1. Cutaneous Signs of Bioterror Agents Adam Goldstein, MD, MPH Associate Professor UNC Department of Family Medicine Chapel Hill, NC aog@med.unc.edu

2. Objectives Improve ability to: Improve ability to:  diagnose and manage cutaneous illness associated with suspected cases of bioterror  Anthrax, plague, tularemia, smallpox, mustard gas

4. Why worry? “Subnational attacks using genetically engineered organisms are inevitable” “Subnational attacks using genetically engineered organisms are inevitable” “Biologic agents now join nuclear agents” “Biologic agents now join nuclear agents” Deaths Deaths  1 KT H-BOMB.6M – 2M  100 Kg ATX 1M – 3M (Stansfield Turner, CIA, 2001)

5. Anthrax Anthrakos = ‘coal’ b/c of black eschar Anthrakos = ‘coal’ b/c of black eschar B. anthracis is gram-positive sporulating bacillus B. anthracis is gram-positive sporulating bacillus Spores are resistant to heat, cold, drying, & chemical disinfection Spores are resistant to heat, cold, drying, & chemical disinfection Anthrax is endemic in western Asia (Iran Turkey Afghanistan,) & western Africa Anthrax is endemic in western Asia (Iran Turkey Afghanistan,) & western Africa (McGovern, Elect Text Dermatol, 1999)

7. Anthrax Spores viable for years top 6 cm of soil & in animal products Spores viable for years top 6 cm of soil & in animal products Disease transmitted from infected animals or products via skin abrasions > 90% of cases Disease transmitted from infected animals or products via skin abrasions > 90% of cases Goats > sheep > cattle > horses > pigs > dogs Goats > sheep > cattle > horses > pigs > dogs

8. Anthrax Burn dead animals, not buried, to prevent long-term environmental contamination Burn dead animals, not buried, to prevent long-term environmental contamination

9. History of Anthrax 1500 B.C. -- Fifth/sixth Egyptian plagues, ? Anthrax 1500 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 anthrax on way to Europe during WW I 1915 -- German agents in U.S. inject horses/cattle with anthrax on way to Europe during WW I 1937 -- Japan starts biological warfare program 1937 -- 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 sheep 1945 -- Anthrax outbreak in Iran kills 1 million sheep

10. Historical 1950s and '60s -- U.S. biological program continues 1950s 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. FDA 1970 -- Anthrax vaccine approved by U.S. FDA 1972 -- International convention outlaws development or stockpiling of biological weapons 1972 -- International convention outlaws development or stockpiling of biological weapons 1978-80 -- Human anthrax epidemic strikes Zimbabwe, infecting > 6,000 and killing 100 1978-80 -- Human anthrax epidemic strikes Zimbabwe, infecting > 6,000 and killing 100 1979 -- Aerosolized anthrax spores released at Soviet military facility, killing 68 1979 -- Aerosolized anthrax spores released at Soviet military facility, killing 68 1991 -- U.S. troops vaccinated for Gulf War I 1991 -- U.S. troops vaccinated for Gulf War I 1990-93 -- Terrorists release anthrax in Tokyo; no injuries 1990-93 -- Terrorists release anthrax in Tokyo; no injuries

11. Historical 1995 -- Iraq produced concentrated anthrax in biological weapons program 1995 -- Iraq produced concentrated anthrax in biological weapons program 1998 -- U.S. approves anthrax vaccinations for all military 1998 -- U.S. approves anthrax vaccinations for all military 2001 -- Letter with anthrax spores mailed to NBC one week after 9/11 terrorist attacks on Pentagon & WTC. Several die after inhaling. 2001 -- Letter with anthrax spores mailed to NBC one week after 9/11 terrorist attacks on Pentagon & WTC. Several die after inhaling.

12. Anthrax pilot plant used to produce billions of anthrax spores at Fort Detrick, Md. U.S. ended offensive biological weapons research in 1969

13. Al Hakam, Iraq's major facility for production of biological agents. Plant destroyed by Iraqi workers in 1996.

14. Forms of Anthrax

15. Pulmonary Anthrax Wool-sorter’s disease Wool-sorter’s disease 18 cases reported in U.S. 1900-1980 18 cases reported in U.S. 1900-1980 Symptoms: vague prodrome with fever, malaise, myalgias and cough Symptoms: vague prodrome with fever, malaise, myalgias and cough Within days- rapidly developing precordial discomfort, cyanosis, stridor, diaphoresis, moist rales, pleural effusion and death Within days- rapidly developing precordial discomfort, cyanosis, stridor, diaphoresis, moist rales, pleural effusion and death

16. Pulmonary Anthrax

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

18. X-ray findings

19. Cutaneous Anthrax Incubation period 7 days (1-12 range) 1)Initial painless papule (head, neck, extremity) May resemble spider bite and may itchMay resemble spider bite and may itch Surrounding erythema & edemaSurrounding erythema & edema 2)Vesicle or bulla rapidly evolves 3)Painless hemorrhage & necrosis Fluid becomes blackFluid becomes black Lesion ulcerates & develops black eschar with surrounding edemaLesion ulcerates & develops black eschar with surrounding edema Pearl-like satellite vesicles may occurPearl-like satellite vesicles may occur

20. Cutaneous Anthrax Lesions progress from: Lesions progress from:  papule - erythema - vesicle - necrosis - ulcer - eschar  with or without antibiotic therapy  progression d/t toxin 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 lymphadenopathy  Fatigue  Fever and/or chills (Caruscci, JAAD 2001)

21. Cutaneous Anthrax - Painless Lesions Surrounding edema or regional lymphadenopathy may be painful. Surrounding edema or regional lymphadenopathy may be painful. Debridement of skin lesions not indicated b/c risk of spreading infection Debridement of skin lesions not indicated b/c risk of spreading infection

22. Cutaneous Anthrax

23. Cutaneous Anthrax- painless papule

24. Cutaneous Anthrax- vesicle with edema

25. Cutaneous Anthrax- early necrosis

26. Cutaneous Anthrax- eschar

27. Cutaneous Anthrax

35. Cutaneous Anthrax: Diagnosis Notify local Health Department Notify local Health Department  Before doing diagnostic tests Mask not required & personnel not at risk Mask not required & personnel not at risk  Disease acquired through contact with spores, not active bacteria

36. Diagnosis Swab exudates for Gram stain & culture (fresh vesicles) Swab exudates for Gram stain & culture (fresh vesicles) 4-mm punch biopsy full-thickness (through entire dermis) 4-mm punch biopsy full-thickness (through entire dermis)  permanent sections  immunohistochemistry studies  polymerase chain reaction (PCR) A second punch biopsy for Gram stain, bacterial, fungal & atypical mycobacterial cultures A second punch biopsy for Gram stain, bacterial, fungal & atypical 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 caused by toxins Negative bx does not r/o cut. anthrax b/c skin lesions caused by toxins

37. 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 & subsequent storage at –70°C- label tube: “Anthrax serology.  Store serum at –70°C for special pick-up.” Draw 5 mL of blood into a purple-topped tube Draw 5 mL of blood into a purple-topped tube  Refrigerate  Hold for pick-up- PCR diagnostic tests by CDC

38. Gram Stain

39. Culture (24-36 hours)

40. Differential Diagnosis: (eschar/ulceration) Pruritic and papular arthropod bites Pruritic and papular arthropod bites Brown recluse and other spider bites Brown recluse and other spider bites Pustular diseases Pustular diseases Antiphospholipid antibody syndrome ulcers Antiphospholipid antibody syndrome ulcers Aspergillosis Aspergillosis Coumadin or heparin necrosis Coumadin or heparin necrosis Ecthyma gangrenosum Ecthyma gangrenosum Cutaneous leishmaniasis Mucormycosis Plague Rickettsial pox Staphylococcal & streptococcal ecthyma Tropical ulcer Tularemia Typhus, scrub and tick

41. Differential Diagnosis: (ulceroglandular) Chancroid Chancroid Glanders Glanders Herpes simplex Herpes simplex Cutaneous leishmaniasis Cutaneous leishmaniasis Lymphogranuloma venereum Lymphogranuloma venereum Melioidosis Melioidosis Cutaneous nocardiosis Plague Sporotrichosis & other deep fungal diseases Staphylococcal & streptococcal adenitis Tuberculosis Tularemia

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

43. Treatments If suspected anthrax, begin appropriate tx If suspected anthrax, begin appropriate tx Tx regimen differs by symptomatology (systemic or localized), location (extremity vs head/neck), edema (extensive or not) Tx regimen differs by symptomatology (systemic or localized), location (extremity vs head/neck), edema (extensive or not) If systemic signs, head or neck location, or extensive edema, IV therapy indicated If systemic signs, head or neck location, or extensive edema, IV therapy indicated

44. Treatment for cutaneous anthrax patients without systemic symptoms, not located on the head or neck, not with extensive edema, & not in children younger than 2 years Category Initial oral therapy Duration (days) Category Initial oral therapy Duration (days) Adults Ciprofloxacin, 500 mg bid 60 Adults Ciprofloxacin, 500 mg bid 60 or doxycycline, 100 mg bid or doxycycline, 100 mg bid Children Ciprofloxacin, 15 mg/kg q12h 60 Children Ciprofloxacin, 15 mg/kg q12h 60 (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 q12h PregnantCiprofloxacin, 500 mg bid (preferred)60 PregnantCiprofloxacin, 500 mg bid (preferred)60 or doxycycline, 100 mg bid Immunocomp Same 60 Immunocomp Same 60

45. Treatment of cutaneous anthrax with systemic symptoms, extensive edema, involving the head or neck, or children < than 2 yo (same as for inhalational anthrax) Category IV therapyDuration (days) Category IV therapyDuration (days) Adults Ciprofloxacin, 400 mg q12h, IV initially, oral Adults Ciprofloxacin, 400 mg q12h, IV initially, oral or doxycycline,100 mg q12h, when stable, 60 days and 1-2 additional agents Children Ciprofloxacin, 10 mg/kg q12h IV initially, oral (not to exceed 1 g/d)| or when stable, 60 days doxycycline: >8 y old and >45 kg, 100 mg q12h; all other, 2.2 mg/kg 100 mg q12h; all other, 2.2 mg/kg q12h and 1-2 additional agents q12h and 1-2 additional agents Pregnant & Same as for nonpregnant Same Pregnant & Same as for nonpregnant Same Immunocomand immunocompetent adults Immunocomand immunocompetent adults & children & children

47. Spider bites: Usually painful Usually painful Usually painful Bites from spiders of the genus Loxoceles begin as pale ecchymotic lesions that rapidly turn purple. Bites from spiders of the genus Loxoceles begin as pale ecchymotic lesions that rapidly turn purple. Lesions may ulcerate and develop necrotic centers Lesions may ulcerate and develop necrotic centers Borders are irregular, ill- defined and without the significant surrounding edema. Borders are irregular, ill- defined and without the significant surrounding edema.

48. Spider bites

52. Plague Boubon is Greek for groin Boubon is Greek for groin Y. Pestis, 200 million deaths in history Y. Pestis, 200 million deaths in history http://www.emedicine.com/derm/topic905.htm#target11

53. Plague Gram neg non–spore-forming coccobacillus Gram neg non–spore-forming coccobacillus http://www.emedicine.com/derm/topic905.htm#target11

54. Plague Tender, erythematous lymphadenopathy Tender, erythematous lymphadenopathy Most cases involve bubonic plague Most cases involve bubonic plague Tx with streptomycin, gentamicin, tetracycline & doxycycline Tx with streptomycin, gentamicin, tetracycline & doxycycline

55. Plague In bloodstream causes septicemia In bloodstream causes septicemia

56. Tularemia 6 clinical forms: 6 clinical forms:  ulceroglandular, glandular, oropharyngeal or gastrointestinal, typhoidal, septicemic, and pulmonary Sudden onset of: Sudden onset of:  Fever, chills, headache, generalized myalgias and arthralgias  Incubation 2-10 days  Ulcer generally seen at bite or inoculation site

57. Tularemia Painful, pruritic, ulcer w/ RAISED borders Painful, pruritic, ulcer w/ RAISED borders

58. Tularemia Ulcero- glandular 80% Ulcero- glandular 80%

59. Tularemia In ‘50s and ‘60s, the U.S. made biologic weapons containing tularemia In ‘50s and ‘60s, the U.S. made biologic weapons containing tularemia Streptomycin and tetracyclines are drugs of choice Streptomycin and tetracyclines are drugs of choice

60. Meliodiosis Whitmore’s disease Whitmore’s disease Infectious disease caused by Burkholderia pseudomallei Infectious disease caused by Burkholderia pseudomallei Endemic in SE Asia and northern Australia Endemic in SE Asia and northern Australia Common causative agent of community-acquired septicemia Common causative agent of community-acquired septicemia (Tran, Clinical & Experimental Dermatology, 2002)

61. Meliodiosis

62. Glanders An infectious disease caused by bacterium Burkholderia mallei, also called “farcy” An infectious disease caused by bacterium Burkholderia mallei, also called “farcy” Primarily affects horses Primarily affects horses Cutaneous via cut or scratch in the skin, with ulceration and pus 1-5 days at site Cutaneous via cut or scratch in the skin, with ulceration and pus 1-5 days at site No cases in U.S. > 60 years No cases in U.S. > 60 years

63. Mustard Gas Odor/taste (mustard, garlic, onion), & color (tan to brown to yellow) Odor/taste (mustard, garlic, onion), & color (tan to brown to yellow) Oily liquid is DNA alkylating Oily liquid is DNA alkylating Absorbed within minutes Absorbed within minutes Symptoms begin 2-24 hours later Symptoms begin 2-24 hours later Skin erythema followed by vesicles Skin erythema followed by vesicles

64. Mustard Gas

65. Eyes develop conjunctivitis Eyes develop conjunctivitis Pulmonary symptoms- hoarseness Pulmonary symptoms- hoarseness Death rate during World War I: 3% Death rate during World War I: 3% Decontaminate w/ 0.5% hypochlorite (1/10 bleach to water) Decontaminate w/ 0.5% hypochlorite (1/10 bleach to water)

66. Smallpox Classic generalized exanthem Classic generalized exanthem Latin word for “spotted” referring to raised bumps on the face and body Latin word for “spotted” referring to raised bumps on the face and body http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp

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

68. Smallpox (Days 3, 5, 7)

69. Smallpox Exanthem from vaccination Exanthem from vaccination  1/100,000  Vaccinia rash or outbreak of sores  Generalized vaccinia  Erythema multiforme http://www.bt.cdc.gov/agent/smallpox /

70. Smallpox Exanthem from vaccination Exanthem from vaccination  1/100,000  Vaccinia rash or outbreak of sores  Generalized vaccinia  Erythema multiforme

71. Smallpox Exanthem from vaccination Exanthem from vaccination  1/100,000  Vaccinia rash or outbreak of sores  Generalized vaccinia  Erythema multiforme

72. Smallpox From Vaccination From Vaccination  1/50,000  Eczema vaccinatum  Progressive vaccinia  Postvaccinal encephalitis

73. Smallpox From Vaccination From Vaccination  1/50,000  Eczema vaccinatum  Progressive vaccinia  Postvaccine encephalitis

74. Monkeypox Virus

80. References Carucci JA, McGovern TW, Norton AS. Cutaneous anthrax management algorithm. J Am Acad Dermatol 2001; online at: http://www.eblue.org/scripts/om.dll/serve?action=searchDB&searchD Bfor=art&artType=fullfree&id=a121613 Carucci JA, McGovern TW, Norton AS. Cutaneous anthrax management algorithm. J Am Acad Dermatol 2001; online at: http://www.eblue.org/scripts/om.dll/serve?action=searchDB&searchD Bfor=art&artType=fullfree&id=a121613 Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001;50:909-19. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep 2001;50:909-19. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999;341:815-26. http://content.nejm.org/cgi/content/fall/341/11/815 Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N Engl J Med 1999;341:815-26. http://content.nejm.org/cgi/content/fall/341/11/815 Inglesby TV, Henderson DA, Bartlett JT, Ascher MS, Eitzen E, Friedlander AM, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999;281:1735-45. http://jama.amaassn.org/issues/v281n18/ffull/jst80027.html Inglesby TV, Henderson DA, Bartlett JT, Ascher MS, Eitzen E, Friedlander AM, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999;281:1735-45. http://jama.amaassn.org/issues/v281n18/ffull/jst80027.html

81. Thank you.