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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
[email protected]@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.