El Ántrax como Arma Biológica
Material
extraído del sitio de JAMA,. el Journal de la Asociación Médica
Americana, dirigido a los profesionales de la salud del mundo para combatir
eficazmente el ántrax como arma biológica de ataque masivo a la población. Es
el resultado de un trabajo realizado por un conjunto de 21 representantes de
Centros Académicos y de Investigación, del gobierno, de las fuerzas armadas,
de la salud pública y de agencies e instituciones dedicadas al tratamiento de
emergencias y ataques a la población civil.
Dada la
premura en difundirlo lo brindamos en Inglés pues el sitio de la JAMA suele
estar muy sobrecargado. Hemos traducido solo la introducción, Métodos de
Consenso e Historia de las Amenazas.
Centros
de Recurrencia sobre Bioterrorismo y Biodefensa a nivel Mundial
JAMA, JAMA-AMA,
Journal de la Asociación Médica Americana
 CDC, Centro de Control de Enfermedades
 HHS – Departamento
de Salud y Servicios Humanos
 CCBS – JHU, Centro
Johns Hopkins de Estudios de Biodefensa Civil
MEDLINE,
Publicaciones Médicas de la Biblioteca Nacional de Medicina de los Estados
Unidos con más de 11 millones de citaciones.
Epidemiology
Microbiology
Pathogenesis And Clinical Manifestations
Diagnosis
Vaccination
Therapy
Infection Control
Decontamination
Additional Research
References
Introducción
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
Objetivo Crear
recomendaciones basadas en el consenso sobre medidas a ser tomadas por los
médicos y los profesionales de la salud ante ataques a la población civil con
ántrax como arma biológica.
Participantes El
grupo de trabajo incluyó 21 representantes de los mayores centro académicos y
de investigación, gobierno, militares, salud pública e instituciones y
agencies dedicadas a la administración de emergencias públicas.
Evidencia Las
bases de datos de MEDLINE fueron consultadas desde Enero 1966 a Abril 1998,
usando las palabras médicas clave anthrax, Bacillus anthracis, biological
weapon, biological terrorism, biological warfare, y biowarfare.
La revisión de las referencias identificadas por ésta investigación condujo a
la identificación de “autoridades” documentales publicadas antes de 1966.
Además, los participantes identificaron otras referencias y Fuentes aún no de
conocimiento público.
Proceso de consenso El primer borrador del consenso fue una síntesis de la información
obtenida sobre el proceso de búsqueda de evidencias. Miembros del grupo de
trabajo suministraron informes escritos, los que fueron incorporados en un
Segundo borrador. El grupo de trabajo revisó el borrador en Junio 12 1998. En
un tercer borrado no se incorporaron disidencias ni comentarios. El cuarto y
final documento fue el consenso, que incorporó todas las evidencias
relevantes obtenidas de la literatura recuperada conjuntamente con recomendaciones
finales apoyadas por unanimidad de todos los componentes del grupo de
trabajo.
Conclusiones Se
hicieron recomendaciones específicas sobre el diagnóstico del ántrax,
indicaciones para su vacunación, terapia para las personas expuestas, profilaxis
posteriores a la exposición, recontaminación del medio ambiente afectado y
necesidades de investigaciones adicionales.
JAMA. 1999;281:1735-1745
CONSENSUS
METHODS
Métodos de Consenso
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.
El grupo de trabajo
se formó con 21 representantes de los mayores centro académicos y de
investigación, gobierno, militares, salud pública e instituciones y agencies
dedicadas a la administración de emergencias públicas.
Se consultaron las
bases de datos de MEDLINE desde Enero 1966 a Abril 1998, usando las palabras
médicas clave anthrax, Bacillus anthracis, biological weapon,
biological terrorism, biological warfare, y biowarfare.
La revisión de las referencias identificadas por ésta investigación condujo a
la identificación de “autoridades” documentales publicadas antes de 1966.
Además, los participantes identificaron otras referencias y Fuentes aún no de
conocimiento público.
El primer borrador
del consenso fue una síntesis de la información obtenida sobre el proceso de búsqueda
de evidencias. Miembros del grupo de trabajo suministraron informes escritos,
sobre el primer borrador en Mayo 1998, los que fueron incorporados en un
Segundo borrador. El grupo de trabajo revisó el borrador en Junio 12 1998 en
el Centro Johns Hopkins para Estudios sobre
Biodefensa Civil, en Baltimore, Maryland. En un tercer borrado no se incorporaron disidencias ni
comentarios. El cuarto y final documento fue el consenso, que incorporó todas
las evidencias relevantes obtenidas de la literatura recuperada conjuntamente
con recomendaciones finales apoyadas por unanimidad de todos los componentes
del grupo de trabajo. Los fondos para el desarrollo de éste trabajo fueron
suministrados por cada una de las entidades representadas. La Oficina de
Alertas, del Departamento de Salud y Servicios Humanos (DHHS), suministró los
fondos de viaje para 4 miembros del grupo.
Las recomendaciones
y conclusiones que aquí se presentan representan el mejor juicio del grupo de
trabajo basado en la información actualmente disponible. A medida que se
disponga de nueva información las conclusiones y recomendaciones serán
actualizadas.
HISTORY OF CURRENT THREAT
Historia de Amenazas recientes
For centuries, anthrax has caused
disease in animals and, uncommonly, serious illness in humans throughout the
world.2 Research on
anthrax as a biological weapon began more than 80 years ago.3 Today, at
least 17 nations are believed to have offensive biological weapons programs4; it is
uncertain how many are working with anthrax. Iraq has acknowledged producing
and weaponizing anthrax.5
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 dispersed aerosols of anthrax and
botulism throughout Tokyo on at least 8 occasions. For unclear reasons, the
attacks failed to produce illness.7
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 An anthrax aerosol would be odorless
and invisible following release and would have the potential to travel many
kilometers before disseminating.9, 10 Evidence suggests that following an
outdoor aerosol release, persons indoors could be exposed to a similar threat
as those outdoors.11
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 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, area lethality
matching or exceeding that of a hydrogen bomb.12 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
Por
siglos, el ántrax ha causado enfermedades y en animales y en forma inusual
enfermedades serias en humanos. Las investigaciones sobre el ántrax como arma
biológica comenzaron hace más de 80 años. Hoy, se cree que al menos 17
naciones sustentan programas ofensivos con armas biológicas, siendo incierto
saber cuántas de ellas están trabajando con ántrax. De Irak, por ejemplo, se
sabe que produce ántrax con fines ofensivos.
La mayor parte de los expertos
confirman que la fabricación de ántrax en aerosol requiere una tecnología que
va más allá de la capacidad de grupos sin acceso a biotecnología de avanzada.
Sin embargo, grupos autónomos con considerables fondos económicos pueden ser
capaces de adquirir los materiales y la tecnología necesaria para ataques
exitosos. Un grupo terroristas, el Aum Shinrikyo, que fue el responsable del
ataque con gas sarín en el subterráneo de Tokio, dispersó aerosoles de ántrax
y de botulismo en Tokio en al menos 8 oportunidades. Por rezones que se
desconocen, esos ataques no produjeron enfermedad.
La liberación
accidental de esporas de ántrax en aerosol de un laboratorio de microbiología
militar en el año 1979 en la Ex Unión Soviética, resultó en 79 casos de
infección con 68 muertes, demostrando así la capacidad letal del ántrax en
aerosol. El aerosol de ántrax es inodoro e invisible y podría recorrer largas
distancias antes de diseminarse. Evidencias sugieren que luego de una liberación
de aerosol al aire libre, las personas en interiores estarán tan expuestas
como las que son sorprendidas al aire libre.
En
1970, un Comité de Expertos de la Organización Mundial de la Salud estimó que
las pérdidas de vidas luego de una difusión teórica de 50 kilos de ántrax
sobre una población urbana de 5 millones de personas sería de 250.000.
100.000 de las cuales morirían sin tratamiento. Un informe de 1993 de la
Oficina de Asesoramiento tecnológico del Congreso de Estados Unidos estimó
que entre 130.00 a 3 millones de muertes podrían ocurrir si se liberasen 100
kilos de esporas de ántrax sobre
Washington D.C. en la dirección del viento, comparable al poder destructor de
vidas de una bomba de Hidrógeno. Un modelo económico desarrollado por el CD ,
Centro de Control y Prevención de Enfermedades adelantó un costo de $26.200
millones de dólares por cada 100.000 personas expuestas.
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 Animal
vaccination programs have reduced drastically the animal mortality from the
disease.15 However,
anthrax spores continue to be documented in soil samples from throughout the
world.16-18
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
Cutaneous
anthrax is the most common naturally occurring form, with an estimated 2000
cases reported annually.18 Disease typically follows exposure to
anthrax-infected animals. In the United States, 224 cases of cutaneous
anthrax were reported between 1944 and 1994.20 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
Gastrointestinal
anthrax is uncommonly reported.18, 22, 23 However, gastrointestinal outbreaks
have been reported in Africa and Asia.24 Gastrointestinal anthrax follows
ingestion of insufficiently cooked contaminated meat and includes 2 distinct
syndromes, oral-pharyngeal and abdominal.22, 24-27 In 1982, there were 24 cases of
oral-pharyngeal anthrax in a rural northern Thailand outbreak following the
consumption of contaminated buffalo meat.24 In 1987, there were 14 cases of
gastrointestinal anthrax reported in northern Thailand with both
oral-pharyngeal and abdominal disease occurring.25
No case of
inhalational anthrax has been reported in the United States since 1978,19, 20 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, 28 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 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
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). 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
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, 17 Full virulence requires the presence
of both an antiphagocytic capsule and 3 toxin components (ie, protective
antigen, lethal factor, and edema factor).30 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 This contrasts with the
environmentally hardy properties of the B anthracis spore, which can
survive for decades.30
Pathogenesis And Clinical
Manifestations
Inhalational
Anthrax
Inhalational anthrax follows deposition of spore-bearing particles of 1 to 5
µm into alveolar spaces.31, 32 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, 29, 33 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 In experimental monkeys, fatal disease
occurred up to 58 days28 and 98 days34 after exposure. Viable spores have
been demonstrated in the mediastinal lymph nodes of monkeys 100 days after
exposure.35
Once
germination occurs, disease follows rapidly. Replicating bacteria release
toxins leading to hemorrhage, edema, and necrosis.23, 36 In experimental animals, once toxin
production has reached critical threshold, death occurs even if sterility of
the bloodstream is achieved with antibiotics.19 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
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 These findings are consistent with
other human case series and experimentally induced inhalational anthrax in
animals.33, 39, 40
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, 19 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, 19, 41
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, 43 A chest radiograph most often showed a
widened mediastinum consistent with lymphadenopathy (Figure 2).42 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, 19, 41
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 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 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
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 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, 45 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, 46 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 After the spore germinates in skin
tissues, toxin production results in local edema (Figure 3). 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, 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
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 An oral or esophageal ulcer leads
to development of regional lymphadenopathy, edema, and sepsis.24-26 The latter results in primary
intestinal lesions occurring predominantly in the terminal ileum or cecum,38 presenting initially with nausea,
vomiting, and malaise and progressing rapidly to bloody diarrhea, acute
abdomen, or sepsis.22 Massive ascites has occurred in some
cases of gastrointestinal anthrax.27 Advanced infection may appear similar
to the sepsis syndrome occurring in either inhalational or cutaneous anthrax.2 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, 22
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). Currently, there
are no effective atmospheric warning systems to detect an aerosol cloud of anthrax
spores.47
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 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) in a previously
healthy patient with evidence of overwhelming flulike illness is essentially
pathognomonic of advanced inhalational anthrax and should prompt immediate
action.23, 42 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). 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
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 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 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, 43 Hemorrhagic meningitis should also
raise strong suspicion of anthrax infection.23, 38, 43, 50 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 The vaccine is made from the cell-free
filtrate of a nonencapsulated attenuated strain of B anthracis.52 The principal antigen responsible for
inducing immunity is the protective antigen.18, 23 A similar vaccine has been shown in 1
small placebo-controlled human trial to be efficacious against cutaneous
anthrax.53 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
A human live
attenuated vaccine is produced and used in countries of the former Soviet
Union.55 In the Western world, live attenuated
vaccines have been considered unsuitable for use in humans.55
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, 57 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, 59 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, 56, 57 as is doxycycline.60 In studies of small numbers of monkeys
infected with susceptible strains of B anthracis, oral doxycycline has
proved efficacious.41
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, 41, 61 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
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 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. 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). 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, 62 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 and Table 3 would be suitable
alternatives if antibiotic susceptibility is proved. Although previous
guidelines have suggested treating cutaneous anthrax for 7 to 10 days,23, 49 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
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, 59, 64 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, 59, 64 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 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).
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 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). 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 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). In a mass
casualty setting and as postexposure prophylaxis, the working group
recommends that children receive oral antibiotics (Table 3).
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 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 and Table 3). 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
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 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 and Table 3).
Infection Control
There are no
data to suggest patient-to-patient transmission of anthrax occurs.8, 46 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 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, 67 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, 66
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 If autopsies are performed, all
related instruments and materials should be autoclaved or incinerated.66 Animal transmission might occur if
infected animal remains are not cremated or buried.16, 21
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, 65 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 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 The epidemic curve (Figure 4) 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, 44 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 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 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
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, 71
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 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 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 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 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: tvi@jhmi.edu).
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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Proceedings of the Seminar on Responding to the Consequences
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