Response of the academic medical center to the threat of bioterrorism?

1. Response of the academic medical center to the threat of bioterrorism? Short term? Long term?

2. Overview • Definition of the biological threat • How should the academic med ctr response differ? • Selected pathogens - Anthrax and Smallpox • Integration of short-term and long-term responses

3. Definition of the Biological Threat • Man-made bioterrorism - e.g., current events • Evolutionary biological threats - e.g., HIV-TB copathogenesis, global influenza pandemics • Man-made BT is “new” and more frightening • Evolutionary biological threats may be more devastating in the long run • Message - Strategies should address both!

4. How Should the Academic Med Ctr Response Differ? Common to All Med Ctrs Hospital / Clinic response Lab diagnosis Distribution of therapeutics Patient care Responsibility of Academic Med Ctrs Education Research

5. Ability of Hospitals to Respond? “The 1999-2000 flu season stymied US hospitals in ways that parallel 1918.” • “The disruption was the result . . . of a health care system unable to cope with a nominal upswing in demand. Hospitals have had to employ strategies (e.g., fewer staffed acute beds) to assure survival in a harsh fiscal climate. . . leaving the country ill-prepared to deal with a mass casualty scenario.” • Clin Inf Dis 31:1409, 2000

6. Perspective1918-1919 Influenza Pandemic(U.S. census - 103 million) • Globally • 1 billion sick • 20-40 million deaths • U.S. • 28% of U.S. population infected • 500,000 more deaths annually than during an average year (1.3 million using today’s census)

7. Biological Terrorism: Agents • Category A: Easily disseminated or transmitted, high mortality, social disruption, special preparation needed • Smallpox Botulism • Anthrax Tularemia • Plague Viral Hemorrhagic Fever • http://www.bt.cdc.gov/Agent/Agentlist

8. Category B: Moderately easy to disseminate, moderate morbidity and low mortality Q Fever Brucellosis Viral encephalitides Staphylococcal enterotoxin B Food/Waterborne (e.g. Salmonella) Biological Terrorism: Agents

9. Biological Terrorism: Agents • Category C: Emerging pathogens that could be engineered for mass dissemination in the future • Nipah virus • Hantavirus • Tickborne hemorrhagic fever • Yellow fever • Multidrug-resistant tuberculosis

10. We overestimate our ability to predict bioterror risks • “No casualty producing terrorist use of anthrax has occurred, and the FBI has ‘no intelligence that state sponsors of terrorism, international terrorist groups, or domestic terrorist groups are currently planning to use these deadly weapons in the U.S.’ ” • Medical Progress: Anthrax NEJM 341:815, 1999

11. Anthrax Overview • Greek - anthrakis = coal • Primarily disease of herbivores • Natural transmission to humans by contact with infected animals or animal products • Diseases (20-100,000 cases globally/yr) • Cutaneous - 95% (“woolsorter’s”) • Inhalational - 5% • Gastrointestinal - rare • Human LD50 - 2,500 - 55,000 inhaled spores (estimates from primate studies) • Microbiology - Gram+rod, nonmotile, nonhemolytic CDC: Gram stain of B. anthracis

12. Anthrax: Risk / Cost Assessment • 1. World Health Organization • 50 kg - 5 million population - 250,000 deaths • 2. Congressional Office of Technology • 100 kg - Washington, D.C. - 130,000-3 million deaths • 3. CDC Economic Burden Model • $26.2 billion cost / 100,000 people exposed

13. Lessons from the Soviet Union Sverdlosk • Anthrax spores released from military microbiology facility in 1979 (Official explanation - “contaminated meat”) • 79 cases - 68 deaths • Incubation period - 2 - 43 days • Latest onset of skin disease - 12 days after release • Latest onset of inhalational disease - 43 days after release • Mean time from onset to death - 3 days (range 1-10) • Unknown if the B. anthracis strain was drug-resistant

14. Modal time to dx = 10 days Reduced death rate with late onset Sverdlosk - A Common Source Outbreak

15. B. anthracis Anthrax - Pathogenesis pXO2 PA-small frag capsule PA cellular protease pXO1 3 toxins Macrophage LF Protective Ag (PA) PA-large fragment “receptor” Edema Factor (EF) Lethal Factor (LF) EF • Reactive oxygen species • Cytokines (TNF alpha, IL-1beta) • Decreased neutrophil function • Edema Shock Death

16. Cutaneous Anthrax macule -- papule -- vesicle -- ulcer (depressed, black, painless) -- eschar surrounded by edematous border (“ring of pearls”) DDX Insect bite Staph (painful) Rare problems: Plague Tularemia Exposed areas Head / neck Extremities ***Do not squeeze to express exudate or do I&D.*** --> Risk for dissemination! Gently collect exudate with moist swab. Few PMNs Many Gram pos bacilli

17. Inhalational Anthrax Hemorrhagic mediastinitis-- not pneumonia 50% develop meningitis Sputum Gram stain and culture - not helpful. DDX = Acute bacterial mediastinitis Dissecting aortic aneurysm Superior vena cava syndrome Mediastinal tumor

18. Anthrax - Case Definition • Compatible clinical syndrome • Laboratory confirmation • Positive culture • Positive serology • Identification of organism in tissue

19. Anthrax - Laboratory Diagnosis • Culture • (grows well on conventional media) • Gram+rod, nonmotile, nonhemolytic • Referred to State Health Lab for Bacillus speciation • CDC Studies • Serology • Immunohistochemistry • PCR

20. Bottom line = Current empiric therapy for community-acquired pneumonia is inadequate. Anthrax - Susceptibility testing data from 11 “bioterror cases” in U.S. Susceptible MIC (ug/ml) Penicillin <0.06 - 0.12 Amoxicillin <0.03 Doxycycline <0.03 Tetracycline <0.06 Ciprofloxacin <0.06 Clarithromycin 0.25 Clindamycin <0.5 Rifampin <0.5 Vancomycin 1-2 Intermediate - Resistant MIC (ug/ml) Ceftriaxone 16-32 Erythromycin 1.0 Azithromycin (marginal) 2.0 B. anthracis is also naturally resistant to: Trimethoprim-sulfamethoxazole (TMP-SMX) Cefuroxime, ceftazidime, cefotaxime Aztreonam

21. Outpatient Management(CDC guidelines) • Asmyptomatic -- No known exposure (“worried well”) • Reassure • No nasal swabs (used for epidemiology) • Asmyptomatic -- Suspected / known exposure • Risk assessment for post-exposure prophylaxis • CDPH - 311 or ID Consultation for support • Decontaminate skin with soap and water • Symptoms and signs compatible with Anthrax • Confirm the diagnosis • Report the case to the CDPH - 311 • Obtain consultation as needed and treat

22. Post-exposure Prophylaxis for Anthrax JAMA 281:1735-45, May 12, 1999 • Points: • Cipro is recommended, in case the Russian, drug-resistant strain is encountered. • Tetracycline is not used in children (skeletal growth and staining of teeth). • Cipro (? risks) and tetracyclines (hepatic toxicity) are usually not used in pregnancy.

23. Antibiotic Therapy for Inhalational Anthrax JAMA 281:1735-45, May 12, 1999 Main Point: Standard, empiric therapy for community-acquired pneumonia (i.e., 3rd generation cephalosporin + erythro/azithro) in not adequate.

24. Anthrax Vaccine • Primarily targeted against protective antigen (PA) • “All active- and reserve-duty military personnel” • Not available for civilian use • Dosing - 0, 2, 4 weeks; 6, 12, 18 months • 6 doses and periodic booster • 2 doses may protect in post-exposure setting • Few adverse reactions (still not well accepted in military)

25. Anthrax - Infection Control • Not transmitted person-to-person • No isolation - standard barrier precautions • No immunization of contacts or health care workers (vaccine not available anyway) • Laboratories - standard BSL-2 procedures

26. Anthrax Summary • A noncommunicable agent • Cutaneous form can be treated • Inhalational form is usually fatal • ? Value of earlier therapy • ? Value of cytokine modulation therapy • Need earlier diagnosis for systemic disease • Need an improved vaccine • Need improved methods of detection • Need improved methods of decontamination

27. Smallpox - Limited History • 1796 - Jenner - cowpox (vaccinia) protects • 1972 - Routine vaccination ends in U.S. • 1977 - WHO eradicates smallpox globally • 1980 - All vaccination is stopped globally • 1980 - USSR starts smallpox weapons program -- “producing tons / year” • After 1980 - Lab accidents and limited spread and other concerns stimulated call for elimination of all stocks of smallpox (Clin Inf Dis 33:1057, 2001)

28. Smallpox - Why worry? • Stable virus • Small infectious dose (few virions) • Highly communicable • 10-20 new cases per active case (log amplification) • 30% case fatality rate • No therapy • “No” or rapidly waning immunity • Vaccine - inadequate supplies, side effects

29. Smallpox rash infection -- LN -- asympt viremia -- LN, spleen, BM -- 2 viremia -- rash Distribution Smallpox - mouth / face -- forearms Later trunk and legs Chickenpox - greater rash on trunk than on face and extremities Transmission Most contagious 1st 10 days after rash Greater transmission in winter (virus less stable with T & humidity)

30. Smallpox Vaccination • Who is protected? • No one born after 1972 - 40% of U.S. population is < 29 y.o. • Waning immunity of those vaccinated < 1972? • How much vaccine is there? • U.S. - 15 million doses (Fauci) • WHO - 0.5 million doses • Other countries - ?? • Will diluted virus “work?” • Undiluted - 95% take • 1:5 dilution - 90% take • 1:10 dilution - 70% take • (estimates)

31. Smallpox Vaccination Complications(a live virus vaccine) • Disseminated vaccinia • Eczema vaccinatum Pre-AIDS! • Points: • For each 1 million vaccinated, there were ~ 250 complications • Vaccine immune globulin (VIG) Rx is needed - short supply

32. Smallpox Summary • A highly infectious and contagious agent • Diagnosis is a problem, when most HCWs have not seen this disease and laboratory studies are BSL-4. • Vaccine is available but in limited supply and its use is not without problems, especially in the era of AIDS. • There is no effective antiviral therapy -- new antiviral agents needed. • The magnitude of the societal and global implications of an outbreak are difficult to imagine!

33. Research Needs • Existing -- most academic medical center bioterrorism efforts are focused on education and threat response analysis • Proposed -- increased basic science effort to seek new solutions and advances that are common to: • Man-made bioterrorism • Evolutionary biological threats

34. Research NeedsPathogen Detection • “Signatures” of biological agents in the presence of large quantities of microbial contamination and interfering agents • Identification of genetically engineered pathogens or previously “normal” organisms • Bacteria • Viruses • “Stealth viruses” being developed for gene Rx

35. Research NeedsAreas for Increased Focus • Immunopathogenesis - improved understanding of the cytokine response to infection (crossover advances for other problems) • Organ-specific damage, autoimmune disease, transplantation biology • Microbial pathogenesis • Adhesion and penetration • Virulence factor / toxin function • Co-pathogenesis • Vaccine - new strategies and technology • Better Anthrax vaccine • Alternative(s) to Vaccinia for Smallpox vaccination and therapy • Antiviral drugs - strategies for more broadly active agents or ways to increase the application of existing agents

36. References • Web sites • idsociety.org • cdc.gov • IOM Report - Chem and Biol Terrorism - R&D to Improve Civilian Medical Response. National Academy Press, 1999 • Emerging Viruses - Ed. Stephen S. Morse. Oxford Univeristy Press, 1993.