Medical and Public Health Responses to Bioterrorism:

1
Medical and Public Health Responses to
Bioterrorism

• George W. Rutherford, M.D.
• Institute for Global Health
• University of California, San Francisco

2
Unconventional Warfare and Terrorism

• Nuclear
• Biologic
• Bacteria
• Viruses
• Biologic toxins
• Chemical
• Biological agents can be directed against humans,
  livestock and plants

3
Prior Uses of Biological Warfare

• 14th century, Crimea Catapulting of cadavers
  with plague into a city under siege
• 18th century, North America Distribution by
  British of blankets and a handkerchief from
  smallpox patients to Native Americans hostile to
  the British
• World War I Attempts by Germany to infest
  livestock and contaminate animal feed with B.
  anthracis and B. mallei
• World War II Japanese in China used B.
  anthracis, V. cholerae, Shigella, Salmonella and
  Y. pestis in food, water, aerial spraying and
  release of fleas (Unit 731, Ping Fan)

4
Biological Warfare/Bioterrorism

• Is the threat real?
• U.S. Offensive biowarfare program at Fort
  Detrick, Maryland, discontinued in 1969
• U.S.S.R./Russia Biopreparat - still conducting
  offensive biowarfare research?
• Other countries Known or suspected of
  having/doing research on biowarfare Iraq, Iran,
  Libya, Syria, North Korea, China, India,
  Pakistan, South Africa and Israel

5
Biological warfare/Bioterrorism

• Is the threat real?
• Alleged/rumored Russian advances
• An engineered strain of anthrax resistant to
  antimicrobial agents and against which the
  current vaccine ineffective
• Mass production of smallpox virus
• A multi-drug resistant strain of Y. pestis
• A recombinant Ebola-smallpox chimera
• Variant strain of Marburg virus

6
Biological Warfare/Bioterrorism

• Is the threat real?
• IraqAcknowledged offensive weapons program that
  included research on B. anthracis, C. perfringens
  (gas gangrene), rotavirus, camelpox virus, yellow
  fever, Congo-Crimean hemorrhagic fever virus,
  aflatoxin, botulinum toxin, mycotoxin, and
  anti-crop biological agents. 8,500L of a
  solution containing an anthrax spore count of
  109/ml was produced, 6,500L of which was used to
  fill weapons (SCUD warheads and bombs).

7
Biological Warfare/Bioterrorism

• Is the threat real?
• 1995
• Aum Shinrikyo cult (which released nerve agent
  sarin in the Tokyo subway system) was conducting
  research with B. anthracis, C. botulinum, and C.
  burnettii had attempted to use B. anthracis in
  the Tokyo subway system and had drone aircraft
  equipped with spray tanks. In 1992, cult members
  had traveled to Zaire in an attempt to obtain
  Ebola virus.

8
Biological Warfare/Bioterrorism

• Can it happen here?
• Salmonella typhimurium 751 cases, The Dalles,
  Oregon, 1984
• B. anthracis 23 cases 4 deaths 10,000
  treated with antibiotics prophylactically
  Florida, New York, New Jersey, Virginia,
  Washington DC, 2001

9
Biological Warfare/Bioterrorism

• What are the characteristics of a good agent?
• Dispersible in aerosols of 1-5 µ for penetration
  of bronchioles and alveoli
• Predictably high number disease-to-infection
  ratio in a few days
• Immunization or prophylaxis exist
• Maintains viability/infectivity in environment
  (spores and toxins ideal)
• Causing illness better than causing death

10
Biological Warfare/Bioterrorism

• Category A agents
• Bacillus anthracis (anthrax)
• Botulinum toxins (Clostridium botulinum)
• Brucella suis and melitensis (brucellosis)
• Francisella tularensis (tularemia)
• Smallpox
• Yersinia pestis (plague)
• Category A biologic agents (High-priority
  agents that pose a risk to national security
  because they can be easily disseminated or
  transmitted person-to-person, cause high
  mortality with potential for major public health
  impact, might cause public panic and social
  disruption, and require special action for public
  health preparedness)

11
Biological warfare/Bioterrorism

• Anthrax
• Three clinical forms
• Cutaneous anthrax
• Inhalational anthrax
• Gastrointestinal anthrax
• Previously occupational disease in US
  (woolsorters disease)
• Cutaneous anthrax least serious and may be a
  sentinel event for a larger release

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Biological warfare/Bioterrorism

• Cutaneous anthrax
• Cutaneous inoculation of spores on exposed areas
  (forearms, hands, neck)
• Incubation period, 0.5-12 days
• Painless papule progressing to fluid-filled
  vesicle in 1-2 days that erodes to a depressed
  coal-black eschar (hence, anqrax Greek, coal)
  with circumferential edema, erythema, satellite
  vesicles, regional adenopathy systemic symptoms
• Untreated case fatality rate, 20

14
Cutaneous Anthrax
From the UCSF Infection Control Website
15
Biological Warfare/Bioterrorism

• Inhalational Anthrax
• Incubation period, 1 to 5 days (up to 44 d)
• Initial phase nonspecific prodrome -
• malaise, fatigue, mild fever, non-productive
  cough, chest pain or chest constriction
• Acute phase (toxin-mediated causing hemorrhagic
  lymphadenitis) 2-4 days later, sudden onset of
  severe respiratory distress, dyspnea, cyanosis,
  CXR evidence of widened mediastinum, meningitis
  (50)
• Not transmitted person-to-person
• Case-fatality rate approaches 100

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Inhalational anthrax
17
Sverdlovsk anthrax outbreak, 1979

• April - May, 1979
• Outbreak of anthrax among people
• and livestock living in and up to 50 km south of
  Sverdlovsk (now Yekaterinburg), a city of
  1,200,000 people 1400km east of Moscow and site
  of a military microbiology facility.

18
Sverdlovsk anthrax outbreak, 1979

• A 1993 pathology report showed that fatal cases
  had inhalation anthrax
• Follow-up investigation most consistent with a
  release of an aerosol of anthrax from military
  microbiology facility on April 2, 1979
• 77 patients (66 died)
• Incubation period, 2-43 days (9-10 modal)
• Mean time onset to death, 3 days
• Estimated total weight of spores was between a
  few milligrams and nearly a gram

19
Onset of fatal cases by week post exposure,
Sverdlovsk, 1979
Meselson M, Guillemin J, Hugh-Jones M, et al.
The Sverdlovsk anthrax outbreak of 1979. Science
1994 2661202-8.
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Prevention and treatment of anthrax

• Prevention
• Pre-exposure
• Anthrax vaccine
• 6-dose series (0, 2, 4 wks 6, 12, 18 mos) then
  annually
• Postexposure
• Ciprofloxacin or doxycycline x 60 d
• Military uses 4-wk regimen plus vaccine

• Treatment
• Antibiotics
• Ciprofloxacin or doxycycline
• 1-2 additional antibiotics for inhalational
  anthrax
• Steroids?
• Antitoxin?

21
Complications of anthrax prophylaxis

• Ciprofloxacin prophylaxis in 3,428 postal workers
• Complications
• 666 (19) severe nausea, vomiting, diarrhea or
  abdominal pain
• 484 (14) fainting, light headedness or
  dizziness
• 250 (7) heartburn or acid reflux
• 216 (6) hives or itchy skin
• 287 (8) discontinued ciprofloxacin
• 116 (3) because of adverse reactions

CDC. MMWR 2001 501051-4.
22
Smallpox
From the UCSF Infection Control Website
23
Smallpox
From the UCSF Infection Control Website
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Biological Warfare/Bio-Terrorism

• Smallpox
• Incubation period, 7 to 17 days
• Prodrome, non-specific illness with high fever
  (102-106F) for 3-4 days before rash with
  headache, back ache, vomiting defervescence with
  rash onset. Rash is erythematous to
  maculopapular to vesicular all lesions are the
  same age (unlike varicella) rash is centripetal
• Case fatality ratio 25 - 30
• Infectious for few hours before rash onset
  until scabs fall off (airborne contact)

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Biological Warfare/Bio-terrorism

• Smallpox vaccination
• Vaccination with live vaccinia virus (cowpox, a
  related orthomyxovirus) intradermal
  administration on left deltoid
• Routine vaccination of civilians in the U.S.
  was stopped in 1972
• Routine vaccination of U.S. military stopped in
  1989
• Less than 10 of the U.S. civilian population
  is currently immune to smallpox

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Biological Warfare/Bio-terrorism

• Smallpox vaccination
• Approximately 15 million doses of smallpox
  vaccine are currently stored in a single location
  in the U.S. Up to half may be expired. The
  number of doses available may be able to be
  increased by giving a smaller dose.
• Current plans call for the manufacture of
  300,000,000 doses of a new vaccine.
• Post-exposure prophylaxis with vaccine (lt3d) and
  vaccinia immune globulin 0.6 ml/kg), cidofovir?,
  ribavirin?

27
Biological Warfare/Bio-terrorism

• Infectivity of smallpox
• Yugoslavia, 1972
• A single case of smallpox transferred multiple
  times before the diagnosis was made infected 11
  others, who in turn infected 138 more people,
  leading to isolation of 10,000 people and
  vaccination of 20,000,000 people.

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At present, only two. . . laboratories in the
world contain smallpox virus. If for any reason
this virus were once again introduced to humans,
the resulting disease could be easily contained
by vaccination of identified contacts.

• Principles and Practice of Infectious Diseases
• Fourth Edition, 1995
• Editors Mandell, Bennett, and Dolin

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Smallpox, 1998

• Smallpox has been eradicated, but the etiologic
  agent is not extinct. The virus continues to
  exist in freezers in secure facilities at one
  institution in the United States and another in
  the Russian Federation. During the past 10
  years, various individuals and three WHO
  committees have recommended destruction of virus
  stocks on the grounds that the world needs to be
  assured that smallpox will never again be a
  threat to humankind. In opposition to virus
  destruction are equally strong views that
  laboratory stocks serve as a counterbalance to
  terrorism and a source of unknown future benefits
  to humankind. In May, 1996, the World Health
  Assembly recommended, subject to further review,
  that all stocks be destroyed in June, 1999.
  MMWR, 10/24/97
• Editorial note accompanying the re-publication of
  MMWR reports from 1978, to commemorate twenty
  years of freedom from smallpox.

30
Smallpox, 2001

• Stocks of smallpox virus were not destroyed in
  June, 1999 because of concerns that vials of the
  virus may have gone to and still be in the hands
  of other governments or groups. The World Health
  Assembly has called for the destruction of
  smallpox viral stocks in December, 2002.

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Biological Warfare/Bio-terrorism

• Current U.S. plans for smallpox control
• Immediate identification and isolation of
  infected persons
• Ring vaccination of close contacts of case and
  secondary contacts -- initial strategy now
  apparently replaced by nationwide vaccination
• Cautious use of vaccine pre-attack

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Biological Warfare/Bio-terrorism

• ACIP recommendations
• Under current circumstances, with no confirmed
  smallpox, and the risk of an attack assessed as
  low, vaccination of the general population is not
  recommended, as the potential benefits of
  vaccination do not outweigh the risks of vaccine
  complications.

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Biological Warfare/Bio-terrorism

• ACIP recommendations
• Persons who would conduct investigation and
  follow-up of initial cases that would necessitate
  direct patient contact
• Selected personnel in facilities pre-designated
  to serve as referral centers to provide care for
  the initial cases of smallpox

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Biological Warfare/Bioterrorism

• Challenges to responding promptly to an act of
  bioterrorism
• Recognition/diagnosis of the illness
• Availability of isolation beds/facilities
• Availability of vaccines/therapeutics
• Dealing with panic and public safety

35
Biological Warfare/Bioterrorism

• Prevention
• Secondary prevention
• Immunization
• Smallpox?
• Anthrax?
• Vaccine development efforts
• Tertiary prevention
• Improved detection
• Improved post-exposure prophylaxis and treatment
  regimens

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Handling of suspicious packages or envelopes

• Do not shake or empty the contents
• Do not carry it, show it to others or allow
  others to examine it
• Put it on a stable surface do not sniff, touch,
  taste or look closely at it or any contents that
  may have spilled
• Alert others in the area. Leave the area, close
  any doors and take actions to prevent others from
  entering the area. If possible, shut off the
  ventilation system.

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Biological Warfare/Bioterrorism

• Prevention
• Primary prevention
• Restriction of access to potential weaponizable
  agents
• Biological warfare treaties
• Enforcement
• Inspection
• Smallpox destruction
• Other?

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Inhalational and Cutaneous Anthrax Outbreak,
October-November 2001

• Investigation (November 30, 2001)
• 18 confirmed and 5 suspected cases of anthrax in
  CT, DC, FL, NJ, NY from intentional exposure
• Newest cases in CT, NJ, NY unrelated to mail or
  media
• 11 inhalational, 12 cutaneous 4 deaths
• 9/11 inhalational cases in mail carriers or
  sorters
• 4 letters (2 to NY, 2 to DC) known to contain
  anthrax spores - weaponized?
• 12 isolates are indistinguishable (Ames, 1950) -
  susceptible to ciprofloxacin, doxycycline,
  penicillin similar to US military-grade strains

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Inhalational and Cutaneous Anthrax Outbreak,
October-November 2001

• Recommendations
• Unknown number of letters mailed (4 identified)
• Anthrax spores probably can leak out of sealed
  envelopes during automated sorting
• What does a suspicious package or letter look
  like?
• Inappropriate or unusual labeling
• Strange return address or no return address
• Postmarks from a city or state different from the
  return address
• Excessive packaging material