Introduction
Well before the 2001 anthrax outbreak, public health and government leaders in the United States recognized the need for increased preparedness to detect and respond to acts of biologic terrorism. Concern about the vulnerability of the United States to a biologic attack grew with revelations about the offensive biologic weapons programs of the former Soviet Union and Iraq, as well as uncertainty about the whereabouts of and accountability for biologic agents produced through those programs; the successful chemical attack on the Tokyo subway system by the Aum Shinrikyo cult, coupled with information that the cult was actively experimenting with biologic agents; and information about the potential for domestic bioterrorism.[1-5]
In April 2000, the Centers for Disease Control and Prevention (CDC) published a strategic plan for preparedness and response to biologic and chemical terrorism.[6] This subsection describes the clinician's role in recognizing and responding to biologic terrorism, as presented in the CDC plan; summarizes current information on the diagnosis and management of the most likely agents of bioterrorism; and describes current resources for authoritative information and guidelines related to bioterrorism.
The Clinician's Role in Bioterrorism Preparedness and Response
For clinicians, the response to a bioterrorism attack is in many ways the same as the response to naturally occurring outbreaks of communicable disease.[7,8] Both situations typically require early identification of ill or exposed persons, rapid implementation of preventive therapy, special infection control considerations, and collaboration or communication with the public health system. Examples of naturally occurring communicable diseases that require such a response include meningococcal disease[9]; enteric infection with Escherichia coli 0157:H7, Salmonella, or Shigella[10]; pertussis, rubella, measles, or chickenpox occurring in health care facilities and clinics[11-14]; unusual or newly emerging infections such as West Nile virus and hantavirus pulmonary syndrome[15-17]; and the inevitable reappearance of pandemic influenza.[18]
The first indication of an unannounced biologic attack will likely be an increase in the number of persons seeking care from primary care physicians. In the 2001 anthrax outbreak, as well as in the outbreaks of E. coli 0157:H7 disease and hantavirus pulmonary syndrome in 1993 and West Nile virus in 1999, alert clinicians initiated the public health response by recognizing an unusual clinical syndrome, ordering appropriate laboratory tests, and notifying public health officials.[10,16,17] Similarly, primary care physicians and subspecialists alike must be familiar with both the specific clinical syndromes associated with agents of bioterrorism and the ways to rapidly notify public health authorities. In addition to identifying cases and treating ill patients, clinicians also play a critical role in managing postexposure prophylaxis and its complications, as well as psychological and mental health problems brought on by the event.
During both bioterrorism attacks and naturally occurring outbreaks, clinicians are faced with the challenge of excluding the outbreak disease in persons who are worried about potential exposure or who are ill with signs and symptoms similar to those of the outbreak disease. The clinician must have knowledge of the modes of transmission, incubation periods, and communicable periods of these diseases, as well as skill in both clinical evaluation and eliciting an appropriate and thorough history, including relevant occupational, social, and travel information. In the 2001 anthrax outbreak, for example, the epidemiologic setting of cases played an important role in guiding diagnostic tests and treatment.[19] The primary care clinician has the best opportunity to obtain relevant information early in the evaluation; this is important because such information may be more difficult to obtain as time goes on, particularly if the patient's condition deteriorates.
Physicians and other health care providers should have a working knowledge of the basic classes of isolation and infection control measures recommended for patients exposed to agents of potential bioterrorism. Again, these measures are also used in the management of common communicable diseases.[14,20-22]
Recognition of Potential Bioterrorism Agents
The CDC has developed a list of bacteria, viruses, and toxins thought to pose the greatest risk for use in a bioterrorist attack [see Table 1].[23] Agents were included in the list on the basis of their ability to cause disease that (1) is easily disseminated or transmitted from person to person; (2) has high mortality, with potential for major public health impact; (3) may result in panic and social disruption; and (4) requires special action for public health preparedness. Category A agents are thought to pose the highest immediate risk for use as biologic weapons; and category B agents, the next highest risk. Category C agents are thought to pose a potential, but not immediate, risk for use as biologic weapons.
As in naturally occurring outbreaks, early recognition of a bioterrorist attack is critical for rapid implementation of preventive measures and treatment. Early recognition can be challenging, however, because patients presenting for medical care after exposure to a biologic agent may initially exhibit nonspecific symptoms, and pathogens that ordinarily occur in the community, particularly enteric organisms, may be used in a biologic attack.[24,25] A heightened level of suspicion, plus knowledge of the relevant epidemiologic clues, should help physicians recognize changes in illness patterns, including clusters and increases in observed cases over the number expected [see Table 2].[26] Physicians should also be able to recognize diagnostic clues in single cases of a syndrome of concern (e.g., inhalational anthrax, plague and tularemia, botulismlike illness, and possible smallpox).[27] Familiarity with the clinical features of diseases from potential bioterrorist agents and diseases prevalent in the community will allow recognition of potentially significant differences from naturally occurring cases. One of the most important lessons learned from the 2001 anthrax attack was that clinical illness caused by agents prepared as biologic weapons may differ from typical natural infections.
The identification of a bioterrorist attack requires clinicians to be prepared, alert, and open-minded [see Sidebar Internet Resources on Bioterrorism] Many local and state health departments post current information about communicable diseases on their Web sites and distribute informational newsletters with relevant data. The CDC's weekly bulletin, Morbidity and Mortality Weekly Report (MMWR), contains current information on medical conditions of public health importance in the United States. Subscriptions to MMWR are available online at http://www.cdc.gov/mmwr/mmwrsubscribe.html.
Communication with Authorities
Once a potential outbreak or significant cluster or event has been detected, prompt consultation with appropriate medical specialists and public health authorities is indicated. Clinicians must have reliable, around-the-clock contact information for emergency resources in the geographic area where they practice; these resources include specialist consultants (e.g., consultants in infectious disease, dermatology, or pulmonary medicine) and infection control professionals or hospital epidemiologists. All clinicians should know how to contact their local or state public health department 24 hours a day to report suspicious or otherwise immediately notifiable cases or for consultation. Many local and state health departments have such contact numbers on their Web sites. Clinicians should have these numbers readily accessible and keep them current.
Clinicians must also ensure that they have a reliable way to promptly receive urgent communications from public health authorities, both for naturally occurring outbreaks of local significance and for a bioterrorist event or outbreak. Increasingly, public health authorities are disseminating health alerts over the Internet, through Web sites and e-mail listserves.
Smallpox
Smallpox is caused by variola virus, an orthopox virus unique to humans. No known animal or insect reservoirs or vectors exist.[28] Related orthopox viruses infecting humans include vaccinia (smallpox vaccine), monkeypox, and cowpox. Smallpox existed in two forms: variola major, which accounted for most morbidity and mortality, and a milder form, variola minor. Variola major is the type of concern in the context of biologic terrorism.
Smallpox was declared eradicated in 1980, 3 years after the last naturally occurring case was reported from Somalia. Stocks of smallpox virus were retained, however, by World Health Organization (WHO) reference laboratories at the Institute of Virus Preparations in Moscow, Russia, and at the CDC in Atlanta, Georgia. In the late 1990s, allegations were published describing the production of large quantities of smallpox virus by the former Soviet Union. These stores, which may have become disseminated after the breakup of the Soviet Union, would presumably be the source for a bioterrorist attack involving smallpox.
Smallpox is stable and highly infectious in the aerosol form. The risk for a smallpox attack currently is considered low but not zero.[1,4,29,30]
Classification
On the basis of a study from India, the WHO has classified smallpox into five clinical forms: ordinary, flat-type, hemorrhagic, modified, and sine eruptione.[31] These forms reflect different host reactions to the same strain of virus.
Ordinary Smallpox. Ordinary smallpox is the most common form seen in nonimmune persons; it accounted for 90% of cases in the WHO study and had an average case-fatality rate of 30%. The incubation period is 7 to 17 days (mean, 10 to 12 days). Symptoms of the prodromal phase include the acute onset of high fever, malaise, headache, backache, and prostration. Other prominent symptoms include vomiting and abdominal pain.
The characteristic rash occurs 2 to 3 days later, appearing first on the face and forearms. An enanthem involving the oropharyngeal mucosa precedes the rash by a day. The rash progresses slowly, from macules to papules to vesicles and pustules and finally to scabs, with each stage lasting 1 to 2 days. The lesions are firm, discrete vesicles or pustules (4 to 6 mm in diameter) deeply embedded in the dermis; they may become umbilicated or confluent as they evolve [see Figure 1]. The patient remains febrile throughout the evolution of the rash, which may become painful as pustules enlarge. A second fever spike 5 to 8 days after onset of the rash may signify a secondary bacterial infection. Pustules remain for 5 to 8 days, after which umbilication and crusting occur. Lesions are in the same stage of development on any given part of the body. They are peripherally distributed, more concentrated on the face and distal extremities than on the trunk, and may involve the palms and soles. Scarring occurs with scab separation from destruction of sebaceous glands.
Experience during the global smallpox eradication program suggests that
the onset of communicability coincides with the development of rash,
approximately 2 days after the onset of the acute febrile prodrome.
However, because the oropharyngeal enanthem and associated release of
virus into oral secretions may precede rash onset, it is recommended that
for the purposes of postexposure management, anyone who has contact with
smallpox patients from the time of onset of fever should be considered
potentially exposed [see Infection Control,
below].[32] Complications of smallpox include fluid and electrolyte disturbances;
extensive desquamation that clinically resembles burns; bronchitis and
pneumonitis; panophthalmitis and blindness from viral keratitis or
secondary infection of the eye; arthritis (developing in up to 2% of
children); and encephalitis (less than 1% of cases). Death results from
toxemia associated with circulating immune complexes and variola
antigens.[33] Other Forms of Smallpox. Flat-type (or malignant) smallpox
occurs in 5% to 10% of cases and is severe, with a 97% case-fatality rate
among unvaccinated persons. In this form, lesions are flat and become
densely confluent, evolving slowly and coalescing with a soft, velvety
texture. Hemorrhagic smallpox was reported in less than 3% of cases,
occurring particularly in pregnant women. It is a severe, rapidly
progressive, uniformly fatal illness. A dusky erythema develops, followed
by hemorrhages into the skin and mucous membranes. Both hemorrhagic and
flat-type smallpox have an accelerated and more severe prodromal phase and
are thought to be associated with underlying immune dysfunction. Modified smallpox is a mild form that accounted for 2% of cases in
unvaccinated patients and 25% in previously vaccinated patients. This form
rarely resulted in death, and these patients had fewer, smaller, more
superficial, and more rapidly evolving lesions. Smallpox sine eruptione
(without rash) occurs in previously vaccinated persons or children with
maternal antibodies to smallpox. It is a mild or asymptomatic illness that
has not been documented to be transmissible.[31,33-35] A suspected case of smallpox is a public health emergency. Local and
state health authorities, the hospital epidemiologist, and other members
of a hospital response team for biologic emergencies should be notified
immediately (see the CDC Interim Smallpox Response Plan and Guidelines at
http://www.bt.cdc.gov/documentsapp/SmallPox/RPG/ContactInfo.asp). The differential diagnosis of smallpox includes other illnesses that
can cause fever and a rash [see Table 3]. Severe varicella is the disease
most likely to be confused with smallpox. However, familiarity with the
clinical features of the two diseases, particularly the rash, should help
differentiate them [see Table 4]. Additional information that may be
useful in differentiating smallpox from chickenpox includes a history of
exposure to persons with chickenpox, a personal history of chickenpox, a
history of vaccination against varicella or smallpox, and the clinical
course of illness. If shingles or disseminated herpes infection is a consideration, direct
fluorescent antibody testing for varicella-zoster virus can rapidly
confirm varicella-zoster virus and herpes simplex virus infection in
patients not considered at high risk for smallpox. Such testing should not
be done in patients who are considered at high risk, to avoid exposing
laboratory workers to smallpox virus. Certain laboratories can also
perform polymerase chain reaction (PCR) testing for herpes simplex virus
and varicella-zoster virus. Consultation with an infectious disease
specialist, a dermatology specialist, or both is recommended. Flat-type and hemorrhagic smallpox may be difficult to recognize
because of the absence of the characteristic rash of ordinary smallpox,
yet these cases are highly infectious. Hemorrhagic smallpox cases may be
mistaken for meningococcemia or acute leukemia. All patients with
potential smallpox should be asked about their travel history, level of
immunocompetence, and current medications. The local or state health department should be contacted to facilitate
specimen collection for smallpox testing (http://www.statepublichealth.org/). Protocols for
specimen collection for smallpox testing have been published by the CDC
and are available at the following Internet address: http://www.bt.cdc.gov/documentsapp/SmallPox/RPG/GuideD/Guide-D.pdf.
These protocols are also available through the CDC's smallpox information
Web page: http://www.bt.cdc.gov/Agent/Smallpox/SmallpoxGen.asp. Diagnostic testing is available at designated biosafety level 4 (BSL-4)
laboratories and includes electron microscopy, immunohistohemical tests,
and viral culture with PCR and restriction fragment length polymorphism
(RFLP) testing. Only personnel who have undergone successful smallpox
vaccination recently (within 3 years) and who are wearing appropriate
barrier protection (gloves, gown, and shoe covers) should be involved in
specimen collection for suspected cases of smallpox. Respiratory
protection is not needed for personnel with recent, successful
vaccination. Masks and eyewear or face shields should be used if splashing
is anticipated. If unvaccinated personnel must collect specimens, only
those who are without contraindications to vaccination should do so,
because they would require immediate vaccination if the diagnosis of
smallpox were confirmed. Vesicular or pustular fluid, scabs, punch
biopsies of skin lesions, blood, and tissue from autopsy specimens should
be obtained, packaged, and transported according to CDC protocol (http://www.bt.cdc.gov/labissues/PackagingInfo.pdf; http://www.bt.cdc.gov/documentsapp/SmallPox/RPG/index.asp).
[32,35] The CDC has developed a protocol in poster format for evaluating
patients with an acute vesicular or pustular rash illness and for
determining the risk of smallpox. The protocol, including color pictures
of smallpox lesions, is available on the Internet at the following
address: http://www.bt.cdc.gov/agent/smallpox/index.asp. In the event of a limited outbreak, patients should be admitted to the
hospital and confined to rooms that are under negative atmospheric
pressure and equipped with high-efficiency particulate air (HEPA)
filtration. Standard, contact, and airborne precautions, including use of
gloves, gowns, and masks, should be strictly observed. Unvaccinated
personnel caring for patients suspected of having smallpox should wear
fit-tested N95 or higher-quality respirators. Once successful vaccination
is confirmed, care providers are no longer required to wear an N95
mask.[35] Patients should wear a surgical mask and be wrapped
in a gown or sheet to cover the rash when they are not in a
negative-airflow room. All laundry and waste should be placed in biohazard
bags and autoclaved before being laundered or incinerated. Surfaces that
may be contaminated with smallpox virus can be decontaminated with
disinfectants that are used for standard hospital infection control, such
as hypochlorite and quaternary ammonia. Persons suspected of being infected with smallpox should be immediately
isolated, and all their household members and others who have had
face-to-face contact with the infected patient after the onset of fever
should be vaccinated and placed under surveillance. Because persons who
have had contact with an infected patient would not be contagious until
the onset of rash, they should take their temperatures at least once
daily, preferably in the evening. Any temperature higher than 101° F
(38.3° C) during the 17-day period after the last exposure to the infected
patient would suggest the possibility of the development of smallpox. This
would be cause for immediate isolation until the diagnosis can be
determined clinically, by laboratory examination, or both. In the event of an outbreak, the following high-risk groups should be
given priority for vaccination: (1) persons exposed to the initial release
of the virus; (2) contacts of suspected or confirmed smallpox patients;
(3) personnel who are directly involved in medical or public health
evaluation of suspected or confirmed smallpox patients, as well as the
care or transportation of such patients; (4) laboratory workers involved
in the collection or processing of possible smallpox specimens; (5) other
persons who may be in contact with infectious material, such as hospital
laundry, medical waste, and mortuary workers; (6) other groups essential
to response activities, such as law enforcement, emergency response, or
military personnel; and (7) all persons in a hospital where there is a
smallpox patient who is not isolated appropriately. Employees for whom
vaccination would be contraindicated (see below) should be
furloughed.[32,35] Smallpox Vaccine. Vaccinia vaccine does not contain smallpox
(variola) virus. The currently available vaccines were prepared from calf
lymph with a seed virus derived from the New York City Board of Health
strain of vaccinia virus (Dryvaxâ vaccine). A supply of licensed Dryvaxâ
vaccine is being used in the first stages of the National Smallpox
Vaccination Plan to immunize smallpox health care and public health teams.
A reformulated vaccine, produced by using cell-culture techniques, is
being developed. The immune status of those vaccinated more than 27 years ago is not
clear. Studies have demonstrated persistence of T cell and humoral
responses, but absolute levels of neutralizing antibodies decline
substantially during the first 5 to 10 years after vaccination.
Epidemiologic studies conducted during endemic smallpox outbreaks
suggested that remote vaccination can ameliorate disease but does not
prevent disease in most persons with high-risk
exposures.[30] Complications of smallpox vaccination. Current data on
complication rates after primary vaccination are derived from observations
made when smallpox vaccine was in routine use in the United States, over
30 years ago.[28] Higher rates of vaccine complications would
likely occur today, given the increased number of persons with medical
conditions or medications that compromise the immune system. Moderate and
severe complications of vaccinia vaccination include eczema vaccinatum,
generalized vaccinia, progressive vaccinia, and postvaccinial
encephalitis. These complications are rare but are at least 10 times more
common after primary vaccination than after revaccination; they occur more
frequently in infants than in older children and adults. The most common complication of smallpox vaccination, occurring in
529.2 cases per million doses, is localized vaccinia infection resulting
from inadvertent transfer (autoinoculation) of vaccinia from the
vaccination site to other parts of the body. In addition, transmission of
vaccinia virus can occur when a recently vaccinated person has contact
with a susceptible person; in one study, approximately 30% of eczema
vaccinatum cases were persons who had had such contact.[28,36]
Inadvertent transfer of vaccinia from the vaccination site to other parts
of the body can be prevented by careful hand washing after touching the
vaccination site and by keeping the site covered. Eczema vaccinatum (38.5/million doses) is a localized or systemic
dissemination of vaccinia virus that occurs in persons who have eczema or
a history of eczema or other chronic or exfoliative skin conditions (e.g.,
atopic dermatitis). Illness is usually mild and self-limited but can be
severe or fatal. Severe cases have also been observed in persons with
active eczema or a history of eczema, after contact with recently
vaccinated persons. Generalized vaccinia (241.5/million doses) is characterized by a
vesicular rash of varying extent that can occur in persons without
underlying illness. The rash is generally self-limited and requires minor
or no therapy except in patients whose condition might be toxic or who
have serious underlying immunosuppressive illnesses. Progressive vaccinia (vaccinia necrosum, 1.5/million doses) is a
severe, potentially fatal illness characterized by progressive necrosis in
the area of vaccination, often with metastatic lesions. It has occurred almost exclusively in persons with cellular
immunodeficiency. The most common serious complication is postvaccinial encephalitis
(12.3/million doses). It occurs mostly in infants younger than 1 year and,
less often, in adolescents and adults receiving a primary vaccination.
Rates of this complication were influenced by the strain of virus used in
the vaccine and were higher in Europe than in the United States. The
principal strain of vaccinia virus used in the United States--the New York
City Board of Health (NYCBOH) strain--was associated with the lowest
incidence of postvaccinial encephalitis. Approximately 15% to 25% of
affected vaccinees with this complication die, and 25% have permanent
neurologic sequelae. Fatal complications caused by vaccinia vaccination are rare, with
approximately one death per million primary vaccinations and 0.25 deaths
per million revaccinations. Death is most often the result of
postvaccinial encephalitis or progressive vaccinia. Contraindications. Groups at special risk for complications
include persons with eczema or other significant exfoliative conditions;
patients with leukemia, lymphoma, or generalized malignancy who are
receiving therapy with alkylating agents, antimetabolites, radiation, or
large doses of corticosteroids; patients with HIV infection; persons with
hereditary immune disorders; and pregnant women. In persons with
contraindications who require vaccination because of exposure to smallpox
virus from a bioterrorist attack, the risk of complications can be reduced
by giving vaccinia immune globulin (VIG; see below) simultaneously with
vaccination. However, current stores of VIG are insufficient to allow its
prophylactic use. Even if VIG is not available, vaccination may still be
warranted, given the far higher risk of an adverse outcome from smallpox
than from vaccination. Vaccinia immune globulin. Complications of vaccinia vaccination
can be prevented or treated with VIG, which is an isotonic sterile
solution of the immunoglobulin fraction of plasma from persons vaccinated
with vaccinia vaccine. For prophylactic use, in persons with
contraindications who require vaccination, VIG is given along with
vaccinia vaccine.[28] Very large amounts are required: VIG is
administered intramuscularly in a dose of 0.3 ml/kg (e.g., 22.5 ml I.M.
for a 75 kg patient) At present, however, supplies of VIG are so limited
that its use should be reserved for treatment of patients with the most
serious vaccine complications. For treatment of vaccinia vaccination complications, VIG is
administered intramuscularly; 0.6 ml/kg is given in divided doses over a
24- to 36-hour period. A repeat dose may be given 2 to 3 days later if
improvement does not occur. VIG is effective for treatment of eczema
vaccinatum and certain cases of progressive vaccinia; it might be useful
also in the treatment of ocular vaccinia resulting from inadvertent
implantation. VIG is contraindicated for the treatment of vaccinial
keratitis. VIG is recommended for severe generalized vaccinia if the
patient is extremely ill or has a serious underlying disease. VIG provides
no benefit in the treatment of postvaccinial encephalitis and has no role
in the treatment of smallpox.[28,32]
Anthrax is a zoonotic disease caused by the spore-forming bacterium
Bacillus anthracis, a large, nonmotile, nonhemolytic, gram-positive
rod [see 7:IV Infections Due to Gram-Positive Bacilli]. The
organism is distributed worldwide in soil. Animals, primarily herbivores,
become infected through grazing in contaminated areas. Under natural
conditions, humans contract the disease after close contact with infected
animals or contaminated animal products such as hides, wool, or
meat.[37] Hardy spores resistant to heat and environmental
degradation are the usual infective form. The spores develop in response
to exposure to ambient air. On exposure to favorable, nutrient-rich
environmental conditions such as tissues or blood of an animal or human
host, the spores germinate, producing vegetative cells.[38] Anthrax occurs in three clinical forms in humans: inhalational,
cutaneous, and gastrointestinal. In a biologic attack, aerosol exposure to
anthrax spores would be most likely.[29] Only 18 cases of
inhalational anthrax were reported in the United States in the 20th
century, none of them after 1976. Sixteen of these cases were attributable
to an industrial source of infection, and two cases were laboratory
associated.[39] Before 2001, exposure to powdered anthrax
spores in an envelope or package was not thought to be an efficient means
of causing inhalational disease. However, exposure to anthrax spores sent
through the United States mail in the 2001 anthrax attack resulted in 11
cases of inhalational anthrax and 11 cases of cutaneous
disease.[19,40,41] Recent research has demonstrated the
unanticipated potential for significant dispersion of respirable aerosol
particles of spores through opening of a contaminated
envelope.[42] In addition, expected clinical findings based on
previous experience with naturally occurring anthrax infections did not
entirely correspond to the clinical presentation in persons exposed to
anthrax in the context of a biologic attack, although there was
considerable overlap between the two. Cutaneous anthrax accounts for the majority of naturally occurring
anthrax cases worldwide. It results from inoculation of spores
subcutaneously through a cut or abrasion.[43] Given that
cutaneous anthrax cases occurred during the 2001 anthrax outbreak, it is
possible that a bioterrorist attack could be detected through recognition
of cutaneous anthrax cases.[19] Gastrointestinal and
oropharyngeal anthrax occur in rural parts of the world where anthrax is
endemic. They result from ingestion of meat contaminated with spores or
large numbers of vegetative cells.[44] No cases of
gastrointestinal anthrax occurred during the 1979 accidental release of
anthrax from a military facility in Sverdlovsk, Russia, in which 77
inhalational cases occurred, or during the 2001 outbreak in the United
States. Because of the logistic difficulty of effectively contaminating
food and water supplies, it is thought that this form of anthrax would be
less likely to occur as a result of a biologic attack.[29] Anthrax is a toxin-mediated disease. In inhalational anthrax, 1 to 5 µm
particle-bearing spores are deposited in the terminal airways or alveoli,
phagocytized by alveolar macrophages, and transported to mediastinal and
peribronchial lymph nodes. Spores may stay in the mediastinal lymph nodes
for extended periods and can germinate for up to 60 days or
longer.[45] Cases of inhalational anthrax occurred up to 43
days after exposure in the Sverdlovsk outbreak.[46] Spores
germinate into vegetative cells, which escape from the macrophages,
multiply in the lymphatics, and ultimately gain access to the bloodstream,
where they can reach high concentrations (107 to 108 organisms per
milliliter of blood). Hemorrhagic meningitis is a complication of
bacteremic spread; it develops in up to one half of cases. In anthrax, tissue damage is mediated by two toxins: edema toxin and
lethal toxin. These two toxins are composed of edema factor, lethal
factor, and protective antigen. These three components of edema toxin and
lethal toxin are produced by vegetative cells. Vegetative cells also
produce an antiphagocytic capsule that is necessary for
virulence.[47] Lethal toxin is a combination of lethal factor
and protective antigen that interferes with cellular protein synthesis; it
causes macrophages to release tumor necrosis factor and interleukin-1. In
severe cases, it contributes to sudden death from toxemia. Edema toxin is
a combination of edema factor and protective antigen that causes increased
cellular levels of cyclic adenosine monophosphate (cAMP) and altered water
homeostasis, resulting in massive edema. Together, edema toxin and lethal
toxin cause edema, hemorrhage, necrosis, and shock. In cutaneous and
gastrointestinal anthrax, toxin production results in a similar
pathophysiologic process that causes edema and hemorrhagic necrosis in the
skin and gastrointestinal mucosa, respectively. Clinical Presentation and Diagnosis. Recent information on the
clinical manifestations of inhalational anthrax from the 2001 anthrax
outbreak both confirms many of the features reported in naturally
occurring anthrax cases and reveals unanticipated
differences.[39,45,48] The infectious dose of anthrax is not
known with certainty. Animal data suggest that the median lethal dose
(LD50, which is the dose sufficient to kill 50% of exposed
subjects) is 2,500 to 55,000 inhaled spores. Data from naturally occurring
cases and from two cases in the 2001 outbreak suggest that the infectious
dose may be very low in some persons, particularly those with underlying
pulmonary disease.[45,49] Clinical symptoms develop rapidly after germination of anthrax spores.
The incubation period for inhalational disease is most commonly reported
as 1 to 6 days but may be prolonged by antibiotic administration or,
presumably, a low infectious dose.[50,51] In the 2001 anthrax
outbreak, the median incubation period was 4 days (range, 4 to 6 days) for
the six cases in which it could be calculated. Inhalational anthrax has been described as a two-stage disease. The
initial stage is a nonspecific, flulike illness lasting from several hours
to a few days. In the 2001 bioterrorism-associated anthrax cases, this
early clinical presentation included some combination of fever, myalgia,
headache, cough, mild chest discomfort, weakness, abdominal pain, and
chest pain. Profound malaise, fever, and drenching sweats were prominent
symptoms, and nausea and vomiting were frequent. Classically, the initial
stage is followed 1 to 3 days later, sometimes after brief improvement, by
the rapidly progressive second stage, characterized by fever, dyspnea,
diaphoresis, cyanosis, and shock. In the 2001 cases, no brief improvement
between stages was observed. Laboratory studies are nonspecific or unremarkable during the early
stage of disease.[48] Chest x-rays were abnormal on initial
presentation in all 10 recent cases, although only seven patients had the
classic finding of mediastinal widening . Pleural
effusions were present in all cases. These effusions were often small on
presentation and were progressive, requiring drainage in the majority of
patients. In contrast to previous descriptions, seven patients had
pulmonary infiltrates consistent with pneumonia at presentation, and one
patient was thought to have heart failure with pulmonary congestion. Other
abnormalities included paratracheal and hilar fullness. The CT scan was
valuable in further characterizing abnormalities in the lungs and
mediastinum and was more sensitive than the chest x-ray in revealing
mediastinal changes. Blood cultures can be diagnostic, although
appropriate antibiotic therapy rapidly reduces the likelihood of isolating
the organism. In the 2001 cases, B. anthracis was isolated from
blood cultures obtained before antibiotic therapy was given, but not from
those obtained afterward. The initial manifestations of inhalational anthrax are nonspecific and
are consistent with flulike illnesses caused by a variety of respiratory
viruses, as well as with community-acquired bacterial infections. Adults
can average one to three episodes of flulike illness a year, and millions
of cases occur throughout the United States.[52] Because of the
high frequency of flulike illnesses and the low likelihood of inhalational
anthrax in a given patient, a combination of epidemiologic, clinical, and
(if indicated) laboratory testing should be used to evaluate potential
cases of inhalational anthrax [See Figure 4]. According to CDC
guidelines, consideration of inhalational anthrax hinges on a history of
exposure or occupational/environmental risk within 2 to 5 days before
illness onset.[19] Whenever possible, exposure and risk
determinations should be made in consultation with public health
authorities before initiating treatment or preventive therapy.
Diagnostic testing for anthrax should be done in patients whose signs
and symptoms are consistent with anthrax and when one or more of the
following conditions are present: a history of a recent anthrax case or
outbreak in the community; a credible threat of anthrax exposure, as
determined by law enforcement and public health authorities; a cluster of
anthraxlike cases characterized by rapid deterioration. Anthrax should
also be considered in any patient with compatible symptoms and rapid
deterioration. All cases of suspected anthrax should be reported
immediately to local or state public health authorities and the hospital
epidemiologist (http://www.statepublichealth.org/). The clinical
laboratory should also be alerted when diagnostic specimens of suspected
anthrax are submitted to ensure that appropriate precautions are taken to
protect laboratory staff, facilitate proper evaluation of the isolate, and
expedite confirmatory testing at the nearest laboratory that belongs to
the public health Laboratory Response Network.[6] There is no rapid screening test to diagnose inhalational anthrax in
its early stages. In persons with a compatible clinical illness for whom
there is a heightened suspicion of anthrax based on clinical and
epidemiologic data, the appropriate initial diagnostic tests are a chest
x-ray or chest CT scan, or both, and culture and smear of peripheral
blood. On chest x-rays, the posteroanterior and lateral view may be more
sensitive than the anteroposterior (portable) view in detecting pulmonary
abnormalities. Mediastinal widening or hyperdense mediastinal
lymphadenopathy (secondary to hemorrhagic lymph nodes) on a nonenhanced CT
scan should raise the suspicion of pulmonary anthrax]. Most persons with flulike
illnesses do not have radiologic findings of pneumonia; such findings
occur most often in the very young, the elderly, and persons with chronic
lung disease. Pleural fluid and cerebrospinal fluid, as well as biopsy specimens
taken from the pleura and lung, are also potentially useful for culture
and other testing when disease is present in these sites, whereas sputum
culture and Gram stain are unlikely to be useful. In highly suspicious
cases, local or state health departments can arrange for additional
diagnostic testing, including immunohistochemical staining and PCR at the
CDC. Serologic testing is not useful in clinical management but may be
used in epidemiologic investigations. Similarly, nasal swabs are of
potential value in epidemiologic investigations for determining the route
and extent of spread of anthrax in a population, but they have no role in
clinical management. A rapid influenza test can be used when influenza itself is a
consideration in a patient with flulike illness, but these kits have
limited value because their sensitivity can be relatively low (45% to
90%). However, rapid influenza testing with viral culture can help
indicate whether influenza viruses are circulating among certain
populations, and this epidemiologic information can be useful in
diagnosing flulike illnesses.[52] Treatment. Early intravenous antibiotic treatment may improve
survival in inhalational anthrax.[53] In contrast to the
reported case-fatality rate of 85% for 20th-century inhalational anthrax
cases, 6 of 11 patients in the 2001 outbreak survived; all the survivors
presented during the initial phase of the illness and received treatment
the same day with antibiotics active against B. anthracis. Fatal
cases occurred in patients who had severe disease by the time they first
received antibiotics with activity against B. anthracis. Aggressive
supportive care--including attention to fluid, electrolyte, and acid-base
disturbances and drainage of pleural effusions--also played an important
role in treatment.[48] Current CDC treatment recommendations and related guidelines and
information can be obtained at http://www.bt.cdc.gov/HealthProfessionals/index.asp.
Before initiating treatment, clinicians should review this site to stay
informed of revisions and updates. The Working Group on Civilian
Biodefense has published similar recommendations with a detailed
accompanying text.[45] At present, intravenous ciprofloxacin or doxycycline plus one or two
additional antimicrobials with in vitro activity against B.
anthracis are recommended for initial empirical treatment [see Table 5]. Antibiotic therapy should be
modified according to the results of antimicrobial susceptibility testing
to ensure that the most effective and least toxic regimen is used. The
duration of antimicrobial therapy should be at least 60 days. Once
clinical improvement occurs, it may be possible to complete the course of
treatment with one or two agents given orally. Corticosteroid therapy has
been suggested as adjunct therapy for inhalational anthrax associated with
extensive edema, respiratory compromise, and
meningitis.[19,43,45] Prevention. Ciprofloxacin and doxycycline are recommended
first-line agents for prophylaxis in persons exposed to inhalational
anthrax. In vivo data suggest that other fluoroquinolone antibiotics would
have efficacy equivalent to that of ciprofloxacin.[45]
High-dose amoxicillin is an option when ciprofloxacin or doxycycline is
contraindicated [see Table 6]. Postexposure prophylaxis should
continue for at least 60 days.[54] Given the uncertainty about
the length of time viable spores can persist in the lungs, patients should
be instructed to seek prompt medical evaluation if symptoms compatible
with anthrax develop after discontinuance of postexposure prophylaxis.
Because of uncertainty about the length of time that anthrax spores can
remain viable in the lungs, the United States Department of Health and
Human Services made two additional options available for preventive
treatment for persons exposed to inhalational anthrax in the 2001
outbreak. These options were to follow a 60-day course of antibiotic
treatment with either (1) an additional 40 days of antibiotic treatment or
(2) an additional 40 days of antibiotic treatment plus three doses of
anthrax vaccine over a 4-week period.[55] Anthrax vaccine. The only licensed human anthrax vaccine
available in the United States is anthrax vaccine adsorbed (AVA). This is
an inactivated, cell-free filtrate of a nonencapsulated attenuated strain
of B. anthracis (BioPort Corporation, Lansing,
Michigan).[51] Primary vaccination consists of three
subcutaneous injections at 0, 2, and 4 weeks and three booster
vaccinations at 6, 12, and 18 months. To maintain immunity, the
manufacturer recommends an annual booster injection. The basis for this
recommended schedule of vaccination is not well defined. Vaccination of adults with the licensed vaccine induced an immune
response, as measured by indirect hemagglutination, in 83% of vaccinees 2
weeks after the first dose and in 91% of vaccinees who received two or
more doses. Approximately 95% of vaccinees undergo seroconversion after
three doses, with a fourfold rise in titers of IgG against protective
antigen (the principal antigen responsible for inducing immunity).
However, the precise correlation between antibody titer (or concentration)
and protection against infection is not defined. The vaccine has shown
efficacy in experiments involving animal models of inhalational anthrax in
preexposure settings and, in combination with antibiotics, in postexposure
settings.[45,52] Anthrax vaccine is considered acceptably safe by the Advisory Committee
on Immunization Practices and the Institute of Medicine.[51,56]
Supplies of anthrax vaccine are limited and are held by the United States
Department of Defense. A combination of antibiotics and anthrax vaccine,
if available, is recommended for exposed persons after a biologic
attack.[45,57] At this time, preexposure use of anthrax vaccine
is not recommended. After an incubation period of approximately 7 days (range, 1 to 12
days), the primary lesion of cutaneous anthrax appears as a nondescript,
painless, pruritic papule, usually on an exposed area such as the face,
head, neck, or upper extremity. The papule enlarges and develops a central
vesicle or bullae with surrounding brawny, nonpitting edema. The central
vesicle enlarges and ulcerates over 1 to 2 days, becoming hemorrhagic,
depressed, and necrotic and leading to a central black eschar. Satellite vesicles may be present. The eschar dries and
falls off over the next 1 to 2 weeks. The findings of a painless lesion
and edema out of proportion to the size of the lesion and the fact that
pustules are rarely present in cutaneous anthrax are clinically useful.
Tender regional lymphadenopathy, fever, chills, and fatigue may occur.
Systemic disease has been reported to have a mortality of 20% if
untreated. Cutaneous anthrax of the face or neck may lead to respiratory
compromise from massive edema.[43,45,47,58] The differential diagnosis of cutaneous anthrax includes other causes
of eschar and ulceration and the ulceroglandular syndrome.[57]
Guidelines for the diagnosis of cutaneous anthrax have been published by
the American Academy of Dermatology (http://www.aad.org/BioInfo/anthrax.html). For patients with the typical appearance and progression of cutaneous
anthrax, a Gram stain and culture of the skin lesion should be obtained
using a dry swab for unroofed vesicle fluid and a moist swab for the base
of the ulcer and edges underneath the eschar. Blood cultures are also
recommended. If the patient is taking antimicrobial drugs or if the Gram
stain and culture are negative for B. anthracis or clinical
suspicion remains high, two punch biopsies for culture (with the specimen
placed in saline) and immunohistochemical staining should be performed;
PCR (with the specimen placed in formalin) should be performed, or both
should be considered [see Figure 7]. Immunohistochemical staining
and PCR testing at the CDC should be arranged through local public health
authorities.[19,45]
Management. Antibiotic treatment is curative in cutaneous
anthrax and can be initiated pending confirmation of anthrax infection.
Ciprofloxicin and doxycycline are first-line agents for the empirical
treatment of cutaneous anthrax and may be administered orally. Intravenous
therapy with multiple drugs, as for inhalational anthrax (see above), is
recommended for patients with signs of systemic involvement, extensive
edema, or lesions of the face and neck.[53] Symptoms appear 2 to 5 days after ingestion of contaminated food and
include nausea, vomiting, fever, malaise, and abdominal pain. Severe
bloody diarrhea with rebound abdominal tenderness develops. Ulcerative
lesions occur primarily in the terminal ileum and cecum. Gastric ulcers
with hematemesis, hemorrhagic mesenteric lymphadenitis, and marked ascites
may occur. Mediastinal widening has also been reported with
gastrointestinal anthrax. Morbidity results from blood loss, fluid and
electrolyte imbalances, and shock. The case-fatality rate is reportedly
greater than 50%; death results from toxemia or intestinal
perforation.[29,44,45] Oropharyngeal anthrax is characterized by sore throat, fever,
dysphagia, and marked edema and lymphadenitis. Ulcerative lesions may have
an associated pseudomembrane. Specimens for diagnosis of gastrointestinal
anthrax may include ascitic fluid for Gram stain and culture, blood
cultures, and tissue samples from affected mucosal sites. Treatment for gastrointestinal anthrax and oropharyngeal anthrax is the
same as that for inhalational anthrax (see above). Person-to-person transmission of anthrax is not known to occur.
Patients may be hospitalized in a standard hospital room with standard
barrier isolation precautions. No treatment is necessary for contacts of
cases. The microbiology laboratory should be notified upon suspicion of
anthrax to ensure that appropriate precautions are taken under BSL-2
conditions when specimens are processed for culture.[59]
Sporicidal solutions approved for use in hospitals and commercially
available bleach or a 0.5% hypochlorite solution (1:10 dilution of
household bleach) are effective for decontamination of contaminated areas.
Precautions should be taken during autopsies, and cremation of human
remains should be considered to prevent further transmission of
disease.[20]
Plague is caused by the gram-negative coccobacillus Yersinia
pestis, of the family Enterobacteriaceae. Wild rodents are the animal
reservoir for the disease. Under natural conditions, plague is transmitted
to humans by the bite of an infectious flea and, less frequently, by
direct contact with infectious body fluids or tissues of an infected
animal or by inhaling infectious droplets.[60] Plague has a
long history of use and development as a biologic weapon, including the
catapulting of plague victims' corpses over the walls of a besieged city
in the 14th century. The most likely presentation after a biologic attack
is primary pneumonic plague.[29] Additional information on
plague, including the nonpneumonic forms (bubonic and septicemic plague),
microbiology, and pathogenesis, is available elsewhere [see 7:XI
Infections Due to Brucella, Francisella, Yersina Pestis, and
Bartonella]. Plague is a severe febrile illness. Pneumonic plague, the most fatal
form of the infection, can develop from inhalation of plague bacilli
(primary pneumonic plague) or from hematogenous spread secondary to
septicemic plague. Approximately 12% of cases of bubonic and primary
septicemic plague develop into secondary pneumonic plague. Conversely,
septicemic plague can be secondary to primary pneumonic plague. The incubation period for pneumonic plague is typically 2 to 4 days
(range, 1 to 6 days). Presenting symptoms typically include the acute
onset of malaise, high fever, chills, headache, chest discomfort, dyspnea,
and cough concomitant with or followed rapidly by clinical sepsis.
Hemoptysis is a classic sign that should suggest plague in the appropriate
clinical context, but sputum may be watery or purulent. Gastrointestinal
symptoms may be prominent with pneumonic plague; these include nausea,
vomiting, diarrhea, and abdominal pain. A cervical bubo is infrequently
present. The disease is rapidly progressive, with increasing dyspnea, stridor,
and cyanosis. Rapidly progressive respiratory failure and sepsis within 2
to 4 days of onset of illness is typical of pneumonic plague.
Abnormalities on chest x-ray are variable but frequently show bilateral
patchy infiltrates or consolidation. The mortality for pneumonic plague is
reported to be 57% and is extremely high when initiation of treatment is
delayed beyond 24 hours after symptom onset.[61] Complications
of septicemic plague include disseminated intravascular coagulation (DIC),
purpuric skin lesions and gangrene of extremities (so-called black death),
acute respiratory distress syndrome (ARDS), meningitis, and multiorgan
failure with shock.[29,62-64] During a confirmed outbreak of pneumonic plague after a biologic
attack, a presumptive diagnosis can be made on the basis of symptoms,
especially if there is a high index of suspicion. However, other causes of
severe pneumonia or rapidly progressive respiratory infection with or
without sepsis should be considered. Suspected cases of plague should be
immediately reported to the local public health department and the
hospital epidemiologist. There are no widely available, rapid confirmatory tests for Y.
pestis. Specimens for bacteriologic and serologic testing should be
collected before initiating therapy. Sputum, blood, and lymph node
aspirate should be submitted for Gram stain and culture. Microscopic
examination of clinical specimens or buffy coat may show a gram-negative
coccobacillus; Wright, Giemsa, or Wayson stains may show bipolar (safety
pin) staining. Sera for acute and convalescent antibody detection should
be obtained, but findings are primarily of epidemiologic value. Additional
diagnostic testing, including antigen detection, IgM immunoassay,
immunostaining, PCR testing, and antimicrobial susceptibility testing, is
available through the CDC and designated public health laboratories (http://www.statepublichealth.org/). Specimen submission
should be arranged through local public health authorities. The laboratory
should be notified whenever plague is suspected, to help prevent exposures
to staff and to facilitate appropriate testing.[29,61,64] Laboratory findings are consistent with the systemic inflammatory
response syndrome. The leukocyte count is elevated and the differential
shows a neutrophil predominance, including immature forms. Platelets may
be normal or low. Coagulation abnormalities include increased fibrin
degradation products, hypofibrinogenemia, and prolongation of the
prothrombin time (PT) and partial thromboplastin time (PTT). Elevated
liver function tests and abnormal renal function tests are seen with
systemic disease. When plague is suspected, antibiotic treatment should begin before
laboratory confirmation of the diagnosis [see Table 7]. Whenever possible, specimens
should be collected for bacteriologic and serologic testing before the
start of therapy. Antibiotic resistance is rare with naturally occurring
Y. pestis but may be present in strains used as biologic weapons.
Treatment should be continued for 10 days or for 3 days after
defervescence and improvement in symptoms. The route of administration can
be changed from intravenous to oral after the patient is clinically
stable. The choice of antibiotic may be modified after microbial
sensitivity testing is completed. The CDC bioterrorism Web site or local
public health authorities should be consulted for updated treatment
recommendations.[29,61,64] Postexposure Prophylaxis for Pneumonic Plague. All persons
potentially exposed to aerosolized Y. pestis and all persons in
close contact with pneumonic plague patients (close contact is defined as
exposure within 2 m [6.5 ft]) should be treated for 7 days after the last
exposure [see Table 8]. Persons receiving prophylactic
antibiotic treatment should seek medical evaluation immediately if fever
or illness with cough develops. There is no currently available vaccine for pneumonic plague. The
previously available licensed plague vaccine in the United States was
discontinued in 1999. That vaccine was demonstrated to reduce the severity
of illness with bubonic plague but not pneumonic
plague.[62] Communicability and Infection Control Considerations. Pneumonic
plague is transmitted person to person through respiratory droplets.
Aerosol transmission has not been demonstrated. For patients with
pneumonic plague, respiratory droplet precautions as well as standard
precautions are recommended, including the use of gowns, gloves, eye
protection, and surgical masks for the first 48 hours of antimicrobial
therapy and until clinical improvement occurs. Hospitalized patients
should remain in isolation for the first 48 hours of antimicrobial therapy
and until clinical improvement occurs. Hospitalized patients should wear a
mask during transport. Y. pestis is rapidly destroyed by sunlight and drying.
Environmental surfaces can be decontaminated with a standard disinfectant.
Persons exposed to aerosolized plague bacilli during a biologic attack
should shower with warm water and soap. Clothing of persons exposed to an
aerosol of Y. pestis and linens of plague patients should be washed
in hot water.[20,62,63]
Botulism is a paralytic illness caused by a potent neurotoxin produced
by Clostridium botulinum, an anaerobic, spore-forming bacterium.
Natural forms of the disease are foodborne botulism, wound botulism, and
infant botulism. Foodborne botulism results from ingestion of improperly
processed foodstuffs containing preformed toxin produced by C.
botulinum. Wound botulism results from production of botulinum toxin
by C. botulinum organisms that contaminate wounds. Infant botulism
results from the colonization of the intestinal tract of infants after
ingestion of spores. Botulinum toxin has been developed as a biologic
weapon. An aerosol attack is considered the most likely use of botulinum
toxin for bioterrorism, although intentional contamination of food
supplies is possible.[29,65] Additional information about the
pathogenesis and epidemiology of noninhalational forms of botulism is
available elsewhere [see 7:V Anaerobic Infections]. Botulinum toxin is the most potent lethal toxin known. The estimated
toxic dose of type A botulinum toxin is 0.001 µg/kg of body weight. There
are seven distinct antigenic types of botulinum neurotoxins--types A
through G--produced by different strains of C. botulinum. Human
botulism is caused primarily by toxin types A, B, and E. Botulinum toxin
acts to block neurotransmission by binding irreversibly to the presynaptic
nerve terminal at the neuromuscular junction and preventing the release of
acetylcholine, resulting in bulbar palsies and skeletal muscle weakness.
The toxin is colorless, odorless, and presumably
tasteless.[29,66,67] The incubation period for foodborne botulism is 2 hours to 8 days; the
typical incubation period is 12 to 72 hours. The incubation period for
inhalational botulism is not established. Aerosol exposures of monkeys and
accidental aerosol exposure of humans have resulted in clinical illness
developing 12 to 80 hours after exposure. Type A toxin is associated with
more severe disease and a higher fatality rate than type B or E. The
neurologic features of all forms of botulism are
similar.[29,66,67] Although initial symptoms in foodborne
botulism may include nausea, vomiting, abdominal cramps, and diarrhea,
these symptoms are thought to result from other bacterial metabolites in
contaminated food and may not occur in inhalational botulism. The so-called classic triad of botulism summarizes the clinical
presentation: an afebrile patient, symmetrical descending flaccid
paralysis with prominent bulbar palsies, and a clear
sensorium.[66-68] Symptoms of cranial nerve abnormalities
nearly always begin in the bulbar musculature; patients typically present
with difficulty seeing, speaking, or swallowing. Clinical hallmarks
include ptosis, blurred vision, and the so-called four Ds: diplopia,
dysarthria, dysphonia, and dysphagia. Cranial nerve abnormalities and
bulbar weakness are followed by symmetrical descending weakness and
paralysis with progression from the head to the arms, thorax, and legs.
The extent of paralysis and rapidity of onset of symptoms are proportional
to the dose of toxin absorbed into the circulation. Recovery depends on
the regeneration of new motor axon twigs to reinnervate paralyzed muscle
fibers; recovery may take weeks to months. Anticholinergic symptoms are common, including dry mouth, ileus,
constipation, nausea and vomiting, urinary retention, and mydriasis. Other
symptoms include dizziness and sore throat. Sensory findings are not
present, with the exception of circumoral and peripheral paresthesias
secondary to hyperventilation resulting from anxiety. Botulinum toxin does
not cross the blood-brain barrier. Cranial nerve dysfunction and facial
nerve weakness may make communication difficult; these symptoms may be
mistaken for lethargy and signs of central nervous system involvement. Initiation of treatment with botulinum antitoxin should be based on the
clinical diagnosis and should not await laboratory confirmation. A
clinician who suspects botulism should immediately contact the local or
state health department to facilitate procurement of antitoxin for
treatment; arrangements should be made for confirmatory diagnostic testing
and initiation of an epidemiologic investigation to identify the source of
infection. In cases of potential foodborne botulism, any leftover
foodstuffs or containers should be held for testing by the public health
laboratory. Demonstration of botulinum toxin in serum samples by mouse bioassay is
diagnostic. Samples of serum (in adults, > 30 ml blood in a tiger-top
or red-top tube) obtained before administration of botulinum antitoxin
should be submitted for testing. For potential foodborne botulism, samples
of stool, gastric aspirate, emesis, and suspect foods should also be
submitted.[67] The likelihood of finding toxin in the sera of
affected patients decreases with time; it is detectable in only 13% to 28%
of patients more than 2 days after ingestion.[69] The possibility of a bioterrorist attack should be considered in any
outbreak of botulism. A bioterrorist attack should especially be
considered when a cluster of cases occurs; when an outbreak has a common
geographic location but there is no common dietary exposure (suggestive of
possible aerosol exposure); when there is an outbreak of an unusual
botulinum toxin type; or when multiple simultaneous outbreaks occur. A
careful dietary and travel history must be taken to help identify the
source. Patients should be asked if they know of others with similar
symptoms. The differential diagnosis of botulism includes stroke and other
neuromuscular disorders.[66,67] A CT scan of the head may be
used to exclude cerebrovascular accident, although it is relatively
insensitive in early ischemic stroke [see 11:IV Cerebrovascular
Disorders]. Patients with myasthenia gravis will often have
characteristic electromyographic findings and serum antibody tests. A test
dose of edrophonium (Tensilon) may briefly reverse paralysis in patients
with myasthenia gravis but also, reportedly, in some cases of botulism.
Guillain-Barré syndrome typically results in ascending paralysis and
sensory abnormalities. Cerebrospinal fluid protein is normal in patients
with botulism and is normal or elevated in patients with Guillain-Barré
syndrome. The rare Miller-Fisher variant of Guillain-Barré syndrome is
characterized by descending paralysis and may be confused with botulism.
Other conditions that mimic botulism include tick paralysis;
poliomyelitis; Eaton-Lambert syndrome; paralytic shellfish poisoning;
pufferfish ingestion; and anticholinesterase intoxication with
organophosphates, atropine, carbon monoxide, or aminoglycosides. The electromyogram (EMG) can help distinguish different causes of
paralysis. The EMG in botulism demonstrates normal nerve conduction
velocity, normal sensory nerve function, and small amplitude motor
potentials with facilitation to repetitive stimulation at 50
Hz.[70] The mainstay of treatment for botulism is supportive care, including
intensive care, mechanical ventilation, and parenteral nutrition.
Morbidity and mortality are usually from pulmonary aspiration secondary to
loss of the gag reflex and dysphagia leading to inability to control
secretions, respiratory failure secondary to inadequate tidal volume from
diaphragmatic and accessory respiratory muscle paralysis, and airway
obstruction from pharyngeal and upper airway muscle paralysis. Careful and
frequent monitoring of the gag and cough reflexes, swallowing, oxygen
saturation, vital capacity, and inspiratory force are critical. Airway
intubation is indicated for inability to control secretions and impending
respiratory failure. Secondary infections are common and should be sought
in patients who develop fever. Trivalent (ABE) equine antitoxin is available from the CDC through
state and local health departments and should be administered as soon as
possible after clinical diagnosis. Antitoxin can prevent progression of
disease caused by subsequent binding of toxin but does not reverse the
effects of already bound toxin. For this reason, antitoxin is not useful
if the patient is no longer showing progression of disease or is improving
from maximum paralysis. The amount of neutralizing antibody present in the
standard treatment dose of antitoxin far exceeds maximum serum toxin
concentrations in foodborne botulism patients, and repeat doses are
usually not required. In a biologic attack, however, patients may be
exposed to unusually high concentrations of toxin, so serum toxin levels
should be assessed after initiation of treatment in such cases to
determine the need for repeat doses. Botulism caused by toxin types other
than A, B, or E would not respond to the trivalent antitoxin. Limited
quantities of an investigational heptavalent (A-G) antitoxin are held by
the United States Army. However, because of the time delay involved in
typing the toxin, the utility of this product in a biologic attack is
probably minimal.[66,68] Hypersensitivity reactions, including anaphylaxis, have occurred after
administration of botulism antitoxin. For that reason, all patients should
undergo a skin test before receiving the antitoxin, and resuscitation
equipment should be immediately available. Patients showing a positive
hypersensitivity reaction on the skin test can be desensitized over
several hours.[71,72] Before administering antitoxin, physicians should carefully review the
package insert for dosage and adverse effects. Standard regimens can be
used in children, pregnant women, and immunocompromised persons with
botulism. Botulism immune globulin intravenous is an investigational
human-derived neutralizing antibody that is available only for treatment
of infant botulism from the California Department of Health Services,
Berkeley. The CDC bioterrorism Web site or local public health authorities
should be consulted for updated treatment
recommendations.[29,66,67] Transmissibility and Infection Control. Botulism is an
intoxication, not an infection, and thus is not transmitted from person to
person. Botulinum toxin does not penetrate intact skin. Standard
infection-control precautions are adequate unless meningitis is suspected,
in which case droplet precautions are indicated. Clothes of persons
exposed to an aerosol release of botulinum toxin should be removed and
washed. Exposed persons should shower with soap and hot water. Exposed
environmental surfaces can be decontaminated with 0.1% hypochlorite bleach
solution.[67]
Tularemia is a zoonotic infection caused by Francisella
tularensis, a small, nonmotile, gram-negative, pleomorphic
coccobacillus. The disease is typically acquired through contact with
blood or tissue fluids of infected animals or through the bite of an
infected deerfly, tick, or mosquito.[73] Inhalation of
organisms aerosolized from the environment and the drinking of
contaminated water can also result in human infection.[74]F.
tularensis was developed for use as a biologic weapon by the United
States (before its offensive biologic weapons program was terminated) and
other countries.[29] The epidemiology, pathogenesis, and
clinical manifestations of the naturally occurring forms of tularemia are
discussed in more detail elsewhere [see 7:XI Infections Due to
Brucella, Francisella, Yersina Pestis, and Bartonella]. Tularemia can take several forms in humans, depending on the route of
infection. Ulceroglandular, oculoglandular, glandular, typhoidal, and
pharyngeal tularemia are discussed elsewhere [see 7:XI Infections Due
to Brucella, Francisella, Yersina Pestis, and Bartonella].
Inhalational tularemia is a term used to describe infection resulting from
an aerosol release of F. tularensis.[75] Most patients
with inhalational tularemia develop pleuropulmonary tularemia (tularemia
pneumonia), but many patients may present with an undifferentiated febrile
illness. The infectious dose is as low as one to 50 organisms, and the
incubation period is typically 3 to 5 days (range, 1 to 14
days).[29] The clinical course of inhalational tularemia is less rapidly
progressive than that of pulmonary anthrax or plague. Illness onset is
acute, with some combination of fever, chills, sweats, myalgias, headache,
coryza, and sore throat. Nausea, vomiting, diarrhea, and abdominal pain
are common. Anorexia and weight loss may occur as the illness continues.
Cough may be dry or mildly productive. Hemoptysis is uncommon. Pleuritic
chest pain, substernal chest discomfort, and dyspnea may be present. Chest
x-rays may be normal or minimally abnormal or show a variety of
abnormalities, including peribronchial patchy infiltrates, effusions, and
hilar adenopathy.[76] F. tularensis infection may be mild and nonspecific or rapidly
progressive. Any form of tularemia may result in hematogenous spread with
secondary pleuropneumonia, sepsis, and, rarely, meningitis. If left
untreated, tularemia can progress to respiratory failure; liver, kidney,
and splenic involvement; meningitis; sepsis; shock; and death. There is
usually complete recovery with early diagnosis and treatment. Mortality is
less than 2% if the patient is treated; it can be as high as 60% for
untreated severe disease and pneumonia.[75,77,78] A clustering of sudden, severe pneumonias in previously healthy
patients should raise the possibility of an intentional aerosolized
release of tularemia. Clusters of patients with tularemia and cases in
which there is no natural explanation for the disease should be reported
immediately to the local or state health department (http://www.statepublichealth.org/). There are no rapid
confirmatory tests for F. tularensis. Gram stain of sputum is not
diagnostic but may identify other potential etiologies.[78,79]
In the context of a known or suspected outbreak, a presumptive diagnosis
can be made on the basis of symptoms. A chest x-ray should be obtained for
patients with suspected pleuropulmonary tularemia. The x-ray may show
infiltrates, effusion, hilar adenopathy, or subtle abnormalities, or it
may be normal. Recent experience with inhalational anthrax suggests that
chest CT scans of patients with tularemia may show pulmonary
abnormalities, including infiltrates, effusions, and adenopathy, before
they are evident on x-ray.[48] Specimens of respiratory secretions and blood for bacteriologic and
serologic testing should be collected before initiating therapy.
Pharyngeal washings, sputum specimens, fasting gastric aspirates, and
blood can be cultured for F. tularensis. Growth may be slow, so
cultures should be held for 10 days. Cysteine-enriched culture media
should be used to improve yield. Direct examination (by direct fluorescent
antibody staining or immunohistochemical testing, antigen detection,
microagglutination antibody testing, PCR, and other research tests) is
available through designated public health laboratories. Acute and
convalescent serologies are valuable for epidemiologic
purposes.[75,79] When the index of suspicion is high, antibiotic treatment should be
started before diagnosis is confirmed. Streptomycin or gentamicin is the
preferred agent. All persons potentially exposed to aerosolized F.
tularensis should be treated with doxycycline or ciprofloxacin. Close
contacts of patients with tularemia pneumonia do not need prophylactic
antibiotics. No vaccine for tularemia is currently available. The CDC
bioterrorism Web site, local public health authorities, or both should be
consulted for updated treatment recommendations.[29,75,80] Transmissibility and Infection Control. Tularemia is not
transmitted from person to person, and isolation of patients with
tularemia is not necessary. Standard precautions are recommended for all
patients with tularemia. Microbiology staff must be alerted when tularemia
is suspected, so they can take precautions to prevent laboratory-acquired
infection from culture plates and other infectious materials. Contaminated
environmental surfaces can be disinfected with a 10% bleach solution
followed by cleansing with 70% alcohol.[75]
Hemorrhagic fever viruses (HFVs) are RNA viruses classified in several
taxonomic families. HFVs cause a variety of disease syndromes with similar
clinical characteristics, referred to as acute hemorrhagic fever syndromes
[see 7:XXXI Viral Zoonoses]. The pathophysiologic hallmarks of HFV
infection are microvascular damage and increased vascular permeability.
HFVs that are of concern as potential biologic weapons include
Arenaviridae (Lassa, Junin, Machupo, Guanarito, and Sabia viruses, which
are the causative agents of Lassa fever and Argentine, Bolivian,
Venezuelan, and Brazilian hemorrhagic fevers, respectively); Filoviridae
(Ebola and Marburg viruses); Flaviviridae (yellow fever, Omsk hemorrhagic
fever, and Kyasanur Forest disease viruses); and Bunyaviridae (Rift Valley
fever [RVF]). Under natural conditions, humans are infected through the
bite of an infected arthropod or through contact with infected animal
reservoirs. Hemorrhagic fever viruses are highly infectious by aerosol;
are associated with high morbidity and, in some cases, high mortality; and
are thought to pose a serious risk as biologic weapons.[29] All
suspected cases of HFV infection should be reported immediately to the
local or state health department and the hospital epidemiologist. The exact pathogenesis for HFVs varies according to the etiologic
agent. The major target organ is the vascular endothelium. Immunologic and
inflammatory mediators are thought to play an important role in the
pathogenesis of HFVs. All HFVs can produce thrombocytopenia, and some also
cause platelet dysfunction. Infection with Ebola and Marburg viruses, Rift
Valley fever virus, and yellow fever virus causes destruction of infected
cells. DIC is characteristic of infection with Filoviridae. Ebola and
Marburg viruses may cause a hemorrhagic diathesis and tissue necrosis
through direct damage to vascular endothelial cells and platelets with
impairment of the microcirculation, as well as cytopathic effects on
parenchymal cells, with release of immunologic and inflammatory mediators.
Arenaviridae, on the other hand, appear to mediate hemorrhage via the
stimulation of inflammatory mediators by macrophages, thrombocytopenia,
and the inhibition of platelet aggregation. DIC is not a major
pathophysiologic mechanism in arenavirus infections.[81,82] The incubation period of HFVs ranges from 2 to 21 days. The clinical
presentations of these diseases are nonspecific and variable, making
diagnosis difficult. It is noteworthy that not all patients will develop
hemorrhagic manifestations. Even a significant proportion of patients with
Ebola virus infections may not demonstrate clinical signs of
hemorrhage.[83] Initial symptoms of the acute HFV syndrome may include fever, headache,
myalgia, rash, nausea, vomiting, diarrhea, abdominal pain, arthralgias,
myalgias, and malaise. Illness caused by Ebola, Marburg, Rift Valley fever
virus, yellow fever virus, Omsk hemorrhagic fever virus, and Kyasanur
Forest disease virus are characterized by an abrupt onset, whereas Lassa
fever and the diseases caused by the Machupo, Junin, Guarinito, and Sabia
viruses have a more insidious onset. Initial signs may include fever,
tachypnea, relative bradycardia, hypotension (which may progress to
circulatory shock), conjunctival injection, pharyngitis, and
lymphadenopathy. Encephalitis may occur, with delirium, seizures,
cerebellar signs, and coma. Most HFVs cause cutaneous flushing or a
macular skin rash, although the rash may be difficult to appreciate in
dark-skinned persons and varies according to the causative virus.
Hemorrhagic symptoms, when they occur, develop later in the course of
illness and include petechiae, purpura, bleeding into mucous membranes and
conjunctiva, hematuria, hematemesis, and melena. Hepatic involvement is
common, and renal involvement is proportional to cardiovascular
compromise.[29,81,83,84] Laboratory abnormalities include leukopenia (except in some cases of
Lassa fever), anemia or hemoconcentration, and elevated liver enzymes; DIC
with associated coagulation abnormalities and thrombocytopenia are common.
Mortality ranges from less than 1% for Rift Valley fever to 70% to 90% for
Ebola and Marburg virus infections.[29,81,83-85] The nonspecific and variable clinical presentation of the HFVs presents
a considerable diagnostic challenge. Clinical diagnostic criteria based on
WHO surveillance standards for acute hemorrhagic fever syndrome include
temperature greater than 101° F (38.3° C) of less than 3 weeks' duration;
severe illness and no predisposing factors for hemorrhagic manifestations;
and at least two of the following hemorrhagic symptoms: hemorrhagic or
purple rash, epistaxis, hematemesis, hematuria, hemoptysis, blood in
stools, or other hemorrhagic symptom with no established alternative
diagnosis. Any suspected case of HFV should result in immediate
notification of the hospital epidemiologist, local public health
department, and clinical laboratory personnel.[82,86]
Laboratory testing is currently available only at the CDC and the United
States Army Medical Research Institute for Infectious Diseases. Laboratory
techniques for the diagnosis of HFVs include antigen detection, IgM
antibody detection, isolation in cell culture, visualization by electron
microscopy, immunohistochemical techniques, and reverse
transcriptase-polymerase chain reaction. Submission of clinical specimens,
including processing and transport, should be arranged through
consultation with local public health authorities. The CDC's Packaging
Protocols for Biologic Agents/Diseases are available at (http://www.bt.cdc.gov/). Therapy for HFVs is largely supportive. Treatment of other suspected
causes of infection should be administered pending confirmation of HFV
infection. Hypotension and shock may require early administration of
vasopressors and hemodynamic monitoring with attention to fluid and
electrolyte balance, circulatory volume, and blood pressure. HFV patients
tend to respond poorly to fluid infusions and rapidly develop pulmonary
edema. Secondary infections may occur and should be diagnosed and treated.
Intravenous lines, catheters, and other invasive procedures should be
avoided unless they are clearly indicated. The management of bleeding is
controversial. Recent recommendations include not treating mild bleeding
and use of replacement therapy and heparin for severe bleeding with
DIC.[29] Intramuscular injections and medications that
interfere with platelet function or coagulation should be avoided. No treatments of HFVs have been approved by the Food and Drug
Administration. Ribavirin is a nucleoside analogue with activity against
some Arenaviridae and Bunyaviridae (including the viruses that cause Lassa
fever, Argentine hemorrhagic fever, and Crimean-Congo hemorrhagic fever)
but not against Filoviridae or Flaviviridae. Ribavirin may be used under
an IND protocol for the empirical treatment of HFV patients while awaiting
identification of the etiologic agent. Current treatment protocols and
dosing recommendations for ribavirin should be obtained through local
public health authorities or the CDC's bioterrorism Web site. Postexposure Prophylaxis. Postexposure prophylaxis is currently
recommended only for persons potentially exposed to HFV and for known
high-risk contacts or close contacts of HFV patients who develop fever or
other clinical criteria of HFV infection with no alternative diagnosis,
unless the etiologic agent is known to be a filovirus or a
flavivirus.[81] Infection Control Considerations. Ebola virus, Marburg virus,
Lassa fever virus, and the New World arenaviruses are transmissible from
person to person through direct contact with blood and body fluids.
Airborne transmission of HFVs is unlikely but cannot be completely ruled
out. The risk of person-to-person transmission is highest during the
latter stages of illness, which are characterized by vomiting, diarrhea,
shock, and, often, hemorrhage. The most important step in preventing
transmission of HFVs is strict attention to implementation of appropriate
barrier infection control measures, including double gloves, impermeable
gowns, face shields, eye protection, and leg and shoe coverings. Airborne precautions are recommended during care of patients with
possible HFV infections. Airborne precautions include high-efficiency
particulate respirators such as N-95 masks or powered air-purifying
respirators (PAPRs) for all persons entering the patient's room. Patients
should be placed in a negative-pressure isolation room with 6 to 12 air
changes per hour.[82,87] High-risk contacts of HFV patients include persons having contact with
mucous membranes (e.g., through kissing or sexual intercourse) or with
secretions, excretions, or blood (through percutaneous injury) of the
infected person. Close contacts are persons who have other direct contact
with the patient (e.g., shaking hands or hugging), provide medical care to
the patient, or process laboratory specimens from a patient with HFV
before initiation of infection-control precautions. Persons potentially exposed to HFVs in a bioterrorist attack and their
close and high-risk contacts should be placed under medical surveillance
for 21 days from the day of exposure. Temperatures should be recorded
twice daily, and any temperature of 101° F (38.3° C) or higher should be
reported to the designated clinical or public health authority. Therapy
with ribavirin should be initiated promptly unless an alternative
diagnosis is established or the etiologic agent is known to be a filovirus
or a flavivirus [see Treatment, above].[81] HFVs are highly infectious in the laboratory setting through
small-particle aerosols generated through procedures such as
centrifugation. Laboratory personnel should be alerted when HFV infections
are suspected, and appropriate personal-protection precautions and
laboratory biosafety procedures should be implemented.
EEE - eastern equine encephalitis VEE - Venezuelan equine
encephalitis WEE - western equine
encephalitis Note: The clinical manifestations of infections acquired during a
biologic attack may differ from those of naturally occurring infections.
Clinicians should remain alert for compatible syndromes that vary from
the descriptions given. Note: Treatment recommendations may change over time and according to
antimicrobial susceptibility test results during a biologic attack and
to availability of selected antimicrobial agents. Before initiating
treatment, clinicians should consult with an infectious disease
specialist and public health authorities and should check for revisions
and updates at http://www.bt.cdc.gov/HealthProfessionals/index.asp.
This information is adapted from CDC and Working Group on Civilian
Biodefense recommendations and may not represent FDA-approved
uses. Note: Prophylaxis recommendations may change over time and according
to antimicrobial susceptibility test results during a biologic attack
and to availability of selected antimicrobial agents. Before initiating
prophylaxis, clinicians should consult with an infectious disease
specialist and public health authorities and should check for revisions
and updates at http://www.bt.cdc.gov/HealthProfessionals/index.asp.
This information is adapted from CDC and Working Group on Civilian
Biodefense recommendations and may not represent FDA-approved
uses. Note: Treatment recommendations may change over time and according to
antimicrobial susceptibility test results during a biologic attack and
to availability of selected antimicrobial agents. Before initiating
treatment, clinicians should consult with an infectious disease
specialist and public health authorities and should check for revisions
and updates at http://www.bt.cdc.gov/HealthProfessionals/index.asp.
This information is adapted from CDC and Working Group on Civilian
Biodefense recommendations and may not represent FDA-approved
uses. Note: Prophylaxis recommendations may change over time and according
to antimicrobial susceptibility test results during a biologic attack
and to availability of selected antimicrobial agents. Before initiating
prophylaxis, clinicians should consult with an infectious disease
specialist and public health authorities and should check for revisions
and updates at http://www.bt.cdc.gov/HealthProfessionals/index.asp.
This information is adapted from CDC and Working Group on Civilian
Biodefense recommendations and may not represent FDA-approved
uses.Diagnosis
Infection Control and Postexposure Isolation
Anthrax
Classification and Epidemiology
Pathophysiology
Inhalational Anthrax
Figure 4. Evaluation of Patients with Possible
Inhalational Anthrax.
Cutaneous Anthrax
Figure 7. Evaluation of Patients with Possible
Cutaneous Anthrax.
Gastrointestinal and Oropharyngeal Anthrax
Infection Control
Plague
Clinical Presentation
Diagnosis
Treatment
Botulism
Clinical Presentation
Diagnosis
Treatment
Tularemia
Clinical Presentation
Diagnosis
Treatment and Postexposure Prophylaxis
Hemorrhagic Fever Viruses
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Tables
Table 1. Critical Biologic Agent Categories for Public Health
Preparedness
Category
Biologic Agent
Disease
A (highest immediate risk)
Variola major
Bacillus anthracis
Yersinia
pestis
Clostridium botulinum (botulinum
toxins)
Francisella tularensis
Filoviruses and
arenaviruses (e.g., Ebola virus,
Lassa virus)Smallpox
Anthrax
Plague
Botulism
Tularemia
Viral
hemorrhagic fevers
B (next highest risk)
Coxiella burnetii
Brucella
species
Burkholderia mallei
Burkholderia
pseudomallei
Alphaviruses (VEE, EEE, WEE)
Rickettsia
prowazekii
Toxins (e.g., ricin, staphylococcal enterotoxin
B)
Chlamydia psittaci
Food-safety threats (e.g.,
Salmonella species, E. coli 0157:H7)
Water-safety
threats (e.g., Vibrio cholerae, Cryptosporidium
parvum)Q
fever
Brucellosis
Glanders
Melioidosis
Encephalitis
Typhus
fever
Toxic syndromes
Psittacosis
C (potential, but not immediate, risk)
Emerging-threat agents (e.g., Nipah virus, hantavirus)
Table 2. Epidemiologic Clues of a Biologic Attack
Presence of a large epidemic
Unusually severe disease
or unusual routes of exposure
Unusual geographic area,
unusual season, or absence of normal vector
Multiple
simultaneous epidemics of different diseases
Outbreak of
zoonotic disease
Unusual strains of organisms or
antimicrobial-resistance patterns
Higher attack rates in
persons with common exposures
Credible threat, as
determined by authorities, of biologic attack
Direct
evidence of biologic
attack
Table 3. Diagnosis of Smallpox
Incubation Period
Clinical Presentation
Differential Diagnosis
Diagnostic Testing
7-17 days; mean, 10-12 days
Severe, acute febrile prodrome 1-4 days before rash onset,
with temperature >/= 101° F (38.3° C), headache, backache,
chills, vomitting, abdominal pain, prostration
Enanthem on
oropharyngeal mucosa, followed by rash on face, forearms, distal
extremities, then trunk; lesions most concentrated on face and
distal extremities
Lesions evolve slowly from macules to
papules to deep-seated, firm, nodular, round, well-circumscribed
vesicles or pustules to scrabs over 1-2 days per stage; are in
same stage of evolution on a given area of the body; may become
umbilicated or confluent
Hemorrhagic smallpox: bleeding into
skin and mucous membranes
Flat-type/malignant smallpox: lesions
remain soft and flattened, coalesce
Modified smallpox: less
severe with fewer, more superficial and rapidly evolving
lesionsVaricella (chickenpox); disseminated herpes zoster and
simplex; drug eruptions; erythema multiforme; enteroviral
infections; secondary syphilis; contact dermatitis; impetigo;
scabies; molluscum contagiosum
Hemorrhagic smallpox:
meningococcemia, Rocky Mountan spotted fever, ehrlichiosis,
gram-negative bacterial sepsis, severe acute leukemia
Malignant
smallpox: hemorrhagic chickenpoxDiagnostic testing at BSL-4 laboratory, including skin biopsy,
electron microscopic examination of vesicular and pustular fluid,
culture, PCR; serology
Appropriate infection control
precautions
BSL-4 - biosafety level 4
PCR - polymerase
chain reaction
Table 4. Differentiating Features of Smallpox and
Chickenpox
Clinical Feature
Smallpox
Chickenpox
Prodromal illness
Febrile prodrome lasting 1-4 days; patient appears ill or
toxic
No or mild prodrome; patients typically do not appear
ill
Appearance of lesions
Firm, round, well-circumscribed, deep-seated lesions; may be
umbilicated
Superficial lesions
Stage of lesions on any one part of the body
Lesions are all at the same stage of development on a given
area of the body
Lesions occur in crops with various stages of development
evident on a given area of the body
Initial lesions
Oral mucosa, face, or forearms
Face, then trunk
Oral lesions
Early; may not be evident
May occur
Severity of illness
Typically severe
Typically not severe
Distribution of rash
Centrifugal: lesions concentrated on the face and extremities,
with relative sparing of the trunk
Centripetal: lesions concentrated on the trunk with relative
sparing of the face and extremities
Lesions on palms or soles
Lesions on palms and soles in majority of cases
Lesions on palms and soles uncommon
Rate of evolution of rash
Slow evolution of lesions from macules to papules to pustules
over days
Rapid evolution from macules to papules to crusted lesions
within 24 hours
Presence of pruritus
Lesions may be painful and are not usually pruritic until
scabbing occurs
Often pruritic, typically not painful in the absence of
secondary infection
Hemorrhagic lesions
Can occur
Can occur
Table 5. Treatment of Inhalational Anthrax
Patients
Medication and Dosage
Comments
Adults, including pregnant women and
immunocompromised persons
Ciprofloxacin, 400 mg I.V., q. 12 hr
or
Doxycycline, 100 mg I.V., q. 12
hr
and
One or two additional antimicrobials*If meningitis is suspected, doxycycline may be less optimal
because of poor central nervous system penetration
Modify
regimen on the basis of susceptibility testing of isolate; can
switch to p.o. after patient is clinically stable; continue
treatment for at least 60 days
Consider corticosteroids for
meningitis, severe edema, or respiratory compromise
Children, including those who are
immunocompromised
Ciprofloxacin, 10-15 mg/kg I.V., q. 12 hr, not to exceed 1
g/day
or
Doxycycline
If </= 8 yr and
</= 45 kg, give adult dosage
If </= 8 yr or if > 8 yr
but </= 45 kg, give 2.2 mg/kg q. 12 hr (maximum, 200
mg/day)
and
One or two additional antimicrobials*If meningitis is suspected, doxycycline may be less optimal
because of poor central nervous system penetration
Modify
regimen on the basis of susceptibility testing of isolate; can
switch to p.o. after patient is clinically stable; continue
treatment for at least 60 days
Consider corticosteroids for
meningitis, severe edema, or respiratory
compromise
*Other agents with in vitro activity anthrax include rifampin,
vancomycin, penicillin, ampicillin, chloramphenicol, imipenem,
clindamycin, and clarithromycin.
Table 6. Postexposure Prophylaxis for Anthrax in the Setting of a
Bioterrorist Attack
Patients
Medication
Comments
Adults, including immunocompromised persons
Ciprofloxacin, 500 mg p.o., q. 12 hr
or
Doxycycline, 100 mg p.o., q. 12
hr
or, if strain proved
susceptible,
Amoxicillin, 500 mg p.o., q. 8 hrGive prophylaxis for at least 60 days
Pregnant women
Ciprofloxacin, 500 mg p.o., q. 12 hr
or, if strain proved
susceptible,
Amoxicillin, 500 mg p.o., q. 8 hrGive prophylaxis for at least 60 days
Children, including those
who are
immunocompromisedCiprofloxacin, 10-15 mg/kg p.o., b.i.d., not to exceed
1g/day
or, if strain proved
susceptible,
Amoxicillin
If 3 20 kg:
500 mg p.o., q. 8 hr
If < 20 kg: 80 mg/kg/day p.o., in
divided doses q. 8 hr (maximum, 500 mg/dose)Give prophylaxis for at least 60 days
Table 7. Antimicrobial Treatment of Pneumonic Plague
Patients
Drug
Comments
Adults
Streptomycin, 1 g I.M., b.i.d.
or
Gentamicin, 5 mg/kg I.M. or I.V., q.d., or 2 mg/kg loading dose followed by 1.7 mg/kg
I.M. or I.V., t.i.d.
Alternative choices:
Doxycycline, 100 mg
I.V., b.i.d., or 200 mg I.V., q.d.
Ciprofloxacin, 400 mg I.V.,
b.i.d.
Chloramphenicol, 25 mg/kg I.V., q.i.d.Treat for 10 days; during a community outbreak of pneumonic
plague, all persons developing a temperature >/= 101.3° F
(38.5° C) or greater or a new cough should begin parenteral
antibiotic treatment; oral treatment may be given when resources
for parenteral treatment are limited; pregnant women should not
receive streptomycin or chloramphenicol; tetracycline may be
substituted for doxycycline
Children
Streptomycin, 15 mg/kg I.M., b.i.d. (maximum, 2 g/day)
or
Gentamicin, 2.5. mg/kg I.M. or I.V., t.i.d.
Alternative choices:
Doxycycline: if
>/= 45 kg, adult dosage; if < 45 kg, 2.2 mg/kg b.i.d.
(maximum, 200 mg/day)
Ciprofloxacin, 15 mg/kg I.V., b.i.d.
Chloramphenicol, 25 mg/kg I.V.,
q.i.d.; maintain serum
concentration between 5 and 20 µg/mlUse chloramphenicol in plague meningitis
Table 8. Postexposure Prophylaxis of Pneumonic Plague
Patients
Drug
Comments
Adults, including pregnant women
Doxycycline, 100 mg p.o., b.i.d.
Ciprofloxacin, 500 mg
p.o., b.i.d.
Alternative:
Chloramphenicol, 25
mg/kg p.o., q.i.d.Asymptomatic household contacts, hospital contacts, or other
close contacts should receive postexposure prophylaxis for 7 days;
contacts who develop fever or cough while receiving prophylaxis
should begin antibiotic treatment for plague.
Children
Doxycycline: if >/= 45 kg, adult dosage; if < 45 kg, 2.2
mg/kg p.o., b.i.d. (maximum, 200 mg/day)
Ciprofloxacin, 20
mg/kg p.o., b.i.d.
Alternative:
Chloramphenicol,
25 mg/kg p.o., q.i.d.Asymptomatic household contacts, hospital contacts, or other
close contacts should receive postexposure prophylaxis for 7 days;
contacts who develop fever or cough while receiving prophylaxis
should begin antibiotic treatment for plague. References
http://www.cdc.gov/nip/smallpox/supp_recs.htm
http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html
http://www.usamriid.army.mil/education/bluebook.html
http://www.aad.org/BioInfo/Biomessage2.html
http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm