
Marburg High fever, myalgias, nonpruritic maculopapular rash of the face, neck, trunk, and arms may develop. Bleeding and DIC common
23-70
(Source: JAMA, 2002; 287:2396)
Clinical Characteristics of Hemorrhagic Fever Viruses
Lassa Fever
Gradual onset of fever, nausea, abdominal pain, severe sore throat, cough, conjunctivitis, ulceration of buccal mucosa, exudative pharyngitis, and cervical lymphadenopathy,
late signs: severe swelling of head and neck; pleural and pericardial effusions, hemorrhagic complication less common
15-20
Yellow Fever
Fever, myalgias, facial flushing, and conjunctival injection. Patients either recover or enter a short remission followed by fever, relative bradycardia, jaundice, renal failure, and hemorrhagic complications
20
(Source: JAMA, 2002; 287:2396)
Clinical Characteristics of Hemorrhagic Fever Viruses (Source: JAMA, 2002; 287:2396)
Virus Distinctive Clinical Features
Mortality %
Rift Valley fever Fever, headache, retro-orbital pain, photophobia, and jaundice. Less than 1% develop hemorrhagic fever or encephalitis. Retinitis affects approximately 10%, which may occur at time of acute febrile illness or up to 4 weeks later
<1
Clinical Characteristics of Hemorrhagic Fever Viruses
Virus Distinctive Clinical Features Mortality%
Omsk hemorrhagic fever
Fever, cough, conjunctivitis, papulovesicular eruption to the soft palate, marked hyperemia of the face and trunk (but no rash), generalized lymphadenopathy, and splenomegaly. Pneumonia and CNS dysfunction
0.5-10
Kyasanur Forest disease
Similar to Omsk but biphasic illness: first phase lasts 6-11 days and is followed by an afebrile period of 9-21 days. Up to 50% of patients relapse and develop meningoencephalitis
3-10
(Source: JAMA, 2002; 287:2396)
Case Definition / ConfirmationCase Definition / Confirmation Suspect index case:
–Temperature > 101 of < 3 weeks duration
–No predisposing factors for hemorrhagic symptoms
–Two or more hemorrhagic symptoms:
•hemorrhagic or purple rash,
•Epistaxis (nosebleed),
•Hematemesis (vomiting of blood),
•Hemoptysis (spitting of blood derived from lung or airways),
•blood in stools,
•Other – conjunctival hemorrhage, bleeding gums, bleeding at puncture sites, hematuria(blood in urine)
–No established alternative diagnosis
InfluenzaViral hepatitisStaphylococcal or
gram-negative sepsisToxic shock
syndromeMeningococcemiaSalmonellosisShigellosisRickettsial diseases
(e.g. Rocky Mountain Spotted Fever)
Leptospirosis
BorreliosisPsittacosisDengueHantavirus
pulmonary syndromeMalariaTrypanosomiasisSepticemic plagueRubellaMealsesHemorrhagic
smallpox
Noninfectious bleeding diathesisIdiopathic or thrombotic thrombocytopenic
purpuraHemolytic uremic syndromeAcute leukemiaCollagen-vascular diseases
Leukopenia (except in some cases of Lassa fever – leukocytosis)
Anemia or hemoconcentrationThrombocytopeniaElevated liver enzymes
Jaundice – typical in Rift Valley fever and yellow fever
Coagulation abnormalities – prolonged bleeding time, prothrombin time, and activated partial thromboplastin time
Elevated fibrin degradation products
Decreased fibrinogen
Urinalysis – proteinuria, and hematuria
Blood and serum specimens Environmental samples should be
taken when possible and appropriate for exposure assessment
IgM ELISA, PCR, Viral Isolation, IgG ELISA (recovered), Immunohistopathology testing for deceased
Center for Food Security and Public Health Iowa State University - 2004
Prevention and ControlAvoid 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
Center for Food Security and Public Health Iowa State University - 2004
Prevention and ControlVaccine available for Yellow fever Experimental vaccines under study
Argentine HF, Rift Valley Fever, Hantavirus and Dengue HF
If human case occurs Decrease person-to-person transmissionIsolation of infected individuals
Center for Food Security and Public Health Iowa State University - 2004
Prevention and ControlProtective clothing
Disposable gowns, gloves, masks and shoe covers, protective eyewear when splashing might occur, or if patient is disoriented or uncooperative
WHO and CDC developed manual“Infection Control for Viral Hemorrhagic Fevers
In the African Health Care Setting”
Center for Food Security and Public Health Iowa State University - 2004
Protective equipment worn by a nurse during Ebola outbreak in Zaire, 1995
Center for Food Security and Public Health Iowa State University - 2004
Prevention and ControlAnyone suspected of having a VHF must use a
chemical toiletDisinfect and dispose of instruments
Use a 0.5% solution of sodium hypochlorite (1:10 dilution of bleach)
Center for Food Security and Public Health Iowa State University - 2004
VHF Agents as Biological WeaponsOutbreak of undifferentiated febrile illness 2-
21 days following attackCould include
Rash, hemorrhagic diathesis and shock
Diagnosis could be delayed Unfamiliarity Lack of diagnostic tests
Ribavirin treatment may be beneficial
Center for Food Security and Public Health Iowa State University - 2004
VHF Agents as Biological WeaponsMost are not stable in dry formMost have uncertain stability and
effectiveness in aerosol formArenaviruses have tested effectiveness in
aerosol formMarburg and Ebola have high case fatality
ratesRift Valley is the most stable VHF in liquid
or frozen stateVHFs do pose a threat as aerosolized
agents
The End
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