The threat of bioterrorism: A reason to learn more about anthrax and smallpox
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LECTURES BY
CLEVELAND CLINIC
A N D VISITING
FACULTY
The threat of bioterrorism: A reason to
learn more about anthrax and smallpox
STEVEN M . G O R D O N , M D clear idea of which of the people in the clinic
Department of Infectious Disease, Cleveland Clinic are at risk, how to treat those exposed, or how
to prevent a disease outbreak. However, inter-
• ABSTRACT national and domestic events are forcing us to
Threats of domestic terrorism and interna- realize that the possibility of bioterrorism must
tional news about germ warfare research be taken seriously.
have forced us to recognize the potential The most likely candidates for biological
menace of biological weapons. Both small- weapons are anthrax and smallpox. Both can
pox and anthrax could be used as biological be put into stable aerosol form in particles 5
|im or smaller (the ideal size to be inhaled),
weapons. It is important for physicians to
bypass the oropharynx, and reach the alveoli.
reacquaint themselves with these diseases,
Both have small infective doses: the dose for
because if a domestic attack were to occur, it
anthrax is thought to be fewer than 50,000
might first be recognized when patients with spores, and the dose for smallpox may be as
unusual symptoms began presenting to hos- few as 10 to 100 particles. They are inexpen-
pitals and primary care physicians. In this sive to develop, have a long shelf-life, and
Anthrax and article, w e discuss symptoms and treatments could cause widespread panic that could com-
for smallpox and anthrax, and suggest pound the terror of the disease itself.
smallpox are resources for physicians who wish to learn
the most likely more about the subject. • LESSONS OF THE PLANNED
PARENTHOOD CASE
candidates for A D M I N I S T R A T I V E A S S I S T A N T sitting
N
bioweapons alone at her desk at a Planned The case described above actually occurred in
Parenthood clinic opens a letter. The enve- Indiana in 1998. Hazardous materials (HAZ-
lope contains white powder and a threatening MAT) experts responded to the scene wearing
note saying that the powder is anthrax spores. full protective gear, including self-contained
The assistant immediately dials 911, and respirators. All 31 people in the building were
police arrive in minutes. The letter is sealed in considered possibly exposed to anthrax. They
a plastic bag and collected by the Federal were told to place all clothing and personal
Bureau of Investigation. belongings in labeled plastic bags and take
The next phone call is to you as the physi- decontamination showers with soap, water,
cian on call. While the investigation contin- and a dilute bleach solution in a tent set up on-
ues, you are asked for advice about preventive site. The administrative assistant underwent
health measures for the administrative assis- seven decontamination showers. All were
tant, the police and emergency team respon- taken to local emergency departments, where
ded, and the 31 adults and children who hap- some had to undergo additional decontamina-
pened to be in the clinic when the envelope tion under local hospital policy, and all were
was opened. started on oral ciprofloxacin. The desktop was
What should you do? washed with full-strength household bleach.1
Anthrax occurs so rarely under ordinary The threat was exposed as a hoax after
circumstances that few of us would have a both the state health department and a
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 10 NOVE MBER / D EC E M B E R 1 9 9 9 585
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Department of Defense laboratory failed to germ warfare program was large and well-
find any evidence of anthrax in the powder or funded, and with the fall of the Soviet Union
the envelope. and the collapse of the Russian economy, it is
As we will see later in this article, the feared that Soviet scientists may be willing to
response to the threat was prompt and thor- sell their expertise to other nations.
ough, but may actually have been more Inspections in Iraq have documented
aggressive than necessary. In my opinion, research into biological and chemical
even if the Planned Parenthood hoax had weapons.
involved genuine anthrax, the situation The Aum Shinrikyo cult in Japan, which
would be frightening but not actually very killed 12 and injured 5,000 with a release of
dangerous. A review of the disease's symp- sarin nerve gas into a Tokyo subway in 1995,
toms, forms, and therapies will show why. had a bioterrorism research program and had
stockpiled anthrax and botulinum toxins.
• A BRIEF HISTORY
OF BIOLOGICAL W E A P O N S Recent US incidents
In 1998, there were 38 anthrax hoaxes affect-
C a t a p u l t e d corpses ing 5,000 people in the United States. But
One of the earliest uses of biological weapons bioterrorism in this country should not be
occurred in 1346 when besieging Tartars cata- considered only a hoax. A 1984 salmonella
pulted corpses of their own men who had died outbreak in Oregon was traced to the
of plague, over the walls of the city of Kaffa Rajneeshee cult, whose members had contam-
(now Feodosia, Ukraine). inated salad bars in at least 10 restaurants in a
Smallpox-contaminated clothing was training exercise for a larger attack designed
deliberately distributed to Native Americans to influence a local election.1
by European settlers, contributing to devastat-
ing epidemics in both North and South • ANTHRAX
America.
Anthrax is caused by spore-forming gram-pos- In 1998, there
W o r l d War II and t h e Cold War itive bacilli, and is primarily a disease of sheep
By World War II, biological weapons were the and cattle which under natural circumstances were 38
focus of nationally supported research in infects humans very rarely. Outbreaks in US anthrax hoaxes
Japan, Germany, the United States, and other cattle have declined steadily since 1945. The
countries. By the end of the war, the United last fatal human case in this country was con- in the U.S.
States had stockpiled 5,000 anthrax bombs. tracted in 1976 from wool imported from
Research and development continued until Pakistan. Since 1988, there has been no more
Richard Nixon closed the program and than one human case per year. Thus, a single
ordered the arsenal destroyed by 1973. The case of human anthrax is a sentinel event, and
international Biological Weapons Convention the possibility of bioterrorism should be con-
prohibiting bioweapons use went into effect in sidered.
1975. However, bioweapons research contin-
ued in many countries that signed the treaty as Forms of anthrax
well as in others that did not. Cutaneous anthrax, which accounts for
This was dramatically confirmed in 1992 95% of naturally occurring human anthrax
when Boris Yeltsin conceded what epidemio- infections, develops when spores encounter
logical evidence had already suggested, that a traumatized skin, often on the face or hands.
1979 anthrax outbreak in Sverdlovsk (now A painless black eschar develops and is gener-
Ekaterinburg), Russia, stemmed from an unin- ally accompanied by marked edema. This
tentional release of aerosolized anthrax from a form of anthrax, which can occasionally be
military microbiology laboratory. Seventy- transmitted by contact, can usually be cured
seven cases occurred downwind of the labora- with antibiotics. However, untreated cases
tory, and 66 of the victims died. Incubation may become systemic and fatal. The incuba-
periods ranged from 1 to 43 days.2 The Soviet tion period can be from 1 to 7 days.
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 10 NOVE MBER / D EC E M B E R 1999 585
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MEDICAL GRAND ROUNDS
TABLE 1
Diagnosis and t r e a t m e n t of a n t h r a x and smallpox
AGENT DIAGNOSTIC DIAGNOSTIC PATIENT THERAPY POSTEXPOSURE VACCINE
SAMPLES ASSAY ISOLATION PROPHYLAXIS
PRECAUTIONS
Anthrax Blood Gram stain Standard Ciprofloxacin Ciprofloxacin Licensed vaccine
(handled at Antigen ELISA precautions 400 mg IV 500 mg PO 0.5 mL SC
biosafety Serology every 8 - 1 2 hr twice a day at 0, 2, 4 weeks
level 2) for 4 weeks; and 6 , 1 2 , 1 8 mo;
Doxycycline if unvaccinated annual booster
200 mg IV, begin initial
then 100 mg IV doses of vaccine
every 8 - 1 2 h*
Smallpox Pharyngeal swab ELISA Precautions Cidofovir is Vaccinia immune Licensed vaccine
Scab material PCR for airborne effective in globulin 0.6 rnL/kg is Wyeth calf
(handled at Virus isolation pathogens vitro IM within 3 days lymph vaccinia
biosafety level of exposure
2-3) (best within 24 h) Investigational
cell-culture vaccinia
Vaccination if has been developed
> 3 years since by Department of
last vaccination Defense
"Other alternatives include penicillin, gentamicin, erythromycin, and chloramphenicol
ELISA=enzyme-linked immunosorbent assay; PCR = polymerase chain reaction; PO=by mouth, IV=intravenously; SC=subcutaneously
SOURCE: ADAPTED FROM FRANZ DR, JÄHRLING PB, FRIEDLAND A M , ET AL. CLINICAL RECOGNITION A N D M A N A G E M E N T OF PATIENTS E>POSED TO BIOLOGICAL WARFARE AGENTS.
J A M A 1 9 9 7 ; 2 7 8 : 3 9 9 - 4 1 1.
Inhalational anthrax, a rapidly fatal ill- A n t h r a x as a w e a p o n
ness commonly known as woolsorters' disease, Aerosolized anthrax could be a potent
accounts for most of the remaining natural weapon that could be released from aircraft or
cases. Inhaled spores are ingested by pul- into a building, with a mortality rate of up to
monary macrophages and carried to hilar and 80%. Fortunately, there are limitations to the
mediastinal lymph nodes, where they germi- danger posed by anthrax. The spores are not
nate and multiply. The incubation period may volatile, so they will not aerosolize sponta-
range from 2 to 60 days. Nonspecific flulike neously. Spores can infect cutaneously only
symptoms develop first, followed after 2 to 4 through breaks in the skin, posing little risk to
days by abrupt respiratory failure, hemody' intact skin. In addition, person-to-person
namic collapse, pronounced pulmonary spread has never been documented, meaning
edema, and death. Meningitis occurs in half of that an infected person would not trigger an
cases. Chest radiographs may show a widened epidemic.4
mediastinum and pleural effusions. Gram-pos-
itive bacilli may be noted in blood cultures. A n t h r a x vaccine
Transmission from person to person has never A n anthrax vaccine was developed in the
been documented. 1950s using an avirulent strain that elaborates
Gastrointestinal anthrax is a rare conse- only protective antigen and produces a protec-
quence of eating contaminated meat. tive antibody response in 7 days. The current
Symptoms are pain, nausea, vomiting, and vaccine requires an onerous schedule, with
fever, with bloody diarrhea and hematemesis, doses at 0, 2, and 4 weeks, and 6, 12, and 18
with progression to toxemia and sepsis. This months, followed by annual boosters (TABLE 1 ) . 5
form is difficult to diagnose and almost uni- This vaccine has not been the subject of any
versally fatal. Incubation is 1 to 7 days.3 controlled studies; the only study has shown a
5 9 4 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 10 NOVEMBER / DECEMBER 1999
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protective effect against cutaneous anthrax, The Planned Parenthood case described
hut numbers were too small to determine earlier in this article would have posed little
whether the vaccine also protects against the serious threat of disease, even if the powder in
inhalational form. The US military first vacci- the envelope had been anthrax. As anthrax
nated troops during the Gulf War and now spores are not volatile, it was unlikely that the
routinely vaccinates all personnel, a practice administrative assistant inhaled the spores
that has sparked a political controversy about and very unlikely that anybody else did. The
the vaccine's safety. self-contained respirators used by emergency
personnel responding to the scene were prob-
Therapies for anthrax ably not necessary. The spores would be likely
Antibiotic prophylaxis for inhalational to cause cutaneous infection only if the assis-
anthrax appears to be most effective before tant had preexisting breaks in her skin.
respiratory symptoms develop, but it is diffi- Decontamination showers and prophylaxis
cult in naturally occurring cases to begin ther- were probably indicated for the assistant, but
apy early because the nonspecific prodrome is not for the others in the building.
virtually impossible to distinguish from flu or
other less serious diseases. • SMALLPOX
The Centers for Disease Control and
Prevention (CDC) recommends postexpo- It is important to reeducate physicians about
sure prophylaxis with ciprofloxacin or anoth- smallpox because it has not been seen in the
er fluoroquinolone twice daily, with doxycy- United States since the 1940s. The last nat-
cline the second agent of choice. Although urally occurring case in the world occurred
natural anthrax is very susceptible to peni- in 1977 in Somalia, and in 1980, the World
cillin, military experts decided in 1991 that Health Organization declared smallpox
Iraq and Russia both had the technology to eradicated. Routine childhood vaccination
develop penicillin-resistant strains. The was discontinued in the United States in
quinolones would also be effective against 1972. The strength of any remaining immu-
plague and tularemia, which may be difficult nity among those who were vaccinated as Smallpox rash
to distinguish from anthrax in the field. children is not known, but only about 15%
Antibiotics would have to be taken for at of the population is thought to have any
often develops
least 8 weeks after exposure, because the immunity. on the soles
spores can lie dormant in the hilar lymph Smallpox, caused by the variola virus,
nodes for up to 6 weeks before germinating. used to be a universal disease of childhood,
and palms
Alternately, antibiotics could be given for 4 killing many victims but leaving the sur-
weeks while the first 3 doses of vaccine are vivors with prolonged immunity. The disease
administered.1-3 In either case, these proce- begins with high fever and myalgia, with the
dures would clearly strain local supplies of characteristic rash forming on about the
antibiotics as well as vaccine in the event of fourth day, starting as macules and progress-
a large-scale exposure. ing to papules and vesicles, scabbing over at
1 to 2 weeks. It typically begins on the face,
CDC r e c o m m e n d a t i o n s for anthrax t h r e a t s oropharynx, and arms, spreading later to the
Standards published by the CDC 1 after sever- trunk and legs, and the vesicles often devel-
al recent anthrax hoaxes recommend decont- op on the palms and soles. Smallpox is con-
amination showers with soap and water only, tagious from the formation of the rash until
with no bleach. They also state that exposed scabs separate at about 3 weeks. The lesions
surfaces should be decontaminated with dilute have a synchronous onset. Death, which
bleach solution, not full-strength bleach. generally occurs in the second week of ill-
Chemoprophylaxis is recommended for 8 ness, apparently results from toxemia.
weeks in the absence of a vaccine, for 4 weeks Smallpox is transmitted most often through
in combination with the first 3 doses of the airborne droplets but can also be passed by
vaccine, or until the threat of anthrax has contact. Its incubation period ranges from 7
been excluded. to 17 days, averaging 12 days.6
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 10 NOVE MBER / D EC E M B E R 1999 5 8 5
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Forms of smallpox one of the last European outbreaks. A German
Variola major, the most severe form of returning from a trip to Pakistan in 1970 devel-
smallpox, has a case-fatality rate of about 30% oped a fever and was quarantined with suspect-
in unvaccinated populations. When the rash ed typhoid. He developed the characteristic
and mucous membranes become hemorrhag- smallpox rash 4 or 5 days later and was immedi-
ic, a phenomenon occurring mostly in preg- ately taken to a special smallpox isolation hos-
nant women, the course of the disease is more pital that had been maintained for just such
severe and mortality even higher. A confluent emergencies. Mass vaccinations were conduct-
rash indicates a severe form of smallpox, and a ed in the region, and a number of sick patients
discrete rash a less serious one. Variola minor were also given vaccinia immune globulin
or alastrim is a much less virulent form of (V1G). Even though the index patient had
smallpox with a case-fatality rate of about 1%. been quarantined at the first hospital and the
German population was already well vaccinat-
D i f f e r e n t i a l diagnoses ed, 19 additional cases developed among the
During the onset of smallpox, nonspecific patients and staff at the first hospital. It is
fever and myalgia may simulate flu. Measles thought that the patient's cough, unusual in
may be ruled out if the mouth and throat have smallpox, helped disperse more virus than usual
no Koplik's spots. Chickenpox rash is cen- in aerosolized form. Most alarming, one of the
tripetal, denser on the trunk than on the cases developed in a visitor who opened a hall-
extremities, and virtually never develops on way door about 30 feet from the patient's room
the palms and soles. Also, in chickenpox, to ask directions, spending no more than about
eruptions of different stages of maturation are 15 minutes in the hospital.7
found next to each other, whereas smallpox is
generally at the same stage of development Vaccines and therapies
everywhere on the body. Monkeypox is a rare There are no known treatments for smallpox.
disease very similar to smallpox that may be Cidofovir is effective in vitro (TABLE 1 ) .
ruled out by the absence of history of travel to The vaccine may prevent or ameliorate ill-
western Africa. Generalized vaccinia infec- ness if given within 3 or 4 days of exposure. Smallpox
tion, an occasional consequence of the vac- Passive immunization in the form of vaccinia
cinia vaccine still given to a few high-risk immune globulin is most effective when admin- vaccine is
workers, may also resemble smallpox.3 istered in the first 24 hours after exposure. '3 effective but
Diagnosis can be confirmed by electron Although the vaccinia vaccine is very
microscopy of vesicular scrapings or gel diffu- effective, it would be difficult to reinstitute a has serious
sion testing of vesicular fluid antigen against L i n i v e r s a l vaccine program. First, we have only risks, including
vaccinia antiserum. Light microscopy can a small stockpile of vaccine (5 to 10 million
reveal intracytoplasmic variola particles, the doses in the United States and perhaps 70 death
Guarnieri bodies. million worldwide) and no technology for
rapidly manufacturing more.
S m a l l p o x as a w e a p o n The vaccine is not benign. At least one
Smallpox weapons could be developed in death per 1 million can be expected, as well as
small laboratories with only a few thousand serious complications including secondary
dollars' worth of equipment. Like anthrax, autoinoculations, generalized vaccinia infec-
smallpox can be aerosolized for maximum tion, eczema vaccinatum, and post-vaccine
effect. Although surviving smallpox cultures encephalitis.
are kept in only two labs, a C D C lab in
Atlanta, and a Russian one, the security of the • TO LEARN MORE
Russian lab has been in question ever since
the fall of the Soviet Union. Physicians who wish to learn more about bio-
Smallpox could be an even more devastat- logical weapons should begin with the C D C
ing weapon than anthrax because it is easily Web site (www.cdc.gov), which contains a
spread from person to person. The extreme con- wealth of resources accessible with the search-
tagiousness of smallpox was demonstrated by term "bioterrorism."
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 10 NOVE MBER / D EC E M B E R 1999 585
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1999 REVIEWERS MEDICAL GRAND R O U N D S
•
One important document available on the
W e thank those who reviewed manuscripts submitted to
the Cleveland Clinic Journal of Medicine for the year end-
ing September 30, 1999. Reviewing papers for scientific jour-
site is the "Bioterrorism Readiness Plan: A
Template for Healthcare Facilities," a set of
nals is an arduous task and involves considerable time and guidelines for managing patients with diseases
effort. We are grateful to these reviewers for contributing their that may be related to bioweapons.8
expertise this past year.—John D. Clough, MD, Editor-in-Chief. Guidelines for responding to both genuine
anthrax attacks and anthrax hoaxes have been
Achkar, Edgar Gifford, Ray W Jr Murphy, Daniel J published by the C D C in Morbidity and
Anderson, Charles Gordon, Steven M Nahman, N Stanley Jr Mortality Weekly Report.1
Antman, Elliot Gorensek, Margaret Nally, Joseph V The August 6, 1997 issue of JAMA was
Baker, David Grant, R Peery Nickerson, Paul E dedicated to bioterrorism and contains a valu-
Ballas, Samir Groene, Linda Olin, Jeffrey W able review by Franz et aP of the signs and
Barnett, Gene H Grossman, Joshua Overmoyer, Beth A symptoms of diseases with possible bioweapons
Bartholomew, John R Hall, Phillip M Palmer, Robert M significance. The July-August 1999 issue of
Belinson, Jerome L Handel, Daniel Ploro, Mathilde Emerging Infectious Diseases was also dedicated
Berner, Lynn Hayden, Stephen P Radwany, Steven to coverage of bioterrorism, focusing on the
Blumenthal, David E Hebert, Lee Raisz, Lawrence National Symposium on Bioterrorism held at
Borzak, Steven Hedrick, Sterling Reddy, Sethu K
Johns Hopkins University in February 1999.9
Braun, William E Henry, Catherine A Rein, Michael A recent review article in the New England
Brenner, Robert Hoffman, Gary S Richard, Thomas C
Journal of Medicine contains additional in-
Branson, David L Howard, Robert Richter, Joel E
depth information about anthrax.10
Bukowski, Ronald M Hutzier, Jeffery C Rollins, Michael B In an emergency, physicians are urged to
Burke, Carol A Isaacson, J Harry Rooney, Theodore W contact their local health departments. Further
Cain, Robert A Jaeger, Fredrick J Rosenbaum, Harvey information on diagnostics, medical manage-
Calabrese, Leonard H James, Karen B Roth, Mark ment, and vaccines can be obtained from the
Cannon, Chris Juhasz, Robert S Sahgal, Vinod Commander, US Army Military Research
Caravella, Philip Keys, Thomas F Sandhu, Satinderpal Institute for Infectious Diseases, at (phone)
Carey, William D Kratche, Richard P Schubert, A r m i n 301-619-2833 or (fax) 301-619-4625. •
Carter, Lynne Kunkel, Robert Segal, Allen M
• REFERENCES
Cetin, Derrick C Lalak, Irene C Sharpe, Isabelle
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Colacarro, Robert T Lee, Katherine Smedira, Holly J
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Cornette, Victoria E Leslie, Camilo Snow, Norman 1202-1208.
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Crowe, Joseph P Lichtin, Alan E Sprecher, Dennis L
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