Hemorrhagic fevers

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


Ocular Manifestation Bolivian Hemorrhagic Fever


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


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


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”


Protective equipment worn by a nurse during Ebola outbreak in Zaire, 1995


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)


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


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

Hemorrhagic fevers

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