Viral Hemorrhagic Fevers

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Viral Hemorrhagic Fevers

• Paige Jordan RN, BSN
• Region II Epidemiologist
• January 9, 2004

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Objectives

• To describe the epidemiology of VHFs
• To describe the public health action of VHFs
• To describe prevention and control procedures
  including employee health

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What are Viral Hemorrhagic Fevers (VHFs)?

• A group of illnesses that are caused by several
  distinct families of viruses.
• A severe multisystem syndrome (multiple organ
  systems in the body are affected).
• Vascular system damaged
• Bodys ability to regulate itself is impaired.
• Many cause severe and life-threatening disease.

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What are Viral Hemorrhagic Fevers (VHF)? Cont.

• Classified as biosafety level four (BSL4)
  pathogens.
• Classified as Category A Agent

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How are VHF grouped?

• 4 distinct families
• Arenaviridae
• Filoviridae
• Bunyaviridae
• Flaviviridae

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HFVs as potential biological weapons

• HFVs weaponized by the Russia and US
• Yellow fever may have been weaponized by North
  Korea
• Source JAMA, 2002 2872393

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Epidemiology of HFVs

• All RNA viruses, and all are covered, or
  enveloped, in a fatty (lipid) coating
• Survival depend on an animal or insect host (the
  natural reservoir)
• Geographically restricted to areas where their
  host species live
• Humans - not the natural reservoir but are
  infected via contact with infected hosts or
  arthropod vectors

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Epidemiology of HFVs cont.

• 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

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Epidemiology of HFVs cont.

• Incubation
• Typical 5-10 days
• Range 2-16 days (except Hantavirus 9-35 days)

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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
• Contaminated food/water
• Arenavirus (Lassa)

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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

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Transmission to HumansBW Implications

• With exception of dengue, all VHF agents
  transmitted by aerosol in laboratory (animal
  models)
• Stabilization in aerosols

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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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VHF Evolution

• Prostration
• Pharyngeal, chest or abdominal pain
• Mucous membrane bleeding, ecchymosis
• Shock
• Usually improving or moribund within a week
  (except HFRS, arenaviruses)
• Bleeding, CNS involvement, marked elevation SGOT
  portend poor prognosis
• Mortality agent dependent (lt10-90)

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VHF Sequelae

• Prolonged Convalescence
• Hair Loss, Furrowed Nails
• Deafness (Lassa, EBO)
• Retinitis (RVF, KFD)
• Uveitis (RVF, MBG)
• Encephalitis (AHF, BHF, RVF, KFD, OHF)
• Pericarditis (Lassa)
• Renal insufficiency (HFRS)

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VHF Clinical Lab

• Leukopenia is suggestive, but WBC may be normal,
  elevated, or leukemoid
• Thrombocytopenia is typical, but sometimes mild
  or absent
• Hematocrit normal or increased early
• AST (SGOT) typically elevated prognostic value
• BUN/Cr related to circulatory status (except in
  HFRS)

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VHF Clinical Lab (cont.)

• Bilirubin, amylase may be elevated
• Prothrombin/APTT usually prolonged
• FSP normal or modestly elevated
• Fibrinogen elevated, normal, or decreased
• Proteinuria usual

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VHF Differential Diagnosis

• Bacterial
• typhoid fever, meningoccemia, rickettsioses,
  leptospirosis
• Protozoal
• falciparum malaria
• Other
• vasculitis, TTP, HUS, heat stroke

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How are HFVs transmitted?

• Exposure of urine, fecal matter, saliva, or other
  body excretions from infected reservoir hosts or
  vectors, e.g. rodents
• Vector
• From animals to humans
• Person to person e.g. Ebola, Marburg, Lassa and
  Crimean-Congo hemorrhagic fever

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Arenaviridae

• Classification
• Old World and New World groups
• Life-long association with a rodent reservoir
• Found in 1956 as Tacaribe virus (New World virus)
  and discovered new arenaviruses have been
  discovered every one to three years

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The Arenaviridae (Source Chapter 29, VHFs by
Peter B Jahrling)
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Arenaviridae

• Zoonotic
• Rodents located in Europe, Asia, Africa, and the
  Americas
• Some Old World arenaviruses - rodent population
  generation after generation
• Some New World arenaviruses transmitted among
  adult rodents
• Exception
• Tacaribe virus found in Trinidad isolated from
  a bat

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Arenaviridae

• The viruses - shed into the environment in the
  urine or droppings of the infected hosts
• Human infection incidental
• contact with excretions
• materials contaminated with the excretions of an
  infected rodent
• ingestion of contaminated food,
• or by direct contact with broken skin with rodent
  excrement
• Aerosol transmission (inhalation of tiny
  particles soiled with rodent urine or saliva
• Agricultural work
• Human homes or other buildings domestic
  settings

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Arenaviridae

• Lassa and Machupo viruses
• Associated with secondary person-to-person and
  nosocomial (health-care setting) transmission
• Contact with contaminated objects medical
  equipment

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Filoviridae

• Filovirus
• Marburg 1967 in Marburg, Germany and Yugoslavia
• Ebola 1976 in Zaire and Sudan
• 4 species identified Ivory Coast, Sudan, Zaire,
  Reston
• 18 reports of human outbreak due to Ebola or
  Marburg viruses approximately 1500 cases to
  date
• Most in Africa
• Source of Human infection Unknown
• Incubation Period 3-16 days

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Filoviridae
(Source CDC)
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Filoviridae

• High mortality rate especially percutaneous
  transmission
• Transmission due to needle stick injuries or use
  of contaminated syringes
• Require low inocula for infection

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Filoviridae

• Transmission by mucosal exposure in experimental
  animals
• Human infections through contact of
  contaminated fingers with oral mucosa or
  conjunctiva
• Person to person by small droplet airborne nuclei

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Bunyaviridae
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Flaviridae
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Epidemiology of HFVs cont.

• Symptoms
• Fever, headache, malaise, dizziness
• Myalgias
• Nausea/vomiting
• Initial Signs
• Flushing, conjunctival injection
• Periorbital edema
• Petechiae
• Positive tourniquet test
• Hypotension

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Clinical Manifestations of VHFs

• Nonspecific
• May not be possible to differentiate by clinical
  grounds alone
• Overall incubation period 2 21 days
• Initially nonspecific prodrome lasts less than
  a week
• High fever, malaise, headache, arthralgias,
  myalgias, nausea, abdominal pain, and nonbloody
  diarrhea

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Clinical Manifestations of VHFs

• 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

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Maculopapular RashMarburg Disease
(Source JAMA 2872397)
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Erythematous RashBolivian Hemorrhagic Fever
(Source JAMA 2872397)
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Ocular Manifestation Bolivian Hemorrhagic Fever
(Source JAMA 2872397)
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Clinical Characteristics of Hemorrhagic Fever
Viruses
(Source JAMA, 2002 2872396)
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Clinical Characteristics of Hemorrhagic Fever
Viruses
(Source JAMA, 2002 2872396)
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Clinical Characteristics of Hemorrhagic Fever
Viruses (Source JAMA, 2002 2872396)
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Clinical Characteristics of Hemorrhagic Fever
Viruses
(Source JAMA, 2002 2872396)
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• Case Definition / Confirmation Suspect index
  case
• Temperature gt 101 of lt 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

• Laboratory confirmation _at_ CDC / USAMRIID

JAMA, 2002 2872391
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Differential Diagnosis of VHFs

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

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

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Differential Diagnosis of VHFs cont.

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

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Lab Abnormalities

• Leukopenia (except in some cases of Lassa fever
  leukocytosis)
• Anemia or hemoconcentration
• Thrombocytopenia
• Elevated liver enzymes

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Lab Abnormalitiescont.

• 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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Lab Testing for VHFs

• Blood and serum specimens
• Environmental samples should be taken when
  possible and appropriate for exposure assessment
• Specimens should be sent to OLS which will
  coordinate to submit to CDC
• IgM ELISA, PCR, Viral Isolation, IgG ELISA
  (recovered), Immunohistopathology testing for
  deceased

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Public Health Action

• 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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Public Health Action cont.

• 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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Public Health Action cont.

• 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

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Public Health Action cont.

• 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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Public Health Action cont.

• 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 fevergt101F or VHF symptoms
• Refer symptomatic persons to a clinical center
  for isolation and treatment

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Public Health Action cont.

• 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

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Public Health Action cont.

• If exposed have fever 101F 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

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• 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 2872391
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• Preventive Interventions
• Employee Health And Infection Control
• Impermeable gowns
• Negative pressure isolation room
• N-95 masks or powered air-purifying respirators
• Leg and shoe coverings
• Goggles / face shields
• Restricted access of non-essential staff /
  visitors
• Dedicated medical equipment
• Environmental disinfection with 1100 bleach

JAMA, 2002 2872391
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Infection Control(Arenavirus, Filovirus, CCHF)

• Single room w/ adjoining anteroom as only
  entrance
• Handwashing facility with decontamination
  solution
• 0.5 sodium hypochlorite, 2 glutaraldehyde,
  phenolic detergent, soap
• Changing area/protective equipment
• Negative air pressure air not recirculated
• Prominent hemorrhage, cough, vomiting, diarrhea
• Consider negative air flow room, if available, in
  absense of these sxs/sxs to avoid having to
  transfer pt later

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Infection Control(Arenavirus, Filovirus,
CCHF)(Contd)

• Strict barrier precautions
• gloves, gown, mask, shoe covers, protective
  eyewear/faceshield
• HEPA-filtered mask or respirator
• Prominent hemorrhage, cough, vomiting, diarrhea

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Infection ControlArenavirus, Filovirus, CCHF
(cont.)

• Chemical toilet
• All body fluids disinfected
• Disposable equipment sharps into rigid
  containers containing disinfectant -gt autoclaved
  or incinerated
• Double-bag refuse
• outside bag disinfected then autoclaved or
  incinerated

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Clinical Laboratory Procedures

• Strict barrier precautions
• gloves, gown, mask, shoe covers, protective
  eye/faceshield
• consider respirator with HEPA filter
• handle specimens in biosafety cabinet when
  possible
• Spills/splashes
• immediately cover with disinfectant, allow to
  soak for 30
• wipe with absorbent towel soaked in disinfectant
• Waste disposal
• same as for patient isolation practices

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ExposuresFirst Aid

• Wash/irrigate wound/site immediately
• within 5 minutes of exposure
• Mucous membrane (eye, mouth, nose)
• continuous irrigation with rapidly flowing water
  or sterile saline for gt 15 minutes
• 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

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• Treatment and ProphylaxisJAMA, 2002 2872391
• Prophylaxis none
• Treatment experimental use of ribavirin
• Arenaviridae
• Lassa hemorrhagic fever
• Bunyaviridae
• Rift Valley fever

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VHF Vaccines

• YELLOW FEVER
• licensed 17D vaccine safe and efficacious
• cannot be used in persons with egg allergy
• ARGENTINE HEMORRHAGIC FEVER
• live, attenuated
• safe and efficacious used in 150,000
• protects monkeys against Bolivian HF

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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

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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 2872399
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VHF ManagementCardiovascular

• Hemodynamic resuscitation monitoring
• invasive (S-G catheter) as warranted and feasible
• Careful fluid management
• use of colloid
• hemodialysis or hemofiltration as needed
• esp. HFRS patients
• Vasopressors and cardiotonic drugs
• Cautious sedation and analgesia

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VHF ManagementHematologic

• Coagulation studies and clinical judgement as
  guide
• replacement of clotting factors
• platelet transfusions
• No antiplatelet drugs or IM injections
• DIC may be important in some VHFs (RVF, CCHF,
  Filoviruses)

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VHF ManagementAnti-viral Therapy

• Ribavirin
• Arenaviridae (Lassa, AHF, BHF)
• Bunyaviridae (HFRS, RVF, CCHF)
• Immune (convalescent) plasma
• Arenaviridae (AHF, BHF, ?Lassa)
• Passive immunoprophylaxis post-exposure?

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VHF ManagementOther

• 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