Hemorrhagic Fevers

Hemorrhagic fevers Hanan Fathy Ass. lecturer

Feve rs 

Viral hemorrhagic fevers refer to a group of illnesses that are caused by several distinct families of viruses.

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In general, the term "viral hemorrhagic fever" is used to describe a severe multisystem syndrome.

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Characteristically, the overall vascular system is damaged, and the body's ability to regulate itself is impaired.

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These symptoms are often accompanied by hemorrhage (bleeding); however, the bleeding is itself rarely life-threatening.

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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 Vectors 

Viruses associated with most VHFs are zoonotic. This means that these viruses naturally reside in an animal reservoir host or arthropod vector.

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They are totally dependent on their hosts for replication and overall survival.

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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.

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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.

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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.

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

Viral Hemorrhagic Fever 

Viruses of four distinct families – Arenaviruses – Filoviruses – Bunyaviruses – Flaviviruses

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RNA viruses – Enveloped in lipid coating

Arenaviridae Bunyaviridae

Filoviridae Flaviviridae

Junin

CrimeanCongo H.F.

Ebola

Kyasanur Forest Disease

Machupo

Hantavirus

Marburg

Omsk H.F.

Sabia

Rift Valley fever

Guanarito Lassa

Yellow Fever Dengue

Hemorrhagic Fever Viruses JAMA, 2002; 287:2391

Family

Disease

Filoviridae

Ebola

Vector in Geographic Nature Distribution Unknown Africa

Filoviridae

Marburg

Unknown Africa

Arenaviridae Lassa Rodent Hemorrhagic Fever Arenaviridae New World Rodent Arenaviridae

West Africa

Americas

Hemorrhagic Fever Viruses (2) JAMA, 2002; 287:2391

Family

Disease

Vector in Geographic Nature Distribution

Bunyaviridae

Crimean-Congo Hemorrhagic Fever

Tick

Africa, central Asia, eastern Europe, Middle East

Rift Valley Fever Mosquito

Africa, Saudi Arabia, Yemen

Hemorrhagic Rodent Fever with Renal Syndrome

Asia Balkans, Europe, Eurasia

Hemorrhagic Fever Viruses (3) JAMA, 2002; 287:2391

Family

Disease

Vector in Geographic Nature Distribution

Flaviviridae

Dengue Fever, Mosquito Dengue hemorrhagic fever, Dengue shock syndrome

Asia, Africa, Pacific, Americas

Yellow Fever

Africa, Tropical Americas

Mosquito

Omsk Hemorrhagic Tick Fever

Central Asia

Kyasanur Forrest Disease

India

Tick

Junin virus Machupo virus Guanarito virus Lassa virus Sabia virus

Arenaviridae History First isolated in 1933  1958: Junin virus - Argentina 

– First to cause hemorrhagic fever – Argentine hemorrhagic fever 

1963: Machupo virus – Bolivia – Bolivian hemorrhagic fever

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1969: Lassa virus – Nigeria – Lassa fever

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

Arenaviridae Epidemiology 

Africa – Lassa

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South America – Junin, Machupo, Guanarito, and Sabia

Contact with rodent excreta  Case fatality: 5 – 35%  Explosive nosicomial outbreaks with Lassa and Machupo 

Arenaviridae in Humans 

Incubation period – 10–14 days

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Fever and malaise – 2–4 days

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Hemorrhagic stage – Hemorrhage, leukopenia, thrombocytopenia – Neurologic signs

Rift Valley Fever virus Crimean-Congo Hemorrhagic Fever virus Hantavirus

Bunyaviridae History 

1930: Rift Valley Fever – Egypt – Epizootic in sheep

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1940s: CCHF - Crimean peninsula – Hemorrhagic fever in agricultural workers

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1951: Hantavirus – Korea – Hemorrhagic fever in UN troops

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5 genera with over 350 viruses

Bunyaviridae Transmission 

Arthropod vector – Exception – Hantaviruses

RVF – Aedes mosquito  CCHF – Ixodid tick  Hantavirus – Rodents  Less common 

– Aerosol – Exposure to infected animal tissue

Bunyaviridae Epidemiology 

RVF - Africa and Arabian Peninsula – 1% case fatality rate

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CCHF - Africa, Eastern Europe, Asia – 30% case fatality rate

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Hantavirus - North and South America, Eastern Europe, and Eastern Asia – 1-50% case fatality rate

Bunyaviridae Humans 

RVF – Incubation period – 2-5 days – 0.5% - Hemorrhagic Fever

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CCHF – Incubation period – 3-7 days – Hemorrhagic Fever - 3–6 days following clinical signs

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Hantavirus – Incubation period – 7–21 days – HPS and HFRS

Bunyaviridae Animals 

RVF – Abortion – 100% – Mortality rate  >90% in young  5-60% in older animals

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CCHF – Unapparent infection in livestock

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Hantaviruses – Unapparent infection in rodents

Overview in time  

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1930’s: virus isolated Kenya 1950-1951: outbreak in Kenya 1977-1978: outbreak in Egypt 1987: outbreak in Senegal 1997-1998: outbreak in Kenya – Largest reported – 89.000 human cases478 deaths 2000-2001: outbreak in Saudi Arabia and Yemen

Signs and symptoms 

Incubation 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.

Marburg virus Ebola virus

Filoviridae History 

1967: Marburg virus – European laboratory workers

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1976: Ebola virus – Ebola Zaire – Ebola Sudan

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1989 and 1992: Ebola Reston – USA and Italy – Imported macaques from Philippines

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1994: Ebola Côte d'Ivoire

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

Filoviridae Epidemiology 

Marburg – Africa – Case fatality – 23-33%

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Ebola - Sudan, Zaire and Côte d'Ivoire – Africa – Case fatality – 53-88%

Ebola – Reston – Philippines  Pattern of disease is UNKOWN 

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 

Filoviridae Animals 

Hemorrhagic fever – Same clinical course as humans

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Ebola Reston – High primate mortality - ~82%

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

Flaviviridae History 1648 : Yellow Fever described  17th–20th century 

– Yellow Fever and Dengue outbreaks

1927: Yellow Fever virus isolated  1943: Dengue virus isolated  1947 

– Omsk Hemorrhagic Fever 

1957: Kyasanur Forest virus isolated

virus isolated

Flaviviridae Transmission Arthropod vector  Yellow Fever and Dengue viruses 

– Aedes aegypti – Sylvatic cycle – Urban cycle 

Kasanur Forest Virus – Ixodid tick

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Omsk Hemorrhagic Fever virus – Muskrat urine, feces, or blood

Flaviviridae Epidemiology 

Yellow Fever Virus – Africa and Americas – Case fatality rate – varies

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Dengue Virus – Asia, Africa, Australia, and Americas – Case fatality rate – 1-10%

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Kyasanur Forest virus – India – Case fatality rate – 3–5%

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Omsk Hemorrhagic Fever virus – Europe – Case fatlity rate – 0.5–3%

Flaviviridae Humans 

Yellow Fever – Incubation period – 3–6 days – Short remission

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Dengue Hemorrhagic Fever – Incubation period – 2–5 days – Infection with different serotype

Kyasanur Forest Disease  Omsk Hemorrhagic Fever 

– Lasting sequela

Flaviviridae Animals 

Yellow Fever virus – Non-human primates – varying clinical signs

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Dengue virus – Non-human primates – No symptoms

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Kyasanur Forest Disease Virus – Livestock – No symptoms

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Omsk Hemorrhagic Fever Virus – Rodents – No symptoms

Epidemiology of HFVs  Incubation

–Typical 5-10 days –Range 2-16 days (except Hantavirus: 9-35 days)

Modes of Infection

Transmission to Humans 

Aerosols – Desiccated rodent excreta: Arenaviruses, hantaviruses – Generated by field mice caught in agricultural machinery: New World arenaviruses – Generated during slaughter of infected livestock: CCHF, RVF

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Contaminated food/water – Arenavirus (Lassa)

Transmission to Humans 

Arthropod vectors: – Mosquitoes  Bunyavirus:

RVF  Flaviviruses: Dengue, Yellow fever

– Ticks  Bunyavirus:

CCHF  Flaviviruses: Kyanasur Forest Disease, Omsk HF

– Hematophagous 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 onset – Marburg – 83 days – Lassa – 90 days – Junin – 7-22 days – Lassa fever virus – in urine of patients 32 days after symptom onset

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Entry – Mucous membrane, needle stick – Inhaled Viremia and spread to liver, spleen, lungs Mucosal shedding preceded by fever Incubation period 2 days-3 weeks Coagualation system defects – Hemorrhage, fibrin deposition Vascular endothelium disruption – Loss of integrity of vascular endothelium – Edema

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Filoviruses, Rift Valley fever, and flaviviruses : characterized by an abrupt onset Arenaviruses – more insidious onset Early signs typically include – Fever, hypotension, relative bradycardia, tachypnea, conjunctivitis, and pharyngitis – Cutaneous flushing or a skin rash – Petechiae, mucous membrane and conjunctival hemorrhage Hematuria, hematemesis, and melena – DIC and circulatory shock – CNS dysfunction

Hemorrhagic fever symptom

Maculopapular Rash Marburg Disease

(Source: JAMA; 287:2397)

Erythematous Rash Bolivian Hemorrhagic Fever

(Source: JAMA; 287:2397)

Ocular Manifestation Bolivian Hemorrhagic Fever

(Source: JAMA; 287:2397)

Clinical Characteristics of Hemorrhagic Fever Viruses Virus

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

(Source: JAMA, 2002; 287:2396)

23-70

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

Yellow Fever

Fever, myalgias, facial flushing, and 20 conjunctival injection. Patients either recover or enter a short remission followed by fever, relative bradycardia, jaundice, renal failure, and hemorrhagic complications

(Source: JAMA, 2002; 287:2396)

15-20

Clinical Characteristics of Hemorrhagic Fever Viruses (Source: JAMA, 2002; 287:2396)

Virus

Distinctive Mortality % Clinical Features

Rift Valley fever

Fever, headache, retro- <1 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

Clinical Characteristics of Hemorrhagic Fever Viruses Virus

Distinctive Clinical Features

Omsk Fever, cough, conjunctivitis, hemorrhagic papulovesicular eruption to the soft fever palate, marked hyperemia of the face and trunk (but no rash), generalized lymphadenopathy, and splenomegaly. Pneumonia and CNS dysfunction Kyasanur Forest disease

Mortality % 0.5-10

Similar to Omsk but biphasic illness: first 3-10 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

(Source: JAMA, 2002; 287:2396)

Case 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

JAMA, 2002; 287:2391

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Influenza Viral hepatitis Staphylococcal or gram-negative sepsis Toxic shock syndrome Meningococcemia Salmonellosis Shigellosis Rickettsial diseases (e.g. Rocky Mountain Spotted Fever) Leptospirosis

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Borreliosis Psittacosis Dengue Hantavirus pulmonary syndrome Malaria Trypanosomiasis Septicemic plague Rubella Mealses Hemorrhagic smallpox

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Noninfectious bleeding diathesis – Idiopathic or thrombotic thrombocytopenic purpura – Hemolytic uremic syndrome – Acute leukemia – Collagen-vascular diseases

Leukopenia (except in some cases of Lassa fever – leukocytosis)  Anemia or hemoconcentration  Thrombocytopenia  Elevated 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

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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

Infection Control

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Protect employee health – Identify high risk employees – Educate high risk employees – Personal Protective Equipment (PPE) – Educate health care providers and the public in the recognition and diagnosis of VHF – Educate providers and laboratories to report VHF to the LHD immediately

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When a VHF case is reported – Isolation of case – Confirm cases  Obtain a complete clinical and lab history by using VHF case investigation form  Assure to obtain appropriate lab specimens on each suspected case and send it to OLS  Confirmation of an intentional or unintentional exposure and notification procedure – Checking for natural exposures to HFV, contact of a case or travel to an endemic area within last 21 days – If no clear source is identified, begin active surveillance

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Case Finding – Develop a working case definition for the outbreak investigation – Begin enhanced passive surveillance  Issue

a news release and provide alert to increase health care providers and the public recognition and diagnosis of VHF  Educate providers and lab to immediately report possible VHF infections

Identify contact  Contact Definition 

– Direct Contacts – any person who has had face-to-face contact (within 6 feet) with a suspected, probable, or confirmed case of VHFs during the infectious period (onset of symptoms until time of interview, recovery, or death and burial of case).

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Surveillance of case-contacts and exposed population: – Interview case-contacts and exposed individuals: assure that all case-contacts and exposed are contacted within 24 hours and interview daily for 21 days after last exposure. – Determine if fever>101•F or VHF symptoms – Refer symptomatic persons to a clinical center for isolation and treatment

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Surveillance of exposed: – If exposed does not have fever of 101• F or higher or signs/symptoms of VHF by end of 21 days – discontinue surveillance – Interview all exposed individuals to verify they have no symptoms – indicate status of exposed individual as “closed” on Exposed Individual Line Listing Form

If exposed have fever 101•F or higher, or signs/symptoms of VHF, then assure referral to a MD for diagnostic work-up  Implement appropriate infection control and preventive interventions  Enter status of exposed individual as a case and move to Case Line List Form  Begin contact tracing for this new case 

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

Preventive Interventions: Employee Health And Infection Control •Hand hygiene; wash: –Before donning protective equipment –After removal of gown, leg and shoe covers, gloves –Before removal of face and eye protection

•Double gloves JAMA, 2002; 287:2391

Preventive Interventions: Employee Health And Infection Control Impermeable gowns •

Negative pressure isolation room

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N-95 masks or powered air-purifying respirators

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Leg and shoe coverings

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Goggles / face shields

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Restricted access of non-essential staff / visitors

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Dedicated medical equipment

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Environmental disinfection with 1:100 bleach

JAMA, 2002; 287:2391

Exposures First Aid

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Wash/irrigate wound/site immediately – within 5 minutes of exposure

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Mucous membrane (eye, mouth, nose) – continuous irrigation with rapidly flowing water or sterile saline for > 15 minutes

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Skin – scrub for at least 15’ minutes while copiously soaking the wound with soap or detergent solution  fresh

Dakin's solution (0.5% hypochlorite): dilute 1 part standard laundry bleach (5% hypochlorite) with 9 parts tap water

Treatment and Prophylaxis JAMA, 2002; 287:2391

•Prophylaxis: none •Treatment: experimental use of ribavirin –Arenaviridae •Lassa hemorrhagic fever

–Bunyaviridae –Rift Valley fever

VHF Vaccines  YELLOW

FEVER

– licensed 17D vaccine safe and efficacious – cannot be used in persons with egg allergy  ARGENTINE

FEVER

HEMORRHAGIC

– live, attenuated – safe and efficacious; used in 150,000

VHF Vaccines 

RIFT VALLEY FEVER

– formalin-inactivated safe

but requires 3 shots, intermittent booster limited supply

– live, attenuated MP-12 Phase

II testing  HFRS (HANTAAN) – vaccinia vectored recombinant vaccine

Treatment Recommendation 

The mainstay of treatment – supportive – Fluid maintenance of fluid and electrolyte balance, circulatory volume, and blood pressure – No approved antiviral drugs or vaccines – If a case is suspected, probable or confirmed the following drug therapy is recommended:  Initial supportive and ribavirin therapy immediately while diagnostic confirmation is pending  If infection with Arenaviruses or Bunyaviruses is confirmed, continue 10-day course of ribavirin  If infection with Filovirus or Flavirus is confirmed, or is the diagnosis of VHF is excluded or an alternative diagnosis is established, discontinue ribavirin. Source: JAMA, 2002;

VHF Management: Cardiovascular 

Hemodynamic resuscitation & monitoring – invasive (S-G catheter) as warranted and feasible

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Careful fluid management – use of colloid – hemodialysis or hemofiltration as needed  esp.

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HFRS patients

Vasopressors and cardiotonic drugs

VHF Management Hematologic 

Coagulation studies and clinical judgement as guide – replacement of clotting factors – platelet transfusions

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antiplatelet drugs or IM injections  DIC may be important in some VHFs (RVF, CCHF, Filoviruses)

VHF Management Anti-viral Therapy  Ribavirin

– Arenaviridae (Lassa, AHF, BHF) – Bunyaviridae (HFRS, RVF, CCHF)  Immune

plasma

(convalescent)

– Arenaviridae (AHF, BHF, ?Lassa) – Passive immunoprophylaxis postexposure?

VHF Management Other  R/O

or treat empirically for malaria, typhoid fever, rickettsioses, etc.  vigilance against secondary bacterial infections – nosocomial pneumonia, UTI, bacteremia ONLY INTENSIVE CARE WILL SALVAGE THE SICKEST PATIENTS

The End