Anthrax as a Biological Weapon

Medical and Public Health Management

Author Information <http://jama.ama-assn.org/issues/v281n18/ffull/#aainfo>
Thomas V. Inglesby, MD; Donald A. Henderson, MD, MPH; John G. Bartlett, MD;
Michael S. Ascher, MD; Edward Eitzen, MD, MPH; Arthur M. Friedlander, MD;
Jerome Hauer, MPH; Joseph McDade, PhD; Michael T. Osterholm, PhD, MPH; Tara
O'Toole, MD, MPH; Gerald Parker, PhD, DVM; Trish M. Perl, MD, MSc; Philip K.
Russell, MD; Kevin Tonat, PhD; for the Working Group on Civilian Biodefense
Objective  To develop consensus-based recommendations for measures to be
taken by medical and public health professionals following the use of
anthrax as a biological weapon against a civilian population.
Participants  The working group included 21 representatives from staff of
major academic medical centers and research, government, military, public
health, and emergency management institutions and agencies.
Evidence  MEDLINE databases were searched from January 1966 to April 1998,
using the Medical Subject Headings anthrax, Bacillus anthracis, biological
weapon, biological terrorism, biological warfare, and biowarfare. Review of
references identified by this search led to identification of relevant
references published prior to 1966. In addition, participants identified
other unpublished references and sources.
Consensus Process  The first draft of the consensus statement was a
synthesis of information obtained in the formal evidence-gathering process.
Members of the working group provided formal written comments which were
incorporated into the second draft of the statement. The working group
reviewed the second draft on June 12, 1998. No significant disagreements
existed and comments were incorporated into a third draft. The fourth and
final statement incorporates all relevant evidence obtained by the
literature search in conjunction with final consensus recommendations
supported by all working group members.
Conclusions  Specific consensus recommendations are made regarding the
diagnosis of anthrax, indications for vaccination, therapy for those
exposed, postexposure prophylaxis, decontamination of the environment, and
additional research needs.
JAMA. 1999;281:1735-1745
JST80027
Of the numerous biological agents that may be used as weapons, the Working
Group on Civilian Biodefense has identified a limited number of organisms
that could cause disease and deaths in sufficient numbers to cripple a city
or region. Anthrax is one of the most serious of these diseases.
High hopes were once vested in the Biological Weapons and Toxins Convention,
which prohibited offensive biological weapons research or production and was
signed by most countries. However, Iraq and the former Soviet Union, both
signatories of the convention, have subsequently acknowledged having
offensive biowarfare programs; a number of other countries are believed to
have such programs, as have some autonomous terrorist groups. The
possibility of a terrorist attack using bioweapons would be especially
difficult to predict, detect, or prevent, and thus, it is among the most
feared terrorist scenarios. 1
<http://jama.ama-assn.org/issues/v281n18/ffull/#r1>
Biological agents have seldom been dispersed in aerosol form, the exposure
mode most likely to inflict widespread disease. Therefore, historical
experience provides little information about the potential impact of a
biological attack or the possible efficacy of postattack measures such as
vaccination, antibiotic therapy, or quarantine. Policies and strategies must
therefore rely on interpretation and extrapolation from an incomplete
knowledge base. The Working Group on Civilian Biodefense reviewed the
available literature and expertise and developed consensus recommendations
for medical and public health measures to be taken following such an attack.



CONSENSUS METHODS



The working group comprised 21 representatives from academic medical centers
and research, government, military, public health, and emergency management
institutions and agencies.
MEDLINE databases were searched from January 1966 to April 1998 for the
Medical Subject Headings anthrax,Bacillus anthracis, biological weapon,
biological terrorism, biological warfare, and biowarfare. Review of
references led to identification of additional relevant references published
prior to 1966. In addition, experts in the working group identified
unpublished references and sources.
The first draft of the working group's consensus statement was the result of
synthesis of information obtained in the formal evidence-gathering process.
Members of the working group were asked to make formal written comments on
this first draft of the document in May 1998. Suggested revisions were
incorporated into the second draft of the statement. The working group was
convened to review the second draft of the statement on June 12, 1998, at
the Johns Hopkins Center for Civilian Biodefense Studies, Baltimore, Md.
Consensus recommendations were made; no significant disagreements existed at
the conclusion of this meeting. The third draft incorporated changes
suggested at the conference and working group members had an additional
opportunity to review the draft and suggest final revisions. The final
statement incorporates all relevant evidence obtained by the literature
search in conjunction with final consensus recommendations supported by all
working group members. Funding for the development of the working group
consensus statement was primarily provided by each representative's
institution or agency. The Office of Emergency Preparedness, Department of
Health and Human Services (DHHS), provided travel funds for 4 members of the
group.
The assessment and recommendations provided herein represent the best
professional judgment of the working group based on data and expertise
currently available. The conclusions and recommendations need to be
regularly reassessed as new information becomes available.



HISTORY OF CURRENT THREAT



For centuries, anthrax has caused disease in animals and, uncommonly,
serious illness in humans throughout the world. 2
<http://jama.ama-assn.org/issues/v281n18/ffull/#r2>  Research on anthrax as
a biological weapon began more than 80 years ago. 3
<http://jama.ama-assn.org/issues/v281n18/ffull/#r3>  Today, at least 17
nations are believed to have offensive biological weapons programs 4
<http://jama.ama-assn.org/issues/v281n18/ffull/#r4> ; it is uncertain how
many are working with anthrax. Iraq has acknowledged producing and
weaponizing anthrax. 5 <http://jama.ama-assn.org/issues/v281n18/ffull/#r5>
Most experts concur that the manufacture of a lethal anthrax aerosol is
beyond the capacity of individuals or groups without access to advanced
biotechnology. However, autonomous groups with substantial funding and
contacts may be able to acquire the required materials for a successful
attack. One terrorist group, Aum Shinrikyo, responsible for the release of
sarin in a Tokyo, Japan, subway station in 1995, 6
<http://jama.ama-assn.org/issues/v281n18/ffull/#r6>  dispersed aerosols of
anthrax and botulism throughout Tokyo on at least 8 occasions. For unclear
reasons, the attacks failed to produce illness. 7
<http://jama.ama-assn.org/issues/v281n18/ffull/#r7>
The accidental aerosolized release of anthrax spores from a military
microbiology facility in Sverdlovsk in the former Soviet Union in 1979
resulted in at least 79 cases of anthrax infection and 68 deaths and
demonstrated the lethal potential of anthrax aerosols. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  An anthrax aerosol
would be odorless and invisible following release and would have the
potential to travel many kilometers before disseminating. 9
<http://jama.ama-assn.org/issues/v281n18/ffull/#r9> , 10
<http://jama.ama-assn.org/issues/v281n18/ffull/#r10>  Evidence suggests that
following an outdoor aerosol release, persons indoors could be exposed to a
similar threat as those outdoors. 11
<http://jama.ama-assn.org/issues/v281n18/ffull/#r11>
In 1970, a World Health Organization (WHO) expert committee estimated that
casualties following the theoretical aircraft release of 50 kg of anthrax
over a developed urban population of 5 million would be 250,000, 100,000 of
whom would be expected to die without treatment. 9
<http://jama.ama-assn.org/issues/v281n18/ffull/#r9>  A 1993 report by the US
Congressional Office of Technology Assessment estimated that between 130,000
and 3 million deaths could follow the aerosolized release of 100 kg of
anthrax spores upwind of the Washington, DC, arealethality matching or
exceeding that of a hydrogen bomb. 12
<http://jama.ama-assn.org/issues/v281n18/ffull/#r12>  An economic model
developed by the Centers for Disease Control and Prevention (CDC) suggested
a cost of $26.2 billion per 100,000 persons exposed. 13
<http://jama.ama-assn.org/issues/v281n18/ffull/#r13>



EPIDEMIOLOGY



Naturally occurring anthrax is a disease acquired following contact with
anthrax-infected animals or anthrax-contaminated animal products. The
disease most commonly occurs in herbivores, which are infected by ingesting
spores from the soil. Large anthrax epizootics in herbivores have been
reported; during a 1945 outbreak in Iran, 1 million sheep died. 14
<http://jama.ama-assn.org/issues/v281n18/ffull/#r14>  Animal vaccination
programs have reduced drastically the animal mortality from the disease. 15
<http://jama.ama-assn.org/issues/v281n18/ffull/#r15>  However, anthrax
spores continue to be documented in soil samples from throughout the world.
16-18 <http://jama.ama-assn.org/issues/v281n18/ffull/#r16>
In humans, 3 types of anthrax infection occur: inhalational, cutaneous, and
gastrointestinal. Naturally occurring inhalational anthrax is now a rare
cause of human disease. Historically, wool sorters at industrial mills were
at highest risk. Only 18 cases were reported in the United States from 1900
to 1978, with the majority occurring in special-risk groups, including goat
hair mill or goatskin workers and wool or tannery workers. Two of the 18
cases were laboratory associated. 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19>
Cutaneous anthrax is the most common naturally occurring form, with an
estimated 2000 cases reported annually. 18
<http://jama.ama-assn.org/issues/v281n18/ffull/#r18>  Disease typically
follows exposure to anthrax-infected animals. In the United States, 224
cases of cutaneous anthrax were reported between 1944 and 1994. 20
<http://jama.ama-assn.org/issues/v281n18/ffull/#r20>  The largest reported
epidemic occurred in Zimbabwe between 1979 and 1985, when more than 10,000
human cases of anthrax were reported, nearly all of them cutaneous. 21
<http://jama.ama-assn.org/issues/v281n18/ffull/#r21>
Gastrointestinal anthrax is uncommonly reported. 18
<http://jama.ama-assn.org/issues/v281n18/ffull/#r18> , 22
<http://jama.ama-assn.org/issues/v281n18/ffull/#r22> , 23
<http://jama.ama-assn.org/issues/v281n18/ffull/#r23>  However,
gastrointestinal outbreaks have been reported in Africa and Asia. 24
<http://jama.ama-assn.org/issues/v281n18/ffull/#r24>  Gastrointestinal
anthrax follows ingestion of insufficiently cooked contaminated meat and
includes 2 distinct syndromes, oral-pharyngeal and abdominal. 22
<http://jama.ama-assn.org/issues/v281n18/ffull/#r22> , 24-27
<http://jama.ama-assn.org/issues/v281n18/ffull/#r24>  In 1982, there were 24
cases of oral-pharyngeal anthrax in a rural northern Thailand outbreak
following the consumption of contaminated buffalo meat. 24
<http://jama.ama-assn.org/issues/v281n18/ffull/#r24>  In 1987, there were 14
cases of gastrointestinal anthrax reported in northern Thailand with both
oral-pharyngeal and abdominal disease occurring. 25
<http://jama.ama-assn.org/issues/v281n18/ffull/#r25>
No case of inhalational anthrax has been reported in the United States since
1978, 19 <http://jama.ama-assn.org/issues/v281n18/ffull/#r19> , 20
<http://jama.ama-assn.org/issues/v281n18/ffull/#r20>  making even a single
case a cause for alarm today. As was demonstrated at Sverdlovsk in 1979,
inhalational anthrax is expected to account for most morbidity and
essentially all mortality following the use of anthrax as an aerosolized
biological weapon. 8 <http://jama.ama-assn.org/issues/v281n18/ffull/#r8> ,
28 <http://jama.ama-assn.org/issues/v281n18/ffull/#r28>  In the setting of
an anthrax outbreak resulting from an aerosolized release, cutaneous anthrax
would be less common than inhalational anthrax, easier to recognize, simpler
to treat, and associated with a much lower mortality. In the Sverdlovsk
experience, there were no deaths in patients developing cutaneous anthrax. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  There is little
information available about the risks of direct contamination of food or
water with anthrax spores. Although human infections have been reported,
experimental efforts to infect primates by direct gastrointestinal
instillation of anthrax spores have not been successful. 29
<http://jama.ama-assn.org/issues/v281n18/ffull/#r29>



MICROBIOLOGY



Bacillus anthracis derives from the Greek word for coal, anthrakis, because
the disease causes black, coal-like skin lesions. Bacillus anthracis is an
aerobic, gram-positive, spore-forming, nonmotile Bacillus species. The
nonflagellated vegetative cell is large (1-8 µm in length, 1-1.5 µm in
breadth). Spore size is approximately 1 µm. Spores grow readily on all
ordinary laboratory media at 37°C, with a "jointed bamboo-rod" cellular
appearance and a unique "curled-hair" colonial appearance, and display no
hemolysis on sheep agar ( Figure 1
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f1.html> ). This
cellular and colonial morphology theoretically should make its
identification by an experienced microbiologist straightforward, although
few practicing microbiologists outside the veterinary community have seen
anthrax colonies other than in textbooks. 30
<http://jama.ama-assn.org/issues/v281n18/ffull/#r30>
Anthrax spores germinate when they enter an environment rich in amino acids,
nucleosides, and glucose, such as that found in the blood or tissues of an
animal or human host. The rapidly multiplying vegetative anthrax bacilli, on
the contrary, will only form spores after local nutrients are exhausted,
such as when anthrax-infected body fluids are exposed to ambient air. 16
<http://jama.ama-assn.org/issues/v281n18/ffull/#r16> , 17
<http://jama.ama-assn.org/issues/v281n18/ffull/#r17>  Full virulence
requires the presence of both an antiphagocytic capsule and 3 toxin
components (ie, protective antigen, lethal factor, and edema factor). 30
<http://jama.ama-assn.org/issues/v281n18/ffull/#r30>  Vegetative bacteria
have poor survival outside of an animal or human host; colony counts decline
to undetectable within 24 hours following inoculation into water. 17
<http://jama.ama-assn.org/issues/v281n18/ffull/#r17>  This contrasts with
the environmentally hardy properties of the B anthracis spore, which can
survive for decades. 30 <http://jama.ama-assn.org/issues/v281n18/ffull/#r30>



PATHOGENESIS AND CLINICAL MANIFESTATIONS



Inhalational Anthrax

Inhalational anthrax follows deposition of spore-bearing particles of 1 to 5
µm into alveolar spaces. 31
<http://jama.ama-assn.org/issues/v281n18/ffull/#r31> , 32
<http://jama.ama-assn.org/issues/v281n18/ffull/#r32>  Macrophages ingest the
spores, some of which undergo lysis and destruction. Surviving spores are
transported via lymphatics to mediastinal lymph nodes, where germination may
occur up to 60 days later. 28
<http://jama.ama-assn.org/issues/v281n18/ffull/#r28> , 29
<http://jama.ama-assn.org/issues/v281n18/ffull/#r29> , 33
<http://jama.ama-assn.org/issues/v281n18/ffull/#r33>  The process
responsible for the delayed transformation of spores to vegetative cells is
poorly understood but well documented. In Sverdlovsk, cases occurred from 2
to 43 days after exposure. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  In experimental
monkeys, fatal disease occurred up to 58 days 28
<http://jama.ama-assn.org/issues/v281n18/ffull/#r28>  and 98 days 34
<http://jama.ama-assn.org/issues/v281n18/ffull/#r34>  after exposure. Viable
spores have been demonstrated in the mediastinal lymph nodes of monkeys 100
days after exposure. 35 <http://jama.ama-assn.org/issues/v281n18/ffull/#r35>
Once germination occurs, disease follows rapidly. Replicating bacteria
release toxins leading to hemorrhage, edema, and necrosis. 23
<http://jama.ama-assn.org/issues/v281n18/ffull/#r23> , 36
<http://jama.ama-assn.org/issues/v281n18/ffull/#r36>  In experimental
animals, once toxin production has reached critical threshold, death occurs
even if sterility of the bloodstream is achieved with antibiotics. 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19>  Based on primate data,
it has been estimated that for humans the LD 50 (lethal dose sufficient to
kill 50% of persons exposed to it) is 2500 to 55,000 inhaled anthrax spores.
37 <http://jama.ama-assn.org/issues/v281n18/ffull/#r37>
The term inhalational anthrax reflects the nature of acquisition of the
disease. The term anthrax pneumonia is misleading. Typical bronchopneumonia
does not occur. Postmortem pathological study of patients who died because
of inhalational anthrax in Sverdlovsk showed hemorrhagic thoracic
lymphadenitis and hemorrhagic mediastinitis in all patients. In up to half
of the patients, hemorrhagic meningitis also was seen. No patients who
underwent autopsy had evidence of a bronchoalveolar pneumonic process,
although 11 of 42 patients undergoing autopsy had evidence of a focal,
hemorrhagic, necrotizing pneumonic lesion analogous to the Ghon complex
associated with tuberculosis. 38
<http://jama.ama-assn.org/issues/v281n18/ffull/#r38>  These findings are
consistent with other human case series and experimentally induced
inhalational anthrax in animals. 33
<http://jama.ama-assn.org/issues/v281n18/ffull/#r33> , 39
<http://jama.ama-assn.org/issues/v281n18/ffull/#r39> , 40
<http://jama.ama-assn.org/issues/v281n18/ffull/#r40>
Early diagnosis of inhalational anthrax would be difficult and would require
a high index of suspicion. Clinical information is available from only some
of the 18 cases reported in the United States in this century and from the
limited available information from Sverdlovsk. The clinical presentation has
been described as a 2-stage illness. Patients first developed a spectrum of
nonspecific symptoms, including fever, dyspnea, cough, headache, vomiting,
chills, weakness, abdominal pain, and chest pain. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8> , 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19>  Signs of illness and
laboratory studies were nonspecific. This stage of illness lasted from hours
to a few days. In some patients, a brief period of apparent recovery
followed. Other patients progressed directly to the second, fulminant stage
of illness. 2 <http://jama.ama-assn.org/issues/v281n18/ffull/#r2> , 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19> , 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41>
This second stage developed abruptly, with sudden fever, dyspnea,
diaphoresis, and shock. Massive lymphadenopathy and expansion of the
mediastinum led to stridor in some cases. 42
<http://jama.ama-assn.org/issues/v281n18/ffull/#r42> , 43
<http://jama.ama-assn.org/issues/v281n18/ffull/#r43>  A chest radiograph
most often showed a widened mediastinum consistent with lymphadenopathy
 Figure 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f2.html> ). 42
<http://jama.ama-assn.org/issues/v281n18/ffull/#r42>  Up to half of patients
developed hemorrhagic meningitis with concomitant meningismus, delirium, and
obtundation. In this second stage of illness, cyanosis and hypotension
progress rapidly; death sometimes occurs within hours. 2
<http://jama.ama-assn.org/issues/v281n18/ffull/#r2> , 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19> , 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41>
The mortality rate of occupationally acquired cases in the United States is
89%, but the majority of cases occurred before the development of critical
care units and, in some cases, before the advent of antibiotics. 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19>  At Sverdlovsk, it is
reported that 68 of the 79 patients with inhalational anthrax died, although
the reliability of the diagnosis in the survivors is questionable. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  Patients who had onset
of disease 30 or more days after release of organisms had a higher reported
survival rate compared with those with earlier disease onset. Antibiotics,
antianthrax globulin, and vaccine were used to treat some residents in the
affected area some time after exposure, but which patients received these
interventions and when is not known. In fatal cases, the interval between
onset of symptoms and death averaged 3 days. This is similar to the disease
course and case fatality rate in untreated experimental monkeys, which have
developed rapidly fatal disease even after a latency as long as 58 days. 28
<http://jama.ama-assn.org/issues/v281n18/ffull/#r28>
Modern mortality rates in the setting of contemporary medical and supportive
therapy might be lower than those reported historically. However, the 1979
Sverdlovsk experience is not instructive. Although antibiotics, antianthrax
globulin, corticosteroids, and mechanical ventilation were used, individual
clinical records have not been made public. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  It is also uncertain if
the B anthracis strain to which patients were exposed was susceptible to the
predominant antibiotics that were used during the outbreak.
Physiological sequelae of severe anthrax infection in animal models have
been described as hypocalcemia, profound hypoglycemia, hyperkalemia,
depression and paralysis of respiratory center, hypotension, anoxia,
respiratory alkalosis, and terminal acidosis. 44
<http://jama.ama-assn.org/issues/v281n18/ffull/#r44> , 45
<http://jama.ama-assn.org/issues/v281n18/ffull/#r45>  Those animal studies
suggest that in addition to the rapid administration of antibiotics,
survival might improve with vigilant correction of electrolyte disturbances
and acid-base imbalance, glucose infusion, and early mechanical ventilation
and vasopressor administration.
Cutaneous Anthrax

Cutaneous anthrax occurs following the deposition of the organism into skin
with previous cuts or abrasions especially susceptible to infection. 21
<http://jama.ama-assn.org/issues/v281n18/ffull/#r21> , 46
<http://jama.ama-assn.org/issues/v281n18/ffull/#r46>  Areas of exposed skin,
such as arms, hands, face, and neck, are the most frequently affected. There
are no data to suggest the possibility of a prolonged latency period in
cutaneous anthrax. In Sverdlovsk, cutaneous cases occurred only as late as
12 days after the original aerosol release. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  After the spore
germinates in skin tissues, toxin production results in local edema ( Figure
3 <http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f3.html> ). An
initially pruritic macule or papule enlarges into a round ulcer by the
second day. Subsequently, 1- to 3-mm vesicles may appear, which discharge
clear or serosanguinous fluid containing numerous organisms on Gram stain.
As shown in Figure 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f3.html> ,
development of a painless, depressed, black eschar follows, often associated
with extensive local edema. The eschar dries, loosens, and falls off in the
next 1 to 2 weeks, most often leaving no permanent scar. Lymphangitis and
painful lymphadenopathy can occur with associated systemic symptoms.
Although antibiotic therapy does not appear to change the course of eschar
formation and healing, it does decrease the likelihood of systemic disease.
Without antibiotic therapy, the mortality rate has been reported to be as
high as 20%; with antibiotics, death due to cutaneous anthrax is rare. 2
<http://jama.ama-assn.org/issues/v281n18/ffull/#r2>
Gastrointestinal Anthrax

Gastrointestinal anthrax occurs following deposition and subsequent
germination of spores in the upper or lower gastrointestinal tract. The
former results in the oral-pharyngeal form of disease. 24-26
<http://jama.ama-assn.org/issues/v281n18/ffull/#r24>  An oral or esophageal
ulcer leads to development of regional lymphadenopathy, edema, and sepsis.
24-26 <http://jama.ama-assn.org/issues/v281n18/ffull/#r24>  The latter
results in primary intestinal lesions occurring predominantly in the
terminal ileum or cecum, 38
<http://jama.ama-assn.org/issues/v281n18/ffull/#r38>  presenting initially
with nausea, vomiting, and malaise and progressing rapidly to bloody
diarrhea, acute abdomen, or sepsis. 22
<http://jama.ama-assn.org/issues/v281n18/ffull/#r22>  Massive ascites has
occurred in some cases of gastrointestinal anthrax. 27
<http://jama.ama-assn.org/issues/v281n18/ffull/#r27>  Advanced infection may
appear similar to the sepsis syndrome occurring in either inhalational or
cutaneous anthrax. 2 <http://jama.ama-assn.org/issues/v281n18/ffull/#r2>
Some authors suggest that aggressive medical intervention such as would be
recommended for inhalational anthrax may reduce mortality, although, given
the difficulty of early diagnosis, mortality almost inevitably would be
high. 2 <http://jama.ama-assn.org/issues/v281n18/ffull/#r2> , 22
<http://jama.ama-assn.org/issues/v281n18/ffull/#r22>



DIAGNOSIS



Given the rarity of anthrax infection and the possibility that early cases
are a harbinger of a larger epidemic, the first suspicion of an anthrax
illness must lead to immediate notification of the local or state health
department, local hospital epidemiologist, and local or state health
laboratory. By this mechanism, definitive tests can be arranged rapidly
through a reference laboratory and, as necessary, the US Army Medical
Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Md.
The first evidence of a clandestine release of anthrax as a biological
weapon most likely will be patients seeking medical treatment for symptoms
of inhalational anthrax. The sudden appearance of a large number of patients
in a city or region with an acute-onset flulike illness and case fatality
rates of 80% or more, with nearly half of all deaths occurring within 24 to
48 hours, is highly likely to be anthrax or pneumonic plague ( Table 1
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t1.html> ).
Currently, there are no effective atmospheric warning systems to detect an
aerosol cloud of anthrax spores. 47
<http://jama.ama-assn.org/issues/v281n18/ffull/#r47>
Rapid diagnostic tests for diagnosing anthrax, such as enzyme-linked
immunosorbent assay for protective antigen and polymerase chain reaction,
are available only at national reference laboratories. Given the limited
availability of these tests and the time required to dispatch specimens and
perform assays, rapid diagnostic testing would be primarily for confirmation
of diagnosis and determining in vitro susceptibility to antibiotics. In
addition, these tests will be used in the investigation and management of
anthrax hoaxes, such as the series occurring in late 1998. 48
<http://jama.ama-assn.org/issues/v281n18/ffull/#r48>  They would also be of
value should suspicious materials in the possession of a terrorist be
identified as possibly containing anthrax.
If only small numbers of cases present contemporaneously, the clinical
similarity of early inhalational anthrax to other acute respiratory tract
infections may delay initial diagnosis for some days. However, diagnosis of
anthrax could soon become apparent through the astute recognition of an
unusual radiological finding, identification in the microbiology laboratory,
or recognition of specific pathologic findings. A widened mediastinum on
chest radiograph ( Figure 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f2.html> ) in a
previously healthy patient with evidence of overwhelming flulike illness is
essentially pathognomonic of advanced inhalational anthrax and should prompt
immediate action. 23 <http://jama.ama-assn.org/issues/v281n18/ffull/#r23> ,
42 <http://jama.ama-assn.org/issues/v281n18/ffull/#r42>  Although treatment
at this stage would be unlikely to alter the outcome of illness in the
patient concerned, it might lead to earlier diagnosis in others.
Microbiologic studies can also demonstrate B anthracis and may be the means
for initial detection of an outbreak. The bacterial burden may be so great
in advanced infection that bacilli are visible on Gram stain of unspun
peripheral blood, as has been demonstrated in primate studies ( Figure 1
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f1.html> ). While
this is a remarkable finding that would permit an astute clinician or
microbiologist to make the diagnosis, the widespread use of automated
cell-counter technology in diagnostic laboratories makes this unlikely. 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41>
The most useful microbiologic test is the standard blood culture, which
should show growth in 6 to 24 hours. If the laboratory has been alerted to
the possibility of anthrax, biochemical testing and review of colonial
morphology should provide a preliminary diagnosis 12 to 24 hours later.
Definitive diagnosis would require an additional 1 to 2 days of testing in
all but a few national reference laboratories. It should be noted, however,
that if the laboratory has not been alerted to the possibility of anthrax, B
anthracis may not be correctly identified. Routine laboratory procedures
customarily identify a Bacillus species from a blood culture approximately
24 hours after growth, but most laboratories do not further identify
Bacillus species unless specifically requested to do so. In the United
States, the isolation of Bacillus species most often represents growth of
Bacillus cereus. The laboratory and clinician must determine whether its
isolation represents specimen contamination. 49
<http://jama.ama-assn.org/issues/v281n18/ffull/#r49>  There have been no B
anthracis bloodstream infections reported for more than 20 years. However,
given the possibility of anthrax being used as a weapon and the importance
of early diagnosis, it would be prudent for laboratory procedures to be
modified so that B anthracis is excluded after identification of a Bacillus
species bacteremia.
Sputum culture and Gram stain are unlikely to be diagnostic, given the lack
of a pneumonic process. 30
<http://jama.ama-assn.org/issues/v281n18/ffull/#r30>  If cutaneous anthrax
is suspected, a Gram stain and culture of vesicular fluid will confirm the
diagnosis.
A diagnosis of inhalational anthrax also might occur at postmortem
examination following a rapid, unexplained terminal illness. Thoracic
hemorrhagic necrotizing lymphadenitis and hemorrhagic necrotizing
mediastinitis in a previously healthy adult are essentially pathognomonic of
inhalational anthrax. 38
<http://jama.ama-assn.org/issues/v281n18/ffull/#r38> , 43
<http://jama.ama-assn.org/issues/v281n18/ffull/#r43>  Hemorrhagic meningitis
should also raise strong suspicion of anthrax infection. 23
<http://jama.ama-assn.org/issues/v281n18/ffull/#r23> , 38
<http://jama.ama-assn.org/issues/v281n18/ffull/#r38> , 43
<http://jama.ama-assn.org/issues/v281n18/ffull/#r43> , 50
<http://jama.ama-assn.org/issues/v281n18/ffull/#r50>  Despite pathognomonic
features of anthrax on gross postmortem examination, the rarity of anthrax
makes it unlikely that a pathologist would immediately recognize these
findings. If the case were not diagnosed at gross examination, additional
days would likely pass before microscopic slides would be available to
suggest the disease etiology.



VACCINATION



The US anthrax vaccine, an inactivated cell-free product, was licensed in
1970 and is produced by Bioport Corp, Lansing, Mich (formerly called the
Michigan Biologic Products Institute). The vaccine is licensed to be given
in a 6-dose series and has recently been mandated for all US military
active- and reserve-duty personnel. 51
<http://jama.ama-assn.org/issues/v281n18/ffull/#r51>  The vaccine is made
from the cell-free filtrate of a nonencapsulated attenuated strain of B
anthracis. 52 <http://jama.ama-assn.org/issues/v281n18/ffull/#r52>  The
principal antigen responsible for inducing immunity is the protective
antigen. 18 <http://jama.ama-assn.org/issues/v281n18/ffull/#r18> , 23
<http://jama.ama-assn.org/issues/v281n18/ffull/#r23>  A similar vaccine has
been shown in 1 small placebo-controlled human trial to be efficacious
against cutaneous anthrax. 53
<http://jama.ama-assn.org/issues/v281n18/ffull/#r53>  As of March 1, 1999,
approximately 590,000 doses of anthrax vaccine have been administered to US
Armed Forces (Gary Strawder, Department of Defense, Falls Church, Va, oral
communication, April 1999); no serious adverse events have been causally
related (Miles Braun, Food and Drug Administration, Rockville, Md, written
communication, April 1999). In a study of experimental monkeys, inoculation
with this vaccine at 0 and 2 weeks was completely protective against an
aerosol challenge at 8 and 38 weeks and 88% effective at 100 weeks. 54
<http://jama.ama-assn.org/issues/v281n18/ffull/#r54>
A human live attenuated vaccine is produced and used in countries of the
former Soviet Union. 55 <http://jama.ama-assn.org/issues/v281n18/ffull/#r55>
In the Western world, live attenuated vaccines have been considered
unsuitable for use in humans. 55
<http://jama.ama-assn.org/issues/v281n18/ffull/#r55>
Current vaccine supplies are limited and the US production capacity is
modest. It will be years before increased production efforts can make
available sufficient quantities of vaccine for civilian use. However, even
if vaccine were available, populationwide vaccination would not be
recommended at this time, given the costs and logistics of a large-scale
vaccination program and the unlikely occurrence of a bioterrorist attack in
any given community. Vaccination of some essential service personnel should
be considered if vaccine becomes available. Postexposure vaccination
following a biological attack with anthrax would be recommended with
antibiotic administration to protect against residual retained spores, if
vaccine were available.



THERAPY



Recommendations regarding antibiotic and vaccine use in the setting of a
biological anthrax attack are conditioned by a limited number of studies in
experimental animals, current understanding of antibiotic resistance
patterns, and the possible requirement to treat large numbers of casualties.
A number of possible therapeutic strategies have yet to be fully explored
experimentally or submitted for approval to the FDA. For these reasons, the
working group offers consensus recommendations based on the best available
evidence. The recommendations do not represent uses currently approved by
the FDA or an official position on the part of any of the federal agencies
whose scientists participated in these discussions and will need to be
revised as further relevant information becomes available.
Given the rapid course of symptomatic inhalational anthrax, early antibiotic
administration is essential. A delay of antibiotic treatment for patients
with anthrax infection even by hours may substantially lessen chances for
survival. 56 <http://jama.ama-assn.org/issues/v281n18/ffull/#r56> , 57
<http://jama.ama-assn.org/issues/v281n18/ffull/#r57>  Given the difficulty
in achieving rapid microbiologic diagnosis of anthrax, all persons with
fever or evidence of systemic disease in an area where anthrax cases are
occurring should be treated for anthrax until the disease is excluded.
There are no clinical studies of the treatment of inhalational anthrax in
humans. Thus, antibiotic regimens commonly recommended for empirical
treatment of sepsis have not been studied in this setting. In fact, natural
strains of B anthracis are resistant to many of the antibiotics used in
these empirical regimens, such as those of the extended-spectrum
cephalosporins. 58 <http://jama.ama-assn.org/issues/v281n18/ffull/#r58> , 59
<http://jama.ama-assn.org/issues/v281n18/ffull/#r59>  Most naturally
occurring anthrax strains are sensitive to penicillin, and penicillin
historically has been the preferred therapy for the treatment of anthrax.
Penicillin is approved by the FDA for this indication, 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41> , 56
<http://jama.ama-assn.org/issues/v281n18/ffull/#r56> , 57
<http://jama.ama-assn.org/issues/v281n18/ffull/#r57>  as is doxycycline. 60
<http://jama.ama-assn.org/issues/v281n18/ffull/#r60>  In studies of small
numbers of monkeys infected with susceptible strains of B anthracis, oral
doxycycline has proved efficacious. 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41>
Doxycycline is the preferred option from the tetracycline class of
antibiotics because of its proven efficacy in monkey studies and its ease of
administration. Other members of this class of antibiotics are suitable
alternatives. Although treatment of anthrax infection with ciprofloxacin has
not been studied in humans, animal models suggest excellent efficacy. 28
<http://jama.ama-assn.org/issues/v281n18/ffull/#r28> , 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41> , 61
<http://jama.ama-assn.org/issues/v281n18/ffull/#r61>  In vitro data suggest
that other fluoroquinolone antibiotics would have equivalent efficacy in
treating anthrax infection, although no animal data exist for
fluoroquinolones other than ciprofloxacin. 59
<http://jama.ama-assn.org/issues/v281n18/ffull/#r59>
Reports have been published of a B anthracis vaccine strain that has been
engineered by Russian scientists to resist the tetracycline and penicillin
classes of antibiotics. 62
<http://jama.ama-assn.org/issues/v281n18/ffull/#r62>  Although the
engineering of quinolone-resistant B anthracis may also be possible, to date
there have been no published accounts of this.
Balancing considerations of efficacy with concerns regarding resistance, the
working group recommends that ciprofloxacin or other fluoroquinolone therapy
be initiated in adults with presumed inhalational anthrax infection.
Antibiotic resistance to penicillin- and tetracycline-class antibiotics
should be assumed following a terrorist attack until laboratory testing
demonstrates otherwise. Once the antibiotic susceptibility of the B
anthracis strain of the index case has been determined, the most widely
available, efficacious, and least toxic antibiotic should be administered to
patients and persons requiring postexposure prophylaxis.
In a contained casualty setting (a situation in which a modest number of
patients require therapy), the working group recommends intravenous
antibiotic therapy, as shown in Table 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html> . If the
number of persons requiring therapy is sufficiently high (ie, a mass
casualty setting), the working group recognizes that intravenous therapy
will no longer be possible for reasons of logistics and/or exhaustion of
equipment and antibiotic supplies, and oral therapy will need to be used
 Table 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html> ). The
threshold number of cases at which parenteral therapy becomes impossible
depends on a variety of factors, including local and regional health care
resources.
In experimental animals, antibiotic therapy during anthrax infection has
prevented development of an immune response. 28
<http://jama.ama-assn.org/issues/v281n18/ffull/#r28> , 62
<http://jama.ama-assn.org/issues/v281n18/ffull/#r62>  This suggests that
even if the antibiotic-treated patient survives anthrax infection, risk for
recurrence remains for at least 60 days because of the possibility of
delayed germination of spores. Therefore, the working group recommends that
antibiotic therapy be continued for 60 days, with oral therapy replacing
intravenous therapy as soon as a patient's clinical condition improves. If
vaccine were to become widely available, postexposure vaccination in
patients being treated for anthrax infection might permit the duration of
antibiotic administration to be shortened to 30 to 45 days, with concomitant
administration of 3 doses of anthrax vaccine at 0, 2, and 4 weeks.
The treatment of cutaneous anthrax historically has been with oral
penicillin. The working group recommends that oral fluoroquinolone or
tetracycline antibiotics as well as amoxicillin in the adult dosage
schedules described in Table 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html>  and
Table 3 <http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html>
would be suitable alternatives if antibiotic susceptibility is proved.
Although previous guidelines have suggested treating cutaneous anthrax for 7
to 10 days, 23 <http://jama.ama-assn.org/issues/v281n18/ffull/#r23> , 49
<http://jama.ama-assn.org/issues/v281n18/ffull/#r49>  the working group
recommends treatment for 60 days in the setting of bioterrorism, given the
presumed exposure to the primary aerosol. Treatment of cutaneous anthrax
generally prevents progression to systemic disease, although it does not
prevent the formation and evolution of the eschar. Topical therapy is not
useful. 2 <http://jama.ama-assn.org/issues/v281n18/ffull/#r2>
Other antibiotics effective against B anthracis in vitro include
chloramphenicol, erythromycin, clindamycin, extended-spectrum penicillins,
macrolides, aminoglycosides, vancomycin hydrochloride, cefazolin, and other
first-generation cephalosporins. 58
<http://jama.ama-assn.org/issues/v281n18/ffull/#r58> , 59
<http://jama.ama-assn.org/issues/v281n18/ffull/#r59> , 64
<http://jama.ama-assn.org/issues/v281n18/ffull/#r64>  The efficacy of these
antibiotics has not been tested in humans or animal studies. The working
group recommends the use of these antibiotics only if the previously cited
antibiotics are unavailable or if the strain is otherwise antibiotic
resistant. Natural resistance of B anthracis strains exists against
sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime sodium, aztreonam,
and ceftazidime. 58 <http://jama.ama-assn.org/issues/v281n18/ffull/#r58> ,
59 <http://jama.ama-assn.org/issues/v281n18/ffull/#r59> , 64
<http://jama.ama-assn.org/issues/v281n18/ffull/#r64>  Therefore, these
antibiotics should not be used in the treatment or prophylaxis of anthrax
infection.
Postexposure Prophylaxis

Guidelines regarding which populations would require postexposure
prophylaxis following the release of anthrax as a biological weapon would
need to be developed quickly by state and local health departments in
consultation with national experts. These decisions require estimates of the
timing and location of the exposure and the relevant weather conditions in
an outdoor release. 65 <http://jama.ama-assn.org/issues/v281n18/ffull/#r65>
Ongoing monitoring of cases would be needed to define the high-risk areas,
direct follow-up, and guide the addition or deletion of groups to receive
postexposure prophylaxis.
There are no FDA-approved postexposure antibiotic regimens following
exposure to an anthrax aerosol. For postexposure prophylaxis, the working
group recommends the same antibiotic regimen as that recommended for
treatment of mass casualties; prophylaxis should be continued for 60 days
 Table 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html> ).
Management of Special Groups

Consensus recommendations for special groups as set forth herein reflect the
clinical and evidence-based judgments of the working group and at this time
do not necessarily correspond with FDA-approved use, indications, or
labeling.
Children.
It has been recommended that ciprofloxacin and other fluoroquinolones should
not be used in children younger than 16 to 18 years because of a link to
permanent arthropathy in adolescent animals and transient arthropathy in a
small number of children. 60
<http://jama.ama-assn.org/issues/v281n18/ffull/#r60>  However, balancing
these risks against the risks of anthrax caused by an engineered
antibiotic-resistant strain, the working group recommends that ciprofloxacin
be used in the pediatric population for initial therapy or postexposure
prophylaxis following an anthrax attack ( Table 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html> ). If
antibiotic susceptibility testing allows, penicillin should be substituted
for the fluoroquinolone.
As a third alternative, doxycycline could be used. The American Academy of
Pediatrics has recommended that doxycycline not be used in children younger
than 9 years because the drug has resulted in retarded skeletal growth in
infants and discolored teeth in infants and children. 60
<http://jama.ama-assn.org/issues/v281n18/ffull/#r60>  However, the serious
risk of infection following an anthrax attack supports the consensus
recommendation that doxycycline be used in children if antibiotic
susceptibility testing, exhaustion of drug supplies, or allergic reaction
preclude use of penicillin and ciprofloxacin.
In a contained casualty setting, the working group recommends that children
receive intravenous antibiotics ( Table 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html> ). In a
mass casualty setting and as postexposure prophylaxis, the working group
recommends that children receive oral antibiotics ( Table 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html> ).
The US vaccine is licensed for use only in persons aged 18 to 65 years
because studies to date have been conducted exclusively in this group. 52
<http://jama.ama-assn.org/issues/v281n18/ffull/#r52>  No data exist for
children, but based on experience with other inactivated vaccines, it is
likely that the vaccine would be safe and effective.
Pregnant Women.
Fluoroquinolones are not generally recommended during pregnancy because of
their known association with arthropathy in adolescent animals and small
numbers of children. Animal studies have discovered no evidence of
teratogenicity related to ciprofloxacin, but no controlled studies of
ciprofloxacin in pregnant women have been conducted. Balancing these
possible risks against the concerns of anthrax due to engineered
antibiotic-resistant strains, the working group recommends that
ciprofloxacin be used in pregnant women for therapy and postexposure
prophylaxis following an anthrax attack ( Table 2
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html>  and
Table 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html> ). No
adequate controlled trials of penicillin or amoxicillin administration
during pregnancy exist. However, the CDC recommends penicillin for the
treatment of syphilis during pregnancy and amoxicillin as a treatment
alternative for chlamydial infections during pregnancy. 60
<http://jama.ama-assn.org/issues/v281n18/ffull/#r60>
The working group recommends that pregnant women receive fluoroquinolones in
the usual adult dosages. If susceptibility testing allows, intravenous
penicillin in the usual adult dosages should be substituted for
fluoroquinolones. As a third alternative, intravenous doxycycline could be
used. The tetracycline class of antibiotics has been associated with both
toxic effects in the liver in pregnant women and fetal toxic effects,
including retarded skeletal growth. 60
<http://jama.ama-assn.org/issues/v281n18/ffull/#r60>  Balancing the risks of
anthrax infection with those associated with doxycycline use in pregnancy,
the working group recommends that doxycycline be used in pregnant women for
therapy and postexposure prophylaxis if antibiotic susceptibility testing,
exhaustion of drug supplies, or allergic sensitivity preclude the use of
penicillin and ciprofloxacin. If doxycycline is used in pregnant women,
periodic liver function testing should be performed if possible.
Ciprofloxacin (and other fluoroquinolones), penicillin, and doxycycline (and
other tetracyclines) are each excreted in breast milk. Therefore, a
breast-feeding woman should be treated or given prophylaxis with the same
antibiotic as her infant based on what is most safe and effective for the
infant (see pediatric guidelines herein) to minimize risk to the infant.
Immunosuppressed Persons.
The antibiotic treatment or postexposure prophylaxis for anthrax among those
who are immunosuppressed has not been studied in human or animal models of
anthrax infection. Therefore, the working group consensus recommendation is
to administer antibiotics as for immunocompetent adults and children ( Table
2 <http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t2.html>  and
Table 3
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_t3.html> ).



INFECTION CONTROL



There are no data to suggest patient-to-patient transmission of anthrax
occurs. 8 <http://jama.ama-assn.org/issues/v281n18/ffull/#r8> , 46
<http://jama.ama-assn.org/issues/v281n18/ffull/#r46>  Thus, standard barrier
isolation precautions are recommended for hospitalized patients with all
forms of anthrax infection, but the use of high-efficiency particulate air
filter masks or other measures for airborne protection are not indicated. 66
<http://jama.ama-assn.org/issues/v281n18/ffull/#r66>  There is no need to
immunize or provide prophylaxis to patient contacts (eg, household contacts,
friends, coworkers) unless a determination is made that they, like the
patient, were exposed to the aerosol at the time of the attack.
In addition to immediate notification of the hospital epidemiologist and
state health department, the local hospital microbiology laboratories should
be notified at the first indication of anthrax so that safe specimen
processing under biosafety level 2 conditions can be undertaken. 41
<http://jama.ama-assn.org/issues/v281n18/ffull/#r41> , 67
<http://jama.ama-assn.org/issues/v281n18/ffull/#r67>  A number of
disinfectants used for standard hospital infection control, such as
hypochlorite, are effective in cleaning environmental surfaces contaminated
with infected bodily fluids. 17
<http://jama.ama-assn.org/issues/v281n18/ffull/#r17> , 66
<http://jama.ama-assn.org/issues/v281n18/ffull/#r66>
Proper burial or cremation of humans and animals who have died because of
anthrax infection is important in preventing further transmission of the
disease. Serious consideration should be given to cremation. Embalming of
bodies could be associated with special risks. 66
<http://jama.ama-assn.org/issues/v281n18/ffull/#r66>  If autopsies are
performed, all related instruments and materials should be autoclaved or
incinerated. 66 <http://jama.ama-assn.org/issues/v281n18/ffull/#r66>  Animal
transmission might occur if infected animal remains are not cremated or
buried. 16 <http://jama.ama-assn.org/issues/v281n18/ffull/#r16> , 21
<http://jama.ama-assn.org/issues/v281n18/ffull/#r21>



DECONTAMINATION



Recommendations regarding decontamination in the event of an intentional
aerosolization of anthrax spores are based on evidence concerning
aerosolization, anthrax spore survival, and environmental exposures at
Sverdlovsk and among goat hair mill workers. The greatest risk to human
health following an intentional aerosolization of anthrax spores occurs
during the period in which anthrax spores remain airborne, called primary
aerosolization. The duration for which spores remain airborne and the
distance spores travel before they become noninfectious or fall to the
ground is dependent on meteorological conditions and aerobiological
properties of the dispersed aerosol. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8> , 65
<http://jama.ama-assn.org/issues/v281n18/ffull/#r65>  Under circumstances of
maximum survival and persistence, the aerosol would be fully dispersed
within hours to 1 day at most, well before the first symptomatic cases would
be seen. Following the discovery that a bioweapon has been used, anthrax
spores may be detected on environmental surfaces using rapid assay kits or
culture, but they provide no indication as to the risk of reaerosolization.
The risk that anthrax spores might pose to public health after the period of
primary aerosolization can be inferred from the Sverdlovsk experience,
investigations in animal hair processing plants, and modeling analyses by
the US Army. At Sverdlovsk, new cases of inhalational anthrax developed as
late as 43 days after the presumed date of release, but none occurred during
the months and years afterward. 68
<http://jama.ama-assn.org/issues/v281n18/ffull/#r68>  Some have questioned
whether any of those cases with onset of disease beyond 7 days might have
represented illness following resuspension of spores from the ground or
other surfaces, a process that has been called secondary aerosolization.
While it is impossible to state with certainty that secondary
aerosolizations did not occur, it appears unlikely. It should be noted that
few efforts were made to decontaminate the environment after the accident
and only 47,000 of the city's 1 million inhabitants were vaccinated. 8
<http://jama.ama-assn.org/issues/v281n18/ffull/#r8>  The epidemic curve
 Figure 4
<http://jama.ama-assn.org/issues/v281n18/fig_tab/jst80027_f4.html> ) is
typical for a common-source epidemic, and it is possible to account for
virtually all patients having been within the area of the plume on the day
of the accident. Moreover, if secondary aerosolization had been important,
new cases almost certainly would have continued for a period well beyond the
observed 43 days.
Although persons working with animal hair or hides are known to be at
increased risk of developing inhalational or cutaneous anthrax, surprisingly
few of those exposed in the United States have developed disease. During the
first half of this century, a significant number of goat hair mill workers
were likely exposed to aerosolized spores. Mandatory vaccination became a
requirement for working in goat hair mills only in the 1960s. Meanwhile,
many unvaccinated person-years of high-risk exposure had occurred, but only
13 cases of inhalational anthrax were reported. 19
<http://jama.ama-assn.org/issues/v281n18/ffull/#r19> , 44
<http://jama.ama-assn.org/issues/v281n18/ffull/#r44>  One study of
environmental exposure was conducted at a Pennsylvania goat hair mill at
which workers were shown to inhale up to 510 B anthracis particles of at
least 5 µm in diameter per person per 8-hour shift. These concentrations of
spores were constantly present in the environment during the time of this
study, 44 <http://jama.ama-assn.org/issues/v281n18/ffull/#r44>  but no cases
of inhalational anthrax occurred.
Modeling analyses have been carried out by US Army scientists seeking to
determine the risk of secondary aerosolization. One study concluded that
there was no significant threat to personnel in areas contaminated by 1
million spores per square meter either from traffic on asphalt-paved roads
or from a runway used by helicopters or jet aircraft. 69
<http://jama.ama-assn.org/issues/v281n18/ffull/#r69>  A separate study
showed that in areas of ground contaminated with 20 million Bacillus
subtilis spores per square meter, a soldier exercising actively for a 3-hour
period would inhale between 1000 and 15,000 spores. 70
<http://jama.ama-assn.org/issues/v281n18/ffull/#r70>
Much has been written about the technical difficulty of decontaminating an
environment contaminated with anthrax spores. A classic case is the
experience at Gruinard Island in the United Kingdom. During World War II,
British military undertook explosives testing with anthrax spores on this
island off the Scottish coast. Spores persisted and remained viable for 36
years following the conclusion of testing. Decontamination of the island
occurred in stages, beginning in 1979 and ending in 1987, when the island
was finally declared fully decontaminated. The total cost is unpublished,
but materials required included 280 tons of formaldehyde and 2000 tons of
seawater. 17 <http://jama.ama-assn.org/issues/v281n18/ffull/#r17> , 71
<http://jama.ama-assn.org/issues/v281n18/ffull/#r71>
If an environmental surface is proved to be heavily contaminated with
anthrax spores in the immediate area of a spill or close proximity to the
point of release of an anthrax aerosol, decontamination of that area may
decrease the slight risk of acquiring anthrax by secondary aerosolization.
However, decontamination of large urban areas or even a building following
an exposure to an anthrax aerosol would be extremely difficult and is not
indicated. Although the risk of disease caused by secondary aerosolization
would be extremely low, it would be difficult to offer absolute assurance
that there was not risk whatsoever. Postexposure vaccination, if vaccine
were available, might be a possible intervention that could further lower
the risk of anthrax infection in this setting.
In the setting of an announced alleged anthrax release, such as the series
of anthrax hoaxes occurring in many areas of the United States in 1998, 48
<http://jama.ama-assn.org/issues/v281n18/ffull/#r48>  any person coming in
direct physical contact with a substance alleged to be anthrax should
perform thorough washing of the exposed skin and articles of clothing with
soap and water. 72 <http://jama.ama-assn.org/issues/v281n18/ffull/#r72>
Further decontamination of directly exposed individuals or of others is not
indicated. In addition, any person in direct physical contact with the
alleged substance should receive postexposure antibiotic prophylaxis until
the substance is proved not to be anthrax. If the alleged substance is
proved to be anthrax, immediate consultation with experts at the CDC and
USAMRIID should be obtained.



ADDITIONAL RESEARCH



To develop a maximally effective response to a bioterrorist incident
involving anthrax, the medical community will require new knowledge of the
organism, its genetics and pathogenesis, improved rapid diagnostic
techniques, improved prophylactic and therapeutic regimens, and an improved
second-generation vaccine. 47
<http://jama.ama-assn.org/issues/v281n18/ffull/#r47>  A recently published
Russian study indicates that genes transferred from the related B cereus can
act to enable B anthracis to evade the protective effect of the live
attenuated Russian vaccine in a rodent model. 73
<http://jama.ama-assn.org/issues/v281n18/ffull/#r73>  Research is needed to
determine the role of these genes with respect to virulence and ability to
evade vaccine-induced immunity. Furthermore, the relevance of this finding
for the US vaccine needs to be established. An accelerated vaccine
development effort is needed to allow the manufacture of an improved
second-generation product that requires fewer doses. Finally, an expanded
knowledge base is needed regarding possible maximum incubation times after
inhalation of spore-containing aerosols and optimal postexposure antibiotic
regimens.



Author/Article Information


Author Affiliations: The Center for Civilian Biodefense Studies (Drs
Inglesby, Henderson, Bartlett, O'Toole, Perl, and Russell), and the Schools
of Medicine (Drs Inglesby, Bartlett, and Perl) and Public Health (Drs
Henderson, O'Toole, and Russell), Johns Hopkins University, Baltimore, Md;
Viral and Rickettsial Diseases, California Department of Health, Berkeley
(Dr Ascher); US Army Medical Research Institute of Infectious Diseases,
Frederick, Md (Drs Eitzen, Friedlander, and Parker); Office of Emergency
Management, New York, NY (Mr Hauer); Centers for Disease Control and
Prevention, Atlanta, Ga (Dr McDade); Acute Disease Epidemiology, Minnesota
Department of Health, Minneapolis (Dr Osterholm); and the Office of
Emergency Preparedness, Department of Health and Human Services, Rockville,
Md (Dr Tonat).

Corresponding Author and Reprints: Thomas V. Inglesby, MD, Johns Hopkins
Center for Civilian Biodefense Studies, Johns Hopkins University, Candler
Bldg, Suite 850, 111 Market Pl, Baltimore, MD 21202 (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Ex Officio Participants in the Working Group on Civilian Biodefense: George
Curlin, MD, National Institutes of Health, Bethesda, Md; Margaret Hamburg,
MD, and William Raub, PhD, Office of Assistant Secretary for Planning and
Evaluation, DHHS, Washington, DC; Robert Knouss, MD, Office of Emergency
Preparedness, DHHS, Rockville, Md; Marcelle Layton, MD, Office of
Communicable Disease, New York City Health Department, New York, NY; and
Brian Malkin and Stuart Nightingale, MD, FDA, Rockville.
Funding/Support: Funding for this study primarily was provided by each
participant's institution or agency. The Office of Emergency Preparedness,
DHHS, provided travel funds for 4 members of the group.
Disclaimers: In many cases, the indication and dosages and other information
are not consistent with current approved labeling by the US Food and Drug
Administration (FDA). The recommendations on the use of drugs and vaccine
for uses not approved by the FDA do not represent the official views of the
FDA or of any of the federal agencies whose scientists participated in these
discussions. Unlabeled uses of the products recommended are noted in the
sections of this article in which these products are discussed. Where
unlabeled uses are indicated, information used as the basis for the
recommendation is discussed.
The views, opinions, assertions, and findings contained herein are those of
the authors and should not be construed as official US Department of Defense
or US Department of Army positions, policies, or decisions unless so
designated by other documentation.
Additional Articles: This article is 1 in a series entitled Medical and
Public Health Management Following the Use of a Biological Weapon: Consensus
Statements of the Working Group on Civilian Biodefense.
Acknowledgment: The working group wishes to thank Jeanne Guillermin, PhD,
professor of sociology, Boston College, Boston, Mass, for her comments on
the manuscript. Starting in 1992, Dr Guillermin directed the interview
project to verify onset, hospital, and death data for the 1979 Sverdlovsk
victims, which will be detailed in Anthrax, A Book of Names, from California
Press. We also thank Matthew Meselson, Timothy Townsend, MD, Martin
Hugh-Jones, MA, VetMB, MPH, PhD, and Philip Brachman, MD, for their review
and commentary of the manuscript.




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<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9413092>


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.