A Rash Overview of the Dermatologic Manifestations of Agents of Bioterrorism

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A Rash Overview of the Dermatologic
Manifestations of Agents of Bioterrorism

• Boris D. Lushniak, MD, MPH
• RADM, Asst Surgeon General USPHS
• Asst Commissioner, Counterterrorism Policy FDA

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DISCLOSURE OF RELEVANT RELATIONSHIPSWITH INDUSTRY

• I do not have any relevant relationships with
  industry.
• No relationship with commercial supporters
• No off-label discussion of drugs or devices
• Federal government employee
• Work supported by US Government

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A Rash Overview

• A skin eruption
• Outbreak of activities in a brief period
• Quick in producing an effect
• Marked by ill-considered boldness or haste
• Websters II Dictionary

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Outline

• Overview of bioterrorism (BT)
• Review and update on BT agents with skin
  manifestations
• Emphasis on anthrax and smallpox
• Your role in preparedness and response

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Learning Objectives

• Identify the bioterrorist agents that have
  cutaneous manifestations
• Recognize the cutaneous findings and other health
  effects associated with potential bioterrorist
  agents
• Define your potential role in the event of a
  bioterrorist event

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My Secret Objective

• Always exciting to hear a doctor say,
• Dear God what the hell is that?
• David Letterman 6/10/2003
• Top Ten List
• RE Monkeypox

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Bioterrorism

• Intentional or threatened use of viruses,
  bacteria, fungi, or toxins from living organisms
  to produce death or disease in humans, animals,
  or plants

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History of Biowarfare

• Contamination of food or water supplies
• 6th century BC Assyrians poisoned wells with a
  fungus (rye ergot)
• Launching of potentially infective material into
  strongholds
• 1346 Siege of the Genoans by Tatars of Kaffa
  (Feodosia) in Crimea
• Catapulting of plague corpses

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History of Biowarfare

• Dissemination of infected clothing or blankets
• 1754-63 French and Indian War
• Smallpox tainted blankets from British to the
  Indians
• Microbiologic era
• Germany WWI (anthrax, glanders, plague)
• Japan 1930-1945 (anthrax, botulinum, cholera,
  plague, typhoid)
• USA 1941-1969 (anthrax, botulinum, tularemia, Q
  fever, brucellosis, psittacosis)
• USSR 1920s-1990s? (antibiotic resistant strains
  plague, anthrax, tularemia, glanders, genetically
  altered smallpox)

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Biologics as Weapons and Threats

• History of development for bioweapons
• Easy to obtain, inexpensive to produce
• Potential for dissemination over large areas
• Organisms fairly stable in environment
• Potential high morbidity and mortality
• Person-to-person transmission (smallpox, plague,
  VHF)
• Difficult to diagnose and/or treat
• Can overwhelm medical services
• Perpetrators escape easily

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Biological Agents of Highest Concern (Category A)

• Bacillus anthracis (Anthrax)
• Variola major (Smallpox)
• Yersinia pestis (Plague)
• Francisella tularensis (Tularemia)
• Filoviruses and Arenaviruses (Viral Hemorrhagic
  Fevers)
• Botulinum toxin (Botulism)
• ALL suspected or confirmed cases should be
  reported to health authorities immediately

Cutaneous manifestations
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Anthrax

• Zoonotic disease in herbivores (e.g., sheep,
  goats, cattle) follows ingestion of spores in
  soil
• Three clinical forms
• Cutaneous, Inhalational, Gastrointestinal
• Bacillus anthracis -- Gram-positive,
  spore-forming, non-motile bacillus

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• Cases of Anthrax in Humans
• U.S. 19512000
• (N 409)

Animal (Stern's) vaccination started in 1957.
Recommended for use in animals in endemic areas
thereafter.
2000w
18 were inhalational all others cutaneous
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• Anthrax Current Issues

• Anthrax remains an endemic public health threat
  through annual epizootics
• Farm workers exposed to infected animals
• Industrial processing of wool, hair, hides, or
  bones
• 158 of 236 (67) of cases in US from 1955-1999
• 148 of 158 (94) were cutaneous cases
• Laboratorians with contact to spores

MMWR March 17, 2006 55(10) 280-282
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Anthrax Current Issues

• B. anthracis is one of the most important
  pathogens on the list of bioterrorism threats
• Aerosolized stable spore form
• Human LD50 8,000 to 40,000 spores, or one deep
  breath at site of release

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Inhalational Human Anthrax

• Extremely rare in United States
• Feb 2006 single case associated with dried animal
  skins (NY, PA)
• Incubation period 17 days (up to 42 days?)
• Case fatality (prior to 2001)
• Without antibiotic treatment--97
• With antibiotic treatment--75
• Production of toxins made up of 3 proteins
• Protective antigen, edema factor, and lethal
  factor
• Toxins do not respond to antibiotics

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Inhalational Human Anthrax

• A brief prodrome -- viral-like illness
• Myalgia, fatigue, fever, with or without
  respiratory symptoms
• Followed by hypoxia and dyspnea
• Often with radiographic evidence of mediastinal
  widening
• Meningitis

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Anthrax Inhalational
?Mediastinal widening JAMA 199928117351745
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Cutaneous Anthrax

• Form most commonly encountered in naturally
  occurring cases
• Incubation period 112 days
• Case-fatality
• Without antibiotic treatment20
• With antibiotic treatment1

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Cutaneous AnthraxClinical Progression

• Begins as non-tender pruritic macule then a
  papule
• Progresses into a vesicle or bulla (24-48 hours)
• Bulla 1-2 cm ruptures (satellite vesicles and
  edema)
• Depressed black necrotic ulcer (jet black eschar)
  with raised border and erythematous plaque
• Edema, erythema or necrosis without ulceration
  may occur
• Minimal scarring

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Cutaneous AnthraxClinical Progression
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Anthrax
Roche et al. New Engl J Med. 11/6/2001 on-line.
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Brown recluse spider bite reaction
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Ecthyma gangrenosum (p. aeruginosa)
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Tularemia
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Staphylococcal wound infection
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Herpes labialis
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Anthrax Response 2001
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MMWR 5044 Nov 9, 2001
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Anthrax, U.S.October 4-November 19, 2001

• 11 inhalational, 11 cutaneous
• 5 deaths (all inhalational)
• 20 exposed to worksites where contaminated mail
  processed or received
• Post-exposure chemoprophylaxis initiated for
  32,000 media, government, and mail workers (full
  course recommended for 10,300)

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Anthrax, U.S.October 4-November 19, 2001
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Cutaneous Anthrax 2001 Summary

• 11 cases (7 confirmed, 4 suspect)
• 1 additional case in lab worker
• 6 males and 6 females
• 7 months to 54 years
• Sites
• Head
• Neck
• Upper extremities

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• Anthrax -- Diagnosis

• Cutaneous
• Gram stain, polymerase chain reaction (PCR), or
  culture of vesicular fluid, exudate, or eschar
• Blood culture if systemic symptoms present
• Biopsy for immunohistochemistry, especially if
  person taking antimicrobials

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Cutaneous Anthrax Treatment Protocol for Cases
Associated with Bioterrorist Events
Category Initial Therapy (Oral) Duration Adults
Ciprofloxacin 60 daysw (Including pregnant
women 500 mg BID and immunocompromised) OR
Doxycycline 100 mg BID Children Ciprofloxacin
60 daysw (including immuno- 1015 mg/kg Q 12
hrs compromised) OR Doxycycline gt8 yrs and
gt45 kg 100 mg BID gt8 yrs and lt45 kg 2.2
mg/kg BID lt8 yrs 2.2 mg/kg BID
Ciprofloxacin not to exceed 1 gram daily in
children. w60-day duration is to prevent
inhalational anthrax.
Patient information sheets at www.bt.cdc.gov
Source MMWR 20015090919
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AnthraxVaccine

• Anthrax Vaccine Adsorbed
• Induces immunity to protective antigen
• 6-dose series (0-2-4 wks, 6-12-18 mos, qy)
• Over 600,000 doses to US military
• Some controversy -- but, studied by Institute
  of Medicine and approved by FDA
• Supplies are limited

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Anthrax remains a concern
Oct 2001
Scenario modelling

• 1 gm via letters
• gt 30,000 PEP
• 22 cases
• 5 deaths
• 3 buildings contaminated
• gt1 billion

• 1-2 kg via crop duster
• 1.9-3.4 mill PEP
• gt450,000 cases
• gt380,000 deaths
• City wide contamination
• gt1 trillion

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Smallpox Variola
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Genus OrthopoxvirusFamily Poxviridae

• Double stranded DNA viruses
• Cytoplasmic replication (not in nucleus)
• Can cause human disease
• Variola from Latin varius (stained) or varus
  (mark on the skin) small pockes (sacs)
  syphilis was the great pockes
• Vaccinia, Cowpox, Monkeypox

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200 micron virions
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Smallpox History

• Appeared 10,000 BC in first agricultural
  settlements in NE Africa
• Scars seen on mummies from 1500 BC
• Spread to India and China via merchants
• Spread to Europe in 5-7th centuries and the New
  World in 1400s
• 18th Century Europe 400,000 annual deaths and
  1/3 of survivors went blind
• Common knowledge that survivors became immune
• In Africa, India, China and in 18th century
  Europe practice of inoculation / variolation
  (inoculare to graft)
• 2-3 fatality rate

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Smallpox History

• 1796 Jenners cowpox vaccine
• 1949 last US case
• 1950s -- 50 million cases/year
• 1967 10-15 million cases/year
• 60 of world still threatened
• 1972 vaccinations stopped in US
• 1977 last natural case (Somalia)
• 1980 WHO declares smallpox eradicated
• Virus remains stored at CDC and in Russia
• Impact in 20th century 500 million deaths

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Smallpox

• Highly stable virus
• Infectious by direct contact/aerosol (usually
  within 6 feet)
• 30 of close contacts infected
• Infrequent indirect transmission (fomites such as
  bedding or clothing)
• Two clinical forms
• Variola major severe form, case-fatality gt30
• Variola minor less severe, case-fatality lt 1

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SmallpoxClinical Stages

• Incubation - 7-17 days
• non-infectious
• Prodrome - lasts 2-4 days
• High fever (101-104), prostration, myalgias,
  malaise
• Enanthem (now infectious) small red macules and
  papules on tongue and mouth which ulcerate
• Exanthem
• Centrifugal (face, arms/legs, hands/feet)
• Progression -- macule-papule-vesicle-pustules-crus
  t

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SmallpoxLesion Progression

• Day 0-1 - Macule
• Day 2-3 - Papule
• Day 3-5 - Deep, tense vesicle often umbilicated
• Day 6-12- Deep, round, tense pustules
• (like BB pellet embedded in the skin)
• Day 13-20 - Crusts
• Day 21-28 - Crusts separate
• Long-term - Depressed scars

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Variola Major Clinical Presentations

• Ordinary smallpox
• Discrete 60
• Semi-confluent/Confluent 30
• Flat 6
• Hemorrhagic 3
• Modified (mild in vaccinated) rare

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SmallpoxProgression
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SmallpoxClinical Forms

• Ordinary smallpox
• 3 fatal with vaccination
• 30 fatal without

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Ordinary Smallpox Umbilicated Vesicles
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Varicella
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Variola vs. Varicella
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Molluscum contagiosum
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Hand, foot, and mouth disease (Coxsackievirus)
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Disseminated HSV
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Herpes Zoster
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Pustular Drug Eruption
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Scabies
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Monkeypox

• 1958 found in lab monkeys
• 1970 - human disease
• June 2003 first US cases
• Reservoir animals (prairie dogs)
• Transmission aerosol / direct contact
• Less infectious and lethal than smallpox

www.mcw.edu/derm
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SmallpoxComplications

• Sepsis/toxemia
• Circulating immune complexes
• Usual cause of death
• Encephalitis
• Blindness
• Secondary bacterial infection - uncommon

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Smallpox

• Immediate ID or Derm consult
• Activate infection control measures
• Lab testing for DDx
• Electron microscopy, culture
• DFA (direct fluorescent antibody test)
• Polymerase chain reaction
• Tzanck smear
• confirms varicella and herpes simplex and zoster
• Report to state health department immediately!!!!

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SmallpoxManagement of Patients

• Supportive
• Isolation
• Ring vaccination (effective if given within 3-4
  days of exposure)

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Sarah Nelms
VACCINATION

• Vaccus cow
• Benjamin Jesty (1774) used material from cow
  udders
• Jenner 1796 using material from cowpox lesions
• Vaccinia a live virus vaccine

James Phipps, age 8
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Multipuncture Vaccination with Bifurcated Needle
Scarification Technique
Needle is held perpendicular to the arm
Wrist of vaccinator rests on arm
Drop of vaccine is held in the fork of the needle
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Day 3
Day 6
Day 9
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Day 12
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Day 17
Day 19
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Smallpox VaccinationContraindications for
non-emergency vaccine use

• Immunodeficiency states or immunomodulating meds
• Life-threatening allergic reactions
• Pregnancy
• Cardiovascular diseases
• Skin diseases
• Atopics or epidermal disrupting diseases
• Household members with these

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Smallpox VaccinationLocalized Skin Reactions

• Robust primary
• Autoinoculation
• Peri-ocular

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Robust Primary Reaction
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Accidental Vaccinia (Autoinoculation)
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Periocular Vaccinia
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Smallpox VaccinationGeneralized Skin
Reactionswith Systemic Symptoms

• Generalized vaccinia distant site viremic
  spread
• Progressive vaccinia progressive necrosis
• Vaccinia necrosum / Vaccinia gangrenosum
• Erythema multiforme major (Stevens-Johnson
  Syndrome)
• Mucocutanous reaction to antigenic stimuli
• Eczema vaccinatum localized or systemic
  dissemination in eczema/atopics ( history of)

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Generalized Vaccinia
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Progressive vaccinia (vaccinia necrosum, vaccinia
gangrenosum)
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Progressive Vaccinia in a Military Smallpox
Vaccinee US, 2009

• First confirmed case in US since 1987
• Jan 13, 2009 - healthy 20 yo received vaccine
• Jan 25 - admitted with fever, headache,
  leukopenia (1400 cells/mm3)
• Jan 28 - diagnosed with acute myelogenous
  leukemia (M0)
• Jan 30-Feb 13 - 2 rounds induction chemotherapy
  (cytarabine, idarubicin, dexamethasone)

MMWR 58May 19, 2009
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Progressive Vaccinia in a Military Smallpox
Vaccinee US, 2009

• Before chemo, vaccination site pustule had
  central crust, 1 cm in size, with min erythema
• Dressing changed daily
• March 2 annular lesion with deep bulla,
  bleeding central crust, raised violaceous leading
  edge, 4 x 4 cm
• PCR viral DNA, culture orthopox

MMWR 58May 19, 2009
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Progressive Vaccinia in a Military Smallpox
Vaccinee US, 2009

• Rx with imiquimod, Vaccine Immune Globulin IV,
  oral and topical ST-246 under E-IND
• March - lesion size unchanged, central crust
  sloughed off, leaving shallow ulcer
• March 18 - satellite lesions, viral DNA in blood,
  lesions became vesicular
• March 26 E-IND for CMX001 (lipid conjugate of
  cidofovir)
• March 24 lesions begin crusting healing by May
• Impact -- 200 clinical specimens, 20 conference
  calls, 276 vials of VIGIV (amount originally
  estimated to treat 30 persons)

MMWR 58May 19, 2009
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Progressive vaccinia (vaccinia necrosum, vaccinia
gangrenosum)
April 27
March 5
March 27
MMWR 58May 19, 2009
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Erythema multiforme major (Stevens Johnson)
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Eczema vaccinatum
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Eczema Vaccinatum
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Household Transmission of Vaccinia Virus form
Contact with a Military Smallpox Vaccinee

• First reported EV case since 1988
• Active-duty father vaccinated on 1/26/07
• History of childhood eczema and 2 of 3 children
  with eczema
• Deployment delayed and unplanned visit with
  family 2/16-20
• Reported that vaccination site had scabbed over,
  scab had separated, and was kept covered (not
  confirmed)
• 3/3/07, 28 month old boy with severe
  eczema/failure to thrive presents with
  generalized papular and vesicular rash on
  face/neck, UE
• History of fever since 3/1, skin lesions since
  2/24
• 3/7/07 umbilicated lesions on 50 of skin surface

MMWR May 18, 2007 56(19) 478-481
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Household Transmission of Vaccinia Virus form
Contact with a Military Smallpox Vaccinee

• 3/8/07 PCR positive for orthopox DNA,
  supporting diagnosis of eczema vaccinatum (EV)
• 3/8 3/28 treated with Vaccinia Immune Globulin
  Intravenous (VIG) and cidofovir, vasopressor
  support, mechanical ventilation
• Investigation anti-viral ST-246 (Emergency IND
  use), a smallpox drug candidate with
  antiorthopoxvirus activity inhibiting virus
  maturation
• 4/19 discharged after 48 days of
  hospitalization

MMWR May 18, 2007 56(19) 478-481
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Household Transmission of Vaccinia Virus form
Contact with a Military Smallpox Vaccinee

• 3/6 Mother with mild vesicular lesions on face
  (rested on childs abdomen in hospital) PCR
  positive 3/10 treated with VIGIV and lesions
  scabbed over within 72 hours
• 23 family contacts and 73 health care workers
  monitored daily for 21 days no other cases
• 3/13 environmental swabbing at home positive PCR
• Cell culture from booster seat, toy, slipper
  contained viable virus
• 3/23 disinfection procedures (steam cleaning,
  phenolics)

MMWR May 18, 2007 56(19) 478-481
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Smallpox VaccinationPrimary Complication Rates
Rate per million vaccinees - all ages

• Erythema multiforme 266
• Accidental inoculation 242
• Post-vaccinial encephalitis 165
• Generalized vaccinia 39
• Progressive vaccinia 12
• Eczema vaccinatum 2

Lane et al. J Infect Dis. 122(4)307. 1970.
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DoD Smallpox VaccinationDec 13, 2002 May 28,
2003

• 450,293 vaccinated
• Dermatological complications
• 38 autoinoculation (non-ocular)
• 36 mild generalized vaccinia
• 21 vaccinia transfer to contacts
• 10 ocular auto inoculation
• 6 cases cellulitis
• 1 erythema multiforme
• No eczema vaccinatum
• No progressive vaccinia

JAMA 20032893278-3282
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DoD Smallpox Vaccination

• Neurological
• 1 documented encephalitis
• 23 other neurologic events with unclear
  association to the vaccine
• Cardiac
• 37 acute myopericarditis primary / males
• 8 other cardiac events 2-12 days after

• JAMA 20032893278-3282

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Reported Adverse Events

• Jan 24-Dec 31, 2003 39,213 civilians vaccinated
• Eczema vaccinatum none
• Generalized vaccinia 2-suspected, 1-confirmed
• Inadvertent inoculation (nonocular)
• 11-suspected and 9-confirmed
• Ocular vaccinia 1-suspected, 2 confirmed
• Stevens Johnson none
• Myo/percarditis 16-suspected, 5-probable,
  0-confirmed
• Encephalitis 1-suspected

MMWR 53(05) 106-107
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Your Role in BT as a Health Care Professional

• Education
• www.bt.cdc.gov
• Be aware
• Be involved

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Review

• Overview of bioterrorism (BT)
• Review and update on BT agents with skin
  manifestations
• Emphasis on anthrax and smallpox
• Your role in preparedness and response

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boris.lushniak_at_fda.hhs.gov
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Plague
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PlagueMicrobiology (Yersinia pestis)

• Gram-negative coccobacillus
• Facultative intracellular

• Bipolar safety-pin staining

• Evades immune response

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Bubonic Plague

• Host (mammal)
• Rattus rattus (antiquity)
• Squirrels, cats, coyotes, bobcats
• Vector flea via bite
• Sudden onset with flu-like syndrome
• No person-to-person spread
• Buboes swollen tender lymph nodes
• Untreated -- can result in pneumonic plague

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Pneumonic Plague

• Spread from respiratory droplets (aerosol) of
  infected person or animal
• Fever, cough with bloody sputum, pneumonia,
  rapidly fatal
• Incubation period 1-6 days
• Treatment (within 24 hrs)
• Tetracyclines
• Fluoroquinolones
• Streptomycin
• Gentamicin

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Tularemia
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TularemiaMicrobiology/Epidemiology

• Francisella tularensis G neg coccobacilli
• Very infectious -- As few as 10 organisms
• Reservoirs Wild rabbits, squirrels, mud, water,
  carcasses
• Vectors Blood-sucking insects, mainly ticks
• Northern hemisphere (OK, MO, AR, SD)
• Exposure insect bites, handling tissue,
  contact/ingestion with food/water/soil, aerosol
  inhalation

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TularemiaClinical Types

• Ulceroglandular

• Glandular
• Oropharyngeal/Gastrointestinal
• Oculoglandular
• Typhoidal
• Pneumonic - biothreat

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Tularemia in BT

• Abrupt onset of acute, nonspecific febrile
  illness (38-40 degrees C) in 3-5 days (range 1-14
  days)
• Headaches, chills, body aches, coryza, sore
  throat, pleuropneumonitis
• Dx Gram stain, DFA, PCR, immunohistochem,
  culture, serology
• Rx Strepto, Gent, doxy, cipro
• Case fatality rate 5-30 if untreated
• US and USSR maintained tularemia as bioweapon

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TularemiaCutaneous Manifestations

• Papule

• Vesicle
• Pustule

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TularemiaCutaneous Manifestations

• Punched-out ulcer with raised margins, thin
  yellow exudate
• Proximal lymphadenopathy

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TularemiaCutaneous Manifestations

• Tender necrotic base / Eschar
• Can persist for months and scar

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Tularemia

• Secondary skin eruptions (tularemids) in 3-25
• Papular, macular, pustular, petechial,
  papulovesicular exanthems on extremities and face
  in 2nd week
• E nodosum, E multiforme, Sweets syndrome
  reported

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Viral Hemorrhagic Fevers
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Viral Hemorrhagic FeversTransmission

• RNA viruses
• Rodent reservoirs
• Generally transmitted by arthropods
• Most have potential aerosol spread
• High risk of nosocomial spread
• Lassa fever
• Congo-Crimean hemorrhagic fever
• Marburg disease
• Ebola fever

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Hemorrhagic FeversCutaneous Findings

• Flushing
• Pharyngeal hyperemia
• Petechiae
• Purpura
• Ecchymoses
• Edema
• Morbilliform eruptions

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Ebola FeverClinical Findings

• Abrupt, flu-like illness
• Day 5 - centripetal morbilliform eruption,
  petechiae, ecchymoses

• Day 7 - desquamation
• Psychosis, delirium, seizures, coma
• Hemorrhage
• Day 6-16 - Death