Viral Agents with Bioterrorism Potential

1
Viral Agents with Bioterrorism Potential
2
Acknowledgements

• South Carolina Area Health Education Consortium
  (AHEC)
• Funded by the Health Resources and Services
  Administration.
• Grant number 1T01HP01418-01-00
• P.I. David Garr, MD, Executive Director AHEC
• BT Project Director Beth Kennedy, Associate
  Program Director AHEC
• Core Team
• BT Co-director Ralph Shealy, MD
• BT Project Manager Deborah Stier Carson, PharmD
• BT CME Director William Simpson, MD
• IT Coordinator Liz Riccardone, MHS
• Web Master Mary Mauldin, PhD
• P.R Coordinator Nicole Brundage, MHA
• Evaluation Specialist Yvonne Michel, PhD
• Financial Director Donald Tyner, MBA

3
Acknowledgements
This presentation, and the accompanying
instructors manual (current as of 7/02), were
prepared by Jennifer Brennan Braden, MD, MPH, at
the Northwest Center for Public Health Practice
in Seattle, WA, and Jeff Duchin, MD with Public
Health Seattle King County and the Division
of Allergy Infectious Diseases, University of
WA, for the purpose of educating primary care
clinicians in relevant aspects of bioterrorism
preparedness and response. Instructors are
encouraged to freely use all or portions of the
material for its intended purpose. The
following people and organizations provided
information and/or support in the development of
this curriculum. A complete list of resources
can be found in the accompanying instructors
guide.
Jane Koehler, DVM, MPH Communicable Disease
Control, Epidemiology and Immunization section,
Public Health - Seattle King County Ed
Walker, MD University of WA Department of
Psychiatry
Patrick OCarroll, MD, MPH The Centers for
Disease Control and Prevention Project
Coordinator Judith Yarrow Health Policy
Analysis, University of WA Design and Editing
4
Viral Diseases of BT Potential Objectives

• List the agents most likely to be used in a
  biological weapons attack and the most likely
  mode of dissemination
• Outline the clinical presentation(s) of the Viral
  Category A agents and features that may
  distinguish them from more common diseases
• Outline the diagnosis, treatment recommendations,
  infection control, and preventive therapy for
  management of infection with or exposure to Viral
  Category A agents.

5
Biological Agents of Highest ConcernCategory A
Agents

• Easily disseminated, infectious via aerosol
• Susceptible civilian populations
• Cause high morbidity and mortality
• Person-to-person transmission
• Unfamiliar to physicians difficult to
  diagnose/treat
• Cause panic and social disruption
• Previous development for BW

6
Viral Agents of Highest Concern Category A Agents

• Variola major (Smallpox)
• Filoviruses Arenaviruses (Viral hemorrhagic
  fevers)
• Report ANY suspected illness due to these agents
  to Public Health immediately.

7
Viral Agents of 2nd Highest ConcernCategory B
Agents

• Alphaviruses (Venezuelan, Western and Eastern
  encephalomyelitis viruses)

8
Viral Agents of 3rd Highest ConcernCategory C
Agents

• Emerging pathogens that could be engineered for
  mass dissemination in the future
• Nipah virus
• Hantaviruses
• Tick-borne hemorrhagic fever viruses
• Tick-borne encephalitis viruses
• Yellow fever

9
Smallpox Overview

• Two strains variola major and variola minor
• Variola minor milder disease with case fatality
  typically 1 or less
• Variola major more severe disease with average
  30 mortality in unvaccinated
• Person-to-person transmission

10
Smallpox Overview

• Killed approximately 300,000,000 persons in 20th
  century
• Routine smallpox vaccination in the U.S. stopped
  in 1972
• WHO declared smallpox eradicated in 1980
• Vaccine has significant adverse effects
• No effective treatment

11
Smallpox Overview

• Person-to-person transmission
• Average 30 mortality from variola major in
  unvaccinated
• A single case is considered a global public
  health emergency

12
SmallpoxCase Definition

• Clinical case definition
• An illness with acute onset of fever ?101?F
  followed by a rash characterized by vesicles or
  firm pustules in the same stage of development
  without other apparent cause
• Laboratory criteria for confirmation (Level C/D
  lab)
• Isolation of smallpox virus from a clinical
  specimen, OR
• Identification of variola in a clinical specimen
  by PCR or electron microscopy

initial confirmation of outbreak requires
testing in level D lab (I.e., CDC)
13
SmallpoxCase Classification

• Confirmed laboratory confirmed
• Probable meets clinical case definition has an
  epi link to another confirmed or probable case
• Suspected
• Meets clinical case definition but is not
  laboratory-confirmed and does not have an epi
  link OR
• Atypical presentation not lab confirmed but has
  an epi link to a confirmed or probable case

14
Smallpox Pathogenesis

• Virus implants on oropharynx or respiratory
  mucosa and is transported to regional lymph nodes
  
• Day 3-4 asymptomatic viremia followed by viral
  multiplication in spleen, bone marrow, lymph
  nodes, lung
• Day 8 secondary viremia leads to fever and
  toxemia on day 12-14

15
Smallpox Pathogenesis

• Virus localizes in small blood vessels of
  respiratory and pharyngeal mucosa, then dermis
  characteristic rash and case communicability
• Toxemia circulating immune complexes and variola
  antigens

16
Smallpox Transmission

• Infectious dose extremely low
• Spread primarily by droplet nuclei gtaerosols gt
  direct contact
• Maintains infectivity for prolonged periods out
  of host
• Contaminated clothing and bedding can be
  infectious

17
Smallpox Transmission

• Transmission does not usually occur until after
  febrile prodrome
• Coincident with onset of rash
• Slower spread through the population than
  chickenpox or measles
• Large outbreaks in schools were uncommon
• Less transmissible than measles, chickenpox,
  influenza

18
SmallpoxTransmission

• Secondary cases primarily household, hospital,
  and other close contacts
• Secondary attack rate 37-87 among unvaccinated
  contacts
• Patients with severe disease or cough at highest
  risk for transmission
• Greatest infectivity from rash onset to day 7-10
  of rash
• Infectivity decreases with scab formation and
  ceases with separation of scabs

19
SmallpoxClinical Features

• Prodrome (incubation 7-19 days)
• Acute onset of fever, malaise, headache,
  backache, vomiting, occasional delirium
• Transient erythematous rash
• Exanthem (2-3 days later)
• Preceded by enanthem on oropharyngeal mucosa
• Begins on face, hands, forearms
• Spread to lower extremities then trunk over 7
  days

CDC

• Synchronous progression macules ?
  vesicles ? pustules ? scabs
• Lesions most abundant on face and
  extremities, including palms/soles

20
SmallpoxClinical Course
WHO
21
SmallpoxClinical Presentation
CDC
22
SmallpoxClinical Presentation
WHO
23
SmallpoxClinical Presentation
WHO
24
Smallpox Clinical Progression
WHO
25
Smallpox Clinical Progression
Day 14
Day 10
Day 21
Thomas, D.
26
SmallpoxClinical Progression
27
SmallpoxClinical Types

• Ordinary smallpox 90 of cases
• Case-fatality average 30
• Occurs in non-immunized persons
• Modified smallpox
• Milder, rarely fatal
• Occurs in 25 of previously immunized persons and
  2 of non-immunized persons
• Fewer, smaller,more superficial lesions that
  evolve more rapidly

28
SmallpoxClinical Types

• Hemorrhagic smallpox lt3 of cases
• Immunocompromised persons and pregnant women at
  risk
• Shortened incubation period, severe prodrome
• Extensive viral multiplication, coagulopathy
• Dusky erythema followed by petechiae and
  hemorrhages into skin and mucous membranes
• Almost uniformly fatal within 7 days

29
SmallpoxClinical Types

• Malignant, or flat-type smallpox 7 of cases
• Slowly evolving lesions that coalesce without
  forming pustules
• Associated with cell-mediated immune deficiency
• Usually fatal
• Variola sine eruptione
• Occurs in previously vaccinated persons or
  infants with maternal antibodies
• Asymptomatic or mild illness
• Transmission from these cases has not been
  documented

30
Malignant Smallpox
Thomas, D.
31
SmallpoxComplications

• Encephalitis
• 1 in 500 cases Variola major
• 1 in 2,000 cases Variola minor
• Keratitis, corneal ulceration
• Blindness in 1 of cases
• Infection in pregnancy
• High perinatal fatality rate
• Congenital infection

32
CDC Major Smallpox Criteria

• Febrile prodrome
• Occurring 1-4 days before rash onset fever
  gt102F and at least one of the following
  prostration, headache, backache, chills, vomiting
  or severe abdominal pain
• Classic smallpox lesions
• Deep, firm/hard, round, well-circumscribed may
  be umbilicated or confluent
• Lesions in same stage of development on any one
  part of the body (e.g., face or arm)

33
CDC Minor Smallpox Criteria

• Centrifugal distribution greatest concentration
  of lesions on face and distal extremities
• First lesions on oral mucosa or palate, face,
  forearms
• Patient appears toxic or moribund
• Slow evolution lesions evolve from macules to
  papules to pustules over days
• Lesions on palms and soles (majority of cases)

34
CDC Criteria for Determining Risk of Smallpox

• High risk report immediately
• All three major criteria
• Moderate risk urgent evaluation
• Febrile prodrome and 1 major or ?4 minor criteria
• Low risk manage as clinically indicated
• No viral prodrome or
• Febrile prodrome and lt4 minor criteria (no major
  criteria)

35
CDC Recommended Evaluation of Patients at High
Risk of Smallpox

• Contact and airborne precautions
• Notify infection control
• Infectious disease and/or dermatology consult
• Notify local/state health dept immediately
• Response team advises on management and specimen
  collection
• Specimen testing at CDC

36
CDC Recommended Evaluation of Patients at
Moderate Risk of Smallpox

• Contact and airborne precautions
• Notify infection control
• Infectious disease and/or Dermatology consult
• VZV and/or other lab tests as indicated
• If cannot rule out smallpox, contact local/state
  health dept. immediately

37
CDC Recommended Evaluation of Patients at Low
Risk of Smallpox

• Contact and airborne precautions
• Notify infection control
• Evaluate clinically for VZV
• Test for VZV and other conditions, as indicated

38
Differential Diagnosis Variola vs. Varicella
Source CDC
39
Differential Diagnosis Variola vs. Varicella
Source CDC
40
Variola vs. Varicella Lesion Distribution
Chickenpox
Smallpox
WHO
41
Variola vs. VaricellaLesion Distribution
Smallpox
Chickenpox
WHO
42
Differential Diagnosis of Smallpox

• Varicella
• Disseminated herpes zoster
• Drug eruptions and contact dermatitis
• Disseminated herpes simplex

• Impetigo
• Erythema multiforme
• Scabies, insect bites
• Bullous pemphigoid
• Secondary syphilis
• Molluscum contagiosum
• Enterovirus exanthem

43
SmallpoxMedical Management

• Respiratory and contact isolation for
  hospitalized cases
• Negative pressure room HEPA-filtered exhaust
• All health care workers employ aerosol and
  contact precautions regardless of immunization
  status
• No specific therapy available
• Supportive care fluid and electrolyte, skin,
  nutritional

44
SmallpoxMedical Management

• Antibiotics for secondary infection
• Antiviral drugs under evaluation
• Notify Public Health and hospital epidemiology
  immediately for suspected case

45
SmallpoxDefinition of a Contact

• Contact A person who has had contact with a
  suspected, probable or confirmed case of smallpox
• Cases should be considered infectious from the
  onset of fever, until all scabs have separated
• Close contact Face-to-face contact (?6ft) with a
  smallpox case

46
Smallpox Vaccine

• Made from live Vaccinia virus
• 200 million doses in U.S. stores
• Intradermal inoculation with bifurcated needle
  (scarification)
• Pustular lesion or induration surrounding central
  lesion (scab or ulcer) 6-8 days post-vaccination
• Low grade fever, axillary lymphadenopathy
• Scar (permanent) demonstrates successful
  vaccination (take)
• Immunity not life-long

WHO
47
Smallpox Vaccine Administration
WHO
JAMA 19992811735-45
48
Smallpox Vaccine Take
WHO
49
Smallpox Vaccine Complications

• More common in children and primary vaccinees
• Most common secondary inoculation
• Skin, eye, nose, genitalia
• 50 of all complications
• 529/million (30 in one study were contacts)
• Severe reactions less common
• Primary vaccination 1 death/million
• Revaccination 0.2 deaths/million

50
Smallpox Complications Rates for Primary
Vaccination

• Complication rates lower with revaccination
• Primary vaccination 1 death/million
• Revaccination 0.2 deaths/million
• Most common complication
• Inadvertent auto- and secondary inoculation
  (skin, eye)
• 529/million (30 in one study were contacts)

• Sources MMWR June 22, 2001 / 50(RR10)1-25.
  Vaccinia (Smallpox) Vaccine Recommendations of
  the Advisory Committee on Immunization Practices
  (ACIP), 2001
• Vaccines 3rd Ed. Plotkin SA, Orenstein WA. W.B.
  Saunders, Phila. 1999

51
Smallpox Complication Rates for Primary
Vaccination

• Less common
• Post-vaccination encephalopathy (7-42.3/million)
  
• Post-vaccination encephalitis (12.3/million)
• 25 fatal 23 neurological sequelae
• Progressive vaccinia/vaccinia necrosum
  (1.5/million)
• Generalized vaccinia (241.5/million) severe in
  10
• Eczema vaccinatum (38.5/million)
• Fetal vaccinia - rare

Sourced MMWR June 22, 2001 / 50(RR10)1-25.
Vaccinia (Smallpox) Vaccine Recommendations of
the Advisory Committee on Immunization Practices
(ACIP), 2001 Vaccines 3rd Ed. Plotkin SA,
Orenstein WA. W.B. Saunders, Phila. 1999
52
Smallpox Vaccine Complications
WHO
53
Smallpox Vaccine Complications
WHO
54
Smallpox Vaccine Pre-exposure Contraindications

• Immunosuppression
• Agammaglobulinemia
• Leukemia, lymphoma, generalized malignancy
• Chemo- or other immunosuppressive therapy
• HIV infection
• History or evidence of eczema
• Household, sexual, or other close contact with
  person with one of the above conditions
• Life-threatening allergy to polymixin B,
  streptomycin, tetracycline, or neomycin
• Pregnancy

55
SmallpoxVaccinia Immune Globulin (VIG)

• Treatment of adverse reactions (AR)
• Approximately 25 ARs/100,000 vaccinations
• AR rate may be increased in immunocompromised
  populations
• Post-exposure prophylaxis (if available)
• Pregnant patients VIG vaccinia vaccine
• Eczema VIG vaccinia vaccine
• Immunocompromised patients no consensus on VIG
  alone vs. VIG vaccinia vaccine
• Current supplies very limited, but new lots are
  being produced that conform to IV standards

56
Distinguishing Smallpox from Chickenpox
Similar Epidemiologic Features

• Incubation period 14 (10-21) days
• Person-to-person transmission
• Seasonal transmission of disease highest during
  winter and early spring

57
Distinguishing Smallpox from Chickenpox Epi
Features that Differ

• Chickenpox (varicella)
• Most cases occur in children
• Expected case fatality rate 2-3/100,000
• Secondary attack rate of 80 among susceptible
  household contacts

• Smallpox (variola)
• Most of the population expected to be susceptible
• Expected case fatality rate averages 30
• Secondary attack rate 60 in unvaccinated family
  contacts

58
Distinguishing Smallpox from Chickenpox
Clinical Features that Differ

• Chickenpox (varicella)
• Lesions superficial
• Rash concentrated on trunk
• Lesions rarely on palms or soles
• Lesions in different stages of development
• Rash progresses more quickly

• Smallpox (variola)
• Lesions deep
• Rash concentrated on face extremities
• Lesions on palms soles
• Lesions in same stage of evolution on any one
  area of body
• Rash progresses slowly

CDC
59
Smallpox Summary of Key Points

• The clinical diagnosis of smallpox is a public
  health emergency the local or state health
  department and hospital infection control should
  be notified immediately for suspected cases,
  including cases that meet criteria of the CDC
  smallpox case definition.
• CDC criteria for determining the risk of smallpox
  can help differentiate smallpox from varicella
  and other rash illnesses.

60
Smallpox Summary of Key Points

• Smallpox is transmitted person to person
  standard contact and airborne precautions should
  be initiated in all suspected cases until
  smallpox is ruled out.
• Vaccine-induced immunity wanes with time
  therefore most people today are considered
  susceptible to infection.

61
Smallpox Summary of Key Points

• Smallpox cases should be considered infectious
  from the onset of fever until all scabs have
  separated.

62
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

63
Viral Hemorrhagic Fevers

• Category A agents
• Filoviruses
• Arenaviruses
• Category C agents
• Hantaviruses
• Tick-borne hemorrhagic fever viruses
• Yellow fever

64
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

65
Viral Hemorrhagic FeversPathogenesis

• Destruction of infected cells
• Occurs in filovirus, Rift Valley fever, and
  yellow fever infections
• Coagulopathy from hepatic dysfunction and
  disseminated intravascular coagulation (DIC)
• Most prominent in Rift Valley fever and yellow
  fever

66
Viral Hemorrhagic FeversPathogenesis

• Hemorrhage
• Filoviruses
• From direct damage to vascular endothelial cells
  and platelets ? impaired microcirculation
• Through immunological and inflammatory mediators
• DIC characteristic
• Arenaviruses
• Via stimulation of inflammatory mediators by
  macrophages
• Thrombocytopenia
• Inhibition of platelet aggregation
• DIC not characteristic

67
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

68
Viral Hemorrhagic FeversInitial Symptoms

• Prodromal illness lasting lt 1 week may include

• High fever
• Headache
• Malaise
• Weakness
• Exhaustion

• Dizziness
• Myalgias
• Arthralgias
• Nausea
• Non-bloody diarrhea

69
Viral Hemorrhagic FeversClinical Signs

• Flushing, conjunctival injection
• Pharyngitis
• Petechiae, bleeding (with some agents)

• Edema
• Hypotension
• Positive tourniquet test
• Shock

70
Clinical Identification of Suspected VHF

• Clinical criteria
• Temperature 101?F(38.3?C) for lt3 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 2002287 Adapted from WHO
71
Clinical Identification of Suspected VHF

• Inquire about potential natural exposures
• Travel, insect bites, exposure to animals or ill
  persons
• Report suspected cases immediately to
• Local and state health department
• Hospital infection control professional and
  laboratory personnel

72
Viral Hemorrhagic FeversDifferential Diagnosis

• Severe systemic illness due to other agents
• Bacterial
• Typhoid fever, meningococcemia, rickettsioses,
  leptospirosis, toxic shock syndrome, borreliosis,
  psittacosis, septicemic plague, gram neg sepsis
• Protozoa
• Falciparum malaria, trypanosomiasis
• Viral and Other
• Measles, rubella, hemorrhagic smallpox,
  vasculitis, TTP, Hemolytic Uremic Syndrome (HUS),
  acute leukemia

73
Medical Management of Viral Hemorrhagic Fevers

• Supportive care
• Correct coagulopathies as needed
• No antiplatelet drugs or IM injections
• Investigational treatments, available under
  protocol
• Ribavirin for arenaviridae and bunyaviridae
• Convalescent plasma within 8 days of onset for
  AHF

74
Medical Management of Viral Hemorrhagic Fevers

• Initiate supportive and ribavirin therapy
• If arenavirus or bunyavirus confirmed, continue
  10 day course
• If VHF excluded, or other VHF confirmed,
  discontinue ribavirin

• JAMA 2002287

75
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 ? 101?F(38.3?C)
• 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

76
Viral Hemorrhagic Fevers Management of Exposed
Persons

• Patients convalescing should refrain from sexual
  activity for 3 months post-recovery (arenavirus
  or filovirus infection)
• Only licensed vaccine Yellow Fever
• Investigational vaccines AHF, RV, HV
• Possible use of ribavirin to high risk contacts
  of CCHF LF patients

77
Viral Hemorrhagic Fever 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

78
Viral Hemorrhagic Fever Infection Control

• Dedicated medical equipment for patients
• If available, point-of-care analyzers for routine
  laboratory analyses
• If unavailable, pretreat serum w/Triton X-100
• Lab samples double-bagged and hand-carried to lab
  
• Prompt burial or cremation of deceased with
  minimal handling
• Autopsies performed only by trained personnel
  with PPE

79
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.

80
Viral Hemorrhagic FeversSummary of Key Points

• Contact and airborne precautions are recommended
  for health care workers caring for infected
  patients.
• Diagnostic laboratory testing for viral
  hemorrhagic fevers must be done in a bio-safety
  level 4 lab (i.e., CDC) contact the local or
  state health department before specimen
  collection in suspected cases.

81
Viral Hemorrhagic FeversSummary of Key Points

• Contact and airborne precautions are recommended
  for health care workers caring for infected
  patients.
• Post-exposure management consists of surveillance
  for fever and hemorrhagic symptoms, and possibly
  ribavirin therapy for symptomatic individuals.

82
Summary - Category A Critical Agents
infectious dose may be less in certain
circumstances
Modified from USAMRIIDs Medical Management of
Biological Casualties Handbook
83
SummaryCategory A Critical Agents

• Decontamination of exposed persons
• Showering or washing thoroughly with soap and
  water adequate for most bleach not necessary
• Infection control
• Standard precautions all cases
• Airborne and contact precautions smallpox and
  viral hemorrhagic fevers
• Droplet precautions pneumonic plague

84
(No Transcript)