Cutaneous Signs of Bioterror Agents

Adam Goldstein, MD, MPHAdam Goldstein, MD, MPHAssociate ProfessorAssociate Professor

UNC Department of Family MedicineUNC Department of Family MedicineChapel Hill, NCChapel Hill, NC

aog@med.unc.eduaog@med.unc.edu

Objectives Improve ability to:Improve ability to:

diagnose and manage cutaneous illness diagnose and manage cutaneous illness associated with suspected cases of bioterrorassociated with suspected cases of bioterror

Anthrax, plague, tularemia, smallpox, mustard Anthrax, plague, tularemia, smallpox, mustard gasgas

Why worry?

““Subnational attacks using genetically Subnational attacks using genetically engineered organisms are inevitable”engineered organisms are inevitable”

““Biologic agents now join nuclear agents” Biologic agents now join nuclear agents” DeathsDeaths

1 KT H-BOMB 1 KT H-BOMB .6M – 2M.6M – 2M 100 Kg ATX 100 Kg ATX 1M – 3M1M – 3M

(Stansfield Turner, CIA, 2001)(Stansfield Turner, CIA, 2001)

Anthrax Anthrakos = ‘coal’ b/c of black eschar Anthrakos = ‘coal’ b/c of black eschar B. anthracis is gram-positive B. anthracis is gram-positive sporulatingsporulating

bacillusbacillus Spores are Spores are resistantresistant to heat, cold, drying, & to heat, cold, drying, &

chemical disinfectionchemical disinfection Anthrax is Anthrax is endemicendemic in western Asia (Iran in western Asia (Iran

Turkey Afghanistan,) & western AfricaTurkey Afghanistan,) & western Africa

(McGovern, (McGovern, Elect Text DermatolElect Text Dermatol, 1999), 1999)

Anthrax Spores Spores viableviable for for yearsyears top 6 cmtop 6 cm of soil & in of soil & in

animal productsanimal products Disease transmitted from infected animals or Disease transmitted from infected animals or

products products via skin abrasionsvia skin abrasions > 90% of cases > 90% of cases GoatsGoats > sheep > cattle > horses > pigs > dogs > sheep > cattle > horses > pigs > dogs

Anthrax BurnBurn dead animals, not buried, to prevent dead animals, not buried, to prevent

long-term environmental contaminationlong-term environmental contamination

History of Anthrax 1500 B.C. -- Fifth/sixth Egyptian plagues, ? Anthrax1500 B.C. -- Fifth/sixth Egyptian plagues, ? Anthrax 1600s -- "Black Bane," ? anthrax, kills 60,000 cattle 1600s -- "Black Bane," ? anthrax, kills 60,000 cattle 1876 -- Koch confirms bacterial origin of anthrax 1876 -- Koch confirms bacterial origin of anthrax 1880 -- Immunization of livestock against anthrax 1880 -- Immunization of livestock against anthrax 1915 -- German agents in U.S. inject horses/cattle with 1915 -- German agents in U.S. inject horses/cattle with

anthrax on way to Europe during WW I anthrax on way to Europe during WW I 1937 -- Japan starts biological warfare program1937 -- Japan starts biological warfare program 1942 -- Britain experiments with anthrax 1942 -- Britain experiments with anthrax 1943 -- U.S. begins developing anthrax weapons 1943 -- U.S. begins developing anthrax weapons 1945 -- Anthrax outbreak in Iran kills 1 million sheep1945 -- Anthrax outbreak in Iran kills 1 million sheep

Historical 1950s and '60s -- U.S. biological program continues1950s and '60s -- U.S. biological program continues 1969 -- Nixon ends U.S. offensive biological program. 1969 -- Nixon ends U.S. offensive biological program. 1970 -- Anthrax vaccine approved by U.S. FDA1970 -- Anthrax vaccine approved by U.S. FDA 1972 -- International convention outlaws development or 1972 -- International convention outlaws development or

stockpiling of biological weapons stockpiling of biological weapons 1978-80 -- Human anthrax epidemic strikes Zimbabwe, 1978-80 -- Human anthrax epidemic strikes Zimbabwe,

infecting > 6,000 and killing 100 infecting > 6,000 and killing 100 1979 -- Aerosolized anthrax spores released at Soviet military 1979 -- Aerosolized anthrax spores released at Soviet military

facility, killing 68facility, killing 68 1991 -- U.S. troops vaccinated for Gulf War I1991 -- U.S. troops vaccinated for Gulf War I 1990-93 -- Terrorists release anthrax in Tokyo; no injuries1990-93 -- Terrorists release anthrax in Tokyo; no injuries

Historical 1995 -- Iraq produced concentrated anthrax in 1995 -- Iraq produced concentrated anthrax in

biological weapons program biological weapons program 1998 -- U.S. approves anthrax vaccinations for all 1998 -- U.S. approves anthrax vaccinations for all

militarymilitary 2001 -- Letter with anthrax spores mailed to NBC 2001 -- Letter with anthrax spores mailed to NBC

one week after 9/11 terrorist attacks on Pentagon one week after 9/11 terrorist attacks on Pentagon

& WTC. Several die after inhaling.& WTC. Several die after inhaling.

Anthrax pilot plant used to produce billions of anthrax spores at Fort Detrick, Md.

U.S. ended offensive biological weapons research in 1969

Al Hakam, Iraq's major facility for production of biological agents.

Plant destroyed by Iraqi workers

in 1996.

Forms of Anthrax

Pulmonary Anthrax

Wool-sorter’s diseaseWool-sorter’s disease 18 cases reported in U.S. 1900-198018 cases reported in U.S. 1900-1980 Symptoms: vague prodrome with Symptoms: vague prodrome with feverfever, ,

malaisemalaise, , myalgiasmyalgias and and coughcough Within days- rapidly developing precordial Within days- rapidly developing precordial

discomfort, cyanosis, stridor, diaphoresis, discomfort, cyanosis, stridor, diaphoresis, moist rales, pleural effusion and deathmoist rales, pleural effusion and death

Pulmonary Anthrax

X-ray findings: hemorrhagic mediastinitis, but not true pneumonia; widened mediastinum

X-ray findings

Cutaneous Anthrax

Incubation period 7 days (1-12 range)Incubation period 7 days (1-12 range)1)1) Initial painlessInitial painless papule papule (head, neck, extremity)(head, neck, extremity)

• May resemble spider bite and may itchMay resemble spider bite and may itch• Surrounding erythema & edemaSurrounding erythema & edema

2)2) Vesicle or bulla Vesicle or bulla rapidlyrapidly evolvesevolves3)3) PainlessPainless hemorrhage & necrosis hemorrhage & necrosis

• Fluid becomes black Fluid becomes black • Lesion ulcerates & develops black eschar Lesion ulcerates & develops black eschar

with surrounding edemawith surrounding edema• Pearl-like satellite vesicles may occurPearl-like satellite vesicles may occur

Cutaneous Anthrax

Lesions progress from: Lesions progress from: papule - erythema - vesicle - necrosis - ulcer - escharpapule - erythema - vesicle - necrosis - ulcer - eschar

with or without antibiotic therapy with or without antibiotic therapy progression d/t progression d/t toxintoxin

Lesions may be solitary or multiple (same part of body)Lesions may be solitary or multiple (same part of body) Occasionally associated:Occasionally associated:

Tender lymphadenopathyTender lymphadenopathy FatigueFatigue Fever and/or chillsFever and/or chills

(Caruscci, (Caruscci, JAADJAAD 2001) 2001)

Cutaneous Anthrax - Painless Lesions Surrounding Surrounding edemaedema or regional or regional

lymphadenopathy may be painful.lymphadenopathy may be painful. DebridementDebridement of skin lesions of skin lesions notnot indicatedindicated

b/c risk of spreading infectionb/c risk of spreading infection

Cutaneous AnthraxCutaneous Anthrax

Cutaneous Anthrax- painless papuleCutaneous Anthrax- painless papule

Cutaneous Anthrax- vesicle with edemaCutaneous Anthrax- vesicle with edema

Cutaneous Anthrax- early necrosisCutaneous Anthrax- early necrosis

Cutaneous Anthrax- escharCutaneous Anthrax- eschar

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous AnthraxCutaneous Anthrax

Cutaneous Anthrax: Diagnosis

Notify local Health Department Notify local Health Department BeforeBefore doing diagnostic tests doing diagnostic tests

Mask Mask notnot required & required & personnel not at riskpersonnel not at risk Disease acquired through contact with Disease acquired through contact with

sporesspores, , notnot active bacteria active bacteria

Diagnosis Swab exudatesSwab exudates for Gram stain & culture (fresh vesicles) for Gram stain & culture (fresh vesicles) 4-mm punch biopsy4-mm punch biopsy full-thickness (through entire dermis) full-thickness (through entire dermis)

permanent sectionspermanent sections immunohistochemistry studies immunohistochemistry studies polymerase chain reaction (PCR)polymerase chain reaction (PCR)

A second punch biopsyA second punch biopsy for Gram stain, bacterial, fungal & for Gram stain, bacterial, fungal & atypical mycobacterial culturesatypical mycobacterial cultures

Send clinical history (& lesion picture if possible)Send clinical history (& lesion picture if possible) Negative bx does not r/o cut. anthrax b/c skin lesions Negative bx does not r/o cut. anthrax b/c skin lesions

caused by toxins caused by toxins

Diagnosis Draw 5 mL of blood in red-topped tube Draw 5 mL of blood in red-topped tube

Transfer to laboratory for isolation of serum & Transfer to laboratory for isolation of serum & subsequent storage at –70°C- label tube: subsequent storage at –70°C- label tube: “Anthrax serology. “Anthrax serology.

Store serum at –70°C for special pick-up.”Store serum at –70°C for special pick-up.” Draw 5 mL of blood into a purple-topped tubeDraw 5 mL of blood into a purple-topped tube

Refrigerate Refrigerate Hold for pick-up- PCR diagnostic tests by CDCHold for pick-up- PCR diagnostic tests by CDC

Gram Stain

Culture (24-36 hours)

Differential Diagnosis: (eschar/ulceration)

Pruritic and papular Pruritic and papular arthropod bitesarthropod bites

Brown recluse and other Brown recluse and other spider bitesspider bites

Pustular diseasesPustular diseases Antiphospholipid antibody Antiphospholipid antibody

syndrome ulcers syndrome ulcers Aspergillosis Aspergillosis Coumadin or heparin Coumadin or heparin

necrosis necrosis Ecthyma gangrenosum Ecthyma gangrenosum

Cutaneous leishmaniasis Cutaneous leishmaniasis Mucormycosis Mucormycosis Plague Plague Rickettsial pox Rickettsial pox Staphylococcal & Staphylococcal &

streptococcal ecthyma streptococcal ecthyma Tropical ulcer Tropical ulcer Tularemia Tularemia Typhus, scrub and tickTyphus, scrub and tick

Differential Diagnosis: (ulceroglandular)

Chancroid Chancroid Glanders Glanders Herpes simplexHerpes simplex Cutaneous Cutaneous

leishmaniasisleishmaniasis Lymphogranuloma Lymphogranuloma

venereum venereum MelioidosisMelioidosis

Cutaneous nocardiosisCutaneous nocardiosis Plague Plague Sporotrichosis & other Sporotrichosis & other

deep fungal diseases deep fungal diseases Staphylococcal & Staphylococcal &

streptococcal adenitis streptococcal adenitis Tuberculosis Tuberculosis TularemiaTularemia

Treatments

http://www.bt.cdc.gov/agent/anthrax/index.asp

Treatments

If suspected anthrax, begin appropriate txIf suspected anthrax, begin appropriate tx Tx regimen differs by symptomatology Tx regimen differs by symptomatology

(systemic or localized), location (extremity (systemic or localized), location (extremity vs head/neck), edema (extensive or not)vs head/neck), edema (extensive or not)

If If systemicsystemic signs, signs, headhead or or neckneck location, or location, or extensive extensive edemaedema, , IV therapyIV therapy indicated indicated

Treatment for cutaneous anthrax patients Treatment for cutaneous anthrax patients withoutwithout systemic systemic symptoms, not located on the head or neck, not with symptoms, not located on the head or neck, not with extensive edema, & not in children younger than 2 yearsextensive edema, & not in children younger than 2 years

Category Category Initial oral therapy Initial oral therapy Duration (days)Duration (days)

Adults Adults Ciprofloxacin, 500 mg bid Ciprofloxacin, 500 mg bid 6060

or doxycycline, 100 mg bidor doxycycline, 100 mg bid

Children Children Ciprofloxacin, 15 mg/kg q12h Ciprofloxacin, 15 mg/kg q12h 6060

(not to exceed 1 g/d) (not to exceed 1 g/d)

or doxycycline: >8 y o, >45 kg, or doxycycline: >8 y o, >45 kg,

100 mg q12h; all other children, 100 mg q12h; all other children,

2.2 mg/kg q12h2.2 mg/kg q12h

PregnantPregnant Ciprofloxacin, 500 mg bid (preferred)Ciprofloxacin, 500 mg bid (preferred) 6060

or doxycycline, 100 mg bidor doxycycline, 100 mg bid

Immunocomp Same Immunocomp Same 6060

Treatment of cutaneous anthrax Treatment of cutaneous anthrax withwith systemic symptoms, systemic symptoms, extensive edema, involving the head or neck, or children < extensive edema, involving the head or neck, or children < than 2 yo (same as for inhalational anthrax)than 2 yo (same as for inhalational anthrax) Category Category IV therapyIV therapy Duration (daysDuration (days)) Adults Adults Ciprofloxacin, 400 mg q12h, Ciprofloxacin, 400 mg q12h, IV initially, oralIV initially, oral

or doxycycline,100 mg q12h, or doxycycline,100 mg q12h, when stable, 60 dayswhen stable, 60 daysand 1-2 additional agentsand 1-2 additional agents

Children Ciprofloxacin, 10 mg/kg q12h Children Ciprofloxacin, 10 mg/kg q12h IV initially, oral IV initially, oral

(not to exceed 1 g/d)| or (not to exceed 1 g/d)| or when stable, 60 days when stable, 60 daysdoxycycline: >8 y old and >45 kg,doxycycline: >8 y old and >45 kg,

100 mg q12h; all other, 2.2 mg/kg100 mg q12h; all other, 2.2 mg/kg q12h and 1-2 additional agentsq12h and 1-2 additional agents

Pregnant & Same as for nonpregnant Pregnant & Same as for nonpregnant SameSame ImmunocomImmunocom and immunocompetent adultsand immunocompetent adults & children& children

Spider bites: Usually painful

Usually painfulUsually painful Bites from spiders of the Bites from spiders of the

genus genus LoxocelesLoxoceles begin as pale begin as pale ecchymotic lesions that ecchymotic lesions that rapidly turn purple.rapidly turn purple.

Lesions may ulcerate and Lesions may ulcerate and develop necrotic centers develop necrotic centers

Borders are irregularBorders are irregular, , ill-ill-defineddefined and and withoutwithout the the significant surrounding significant surrounding edemaedema..

Spider bites

Plague BoubonBoubon is Greek for groin is Greek for groin Y. Pestis, 200 million deaths in historyY. Pestis, 200 million deaths in history

http://www.emedicine.com/derm/topic905.htm#target11

Plague Gram neg non–spore-forming coccobacillus Gram neg non–spore-forming coccobacillus

http://www.emedicine.com/derm/topic905.htm#target11

Plague TenderTender, erythematous , erythematous lymphadenopathylymphadenopathy Most cases involve bubonic plagueMost cases involve bubonic plague Tx with streptomycin, gentamicin, Tx with streptomycin, gentamicin,

tetracycline & doxycycline tetracycline & doxycycline

Plague In bloodstream causes septicemia In bloodstream causes septicemia

Tularemia

6 clinical forms: 6 clinical forms: ulceroglandular, glandular, oropharyngeal or gastrointestinal, ulceroglandular, glandular, oropharyngeal or gastrointestinal,

typhoidal, septicemic, and pulmonary typhoidal, septicemic, and pulmonary

Sudden onset of:Sudden onset of: Fever, chills, headache, generalized myalgias Fever, chills, headache, generalized myalgias

and arthralgias and arthralgias Incubation 2-10 daysIncubation 2-10 days Ulcer generally seen at bite or inoculation site Ulcer generally seen at bite or inoculation site

Tularemia PainfulPainful, , pruriticpruritic, ulcer w/ , ulcer w/ RAISED RAISED bordersborders

Tularemia Ulcero-Ulcero-

glandular glandular 80%80%

Tularemia In ‘50s and ‘60s, the U.S. made biologic In ‘50s and ‘60s, the U.S. made biologic

weapons containing tularemia weapons containing tularemia Streptomycin and tetracyclines are drugs of Streptomycin and tetracyclines are drugs of

choicechoice

Meliodiosis Whitmore’s diseaseWhitmore’s disease Infectious disease caused by Infectious disease caused by

Burkholderia pseudomallei Burkholderia pseudomallei Endemic in SE Asia and Endemic in SE Asia and

northern Australianorthern Australia Common causative agent of Common causative agent of

community-acquired septicemiacommunity-acquired septicemia

(Tran, Clinical & Experimental Dermatology, 2002)

Meliodiosis

Glanders

An infectious disease caused An infectious disease caused by bacterium Burkholderia by bacterium Burkholderia mallei, also called “farcy” mallei, also called “farcy”

Primarily affects horsesPrimarily affects horses Cutaneous via cut or scratch in Cutaneous via cut or scratch in

the skin, with ulceration and the skin, with ulceration and pus 1-5 days at sitepus 1-5 days at site

No cases in U.S. > 60 yearsNo cases in U.S. > 60 years

Mustard Gas Odor/taste (mustard, Odor/taste (mustard,

garlic, onion), & color garlic, onion), & color (tan to brown to yellow)(tan to brown to yellow)

Oily liquidOily liquid is DNA is DNA alkylatingalkylating

Absorbed within minutesAbsorbed within minutes Symptoms begin 2-24 Symptoms begin 2-24

hours laterhours later SkinSkin erythemaerythema followed followed

by by vesiclesvesicles

Mustard Gas

Mustard Gas EyesEyes develop conjunctivitis develop conjunctivitis PulmonaryPulmonary symptoms- hoarseness symptoms- hoarseness Death rate during World War I: 3%Death rate during World War I: 3% Decontaminate w/ 0.5% hypochlorite Decontaminate w/ 0.5% hypochlorite (1/10 bleach to water)(1/10 bleach to water)

Smallpox Classic generalized exanthemClassic generalized exanthem Latin word for “spotted” referring to raised Latin word for “spotted” referring to raised

bumps on the face and bodybumps on the face and body

http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp

Smallpox Rash, high fever & mortality rate 30%Rash, high fever & mortality rate 30% Last natural case Somalia in 1977Last natural case Somalia in 1977

Smallpox (Days 3, 5, 7)

Smallpox

Exanthem from Exanthem from vaccinationvaccination 1/100,0001/100,000

Vaccinia rash or Vaccinia rash or outbreak of soresoutbreak of sores

Generalized Generalized vacciniavaccinia

Erythema Erythema multiformemultiforme

http://www.bt.cdc.gov/agent/smallpox/

Smallpox Exanthem from Exanthem from

vaccinationvaccination 1/100,0001/100,000

Vaccinia rash or Vaccinia rash or outbreak of outbreak of soressores

Generalized Generalized vacciniavaccinia

Erythema Erythema multiformemultiforme

Smallpox

Exanthem from Exanthem from vaccinationvaccination 1/100,0001/100,000

Vaccinia rash or Vaccinia rash or outbreak of soresoutbreak of sores

Generalized Generalized vacciniavaccinia

Erythema Erythema multiformemultiforme

Smallpox

From From VaccinationVaccination 1/50,0001/50,000

Eczema Eczema vaccinatumvaccinatum

Progressive Progressive vacciniavaccinia

Postvaccinal Postvaccinal encephalitisencephalitis

Smallpox

From From VaccinationVaccination 1/50,0001/50,000

Eczema Eczema vaccinatumvaccinatum

Progressive Progressive vacciniavaccinia

Postvaccine Postvaccine encephalitisencephalitis

Monkeypox Virus

Monkeypox Virus

References Carucci JA, McGovern TW, Norton AS. Cutaneous anthrax management Carucci JA, McGovern TW, Norton AS. Cutaneous anthrax management

algorithm. J Am Acad Dermatol 2001; online at: algorithm. J Am Acad Dermatol 2001; online at: http://www.eblue.org/scripts/om.dll/serve?http://www.eblue.org/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=fullfree&id=a121613action=searchDB&searchDBfor=art&artType=fullfree&id=a121613

Update: Investigation of bioterrorism-related anthrax and interim guidelines Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001;50:909-19. Morb Mortal Wkly Rep 2001;50:909-19. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm

Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999;341:815-26. http://content.nejm.org/cgi/content/fall/341/11/8151999;341:815-26. http://content.nejm.org/cgi/content/fall/341/11/815

Inglesby TV, Henderson DA, Bartlett JT, Ascher MS, Eitzen E, Friedlander Inglesby TV, Henderson DA, Bartlett JT, Ascher MS, Eitzen E, Friedlander AM, et al. Anthrax as a biological weapon: medical and public health AM, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999;281:1735-management. Working Group on Civilian Biodefense. JAMA 1999;281:1735-45. http://jama.amaassn.org/issues/v281n18/ffull/jst80027.html45. http://jama.amaassn.org/issues/v281n18/ffull/jst80027.html

Thank you.