Reasonable Rascal
12-27-01, 14:55
STAPHYLOCOCCAL ENTEROTOXIN B
SUMMARY
Signs and Symptoms: From 3-12 hours after aerosol exposure, sudden onset of fever, chills, headache, myalgia, and nonproductive cough. Some patients may develop shortness of breath and retrosternal chest pain. Fever may last 2 to 5 days, and cough may persist for up to 4 weeks. Patients may also present with nausea, vomiting, and diarrhea if they swallow toxin. Presumably, higher exposure can lead to septic shock and death.
Diagnosis: Diagnosis is clinical. Patients present with a febrile respiratory syndrome without CXR abnormalities. Large numbers of soldiers presenting with typical symptoms and signs of SEB pulmonary exposure would suggest an intentional attack with this toxin.
Treatment: Treatment is limited to supportive care. Artificial ventilation might be needed for very severe cases, and attention to fluid management is important.
Prophylaxis: Use of protective mask. There is currently no human vaccine available to prevent SEB intoxication.
Isolation and Decontamination: Standard Precautions for healthcare workers. Hypochlorite (0.5% for 10-15 minutes) and/or soap and water. Destroy any food that may have been contaminated.
OVERVIEW
Staphylococcus aureus produces a number of exotoxins, one of which is Staphylococcal enterotoxin B, or SEB. Such toxins are referred to as exotoxins since they are excreted from the organism; however, they
normally exert their effects on the intestines and thereby are called enterotoxins. SEB is one of the pyrogenic toxins that commonly causes food poisoning in humans after the toxin is produced in improperly handled foodstuffs and subsequently ingested. SEB has a very broad spectrum of biological activity. This
toxin causes a markedly different clinical syndrome when inhaled than it characteristically produces when ingested. Significant morbidity is produced in individuals who are exposed to SEB by either portal of entry to the body.
HISTORY AND SIGNIFICANCE
SEB has caused countless endemic cases of food poisoning. Often these cases have been clustered, due to common source exposure in a setting such as a church picnic or other community event in which contaminated food is consumed. Although this toxin would not be likely to produce significant mortality on the battlefield, it could render up to 80 percent or more of exposed personnel clinically ill and unable to perform their mission for 1-2 weeks. Therefore, even though SEB is not generally thought of as a lethal agent, it may severely incapacitate soldiers, making it an extremely important toxin to consider.
TOXIN CHARACTERISTICS
Staphylococcal enterotoxins are extracellular products produced by coagulase-positive staphylococci. They are produced in culture media and also in foods when there is overgrowth of the staph organisms. At least five antigenically distinct enterotoxins have been identified, SEB being one of them. These toxins are heat stable. SEB causes symptoms when inhaled at very low doses in humans: a dose of several logs lower than the lethal dose by the inhaled route would be sufficient to incapacitate 50 percent of those soldiers so exposed. This toxin could also be used (theoretically) in a special forces or terrorist mode to sabotage food or small volume water supplies.
MECHANISM OF TOXICITY
Staphylococcal enterotoxins produce a variety of toxic effects. Inhalation of SEB can induce extensive pathophysiological changes to include widespread systemic damage and even septic shock. Many of the effects of staphylococcal enterotoxins are mediated by interactions with the host's own immune system. The mechanisms of toxicity are complex, but are related to toxin binding directly to the major histocompatibility complex that subsequently stimulates the proliferation of large numbers of T cell
lymphocytes. Because these exotoxins are extremely potent activators of T cells, they are commonly referred to as bacterial superantigens. These superantigens stimulate the production and secretion of various cytokines, such as tumor necrosis factor, interferon, interleukin-1 and interleukin-2, from immune system cells. Released cytokines are thought to mediate many of the toxic effects of SEB.
CLINICAL FEATURES
Relevant battlefield exposures to SEB are projected to cause primarily clinical illness and incapacitation. However, higher exposure levels can presumably lead to septic shock and death. Intoxication with SEB begins 3 to 12 hours after inhalation of the toxin. Victims may experience the sudden onset of fever, headache, chills, myalgias, and a nonproductive cough. More severe cases may develop dyspnea and retrosternal chest pain. Nausea, vomiting, and diarrhea will also occur in many patients due to inadvertently
swallowed toxin, and fluid losses can be marked. The fever may last up to five days and range from 103 to 106 degrees F, with variable degrees of chills and prostration. The cough may persist up to four weeks, and patients may not be able to return to duty for two weeks.
Physical examination in patients with SEB intoxication is often unremarkable. Conjunctival injection may be present, and postural hypotension may develop due to fluid losses. Chest examination is unremarkable except in the unusual case where pulmonary edema develops. The chest X-ray is also generally normal, but in severe cases increased interstitial markings, atelectasis, and possibly overt pulmonary edema or an ARDS picture may develop.
DIAGNOSIS
As is the case with botulinum toxins, intoxication due to SEB inhalation is a clinical and epidemiologic diagnosis. Because the symptoms of SEB intoxication may be similar to several respiratory pathogens such as influenza, adenovirus, and mycoplasma, the diagnosis may initially be unclear. All of these might present with fever, nonproductive cough, myalgia, and headache. SEB attack would cause cases to present in large numbers over a very short period of time, probably within a single 24 hour period. Naturally
occurring pneumonias or influenza would involve patients presenting over a more prolonged interval of time. Naturally occurring staphylococcal food poisoning cases would not present with pulmonary symptoms. SEB intoxication tends to progress rapidly to a fairly stable clinical state, whereas pulmonary anthrax, tularemia pneumonia, or pneumonic plague would all progress if left untreated. Tularemia and plague, as well as Q fever, would be associated with infiltrates on chest radiographs. Nerve agent intoxication would cause fasciculations and copious secretions, and mustard would cause skin lesions in addition to pulmonary findings; SEB inhalation would not be characterized by these findings. The dyspnea associated with botulinum intoxication is associated with obvious signs of muscular paralysis, bulbar palsies, lack of fever, and a dry pulmonary tree due to cholinergic blockade; respiratory difficulties occur late rather than early as with SEB inhalation.
Laboratory findings are not very helpful in the diagnosis of SEB intoxication. A nonspecific neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate may be seen, but these abnormalities are present in many illnesses. Toxin is very difficult to detect in the serum by the time symptoms occur; however, a serum specimen should be drawn as early as possible after exposure. Data from rabbit studies clearly show that SEB in the serum is transient; however, it accumulates in the urine and can be detected for several hours post exposure. Therefore, urine samples should be obtained and tested for SEB. Because most patients will develop a significant antibody response to the toxin, acute and convalescent serum should be drawn which may be helpful retrospectively in the diagnosis.
MEDICAL MANAGEMENT
Currently, therapy is limited to supportive care. Close attention to oxygenation and hydration are important, and in severe cases with pulmonary edema, ventilation with positive end expiratory pressure and diuretics might be necessary. Acetaminophen for fever, and cough suppressants may make the patient more comfortable. The value of steroids is unknown. Most patients would be expected to do quite well after the initial acute phase of their illness, but most would generally be unfit for duty for one to two weeks.
PROPHYLAXIS
Although there is currently no human vaccine for immunization against SEB intoxication, several vaccine candidates are in development. Preliminary animal studies have been encouraging and a vaccine candidate is nearing transition to advanced development and safety and immunogenicity testing in man. Experimentally, passive immunotherapy can reduce mortality, but only when given within 4-8 hours after inhaling SEB.
TULAREMIA
SUMMARY
Signs and Symptoms: Ulceroglandular tularemia presents with a local ulcer and regional lymphadenopathy, fever, chills, headache and malaise. Typhoidal tularemia presents with fever, headache, malaise, substernal discomfort, prostration, weight loss and a non-productive cough.
Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. Chest x-ray may reveal a pneumonic process, mediastinal lymphadenopathy or pleural effusion. Routine culture is possible but difficult. The diagnosis can be established retrospectively by serology.
Treatment: Administration of antibiotics (streptomycin or gentamicin) with early treatment is very effective.
Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. It is administered once by scarification. A two week course of tetracycline is effective as prophylaxis when given after exposure.
Isolation and Decontamination: Standard Precautions for healthcare workers. Organisms are relatively easy to render harmless by mild heat (55 degrees Celsius for 10 minutes) and standard disinfectants.
OVERVIEW
Francisella tularensis, the causative agent of tularemia, is a small, aerobic non-motile, gram-negative cocco-bacillus. Tularemia (also known as rabbit fever and deer fly fever) is a zoonotic disease which humans typically acquire after contact of their skin or mucous membranes with tissues or body fluids of infected animals, or from bites of infected deerflies, mosquitoes, or ticks. Less commonly, inhalation of contaminated dusts or ingestion of contaminated foods or water may produce clinical disease. Respiratory exposure by aerosol would cause typhoidal or pneumonic tularemia. F. tularensis can remain viable for weeks in water, soil, carcasses, and hides, and for years in frozen rabbit meat. It is resistant for months to temperatures of freezing and below. It is rather easily killed by heat and disinfectants.
HISTORY AND SIGNIFICANCE
Tularemia was recognized in Japan in the early 1800's and in Russia in 1926. In the early 1900's, American workers investigating suspected plague epidemics in San Francisco isolated the organism and named it Bacterium tularense after Tulare County where the work was performed. Dr. Edward Francis, USPHS, established the cause of deer-fly fever as Bacterium tularense and subsequently devoted his life to researching the organism and disease, hence, the organism was later renamed Francisella tularensis
Francisella tularensis was weaponized by the United States in the 1950's and 1960's during the U.S. offensive biowarfare program, and other countries are suspected to have weaponized this agent. This organism could potentially be stabilized for weaponization by an adversary and theoretically produced in either a wet or dried form. It could then theoretically be delivered against U.S. forces in a similar fashion to the other bacteria discussed in this handbook.
CLINICAL FEATURES
After an incubation period varying from 1-21 days (average 3-5 days), presumably dependent upon the dose of organisms, onset is usually acute. Tularemia may appear in several forms in man depending upon the route of inoculation: ulceroglandular, glandular, typhoidal, oculoglandular, pharyngeal, and pneumonic tularemia. In humans, as few as 10 to 50 organisms will cause disease if inhaled or injected intradermally, whereas approximately 108 organisms are required with oral challenge.
Ulceroglandular tularemia (75-85 percent of cases) is most often acquired through inoculation of the skin or mucous membranes with blood or tissue fluids of infected animals. It is characterized by fever, chills, headache, and malaise, an ulcerated skin lesion and painful regional lymphadenopathy. The skin lesion is
usually located on the fingers or hand.
Glandular tularemia (5-10 percent of cases) results in fever and tender lymphadenopathy but no skin ulcer.
Typhoidal tularemia accounts for 5-15 percent of naturally occurring cases and occurs mainly after inhalation of infectious aerosols, but can occur after intradermal or gastrointestinal challenge. It manifests as fever, prostration, and weight loss but without lymphadenopathy. Pneumonia may be associated with any form but is most common in typhoidal tularemia. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are non-specific and there frequently is no suggestive exposure history. Respiratory symptoms, substernal discomfort, and a non-productive cough may also be present. Radiologic evidence of pneumonia or mediastinal lymphadenopathy is most common with typhoidal disease but may or may not be present in all other forms of tularemia.
Oculoglandular tularemia (1-2 percent of cases) occurs after inoculation of the conjunctivae with infectious material. Patients have unilateral, painful, purulent conjunctivitis with preauricular or cervical lymphadenopathy. Chemosis, periorbital edema, and small nodular lesions or ulcerations of the palpebral conjunctiva are noted in some patients.
Oropharyngeal tularemia refers to primary ulceroglandular disease confined to the throat. It produces an acute exudative or membranous pharyngotonsillitis with cervical lymphadenopathy.
Pneumonic tularemia is an illness characterized primarily by pneumonia. Pneumonia is common in tularemia. It is seen in 30-80 percent of the typhoidal cases and in 10-15 percent of the ulceroglandular cases. The case fatality rate without treatment is approximately 5 percent for the ulceroglandular form and 35 percent for the typhoidal form. All ages are susceptible, and recovery is followed by permanent immunity.
DIAGNOSIS
Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria. Isolation represents a clear hazard to laboratory personnel and should only be attempted in BL-3 laboratory. The diagnosis can be established retrospectively serologically. A fourfold rise in the tularemia tube agglutination or microagglutination titer is diagnostic of infection. A single convalescent titer of 1:160 or greater is diagnostic of past or current infection. Titers are usually negative the first week of infection, positive the second week in 50-70 percent of cases and reach a maximum in 4-8 weeks.
MEDICAL MANAGEMENT
Standard Precautions are recommended for healthcare workers. Streptomycin (1 gm every 12 hours IM for 10-14 days) is the treatment of choice. Gentamicin 3-5 mg/kg/day parenterally for 10-14 days is also effective. Tetracycline and chloramphenicol treatment are effective as well, but are associated with significant relapse rates. Although laboratory related infections with this organism are very common,
person-to-person spread is unusual and respiratory isolation is not required.
PROPHYLAXIS
Vaccine: A live, attenuated tularemia vaccine is available as an investigational new drug (IND). It is given by scarification. This vaccine has been administered to more than 5,000 persons without significant adverse reactions. It is of proven effectiveness in preventing laboratory acquired tularemia as well as in experimentally exposed human volunteers. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.
Antibiotics: Tetracycline 500 mg PO qid for two weeks is effective as prophylaxis when given after exposure.
VENEZUELAN EQUINE ENCEPHALITIS
SUMMARY
Signs and Symptoms: Sudden onset of illness with generalized malaise, spiking fevers, rigors, severe headache, photophobia, and myalgias. Nausea, vomiting, cough, sore throat, and diarrhea may follow. Full
recovery takes 1-2 weeks.
Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. The white blood cell count often shows a striking leukopenia and lymphopenia. Virus isolation may be made from serum, and in some cases throat swab specimens. Both neutralizing or IgG antibody in paired sera or VEE specific IgM present in a single serum sample indicate recent infection.
Treatment: Supportive only.
Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. A second, formalin-inactivated, killed vaccine is available for boosting antibody titers in those initially receiving the live vaccine.
Isolation and Decontamination: Standard Precautions for healthcare workers. Human cases are infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat (80 degrees centigrade for 30 minutes) and standard disinfectants.
OVERVIEW
Venezuelan equine encephalitis (VEE) virus is an arthropod-borne alphavirus that is endemic in northern South America, Trinidad, Central America, Mexico, and Florida. Eight serologically distinct viruses belonging to the VEE complex have been associated with human disease; the two most important of these pathogens are designated subtype I, variants A/B, and C. These agents also cause severe disease in horses, mules, burros and donkeys (Equidae). Natural infections are acquired by the bites of a wide variety of
mosquitoes. Equidae serve as amplifying hosts and source of mosquito infection. In natural human epidemics, severe and often fatal encephalitis in Equidae always precedes disease in humans. The virus is rather easily killed by heat and disinfectants.
HISTORY AND SIGNIFICANCE
VEE was weaponized by the United States in the 1950's and 1960's before the U.S. offensive biowarfare program was terminated, and other countries have been or are suspected to have weaponized this agent.
This virus could theoretically be produced in either a wet or dried form and potentially stabilized for weaponization. This agent could then theoretically be delivered against friendly forces in a manner similar to the other agents already discussed.
As mentioned above, in natural human epidemics, disease in Equidae always precedes that in humans. A biological warfare attack with virus disseminated as an aerosol would almost certainly cause human disease as a primary event. If Equidae were present, disease in these animals would occur simultaneously with human disease. However, during natural epidemics, illness or death in wild or free ranging Equidae may not be recognized before the onset of human disease, thus a natural epidemic could be confused with a BW event, and data on onset of disease should be considered with caution. A more reliable method for determining the likelihood of a BW event would be the presence of VEE outside of its natural geographic range. Secondary spread by person-to-person contact has not been conclusively shown to occur; however,
observations during a recent outbreak in Columbia suggest that it may occur often enough to sustain epidemics in the absence of Equidae. A BW attack in a region populated by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.
CLINICAL FEATURES
VEE is characterized by inflammation of the meninges of the brain and of the brain itself, thus accounting for the predominance of CNS symptoms in the small percentage of infections that develop encephalitis. The disease is usually acute, prostrating and of short duration. The case fatality rate is less than 1 percent, although is somewhat higher in the very young or aged. Nearly 100 percent of those infected suffer an overt illness. Recovery from an infection results in excellent short-term and long-term immunity.
DIAGNOSIS
After an incubation period varying from 1 to 5 days, onset is usually sudden. It is manifested by generalized malaise, spiking fever, rigors, severe headache, photophobia, and myalgias in the legs and lumbosacral area. Nausea, vomiting, cough, sore throat, and diarrhea may follow. This acute phase lasts 24-72 hours. A prolonged period of asthenia and lethargy may follow, with full health and activity regained after 1-2 weeks. Approximately 4 percent of children during natural epidemics develop signs of central nervous system infection, with meningismus, convulsions, coma, and paralysis. Adults rarely develop neurologic complications. In children manifesting severe encephalitis, the fatality rate may reach 20 percent. Permanent neurologic sequelae are reported in survivors. Experimental aerosol challenges in animals suggest that the incidence of CNS disease and associated morbidity and mortality would be high after a BW attack, as the VEE virus would infect the olfactory nerve and spread directly to the CNS. A VEE infection during pregnancy may cause encephalitis in the fetus, placental damage, abortion, or severe congenital neuroanatomical anomalies.
The white blood cell count shows a striking leukopenia and lymphopenia. In cases with encephalitis, the cerebrospinal fluid may be under increased pressure and contain up to 1,000 white cells/mm3 (predominantly mononuclear cells) and a mildly elevated protein concentration. Viremia during the acute phase of the illness (but not during encephalitis) is generally high enough to allow detection by antigen-capture enzyme immunoassay. Virus isolation may be made from serum, and in some cases throat swab specimens, by inoculation of cell cultures or suckling mice. A variety of serological tests are applicable, including the IgM ELISA indirect FA, hemagglutination inhibition, complement-fixation, and neutralization. For persons without prior exposure to VEE complex viruses, a presumptive diagnosis may be made by finding IgM antibody in a single serum sample taken 5 to 7 days after onset of illness.
MEDICAL MANAGEMENT
Standard Precautions are recommended for healthcare workers. Person-to-person transmission may theoretically occur by means of respiratory droplet infection. There is no specific therapy. Patients with uncomplicated VEE infection may be treated with analgesics to relieve headache and myalgia. Patients who develop encephalitis may require anticonvulsants and intensive supportive care to maintain fluid and electrolyte balance, ensure adequate ventilation, and avoid complicating secondary bacterial infections. Patients should be treated in a screened room or in quarters treated with a residual insecticide for at least 5 days after onset, or until afebrile, as human cases may be infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat and disinfectants.
PROPHYLAXIS
Vaccine: An investigational vaccine, designated TC-83, is a live, attenuated cell-culture-propagated vaccine which has been used in several thousand persons to prevent laboratory infections. The vaccine is given as a single 0.5 ml subcutaneous dose. Febrile reactions occur in up to 18 percent of persons vaccinated, and may be moderate to severe in 5 percent, with fever, myalgias, headache, and prostration. Approximately 18 percent of vaccinees fail to develop detectable neutralizing antibodies, but it is unknown whether they are susceptible to clinical infection if challenged. Contraindications for use include an intercurrent viral infection or pregnancy. TC-83 is a licensed vaccine for Equidae.
A second investigational product that has been tested in humans is the C-84 vaccine, prepared by formalin-inactivation of the TC-83 strain. The vaccine is not used for primary immunization, but is currently used to boost nonresponders to TC-83 (0.5 ml subcutaneously at 2-4 week intervals for up to 3 inoculations or until an antibody response is measured), and probably affords complete protection against aerosol infection from homologous strains in these individuals. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.
Antiviral Drugs: In experimental animals, alpha-interferon and the interferon-inducer poly-ICLC have proven highly effective for post-exposure prophylaxis of VEE. There are no clinical data on which to assess
efficacy in humans.
VIRAL AGENTS
Viruses are the simplest type of microorganism and consist of a nucleocapsid protein coat containing genetic material, either RNA or DNA. In some cases the virus particle is also surrounded by an outer layer of lipids. Viruses are much smaller than bacteria and vary in size from 0.02 m m to 0.2 m m (1 m m = 1/1000 mm). Viruses lack a system for their own metabolism and are therefore dependent on the synthetic machinery of their host cells: viruses are thus intracellular parasites. This also means that the virus, unlike the bacterium, cannot be cultivated in synthetic nutritive solutions but requires living cells in order to multiply. The host cells can be from human beings, animals, plants, or bacteria. Every virus needs its own special type of host cell because a complicated interaction is required between the cell and virus if the virus is to be able to multiply. Many virus-specific host cells can be cultivated in synthetic nutrient solutions and afterwards can be infected with the virus in question. Another usual way of cultivating viruses is to let them grow on chorioallantoic membranes (from fertilized eggs). The cultivation of viruses is costly, demanding, and time-consuming. A virus normally brings about changes in the host cell such that the cell dies. This handbook will cover a virus considered by some to be the most likely viral agent that would be used in a BW attack, the alpha virus that causes Venezuelan equine encephalitis, known as VEE. We also discuss smallpox and hemorrhagic fever viruses which could potentially be employed as BW agents.
SUMMARY
Signs and Symptoms: From 3-12 hours after aerosol exposure, sudden onset of fever, chills, headache, myalgia, and nonproductive cough. Some patients may develop shortness of breath and retrosternal chest pain. Fever may last 2 to 5 days, and cough may persist for up to 4 weeks. Patients may also present with nausea, vomiting, and diarrhea if they swallow toxin. Presumably, higher exposure can lead to septic shock and death.
Diagnosis: Diagnosis is clinical. Patients present with a febrile respiratory syndrome without CXR abnormalities. Large numbers of soldiers presenting with typical symptoms and signs of SEB pulmonary exposure would suggest an intentional attack with this toxin.
Treatment: Treatment is limited to supportive care. Artificial ventilation might be needed for very severe cases, and attention to fluid management is important.
Prophylaxis: Use of protective mask. There is currently no human vaccine available to prevent SEB intoxication.
Isolation and Decontamination: Standard Precautions for healthcare workers. Hypochlorite (0.5% for 10-15 minutes) and/or soap and water. Destroy any food that may have been contaminated.
OVERVIEW
Staphylococcus aureus produces a number of exotoxins, one of which is Staphylococcal enterotoxin B, or SEB. Such toxins are referred to as exotoxins since they are excreted from the organism; however, they
normally exert their effects on the intestines and thereby are called enterotoxins. SEB is one of the pyrogenic toxins that commonly causes food poisoning in humans after the toxin is produced in improperly handled foodstuffs and subsequently ingested. SEB has a very broad spectrum of biological activity. This
toxin causes a markedly different clinical syndrome when inhaled than it characteristically produces when ingested. Significant morbidity is produced in individuals who are exposed to SEB by either portal of entry to the body.
HISTORY AND SIGNIFICANCE
SEB has caused countless endemic cases of food poisoning. Often these cases have been clustered, due to common source exposure in a setting such as a church picnic or other community event in which contaminated food is consumed. Although this toxin would not be likely to produce significant mortality on the battlefield, it could render up to 80 percent or more of exposed personnel clinically ill and unable to perform their mission for 1-2 weeks. Therefore, even though SEB is not generally thought of as a lethal agent, it may severely incapacitate soldiers, making it an extremely important toxin to consider.
TOXIN CHARACTERISTICS
Staphylococcal enterotoxins are extracellular products produced by coagulase-positive staphylococci. They are produced in culture media and also in foods when there is overgrowth of the staph organisms. At least five antigenically distinct enterotoxins have been identified, SEB being one of them. These toxins are heat stable. SEB causes symptoms when inhaled at very low doses in humans: a dose of several logs lower than the lethal dose by the inhaled route would be sufficient to incapacitate 50 percent of those soldiers so exposed. This toxin could also be used (theoretically) in a special forces or terrorist mode to sabotage food or small volume water supplies.
MECHANISM OF TOXICITY
Staphylococcal enterotoxins produce a variety of toxic effects. Inhalation of SEB can induce extensive pathophysiological changes to include widespread systemic damage and even septic shock. Many of the effects of staphylococcal enterotoxins are mediated by interactions with the host's own immune system. The mechanisms of toxicity are complex, but are related to toxin binding directly to the major histocompatibility complex that subsequently stimulates the proliferation of large numbers of T cell
lymphocytes. Because these exotoxins are extremely potent activators of T cells, they are commonly referred to as bacterial superantigens. These superantigens stimulate the production and secretion of various cytokines, such as tumor necrosis factor, interferon, interleukin-1 and interleukin-2, from immune system cells. Released cytokines are thought to mediate many of the toxic effects of SEB.
CLINICAL FEATURES
Relevant battlefield exposures to SEB are projected to cause primarily clinical illness and incapacitation. However, higher exposure levels can presumably lead to septic shock and death. Intoxication with SEB begins 3 to 12 hours after inhalation of the toxin. Victims may experience the sudden onset of fever, headache, chills, myalgias, and a nonproductive cough. More severe cases may develop dyspnea and retrosternal chest pain. Nausea, vomiting, and diarrhea will also occur in many patients due to inadvertently
swallowed toxin, and fluid losses can be marked. The fever may last up to five days and range from 103 to 106 degrees F, with variable degrees of chills and prostration. The cough may persist up to four weeks, and patients may not be able to return to duty for two weeks.
Physical examination in patients with SEB intoxication is often unremarkable. Conjunctival injection may be present, and postural hypotension may develop due to fluid losses. Chest examination is unremarkable except in the unusual case where pulmonary edema develops. The chest X-ray is also generally normal, but in severe cases increased interstitial markings, atelectasis, and possibly overt pulmonary edema or an ARDS picture may develop.
DIAGNOSIS
As is the case with botulinum toxins, intoxication due to SEB inhalation is a clinical and epidemiologic diagnosis. Because the symptoms of SEB intoxication may be similar to several respiratory pathogens such as influenza, adenovirus, and mycoplasma, the diagnosis may initially be unclear. All of these might present with fever, nonproductive cough, myalgia, and headache. SEB attack would cause cases to present in large numbers over a very short period of time, probably within a single 24 hour period. Naturally
occurring pneumonias or influenza would involve patients presenting over a more prolonged interval of time. Naturally occurring staphylococcal food poisoning cases would not present with pulmonary symptoms. SEB intoxication tends to progress rapidly to a fairly stable clinical state, whereas pulmonary anthrax, tularemia pneumonia, or pneumonic plague would all progress if left untreated. Tularemia and plague, as well as Q fever, would be associated with infiltrates on chest radiographs. Nerve agent intoxication would cause fasciculations and copious secretions, and mustard would cause skin lesions in addition to pulmonary findings; SEB inhalation would not be characterized by these findings. The dyspnea associated with botulinum intoxication is associated with obvious signs of muscular paralysis, bulbar palsies, lack of fever, and a dry pulmonary tree due to cholinergic blockade; respiratory difficulties occur late rather than early as with SEB inhalation.
Laboratory findings are not very helpful in the diagnosis of SEB intoxication. A nonspecific neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate may be seen, but these abnormalities are present in many illnesses. Toxin is very difficult to detect in the serum by the time symptoms occur; however, a serum specimen should be drawn as early as possible after exposure. Data from rabbit studies clearly show that SEB in the serum is transient; however, it accumulates in the urine and can be detected for several hours post exposure. Therefore, urine samples should be obtained and tested for SEB. Because most patients will develop a significant antibody response to the toxin, acute and convalescent serum should be drawn which may be helpful retrospectively in the diagnosis.
MEDICAL MANAGEMENT
Currently, therapy is limited to supportive care. Close attention to oxygenation and hydration are important, and in severe cases with pulmonary edema, ventilation with positive end expiratory pressure and diuretics might be necessary. Acetaminophen for fever, and cough suppressants may make the patient more comfortable. The value of steroids is unknown. Most patients would be expected to do quite well after the initial acute phase of their illness, but most would generally be unfit for duty for one to two weeks.
PROPHYLAXIS
Although there is currently no human vaccine for immunization against SEB intoxication, several vaccine candidates are in development. Preliminary animal studies have been encouraging and a vaccine candidate is nearing transition to advanced development and safety and immunogenicity testing in man. Experimentally, passive immunotherapy can reduce mortality, but only when given within 4-8 hours after inhaling SEB.
TULAREMIA
SUMMARY
Signs and Symptoms: Ulceroglandular tularemia presents with a local ulcer and regional lymphadenopathy, fever, chills, headache and malaise. Typhoidal tularemia presents with fever, headache, malaise, substernal discomfort, prostration, weight loss and a non-productive cough.
Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. Chest x-ray may reveal a pneumonic process, mediastinal lymphadenopathy or pleural effusion. Routine culture is possible but difficult. The diagnosis can be established retrospectively by serology.
Treatment: Administration of antibiotics (streptomycin or gentamicin) with early treatment is very effective.
Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. It is administered once by scarification. A two week course of tetracycline is effective as prophylaxis when given after exposure.
Isolation and Decontamination: Standard Precautions for healthcare workers. Organisms are relatively easy to render harmless by mild heat (55 degrees Celsius for 10 minutes) and standard disinfectants.
OVERVIEW
Francisella tularensis, the causative agent of tularemia, is a small, aerobic non-motile, gram-negative cocco-bacillus. Tularemia (also known as rabbit fever and deer fly fever) is a zoonotic disease which humans typically acquire after contact of their skin or mucous membranes with tissues or body fluids of infected animals, or from bites of infected deerflies, mosquitoes, or ticks. Less commonly, inhalation of contaminated dusts or ingestion of contaminated foods or water may produce clinical disease. Respiratory exposure by aerosol would cause typhoidal or pneumonic tularemia. F. tularensis can remain viable for weeks in water, soil, carcasses, and hides, and for years in frozen rabbit meat. It is resistant for months to temperatures of freezing and below. It is rather easily killed by heat and disinfectants.
HISTORY AND SIGNIFICANCE
Tularemia was recognized in Japan in the early 1800's and in Russia in 1926. In the early 1900's, American workers investigating suspected plague epidemics in San Francisco isolated the organism and named it Bacterium tularense after Tulare County where the work was performed. Dr. Edward Francis, USPHS, established the cause of deer-fly fever as Bacterium tularense and subsequently devoted his life to researching the organism and disease, hence, the organism was later renamed Francisella tularensis
Francisella tularensis was weaponized by the United States in the 1950's and 1960's during the U.S. offensive biowarfare program, and other countries are suspected to have weaponized this agent. This organism could potentially be stabilized for weaponization by an adversary and theoretically produced in either a wet or dried form. It could then theoretically be delivered against U.S. forces in a similar fashion to the other bacteria discussed in this handbook.
CLINICAL FEATURES
After an incubation period varying from 1-21 days (average 3-5 days), presumably dependent upon the dose of organisms, onset is usually acute. Tularemia may appear in several forms in man depending upon the route of inoculation: ulceroglandular, glandular, typhoidal, oculoglandular, pharyngeal, and pneumonic tularemia. In humans, as few as 10 to 50 organisms will cause disease if inhaled or injected intradermally, whereas approximately 108 organisms are required with oral challenge.
Ulceroglandular tularemia (75-85 percent of cases) is most often acquired through inoculation of the skin or mucous membranes with blood or tissue fluids of infected animals. It is characterized by fever, chills, headache, and malaise, an ulcerated skin lesion and painful regional lymphadenopathy. The skin lesion is
usually located on the fingers or hand.
Glandular tularemia (5-10 percent of cases) results in fever and tender lymphadenopathy but no skin ulcer.
Typhoidal tularemia accounts for 5-15 percent of naturally occurring cases and occurs mainly after inhalation of infectious aerosols, but can occur after intradermal or gastrointestinal challenge. It manifests as fever, prostration, and weight loss but without lymphadenopathy. Pneumonia may be associated with any form but is most common in typhoidal tularemia. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are non-specific and there frequently is no suggestive exposure history. Respiratory symptoms, substernal discomfort, and a non-productive cough may also be present. Radiologic evidence of pneumonia or mediastinal lymphadenopathy is most common with typhoidal disease but may or may not be present in all other forms of tularemia.
Oculoglandular tularemia (1-2 percent of cases) occurs after inoculation of the conjunctivae with infectious material. Patients have unilateral, painful, purulent conjunctivitis with preauricular or cervical lymphadenopathy. Chemosis, periorbital edema, and small nodular lesions or ulcerations of the palpebral conjunctiva are noted in some patients.
Oropharyngeal tularemia refers to primary ulceroglandular disease confined to the throat. It produces an acute exudative or membranous pharyngotonsillitis with cervical lymphadenopathy.
Pneumonic tularemia is an illness characterized primarily by pneumonia. Pneumonia is common in tularemia. It is seen in 30-80 percent of the typhoidal cases and in 10-15 percent of the ulceroglandular cases. The case fatality rate without treatment is approximately 5 percent for the ulceroglandular form and 35 percent for the typhoidal form. All ages are susceptible, and recovery is followed by permanent immunity.
DIAGNOSIS
Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria. Isolation represents a clear hazard to laboratory personnel and should only be attempted in BL-3 laboratory. The diagnosis can be established retrospectively serologically. A fourfold rise in the tularemia tube agglutination or microagglutination titer is diagnostic of infection. A single convalescent titer of 1:160 or greater is diagnostic of past or current infection. Titers are usually negative the first week of infection, positive the second week in 50-70 percent of cases and reach a maximum in 4-8 weeks.
MEDICAL MANAGEMENT
Standard Precautions are recommended for healthcare workers. Streptomycin (1 gm every 12 hours IM for 10-14 days) is the treatment of choice. Gentamicin 3-5 mg/kg/day parenterally for 10-14 days is also effective. Tetracycline and chloramphenicol treatment are effective as well, but are associated with significant relapse rates. Although laboratory related infections with this organism are very common,
person-to-person spread is unusual and respiratory isolation is not required.
PROPHYLAXIS
Vaccine: A live, attenuated tularemia vaccine is available as an investigational new drug (IND). It is given by scarification. This vaccine has been administered to more than 5,000 persons without significant adverse reactions. It is of proven effectiveness in preventing laboratory acquired tularemia as well as in experimentally exposed human volunteers. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.
Antibiotics: Tetracycline 500 mg PO qid for two weeks is effective as prophylaxis when given after exposure.
VENEZUELAN EQUINE ENCEPHALITIS
SUMMARY
Signs and Symptoms: Sudden onset of illness with generalized malaise, spiking fevers, rigors, severe headache, photophobia, and myalgias. Nausea, vomiting, cough, sore throat, and diarrhea may follow. Full
recovery takes 1-2 weeks.
Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. The white blood cell count often shows a striking leukopenia and lymphopenia. Virus isolation may be made from serum, and in some cases throat swab specimens. Both neutralizing or IgG antibody in paired sera or VEE specific IgM present in a single serum sample indicate recent infection.
Treatment: Supportive only.
Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. A second, formalin-inactivated, killed vaccine is available for boosting antibody titers in those initially receiving the live vaccine.
Isolation and Decontamination: Standard Precautions for healthcare workers. Human cases are infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat (80 degrees centigrade for 30 minutes) and standard disinfectants.
OVERVIEW
Venezuelan equine encephalitis (VEE) virus is an arthropod-borne alphavirus that is endemic in northern South America, Trinidad, Central America, Mexico, and Florida. Eight serologically distinct viruses belonging to the VEE complex have been associated with human disease; the two most important of these pathogens are designated subtype I, variants A/B, and C. These agents also cause severe disease in horses, mules, burros and donkeys (Equidae). Natural infections are acquired by the bites of a wide variety of
mosquitoes. Equidae serve as amplifying hosts and source of mosquito infection. In natural human epidemics, severe and often fatal encephalitis in Equidae always precedes disease in humans. The virus is rather easily killed by heat and disinfectants.
HISTORY AND SIGNIFICANCE
VEE was weaponized by the United States in the 1950's and 1960's before the U.S. offensive biowarfare program was terminated, and other countries have been or are suspected to have weaponized this agent.
This virus could theoretically be produced in either a wet or dried form and potentially stabilized for weaponization. This agent could then theoretically be delivered against friendly forces in a manner similar to the other agents already discussed.
As mentioned above, in natural human epidemics, disease in Equidae always precedes that in humans. A biological warfare attack with virus disseminated as an aerosol would almost certainly cause human disease as a primary event. If Equidae were present, disease in these animals would occur simultaneously with human disease. However, during natural epidemics, illness or death in wild or free ranging Equidae may not be recognized before the onset of human disease, thus a natural epidemic could be confused with a BW event, and data on onset of disease should be considered with caution. A more reliable method for determining the likelihood of a BW event would be the presence of VEE outside of its natural geographic range. Secondary spread by person-to-person contact has not been conclusively shown to occur; however,
observations during a recent outbreak in Columbia suggest that it may occur often enough to sustain epidemics in the absence of Equidae. A BW attack in a region populated by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.
CLINICAL FEATURES
VEE is characterized by inflammation of the meninges of the brain and of the brain itself, thus accounting for the predominance of CNS symptoms in the small percentage of infections that develop encephalitis. The disease is usually acute, prostrating and of short duration. The case fatality rate is less than 1 percent, although is somewhat higher in the very young or aged. Nearly 100 percent of those infected suffer an overt illness. Recovery from an infection results in excellent short-term and long-term immunity.
DIAGNOSIS
After an incubation period varying from 1 to 5 days, onset is usually sudden. It is manifested by generalized malaise, spiking fever, rigors, severe headache, photophobia, and myalgias in the legs and lumbosacral area. Nausea, vomiting, cough, sore throat, and diarrhea may follow. This acute phase lasts 24-72 hours. A prolonged period of asthenia and lethargy may follow, with full health and activity regained after 1-2 weeks. Approximately 4 percent of children during natural epidemics develop signs of central nervous system infection, with meningismus, convulsions, coma, and paralysis. Adults rarely develop neurologic complications. In children manifesting severe encephalitis, the fatality rate may reach 20 percent. Permanent neurologic sequelae are reported in survivors. Experimental aerosol challenges in animals suggest that the incidence of CNS disease and associated morbidity and mortality would be high after a BW attack, as the VEE virus would infect the olfactory nerve and spread directly to the CNS. A VEE infection during pregnancy may cause encephalitis in the fetus, placental damage, abortion, or severe congenital neuroanatomical anomalies.
The white blood cell count shows a striking leukopenia and lymphopenia. In cases with encephalitis, the cerebrospinal fluid may be under increased pressure and contain up to 1,000 white cells/mm3 (predominantly mononuclear cells) and a mildly elevated protein concentration. Viremia during the acute phase of the illness (but not during encephalitis) is generally high enough to allow detection by antigen-capture enzyme immunoassay. Virus isolation may be made from serum, and in some cases throat swab specimens, by inoculation of cell cultures or suckling mice. A variety of serological tests are applicable, including the IgM ELISA indirect FA, hemagglutination inhibition, complement-fixation, and neutralization. For persons without prior exposure to VEE complex viruses, a presumptive diagnosis may be made by finding IgM antibody in a single serum sample taken 5 to 7 days after onset of illness.
MEDICAL MANAGEMENT
Standard Precautions are recommended for healthcare workers. Person-to-person transmission may theoretically occur by means of respiratory droplet infection. There is no specific therapy. Patients with uncomplicated VEE infection may be treated with analgesics to relieve headache and myalgia. Patients who develop encephalitis may require anticonvulsants and intensive supportive care to maintain fluid and electrolyte balance, ensure adequate ventilation, and avoid complicating secondary bacterial infections. Patients should be treated in a screened room or in quarters treated with a residual insecticide for at least 5 days after onset, or until afebrile, as human cases may be infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat and disinfectants.
PROPHYLAXIS
Vaccine: An investigational vaccine, designated TC-83, is a live, attenuated cell-culture-propagated vaccine which has been used in several thousand persons to prevent laboratory infections. The vaccine is given as a single 0.5 ml subcutaneous dose. Febrile reactions occur in up to 18 percent of persons vaccinated, and may be moderate to severe in 5 percent, with fever, myalgias, headache, and prostration. Approximately 18 percent of vaccinees fail to develop detectable neutralizing antibodies, but it is unknown whether they are susceptible to clinical infection if challenged. Contraindications for use include an intercurrent viral infection or pregnancy. TC-83 is a licensed vaccine for Equidae.
A second investigational product that has been tested in humans is the C-84 vaccine, prepared by formalin-inactivation of the TC-83 strain. The vaccine is not used for primary immunization, but is currently used to boost nonresponders to TC-83 (0.5 ml subcutaneously at 2-4 week intervals for up to 3 inoculations or until an antibody response is measured), and probably affords complete protection against aerosol infection from homologous strains in these individuals. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.
Antiviral Drugs: In experimental animals, alpha-interferon and the interferon-inducer poly-ICLC have proven highly effective for post-exposure prophylaxis of VEE. There are no clinical data on which to assess
efficacy in humans.
VIRAL AGENTS
Viruses are the simplest type of microorganism and consist of a nucleocapsid protein coat containing genetic material, either RNA or DNA. In some cases the virus particle is also surrounded by an outer layer of lipids. Viruses are much smaller than bacteria and vary in size from 0.02 m m to 0.2 m m (1 m m = 1/1000 mm). Viruses lack a system for their own metabolism and are therefore dependent on the synthetic machinery of their host cells: viruses are thus intracellular parasites. This also means that the virus, unlike the bacterium, cannot be cultivated in synthetic nutritive solutions but requires living cells in order to multiply. The host cells can be from human beings, animals, plants, or bacteria. Every virus needs its own special type of host cell because a complicated interaction is required between the cell and virus if the virus is to be able to multiply. Many virus-specific host cells can be cultivated in synthetic nutrient solutions and afterwards can be infected with the virus in question. Another usual way of cultivating viruses is to let them grow on chorioallantoic membranes (from fertilized eggs). The cultivation of viruses is costly, demanding, and time-consuming. A virus normally brings about changes in the host cell such that the cell dies. This handbook will cover a virus considered by some to be the most likely viral agent that would be used in a BW attack, the alpha virus that causes Venezuelan equine encephalitis, known as VEE. We also discuss smallpox and hemorrhagic fever viruses which could potentially be employed as BW agents.