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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 disease9; enteric infection with Escherichia coli 0157:H7, Salmonella, or Shigella10; pertussis, rubella, measles, or chickenpox occurring in health care facilities and clinics11-14; unusual or newly emerging infections such as West Nile virus and hantavirus pulmonary syndrome15-17; 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. 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. 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. 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

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.

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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


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. 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

The differential diagnosis of smallpox includes other illnesses that can cause fever and a rash. 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. 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 ( Protocols for specimen collection for smallpox testing have been published by the CDC and are available at the following Internet address: These protocols are also available through the CDC's smallpox information Web page:

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:

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infection control and postexposure isolation

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 vaccine was prepared from calf lymph with a seed virus derived from the New York City Board of Health strain of vaccinia virus (Dryvax® vaccine). A supply of licensed Dryvax® 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 [see Figure 2]. 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

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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

classification and epidemiology

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 m 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.

inhalational anthrax

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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 [see Figure 3]. 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. 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 ( 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

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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

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. 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


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.                      

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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].

clinical presentation

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 ( 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]. 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. 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

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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 g/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

clinical presentation

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

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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].

clinical presentation

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 ( 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

treatment and postexposure prophylaxis

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

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Hemorrhagic Fever Viruses

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 macro-phages, thrombocytopenia, and the inhibition of platelet aggregation. DIC is not a major pathophysiologic mechanism in arenavirus infections.81,82

clinical presentation

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 (


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.

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

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Jeffrey Duchin, m.d.



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