Bioterrorism: A Medical Professional’s Perspective

1. Bioterrorism: A Medical Professional’s Perspective Chris Nelson, M.D. Assistant Professor of Pediatrics University of Kentucky

2. Overview • Biological Terrorism Basics • Agents of Biological Terror: Anthrax, Smallpox, Plague, Tularemia, Botulism • Practical Guide to Biological Terrorism Information Sources for the Medical Professional

3. Bioterrorism Basics Definition:The unlawful use, or threatened use, of microorganisms or toxins derived from living organisms to produce death or disease in humans, animals, or plants. The act is intended to create fear and/or intimidate governments or societies in pursuit of political, religious, or idealogical goals.

4. The World’s Most Wanted Terrorists

5. Bioterrorism Basics Terrorist Havens: Iraq, Iran, Libya, Syria, Sudan, Cuba, North Korea Also: Afghanistan, Somalia, Phillipines, Pakistan Terrorist Organizations: Al-Qaida (Afghanistan), Democratic Front for the Liberation of Palestine (DFLP), Palestinian Islamic Jihad, Hamas (Gaza Strip, Palestine), Hezbollah (Iran), Mujahedeen Khalq (Iran), Abu Nidal Organization Domestic Threats: Anti-Abortion activists, Religious Cults, Anti-Government Militia Groups, Racist Hate Groups, Individuals

6. Bioterrorism Basics What makes the use of biological agents so attractive to the terrorist? • Ease of Acquisition • Information readily accessible on World Wide Web • American Type Culture Collection, other sources • Ease and Economy of Production • Only basic microbiology equipment necessary • Small labs require no special licensing • Investment to cause 50% casualty rate per sq. km: Conventional weapon $2000, nuclear $800, anthrax $1 • Lethality • 50 kg aerosolized anthrax = 100,000 mortality • Sverdlovsk experience, former USSR

7. Bioterrorism Basics What makes the use of biological agents so attractive to the terrorist? • Stability • Infectivity/Contagion • Weaponized agents may be easily spread • Clinical symptoms days to weeks after release • Low Visibility • Ease and Stealth of Delivery • Remote, delayed, undetectable release • Difficult/impossible to trace origin of agent

8. Bioterrorism Basics Routes of Delivery for Biological Agents Aerosol is most likely method of dissemination Easy, silent dispersal Maximum number of victims exposed Inhalation is most efficient and contagious route of infection Food/Water-borne dispersal less likely Less stable, ineffective for some agents Inefficient compared to aerosol

9. Bioterrorism Basics Events Suggesting the Release of a Bioweapon • Multiple people ill at the same time (epidemic) • Previously healthy persons affected • High morbidity and mortality among affected individuals • Identification of diseases and pathogens unusual to a particular region • Recent terrorist claims or activity • Unexplained epizootic of sick or dead animals

10. Bioterrorism Basics What Can We Do As Medical Professionals? • Maintain a high index of suspicion by including biological agents in differential diagnoses • Learn to recognize historical and physical examination findings suggestive of bioweapon exposure • Stay informed of local, regional and national epidemiologic trends • Be knowledgeable about treatment and prophylaxis of patients exposed to biological agents • Know whom to report suspected biological agent exposures and illnesses to (Police, FBI, Infectious Disease Specialists, Local and State Health Officials)

11. Agents of Bioterrorism Bacterial Agents Bacillus anthracis (Anthrax) Yersinia pestis (Plague) Francisella tularensis (Tularemia) Brucella spp. (Brucellosis) Coxiella burnetii (Q Fever) Burkholderia mallei (Glanders) Vibrio cholerae (Cholera)

12. Agents of Bioterrorism Viral Agents Variola virus (Smallpox) Venezuelan Equine Encephalitis Virus (VEE) Hemorrhagic Fever Viruses: Ebola, Marburg, Lassa Fever, Argentine and Bolivian Hemorrhagic Fever Viruses, Hantavirus, Congo-Crimean Virus, Rift Valley Fever Virus, Yellow Fever Virus, Dengue Virus

13. Agents of Bioterrorism Biological Toxins Botulinum Toxins Staphylococcal Enterotoxin B Ricin Mycotoxins (T2)

14. Anthrax • Caused by contact with spores of Bacillus anthracis, a spore-forming, gram-positive rod • Three distinct forms of clinical illness: • Cutaneous by inoculation of skin lesions with spores; common, easily recognized and treated • Inhalational by inhalation of spores into the lower respiratory tract; rare, difficult to recognize, > 80% mortality (classic description = Woolsorter’s disease) • Gastrointestinal by ingestion of spores in contaminated meat; rarely encountered but highly lethal

16. Cutaneous Anthrax • 95% of all cases of anthrax in U.S. • A nondescript, painless, pruritic papule develops 3 to 5 days after introduction of B. anthracis endospores • In 24 to 36 hours, the lesion forms a vesicle that undergoes central necrosis and drying, leaving a characteristic black eschar surrounded by edema and a number of purplish vesicles: resolves without scarring • 80-90% resolve without treatment, but mortality can approach 20%, so cases usually treated

17. Cutaneous Anthrax

18. Cutaneous Anthrax

19. Cutaneous Anthrax

20. Cutaneous Anthrax

21. Inhalational Anthrax Pathogenesis • 1-5 micron Anthrax spore size is optimal for deposition into alveoli • Inhaled spores are ingested by alveolar macrophages and transported to mediastinal and peribronchial lymph nodes, spores germinating en route • Anthrax bacilli multiply in lymph nodes, causing hemorrhagic mediastinitis, and spread throughout the body in the blood

22. Inhalational Anthrax Clinical Presentation • 10 days to 6 weeks after inhalation of spores, infected patients develop fever, non-productive cough, myalgia and malaise • Early in the course of the disease, chest radiographs show a widened mediastinum, which is evidence of hemorrhagic mediastinitis, and marked pleural effusions • After 1-3 days, the disease takes a fulminant course with dyspnea, strident cough, and chills, culminating in hypotension, shock, and death

23. Inhalational Anthrax

24. Inhalational Anthrax

26. Gastrointestinal Anthrax • Not reported in the U.S. • Fever and diffuse abdominal pain with rebound tenderness develop 2-5 days after ingestion of spores in contaminated meat • Melenic or blood-tinged stools, blood-tinged or coffee-ground emesis, and ascites develop • Death results from fluid and electrolyte imbalances, blood loss, shock, intestinal perforation or anthrax toxemia

27. Anthrax Meningitis • Hemorrhagic meningitis is a potential complication of anthrax, and may accompany cutaneous, gastrointestinal, or inhalational anthrax (seen in 50% of inhalational cases) • Death almost universal within 1-6 days after onset of illness • Rare survivors have been treated using appropriate antibiotics in combination with antitoxin, prednisone or both

29. Diagnosis of Anthrax For people with suspected anthrax disease, laboratory testing is essential to diagnosis. Tests may include: • Cultures of blood and spinal fluid (should be done before antibiotic treatment has been initiated) • Cultures of tissue or fluids from affected areas • Microscopic examination of tissue • PCR (polymerase chain reaction) test that amplifies trace amounts of DNA to document that the anthrax bacteria is present

30. Treatment of Anthrax Initial Therapy (Intravenous): Ciprofloxacin 10-15 mg/kg every 12 hours OR Doxycycline >8 yrs. and >45 kg: 100 mg every 12 hrs. >8 yrs. and <45 kg: 2.2 mg/kg every 12 hrs. <8 years: 2.2 mg/kg every 12 hrs. AND One or two of the following: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, clarithromycin Subsequent Therapy (Oral)*: Ciprofloxacin 10-15 mg/kg every 12 hours OR Doxycycline >8 yrs. and >45 kg: 100 mg every 12 hrs. >8 yrs. and <45 kg: 2.2 mg/kg every 12 hrs. <8 years: 2.2 mg/kg every 12 hrs. *Oral therapy may be substituted for IV when clinical improvement is seen. Continued for 60 days total therapy (IV plus PO) MMWR October 26, 2001 / 50(42);909-919

31. Smallpox • Worst-case scenario biological agent • Highly contagious once rash present (not before) • World’s population is largely susceptible • Up to 30% case fatality rate in non-immune • Secondary attack rate of 25-40% (10-20 secondary cases can be expected per index case) • No specific treatment available • Very few physicians currently practicing have seen actual cases • Virus has been weaponized by Soviets, uncertain who exactly owns viable stocks

32. Smallpox • Caused by Variola virus (Orthopox virus) • Immunization of U.S. civilian population suspended in 1980, U.S. military recruits in 1989 • Virus is stable in environment • Spread primarily by respiratory droplets, also by contact, fomites • Two distinct types of smallpox: • Variola Minor (Alastrim): diminutive lesions and mild systemic toxicity • Variola Major: Ordinary (subtypes discrete, semi-confluent, confluent), Modified, Flat, Hemorrhagic

33. Smallpox Clinical Presentation • 7-17 day incubation period • Prodromal phase: 2-4 days of malaise, fever, rigors, headache, backache, delirium • Rash then develops on face, hands, forearms and legs, including palms and soles (centrifugal distribution is important distinguishing feature). • Initial rash is maculopapular. In 1-2 days, lesions become vesicular, then evolve into round, tense pustules deeply imbedded in the dermis. Crusts form on 8th to 9th day of rash • Crusts separate to form depressed, hypopigmented scars

34. Smallpox

35. Smallpox

36. Diagnosis of Smallpox • Recognition of clinical features in early index cases is key • Identification of a single case of smallpox constitutes an international medical emergency, and should be considered evidence of a bioterrorist attack • Confirmation of diagnosis is made by demonstration of characteristic virions on electron microscopy of vesicular scrapings

37. Management of Smallpox • Immediate quarantine of affected and exposed individuals for 17 days • Only supportive care is available. Cidofovir has demonstrated in vitro activity • Immediate vaccination of all exposed persons with Vaccinia virus vaccine by inoculation with a bifurcated needle (scarification) • Administration of Vaccinia Immune Globulin (VIG), 0.6 ml/kg intramuscularly, concomitant with vaccination • Active and passive immunization is effective at preventing disease and death if given within 7 days of exposure

38. Plague • Caused by Yersinia pestis • Natural infection is spread by fleas, but viable bioweapon would likely be small particle aerosol • Several forms of disease: • Bubonic, transmitted by fleas • Septicemic, beginning with GI symptoms, then DIC, ARDS, Shock, Meningitis • Pneumonic, following respiratory exposure • After aerosolized dissemination, an incubation period of 1-6 days would be followed by onset of fever, cough, chest pain, hemoptysis and severe pneumonia • Rapid progression in 2-4 days to septic shock with high mortality if not recognized and treated early • Pneumonic form is transmissible from person-to-person, potentially resulting in secondary infection

39. Plague

40. Plague

41. Plague

42. Plague

43. Plague • Diagnosis • clinical suspicion • direct fluorescent antibody, or culture of respiratory specimens, cervical bubo aspirates, or tissue • Blood cultures • Treatment/ Post-Exposure Prophylaxis • Gentamicin 2.5 mg/kg IM or IV three times daily for 10 days • Streptomycin 15 mg/kg IM twice daily for 10 days (max. 2g/day) • Alternative Agents • Ciprofloxacin 10-15 mg/kg every 12 hours • Doxycycline >8 yrs. and >45 kg: 100 mg every 12 hrs. >8 yrs. and <45 kg: 2.2 mg/kg every 12 hrs. <8 years: 2.2 mg/kg every 12 hrs. • Chloramphenicol 25 mg/kg IV 4 times daily

44. Tularemia • Caused by Francisela tularensis • Organism readily aerosolized, highly contagious • Several forms of disease: • Glandular, Ulceroglandular, Oculoglandular • Pulmonary • Typhoidal • Gastrointestinal • Mortality 35% in untreated individuals • Incubation period of 2-10 days is followed by onset of fever, headache, myalgias, weight loss, fatigue • Pulmonary form: chest pain, non-productive cough, pneumonia with pleural effusions • Typhoidal: meningitis, hepatitis, endocarditis, osteomyelitis, septic shock possible

45. Tularemia

46. Tularemia • Diagnosis • clinical suspicion • direct fluorescent antibody, immunohistochemical staining, culture of respiratory specimens or tissue • rarely isolated from blood; notify lab personnel in all cases • Treatment • Gentamicin 2.5 mg/kg IM or IV three times daily for 10 days • Streptomycin 15 mg/kg IM twice daily for 10 days (max. 2g/day) • Post-Exposure Prophylaxis • Ciprofloxacin 10-15 mg/kg every 12 hours • Doxycycline >8 yrs. and >45 kg: 100 mg every 12 hrs. >8 yrs. and <45 kg: 2.2 mg/kg every 12 hrs. <8 years: 2.2 mg/kg every 12 hrs.

47. Botulinum Toxin • Seven antigenically distinct exotoxins are produced by Clostridium botulinum (Types A-G) • Botulinum toxin is one of the most toxic substances known • Interrupts impulse transmission at the neuromuscular junction by binding to pre-synaptic nerve endings, blocking acetylcholine release • Inhalation route is expected target of bioterrorist attack, food-borne less likely

48. Botulinum Toxin • Following inhalation of botulinum toxin, symptoms would develop within 24 hours to several days (depending on dose), including: • Early: Cranial nerve dysfunction: blurred vision, diplopia, photophobia, dysarthria, dysphonia, dysphagia,Then • Late: Symmetric, descending flaccid paralysis of skeletal muscles • Clinical Examination: alert, awake, oriented, without fever or sensory findings, disconjugate gaze, pupillary dilatation, ptosis, absent gag reflex, orthostatic hypotension, constipation, and urinary retention • Failure of respiratory muscles, requiring ventilatory support (very low mortality if recognized, treated promptly)

49. Plague

50. Botulinum Toxin • Diagnosis • clinical suspicion • Mouse bioassay (fecal and gastric specimens) • Serologic testing (CDC and 20 State and Public Health Laboratories across U.S.) • Electromyogram/Nerve conduction study • Edrophonium chloride (Tensilon) • Treatment • Supportive Care • Equine botulinum antitoxin • Licensed trivalent antitoxin (toxin types A,B, and E) 10 ml vial diluted 1:10 in 0.9% saline, administered by slow IV infusion • Investigational heptavalent antitoxin (ABCDEFG) held by U.S. Army • Pentavalent (ABCDE) toxoid vaccine for lab personnel and military personnel only