Posted on 12/20/2001 8:53:13 AM PST by Gritty
| AUTHOR INFORMATION | Section 1 of 8 |
Authored by Daniel J Dire, MD, FACEP, FAAEM, Associate Professor, Department of Emergency Medicine, University of Alabama at Birmingham
Coauthored by David A Long, MD, Staff Physician, Department of Emergency Medicine, Scott & White Hospital; Lance D Williams, MD, Staff Physician, Department of Emergency Medicine, Scott & White Hospital; Thomas W McGovern, MD, Dermatologist and Mohs Surgeon, Fort Wayne Dermatology, PC
Daniel J Dire, MD, FACEP, FAAEM, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Association of Military Surgeons of the US, and Society for Academic Emergency Medicine
Edited by Edmond Hooker, MD, Assistant Clinical Professor, Department of Emergency Medicine, Bethesda North Hospital, Wright State University; John T VanDeVoort, PharmD, DABAT, Manager, Clinical Assistant Professor, Pharmacy Department, Regions Hospital; Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Raymond J Roberge, MD, MPH, FAAEM, FACMT, Research Director, Department of Emergency Medicine, Ohio Valley Medical Center; Clinical Associate Professor, Department of Emergency Medicine, University of Pittsburgh
| Author's Email: | Daniel J Dire, MD, FACEP, FAAEM |  |
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| Editor's Email: | Edmond Hooker, MD |
eMedicine Journal, October 15 2001, Volume 2, Number 10
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HISTORIC ASPECTS OF BIOLOGICAL WARFARE AGENTS | Section 2 of 8  |
Biological weapons include any organism or toxin found in nature that can be used to incapacitate, kill, or otherwise impede an adversary. Biological weapons are characterized by low visibility, high potency, substantial accessibility, and relatively easy delivery.
The potential spectrum of bioterrorism ranges from hoaxes and use of nonmass casualty agents by individuals or small groups to state-sponsored terrorism that employs classic biological warfare (BW) agents and can produce mass casualties. Such scenarios would present serious challenges for patient treatment and for prophylaxis of exposed persons. Environmental contamination could pose continuing threats.
The use of biological agents is not a new concept, and history is replete with examples of biological weapon use. Prior to the 20th century, biological warfare took on 3 main forms: (1) deliberate poisoning of food and water with infectious material, (2) use of microorganisms or toxins in some form of weapon system, and (3) use of biologically inoculated fabrics.
Attempts to use BW date back to antiquity. Scythian archers infected their arrows by dipping them in decomposing bodies or in blood mixed with manure as far back as 400 BC. Persian, Greek, and Roman literature from 300 BC quote examples of the use of animal cadavers to contaminate wells and other sources of water. In 190 BC, at the Battle of Eurymedon, Hannibal won a naval victory over King Eumenes II of Pergamon by firing earthen vessels full of venomous snakes into the enemy ships.
In the 12th century AD, during the battle of Tortona, Barbarossa used the bodies of dead soldiers to poison wells. In the 14th century AD during the siege of Kaffa, the attacking Tarter force hurled the corpses of those who died of plague into the city to attempt to inflict a plague epidemic upon the enemy. This was repeated in 1710 when the Russians besieging Swedish forces at Reval in Estonia catapulted plague cadavers.
In the 18th century AD during the French and Indian War, British forces in North America gave blankets from smallpox patients to the Native Americans to create a transmission of the disease to the immunologically naïve tribes. In 1863, a confederate surgeon was arrested and charged with attempting to import yellow fever–infected clothes into the northern parts of the US during the Civil War.
Biological warfare became more sophisticated against both animals and humans during the 1900s. During World War I, the Germans developed anthrax, glanders, cholera, and a wheat fungus for use as biological weapons. They allegedly spread plague in St Petersburg, infected mules with glanders in Mesopotamia, and attempted to do the same with the horses of the French Calvary.
In 1925, the Geneva Protocol was signed by 108 nations, including the 5 permanent members of the UN Security Council. This was the first multilateral agreement that extended prohibition of chemical agents to biological agents. No method for verification of compliance was addressed.
During World War II, the Japanese operated a secret BW research facility in Manchuria and carried out human experiments on Chinese prisoners. They exposed more than 3000 victims to plague, anthrax, syphilis, and other agents. Victims were observed for development of disease, and autopsies were performed.
In 1942, the US formed the War Research Service. Anthrax and botulinum toxin initially were investigated for use as weapons, and sufficient quantities of botulinum toxin and anthrax cattle cakes were stockpiled by June 1944 to allow limited retaliation if the Germans first used biological agents. The British tested anthrax bombs on Gruinard Island off the northwest coast of Scotland in 1942 and 1943 and then prepared and stockpiled anthrax-laced cattle cakes.
The US continued research on various offensive biological weapons during the 1950s and 1960s. From 1951-1954, simulants (Bacillus globigii, Serratia marcescens) were released off both coasts of the US to demonstrate the vulnerability of American cities to biological agent attacks. This vulnerability was tested again in 1966 when the simulant B globigii was released in the New York subway system.
In 1957, the British government decided to end its offensive BW capabilities and destroy its weapon stockpiles.
The US terminated its offensive biological weapons program in 1969 for microorganisms and in 1970 for toxins. The US is a signatory nation of the Biological Toxin Weapons Convention of 1972. This convention addressed the prohibition of the development, production, stockpiling, and destruction of bacteriologic and toxin weapons. Signatories to this agreement are required to submit information annually to the United Nations concerning facilities where biological defense research is being conducted, scientific conferences that are held at specified facilities, exchanges of scientists or information, and disease outbreaks. American stockpiles of biological weapons were destroyed completely by 1973.
During the Vietnam War, Vietcong guerrillas used punji stakes dipped in feces to increase the morbidity from wounding by these stakes.
The Soviet Union (USSR) continued to develop biological weapons from 1950-1980. In the 1970s, the USSR and its allies were suspected of having used "yellow rain" (trichothecene mycotoxins) during campaigns in Loas, Cambodia, and Afghanistan. In 1979, an accidental release of anthrax from a weapons facility in Sverdlovsk, USSR, killed at least 66 people. The Russians denied this accident until 1992.
Since the 1980s, terrorist organizations have become users of biological agents. The most frequent bioterrorism episodes have involved contamination of food and water. In September and October of 1984, 751 persons were infected with Salmonella typhimurium after an intentional contamination of restaurant salad bars in Oregon by followers of the Bhagwan Shree Rajneesh.
In 1985, Iraq began an offensive biological weapons program producing anthrax, botulinum toxin, and aflatoxin. During Operation Desert Shield, the coalition of allied forces faced the threat of chemical and biological agents. Following the Persian Gulf War, Iraq disclosed that it had bombs, Scud missiles, 122-mm rockets, and artillery shells armed with botulinum toxin, anthrax, and aflatoxin. They also had spray tanks fitted to aircraft that could distribute 2000 L over a target.
Currently, 17 countries are suspected of having an offensive BW program. In 1992, 20 people were administered chemoprophylaxis after a Virginia man sprayed his roommates with a substance that he claimed was anthrax. In 1994, a Japanese sect of the Aum Shinrikyo cult attempted an aerosolized release of anthrax from the tops of buildings in Tokyo. In 1995, 2 members of a Minnesota militia group were convicted of possession of ricin, which they had produced themselves for use in retaliation against local government officials. In 1996, an Ohio man was able to obtain bubonic plague cultures through the mail.
In 1997, the Defense Against Weapons of Mass Destruction Act directed the Department of Defense to establish a domestic preparedness program to improve the ability of local, state, and federal agencies to respond to biological incidents. During 1998 and 1999, multiple hoaxes occurred involving the threatened release of anthrax in the US that resulted in decontamination and antibiotic prophylaxis for the intended victims. Nearly 6000 persons across the US have been affected by these threats. To date, none of these cases involved actual anthrax bacteria. According to a study by the Centers for Disease Control and Prevention (CDC), an intentional release of anthrax by a bioterrorist in a major US city would result in an economic impact of $477.8 million to $26.2 billion per 100,000 persons exposed.
The threat that biological agents will be used on both military forces and civilian populations is now more likely than at any point in all of history.
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DELIVERY, DISSEMINATION, AND DETECTION OF BIOLOGICAL WARFARE AGENTS | Section 3 of 8 |
Biological agents are easy to acquire, synthesize, and use. The small amount of agents necessary to kill hundreds of thousands of people in a metropolitan area make the concealment, transportation, and dissemination of biological agents relatively easy. In addition, BW agents are difficult to detect or protect against; they are invisible, odorless, tasteless, and their dispersal can be performed silently.
Dissemination of BW agents may occur by aerosol sprays, explosives (artillery, missiles, detonated bombs), or food or water contamination. Variables that can alter the effectiveness of a delivery system include particle size of the agent, stability of the agent under desiccating conditions, UV light, wind speed, wind direction, and atmospheric stability.
The use of an explosive device to deliver and disseminate biological agents is not very effective, since such agents tend to be inactivated by the blast. Contamination of municipal water supplies requires an unrealistically large amount of agent and introduction into the water after it passes through a regional treatment facility.
To be an effective biological weapon, airborne pathogens must be dispersed as fine particles less than 5 mm in size. Infection with an aerosolized agent usually requires deep inspiration of an infectious dose. Advanced weapons systems (eg, warheads, missiles) are not required for the aerosolized delivery of biological agents. Low-technology aerosolization methods including agricultural crop-dusters; aerosol generators on small boats, trucks, or cars; backpack sprayers; and even purse-size perfume atomizers suffice. Aerosolized dispersal of biological agents is the mode most likely to be used by terrorists and military groups.
Detection of biological agents involves either finding the agent in the environment or medical diagnosis of the agent's effect on human or animal victims. Early detection of a biological agent in the environment allows for early specific treatment and time during which prophylaxis would be effective. Unfortunately, currently no reliable detection systems exist for BW agents. The US Department of Defense has placed a high priority on research and development of a detector system. Methods are being developed and tested to detect a biological aerosol cloud using an airborne-pulsed laser system to scan the lower altitudes upwind from a possible target area. A detection system mounted on a vehicle also is being developed. This system will analyze air samples to provide a plot of particle sizes, detect and classify bacterial cells, and measure DNA content, ATP content, and identify agents using immunoassays.
A BW agent attack is likely to be covert. Thus, detection of such an attack requires recognition of the clinical syndromes associated with various BW agents. Physicians must be able to identify early victims and recognize patterns of disease. This requires integrated epidemiologic surveillance systems performing real-time monitoring with information shared at many levels of the health care system (eg, ED to ED or ED to public health officials). Preliminary criteria for suspicious outbreaks of disease that could provide indications of a possible biological weapons event include the following:
Indications of possible BW agent attack include the following:
PROTECTIVE MEASURES
Protective measures can be taken against BW agents. These should be implemented early (if warning is received) or later (once suspicion of BW agent use is made). Currently, available masks such as the military gas mask or high-efficiency particulate air (HEPA) filter masks used for tuberculosis (TB) exposure filter out most BW particles delivered by aerosol. Multilayered HEPA masks can filter 99.9% of 1-5 mm particles, but face-seal leaks may reduce the efficacy by as much as 10-20%. Individual face-fit testing is required to correct seal leak problems.
Most aerosolized biological agents do not penetrate unbroken skin, and few organisms adhere to skin or clothing. After an aerosol attack, simple removal of clothing eliminates a great majority of surface contamination. Thorough showering with soap and water removes 99.99% of the few organisms left on the victim's skin after disrobing. The use of sodium hypochlorite is not recommended over soap and water.
The use of special suits by health care providers is not necessary. Normal clothing provides a reasonable degree of protection against dermal exposure. Latex gloves and universal precautions provide sufficient protection when treating most infected patients. Place patients in a private negative-pressure room and practice proper sanitation with universal precautions. Proper disposal of corpses is essential. In the case of anthrax spores, this should be performed by incineration.
Of the potential BW agents, only plague, smallpox, and viral hemorrhagic fevers are spread readily person to person by aerosol and require more than standard infection control precautions (gown, mask with eye shield, gloves). Regardless, place all potential victims of BW agents in isolation. Medical personnel caring for these patients should wear a HEPA mask in addition to standard precautions pending the results of a more complete evaluation.
Broad-spectrum intravenous antibiotic coverage is recommended initially for victims when a BW agent is suspected. Institute this even prior to the identification of the specific BW agent. Vaccinations currently are available for anthrax, botulinum toxin, tularemia, plague, Q fever, and smallpox. The widespread immunization of nonmilitary personnel has not been recommended by any governmental agency. Immune protection against ricin and staphylococcal toxins may be feasible in the near future.
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BACTERIAL AGENTS | Section 4 of 8 |
INTRODUCTION
Bacillus anthracis is a large, aerobic, gram-positive, spore forming, nonmotile bacillus. The bacterium ordinarily produces a zoonotic disease in domesticated and wild animals such as goats, sheep, cattle, horses, and swine. Humans become infected by contact with infected animals or contaminated animal products. Infection occurs predominantly through the cutaneous route and only rarely via the respiratory or gastrointestinal (GI) route.
Anthrax occurs worldwide. The organism exists in the soil as a spore. The form of the organism in infected animals is the bacillus. Sporulation occurs only when the organism in the carcass is exposed to air.
The true incidence of human anthrax is unknown. Reporting of illness has been unreliable. In 1958, an estimated 20,000-100,000 cases occurred worldwide. In the US, the annual incidence of human anthrax has declined steadily from approximately 127 cases in the early years of this century to approximately 1 per year for the past 10 years.
PATHOPHYSIOLOGY - ANTHRAX
B anthracis possesses 3 known virulence factors, an antiphagocytic capsule and 2 protein exotoxins (lethal and edema toxin). The role of the capsule in pathogenesis was demonstrated in the early 1900s when anthrax strains, lacking a capsule, were demonstrated to be virulent. In more recent years, the genes encoding synthesis of the capsule were found to be encoded on a 110-kilobase plasmid. The capsule is composed of a polymer of poly-D-glutamic acid, which confers resistance to phagocytosis and may contribute to the resistance of anthrax to lysis by serum cationic proteins.
The anthrax toxins, like many bacterial and plant toxins, possess the following 2 components: a cell binding B-domain and an active A-domain. The A-domain confers enzymatic activity and toxicity. Edema toxin, which consists of the same protective antigen together with a third protein, edema factor, causes edema when injected into the skin of experimental animals.
Infection begins when the spores are inoculated through skin or mucosa. It is believed that spores are ingested locally by tissue macrophages. Subsequently, spores germinate within macrophages to the vegetative bacilli, which produce capsules and toxins. Bacteria proliferate at these tissue sites and produce the edema and lethal toxins that impair host leukocyte function and lead to the following distinctive and pathologic findings: edema, hemorrhage, tissue necrosis, and a relative lack of leukocytes. In inhalation anthrax, the spores are ingested by alveolar macrophages, which transport them to the regional tracheobronchial lymph nodes, where germination occurs.
Once in the tracheobronchial lymph nodes, the local production of toxins by extracellular bacilli gives rise to the characteristic pathologic picture of massive hemorrhagic, edematous, and necrotizing lymphadenitis and mediastinitis. The bacillus then can spread to the blood, leading to septicemia and frequently causing hemorrhagic meningitis. Death results from respiratory failure, overwhelming bacteremia, septic shock, and meningitis.
CLINICAL FEATURES - ANTHRAX
Cutaneous: More than 95% of cases of anthrax are cutaneous. After inoculation, the incubation period is 1-5 days. The disease first appears as a small papule that progresses over 1-2 days to a vesicle containing serosanguinous fluid with many organisms and a paucity of leukocytes. This often has been referred to as a malignant pustule; however, this is a misnomer because no pustular lesions are found in anthrax patients. The vesicle ruptures, leaving a necrotic ulcer. The lesion usually is painless, and varying degrees of edema may be present around it. The edema occasionally may be massive, encompassing the entire face or limb, and is described as malignant edema. Patients generally experience fever, malaise, and headache, which may be severe in those with extensive edema. Local lymphadenitis also may be present. The ulcerbase develops a characteristic 1- to 5-cm black eschar. (The black appearance of the eschar gives anthrax its name [Greek anthrakos = coal].) After a period of 2-3 weeks, the eschar separates, often leaving a scar. Septicemia is rare. The mortality rate should be less than 1% with adequate treatment.
Inhalation: Also known as woolsorter's disease, inhalation anthrax has a typical incubation period of 1-6 days, but a latent period as long as 60 days has been described. Initial manifestations are nonspecific and include headache, malaise, fatigue, myalgia, and fever. Associated nonproductive cough and mild chest discomfort may occur. These symptoms usually persist for 2-3 days, and in some patients a short period of improvement may occur. This is followed by the sudden onset of increasing respiratory distress with dyspnea, stridor, cyanosis, increased chest pain, and diaphoresis. Associated edema of the chest and neck may be present. Chest x-ray usually shows the characteristic widening of the mediastinum and often, pleural effusion. Pneumonia is an uncommon finding. The onset of respiratory distress is followed by the rapid onset of shock and death within 24-36 hours. Mortality is nearly 100% despite appropriate treatment. Inhalation anthrax is the most likely form of disease to follow military or terrorist attack. Such an attack likely will involve the aerosolized delivery of anthrax spores.
Oropharyngeal and gastrointestinal: These result from the ingestion of infected meat that has not been cooked sufficiently. After an incubation period of 2-5 days, patients with oropharyngeal disease present with severe sore throat or a local oral or tonsillar ulcer, usually associated with fever, toxicity, and swelling of the neck due to cervical or submandibular lymphadenitis or edema. Dysphagia and respiratory distress also may be present. GI anthrax begins with nonspecific symptoms of nausea, vomiting, and fever. These are followed in most patients by severe abdominal pain. The presenting sign may be an acute abdomen, which may be associated with hematemesis, massive ascites, and diarrhea. Mortality in both forms may be as high as 50%, especially in the GI form.
Meningitis: This may occur following bacteremia as a complication of any of the other clinical forms. Meningitis also may occur, rarely, without any of the other clinical forms of the disease. It often is hemorrhagic and almost invariably fatal.
DIAGNOSIS - ANTHRAX
The most critical aspect in making a diagnosis is a high index of suspicion associated with a compatible history of exposure. Consider cutaneous anthrax following the development of a painless, pruritic papule, vesicle, or ulcer. This area often is associated with surrounding edema that develops into a black eschar. With extensive or massive edema, such a lesion is almost pathognomonic. Gram stain or culture of the lesion confirms the diagnosis. The differential diagnosis should include tularemia and staphylococcal or streptococcal species.
The diagnosis of inhalation anthrax is extremely difficult, but suspect the disease with a history of exposure to a B anthracis–containing aerosol. Early symptoms are entirely nonspecific. The development of respiratory distress in association with radiographic evidence of a widened mediastinum due to hemorrhagic mediastinitis and the presence of hemorrhagic pleural effusions or hemorrhagic meningitis should suggest the diagnosis. Sputum Gram stain and culture usually are not helpful, since pneumonia is an uncommon feature of illness. Gram stain of peripheral blood may be positive for gram-positive bacilli and should be performed.
GI anthrax also is exceedingly difficult to diagnose because of the rarity of the disease and nonspecific symptoms. Diagnosis usually is confirmed only with a history of ingesting contaminated meat in the setting of an outbreak. Once again, cultures generally are not helpful in making the diagnosis.
Meningitis from anthrax is clinically indistinguishable from meningitis due to other etiologies. A distinguishing feature is that the spinal fluid is hemorrhagic in as many as 50% of patients. The diagnosis can be confirmed by identifying the organism in the spinal fluid by microscopy, culture, or both.
Serology can be used to make a retrospective diagnosis. Antibody develops in 68-93% of reported cases of cutaneous anthrax and 67-94% of reported cases of oropharyngeal anthrax. A positive skin test to anthracin also has been used to make a retrospective diagnosis of anthrax.
The most useful microbiologic test is the standard blood culture, which is almost always positive in patients with systemic illness. Blood cultures should show growth in 6-24 hours. If the laboratory has been alerted to the possibility of anthrax, biochemical testing and review of colonial morphology should provide a preliminary diagnosis 12-24 hours later. However, if the laboratory has not been alerted to the possibility of anthrax, B anthracis may not be identified correctly.
New rapid diagnostic tests for B anthracis and its proteins include polymerase chain reaction (PCR), enzyme-linked immunoassay (ELISA), and direct fluorescent antibody (DFA) testing. Currently, these tests are only available at national reference laboratories.
TREATMENT - ANTHRAX
A number of possible therapeutic strategies have yet to be fully explored experimentally or submitted for approval to the Food and Drug Administration (FDA). The recommendations provided do not represent uses currently approved by the FDA but are a consensus based on best available information of recent studies.
Given the fulminant course of inhalation anthrax, early antibiotic administration is essential to maximize patient survival. Given the difficulty in achieving timely microbiologic diagnosis of anthrax, all persons with fever or evidence of systemic disease in an area where anthrax cases are occurring should be treated empirically for anthrax until the disease is excluded.
No clinical studies exist of the treatment of inhalation anthrax in humans. Most naturally occurring strains of anthrax are sensitive to penicillin, and penicillin historically has been the preferred therapy for the treatment of anthrax. Penicillin and doxycycline are FDA-approved antibiotics for anthrax. Doxycycline is the preferred option from the tetracycline class of antibiotics because of its proven efficacy in monkey studies. Experts currently recommend initiation of ciprofloxacin or other fluoroquinolones in adults with presumed inhalation anthrax infection. Following a terrorist attack, assume resistance to penicillin and tetracycline class antibiotics until laboratory testing demonstrates otherwise.
In a contained casualty setting (a situation in which a modest number of patients require therapy), initiate intravenous antibiotics for symptomatic patients. In adults, ciprofloxacin 400 mg IV q12h is recommended. Traditionally, ciprofloxacin and other fluoroquinolones are not recommended for use in children younger than 16-18 years because of a link to permanent arthropathy in adolescent animals and transient arthropathy in a small number of children.
Balancing these small risks against the real risk of death and resistant strains of B anthracis, experts recommend that ciprofloxacin be given to a pediatric population for initial therapy or postexposure prophylaxis following anthrax attack. In children, ciprofloxacin at 20-30 mg/kg/d IV in 2 daily doses (not to exceed 10 g/d) is recommended. If antibiotic susceptibility testing allows, substitute intravenous penicillin for the fluoroquinolones. For adults and children older than 12 years, penicillin G at 4 million U IV q4h is recommended for 60 days. Doxycycline at 100 mg IV q12h for 60 days is an acceptable alternative for adults. For children younger than 12 years, penicillin G is dosed 50,000 U/kg IV q6h for 60 days.
In experimental models, antibiotic therapy during anthrax infection has prevented development of an immune response. This suggests that even if the antibiotic-treated patient survives anthrax infection, risk of recurrence remains for at least 60 days. Oral therapy should replace intravenous therapy as soon as a patient's clinical condition improves.
Historically, the treatment of cutaneous anthrax has been oral penicillin. Recent recommendations suggest that oral fluoroquinolones or tetracycline antibiotics, as well as amoxicillin, are suitable alternatives if antibiotic susceptibility is proven. Although previous guidelines have suggested treating cutaneous anthrax with 7-10 days of therapy, recent recommendations suggest treatment for 60 days in the setting of bioterrorism, given the presumed exposure to the primary aerosol. Treatment of cutaneous anthrax generally prevents progression to systemic disease, although it does not prevent the formation and evolution of the eschar.
Other antibiotics effective against B anthracis in vitro include chloramphenicol, erythromycin, clindamycin, extended spectrum penicillins, macrolides, aminoglycosides, vancomycin, cefazolin, and other first-generation cephalosporins.
In pregnant women, experts recommend that ciprofloxacin be given for therapy and postexposure prophylaxis following anthrax attack. Substitute intravenous penicillin for the fluoroquinolones if microbiologic testing confirms penicillin susceptibility.
PREVENTION/PROPHYLAXIS-ANTHRAX
No FDA-approved chemoprophylactic regimens are available following exposure to an anthrax aerosol. For postexposure prophylaxis, experts recommend the same oral regimen as that recommended for treatment of mass casualties. For adults, administer ciprofloxacin 500 mg PO bid for 60 days. Ciprofloxacin may be changed to amoxicillin at 500 mg PO tid or doxycycline 100 mg PO bid for 60 days if microbiologic testing confirms such antibiotic susceptibility. In children, administer ciprofloxacin at 20-30 mg/kg/d PO taken twice daily (not to exceed 1 g/d) for 60 days. If the strain is susceptible to penicillins and patient weight is greater than 20 kg, amoxicillin may be given at 500 mg PO tid. For a child who weighs less than 20 kg, amoxicillin is administered at 40 mg/kg/d divided tid for 60 days.
A licensed vaccine, an aluminum hydroxide-absorbed preparation, is derived from culture fluid supernatant taken from an attenuated strain. The vaccination series consists of 6 subcutaneous doses at 0, 2, and 4 weeks, then at 6, 12, and 18 months, followed by annual boosters. Insufficient data are available regarding efficacy against inhalation anthrax in humans, although studies in rhesus monkeys indicate that it is protective. If information indicates that a BW attack is imminent or may have occurred, prophylaxis of unimmunized individuals with ciprofloxacin (500 mg PO bid) or doxycycline (100 mg PO bid) is recommended. Initiate the vaccination series for unimmunized individuals. Should an anthrax attack be confirmed, continue chemoprophylaxis for at least 4 weeks and until all those exposed receive 3 doses of vaccine (at 0, 2, and 4 wk).
INTRODUCTION
Plague is a zoonotic infection caused by Yersinia pestis, a gram-negative coccobacillus, which has been the cause of 3 great human pandemics in the Common Era, in the 6th, 14th, and 20th centuries. Throughout history, the oriental rat flea (Xenopsylla cheopis) has been largely responsible for spreading bubonic plague. After the flea ingests a blood meal on a bacteremic animal, bacilli can multiply and essentially block the flea's foregut with a fibrinoid mass of bacteria. When an infected flea with a blocked foregut attempts to feed again, it regurgitates clotted blood and bacteria into the victim's blood stream and so passes the infection onto the next victim, whether rat or human. As many as 24,000 organisms may be inoculated into the host.
Although the largest outbreaks of plague have been associated with X cheopis, all fleas should be considered dangerous in plague-endemic areas. The most important vector in the US is Diamanus montanus, the most common flea of rock squirrels and California ground squirrels. The black rat, Rattus rattus, has been most responsible worldwide for the persistence and spread of plague in urban epidemics.
Plague is characterized by the abrupt onset of high fevers, painful lymphadenopathy, and bacteremia. Septicemic plague sometimes can ensue from untreated bubonic plague or, de novo, after a fleabite. Patients with the bubonic form of the disease may develop secondary pneumonic plague. This complication can lead to human-to-human spread by the respiratory route and cause primary pneumonic plague. Pneumonic plague is the most severe form of disease and, untreated, has a mortality rate approaching 100%.
Mortality from endemic plague continues at low rates throughout the world despite the availability of effective antibiotics. People continue to die of plague, not because the bacilli have become resistant but, most often, because physicians do not include plague in their differential diagnosis, and treatment is delayed.
PATHOPHYSIOLOGY - PLAGUE
Y pestis is a gram-negative, nonacid-fast, nonmotile, nonsporulating coccobacillus. Its bipolar appearance is best appreciated when Wright-Giemsa, Wayson, or Gram stains are used. Y pestis grows optimally at 28°C. Biochemically, the plague bacillus produces no hemolysins; is positive for catalase; and is negative for hydrogen sulfide, oxidase, and urease.
The known virulence factors of Y pestis are encoded on the chromosomes of its 3 plasmids. The pH6 antigen, a protein located on the surface of the bacterium, is necessary for complete virulence. It is induced in vivo at sites of inflammation and cellular necrosis and within phagocytic cells. The low calcium response (LCR) plasmid, which is homologous in Y pestis and the other 2 Yersinia pathogens, Yersinia pseudotuberculosis and Yersinia enterocolitica, codes for several secreted proteins and is also necessary for virulence.
As few as 1-10 organisms of Y pestis are sufficient to infect rodents and primates via the oral, intradermal, subcutaneous, or intravenous routes. After being introduced into the mammalian host by a flea, the organism is thought to be susceptible initially to phagocytosis and killing by neutrophils. However, some of the bacteria may grow and proliferate within tissue macrophages. Within the human host, several environmental signals (temperature of 37°C, contact with eukaryotic cells, location within mononuclear cells, pH) are thought to induce the synthesis and activity of a multitude of factors that contribute to virulence. Bacteria become resistant to phagocytosis and proliferate unimpeded extracellularly.
During the incubation phase, the bacilli most commonly spread to regional lymph nodes, where supportive lymphadenitis develops, producing the characteristic bubo. Dissemination from the local site is thought to be related to the action of both plasminogen activator and Yop M. Infection progresses if untreated; septicemia develops, and the infection spreads to other organs. The endotoxin probably contributes to the development of septic shock, which is similar to the shock states observed with other causes of gram-negative sepsis.
Tissues most commonly infected include the spleen, liver, lungs, skin, and mucous membranes. Late infection of the meninges also occurs, especially if suboptimal antibiotic therapy has been administered.
Primary pneumonic plague, the most severe form of the disease, arises from inhalation of an infectious aerosol. Primary pneumonic plague is more rapidly fatal than the secondary form, because the inhaled droplets already contain phagocytosis-resistant bacilli, which have arisen from their growth in the vertebrate host.
Primary septicemia plague can arise from direct inoculation of bacilli into the bloodstream, bypassing initial multiplication in the lymph nodes.
CLINICAL FEATURES - PLAGUE
In the US, most patients (85-90%) with human plague present clinically with the bubonic form, 10-15% with the primary septicemia form, and 1% with the pneumonic form. Secondary septicemic plague occurs in 23% of patients who present with bubonic plague, and secondary pneumonic plague occurs in 9%. If Y pestis were used as a BW agent, it most likely would be inhaled as an infectious aerosol and result in primary pneumonic plague (epidemic pneumonia). If fleas were used as carriers of disease, bubonic or septicemic plague would result.
Bubonic plague: Buboes manifest after a 1- to 8-day incubation period. Their appearance is associated with the onset of sudden fever, chills, and headache, which often are followed by nausea and vomiting several hours later. Presenting symptoms include severe malaise (75%), headache (20-85%), vomiting (25-49%), chills (40%), altered mentation (26-38%), cough (25%), abdominal pain (19%), and chest pain (13%). Buboes occur in the groin (90% femoral, more frequent femoral than inguinal), axillary, or cervical regions, depending on the site of inoculation, 6-8 hours after the onset of symptoms. Buboes become visible within 24 hours and are characterized by severe pain. Untreated, septicemia develops in 2-6 days. Approximately 5-15% of bubonic plague patients develop secondary pneumonic plague and thus the ability to spread illness from person to person by respiratory droplets.
Septicemia plague: Septicemia plague may occur primarily or secondarily as a result of hematogenous dissemination of bubonic plague. Presenting signs and symptoms of primary septicemic plague are essentially the same as those for any gram-negative septicemia and include fever, chills, nausea, vomiting, and diarrhea; later, purpura, disseminated intravascular coagulation (DIC), and acrocyanosis and necrosis occur.
Pneumonic plague: Pneumonic plague may occur primarily from inhalation of aerosols or secondarily from hematogenous dissemination. Patients typically have a productive cough with blood-tinged sputum within 24 hours of symptom onset. The findings on chest x-ray are variable, but bilateral alveolar infiltrates appear to be the most common findings in pneumonic plague.
Plague meningitis: This is observed in 6-7% of patients. The condition manifests itself most often in children after 9-14 days of ineffective treatment. Symptoms are similar to those of other forms of acute bacterial meningitis.
DIAGNOSIS - PLAGUE
The diagnosis of bubonic plague should be made readily on clinical grounds if a patient presents with a painful bubo, fever, prostration, and history of exposure to rodents or fleas in an endemic area. However, if the patient presents in a nonendemic area or without a bubo, then the diagnosis can be difficult to make. When a bubo is present, the differential diagnosis should include tularemia, cat scratch disease, lymphogranuloma venereum, chancroid, TB, streptococcal adenitis, and scrub typhus.
The differential diagnosis of septicemic plague also includes meningococcemia, gram-negative sepsis, and rickettsioses. A presentation of systemic toxicity, a productive cough, and bloody sputum suggests a large differential diagnosis. However, demonstration of gram-negative coccobacilli in the sputum readily should suggest the correct diagnosis, because Y pestis is perhaps the only gram-negative bacterium that can cause extensive, fulminant pneumonia with bloody sputum in an otherwise healthy, immunocompetent host. In addition, Y pestis has unique bipolar, safety-pin morphology.
In patients with lymphadenopathy, perform a bubo aspiration. Air-dry the aspirate on a slide for Gram, Wright-Giemsa, or Wayson stain. If available, obtain a DFA stain of the aspirate for the presence of Y pestis capsular antigen. A positive DFA is more specific for Y pestis than the other stains listed.
Perform cultures of blood, bubo aspirate, sputum, and cerebrospinal fluid (CSF). Tiny 1- to 3-mm beaten copper colonies appear on blood agar in 48 hours. It is important to remember that colonies may be negative at 24 hours.
Complete blood counts (CBCs) often reveal leukocytosis with a left shift. Platelet counts may be normal or low, and activated partial thromboplastin times (aPTTs) may be increased. When DIC is present, fibrin degradation products are elevated. Because of liver involvement, alanine aminotransferase, aspartate aminotransferase, and bilirubin levels may be increased.
Most naturally occurring strains of Y pestis produce an F1-antigen in vivo, which can be detected in serum samples by immunoassay. Because fractional antigen and antibody do not occur early in the infection, perform titers for both on several sequential blood specimens. A four-fold rise in antibody titer in patient serum is retrospectively diagnostic.
TREATMENT - PLAGUE
Isolate patients with plague for the first 48 hours after treatment initiation. If pneumonic plague is present, continue isolation for 4 days.
Since l948, streptomycin has been the treatment of choice for bubonic, septicemic, and pneumonic plague. Administer it in a dose of 30 mg/kg/d IM divided bid. In patients with meningitis or hemodynamic instability, add intravenous chloramphenicol (50-75 mg/kg/d) divided qid. Gentamicin has had much less clinical usage but can be used as an alternative to streptomycin. Continue treatment for a minimum of 10 days or 3-4 days after clinical recovery. In patients with very mild bubonic plague who are not septic, tetracycline can be used orally at a dose of 2 g/d divided qid for 10 days. Doxycycline, ofloxacin, and ceftriaxone have been demonstrated to be effective in animal models.
In pregnant women, use streptomycin or gentamicin unless chloramphenicol specifically is indicated. Streptomycin is also the treatment of choice for newborns.
If treated with antibiotics, buboes typically recede in 10-14 days and do not require drainage. Patients are unlikely to survive primary pneumonic plague if antibiotic therapy is not initiated within 18 hours of symptom onset. Without treatment, the mortality rate is 60% for bubonic plague and 100% for the pneumonic and septicemic forms.
PREVENTION/PROPHYLAXIS - PLAGUE
All plague control measures must include insecticide use, public education, and reduction of rodent populations with chemicals such as cholecalciferol. Fleas always must be targeted before rodents, because killing rodents may release massive amounts of infected fleas.
Treat contacts of patients with pneumonic plague and individuals who have been exposed to aerosols with tetracycline 15-30 mg/kg/d divided qid for 6 days. If tetracycline is not available, doxycycline 100 mg bid is an effective alternative. Pregnant women and children younger than 8 years should receive trimethoprim/sulfamethoxazole (40 mg sulfa/kg/d) divided bid for 6 days.
Contacts of patients with bubonic plague do not require prophylactic therapy. However, administer prophylaxis to people who were in the same environment and potentially exposed to the same source of infection. In addition, previously vaccinated individuals should receive prophylactic antibiotics if they have been exposed to a plague aerosol.
Only individuals at high risk for plague should be immunized with a licensed, killed, whole cell vaccine. Vaccinate military troops and personnel working in endemic areas, lab personnel working with Y pestis, and people who reside in enzootic or epidemic areas. While epidemiologic evidence supports the efficacy of the current vaccine against bubonic plague, its efficacy against aerosolized Y pestis is believed to be poor.
INTRODUCTION
Cholera is an acute and potentially severe GI disease caused by Vibrio cholerae. V cholerae is a short, curved, motile, gram-negative, nonsporulating rod. Two serogroups (01, 0139) have been associated with cholera in humans. The 01 serotype exists as 2 biotypes, classical and El Tor. The organisms are strongly anaerobic, preferring alkaline and high-salt environments. They do not invade the intestinal mucosa but rather adhere to it. Cholera is the prototype toxigenic diarrhea, which is secretory in nature.
This agent has been investigated in the past as a biological weapon. Cholera does not spread easily from human to human; therefore, it appears that major drinking water supplies would have to be contaminated heavily for this agent to be effective as a biological weapon. The rate of symptomatic-to-asymptomatic cases during exposures is 1:400.
PATHOPHYSIOLOGY- CHOLERA
All strains of V cholerae elaborate the same enterotoxin, a protein molecule with a molecular weight of 84,000 daltons. The entire clinical syndrome is caused by the action of the toxin on the intestinal epithelial cell. Cholera toxin causes active secretion of chloride and blocks sodium absorption in the small intestine, with the colon relatively insensitive to the toxin. The large volume of fluid produced in the upper intestine overwhelms the capacity of the lower intestine to absorb. The diarrhea is classically thin, grayish brown, and mucoid and may reach a rate of 1 L/h.
Transmission is made through direct or indirect fecal contamination of water or foods and by heavily soiled hands or utensils. All populations are susceptible, while natural resistance to infection varies.
Drying easily kills the organism. It is not viable in pure water but survives up to 24 hours in sewage and as long as 6 weeks in certain types of relatively impure water containing organic matter. It can withstand freezing for 3-4 days. It is killed readily by dry heat at 117°C, steam and boiling, short-term exposure to ordinary disinfectants, and chlorination of water.
CLINICAL FEATURES - CHOLERA
Infection generally occurs within a week of exposure and is classically of abrupt onset following a brief nonspecific prodrome. Fever is rare. The syndrome is characterized by sudden onset of nausea and vomiting and profuse diarrhea with a classic rice water appearance. If untreated, the disease generally lasts 1-7 days. The clinical manifestations of cholera are related to the profound fluid and electrolyte depletion that occurs. Acute treatment consists of rapid, aggressive fluid resuscitation with isotonic solutions and potassium.
Children may experience seizures caused by hypoglycemia and hypernatremia and may have potassium depletion severe enough to cause an arrhythmia. The rapid loss of body fluids often leads to toxemia and frequent cardiovascular collapse. The mortality rate can range as high as 50% in untreated cases.
DIAGNOSIS- CHOLERA
The incubation period ranges from 12-72 hours and depends on the dose of ingested organisms. Onset of illness usually is sudden. Initially, the disease presents with intestinal cramping and painless diarrhea. Vomiting, malaise, and headache often accompany the diarrhea, especially early in the illness.
On microscopic examination of the stool, few or no red cells, white cells, and almost no protein are found. The absence of inflammatory cells and erythrocytes reflects the noninvasive character of V cholerae infection of the intestinal lumen. The organism can be identified in liquid stool or enrichment broths by darkfield or phase contrast microscopy and by identifying darting motile Vibrio species. Bacteriologic diagnosis is not necessary for treatment, as it can be diagnosed clinically.
TREATMENT - CHOLERA
Treatment depends on replacement of fluids and electrolyte losses. This is best accomplished using oral rehydration therapy, but intravenous fluid replacement is occasionally necessary for persistent vomiting or high rates of stool loss (10 mL/kg/h). Antibiotics shorten the duration of diarrhea and reduce fluid losses. Tetracycline (500 mg q6h for 3 d) or doxycycline (300 mg once or 100 mg bid for 3 d) is an acceptable alternative. However, due to resistance, ciprofloxacin (500 mg q6h for 3 d) or erythromycin (40 mg/kg/d divided qid for 3 d) also has been accepted.
PREVENTION/PROPHYLAXIS - CHOLERA
A licensed, killed vaccine is available for use in those considered to be at risk for exposure. The vaccine is protective for only approximately 50% of those immunized, and protection lasts for no more than 6 months. The vaccination schedule is an initial dose followed by another dose 4 weeks later, with booster doses every 6 months.
An inactivated oral vaccine (WC/rBs) is safe and provides rapid short-term protection. WC/rBs requires 2 doses and has approximately 85% efficacy lasting 2-3 years for both El Tor and classic biotypes.
INTRODUCTION
Tularemia is a zoonosis caused by the gram-negative, facultative intracellular bacterium Francisella tularensis. The disease is characterized by fever, localized skin or mucous membrane ulceration, regional lymphadenopathy, and occasionally pneumonia. GW McCay discovered the disease in Tulare County, California, in 1911. The first confirmed case of human disease was reported in 1914. Edward Francis, who described transmission by deer flies via infected blood, coined the term tularemia in 1921. F tularensis has been considered an important BW agent because of its high infectivity after aerosolization.
F tularensis is a nonmotile, obligate aerobic, gram-negative coccobacillus with 2 subspecies. F tularensis subsp tularensis is the most common in the US. F tularensis subsp palearctica is more common outside the US. The subspecies are indistinguishable serologically, although they may be distinguished by 169 ribosomal ribonucleic acid (rRNA) analysis. A capsule has been reported to contribute to virulence. No known toxins are produced.
The principal reservoir in North America is the tick. In North America, the rabbit is the most common vertebrate associated with transmission of tularemia. In other areas of the world, tularemia is maintained in water rats and other aquatic animals.
PATHOPHYSIOLOGY - TULAREMIA
F tularensis usually is introduced into the host through breaks in the skin or through the mucous membranes of the eye, respiratory tract, or GI tract. Ten virulent organisms injected subcutaneously and 10-50 organisms given by aerosol can cause infection in humans. After inoculation, F tularensis is ingested by and multiplies within macrophages. The host defense against F tularensis is mediated by a T cell-independent mechanism, which appears early after infection (<3d), and a T cell-dependent mechanism, which appears later(>3 d) after infection. The role of humoral-medicated immunity and neutrophils in the host defense against F tularensis remains unclear.
CLINICAL FEATURES - TULAREMIA
Tularemia can be divided into the ulceroglandular (75% of patients) and typhoidal (25% of patients) forms based on clinical findings. Patients with ulceroglandular tularemia have lesions of the skin or mucous membranes, lymph nodes greater than 1 cm in diameter, or both. Patients with typhoidal tularemia present with lymph nodes less than 1 cm in diameter and without skin or mucous membrane lesions.
After an incubation period of 3-6 days, patients with the ulceroglandular form of the disease develop a constellation of symptoms consisting of fever (85%), chills (57%), headache (45%), cough (38%), and myalgia (31%). Patients also may complain of chest pain, vomiting, arthralgia, sore throat, abdominal pain, diarrhea, dyspnea, back pain, or neck stiffness.
A cutaneous chancrelike ulcer occurs in approximately 60% of patients and is the most common sign of tularemia. Ulcers are generally single lesions with heaped up borders 0.4-3 cm in diameter. Lesions associated with infection acquired from mammalian vectors usually are located on the upper extremities, whereas lesions associated with infection from arthropod vectors usually are located on the lower extremities.
Enlarged lymph nodes are seen in approximately 85% of patients and may be the initial or the only sign of infection. Although enlarged lymph nodes usually occur as single lesions, they may appear in groups. The appearance of enlarged lymph nodes in upper or lower extremities and the correlation with the vector is the same as for ulcerative lesions. Enlarged lymph nodes may become fluctuant, drain spontaneously, or persist for as long as 3 years. When fluctuant, they may be confused with buboes of bubonic plague. A minority of patients with typhoidal disease develop a morbilliform eruption.
Pharyngitis may occur in up to 25% of patients with tularemia. On occasion, patients with pharyngitis also may develop a retropharyngeal abscess or suppuration of regional lymph nodes. Pharyngeal ulcers may be found in patients with aerosol-induced disease.
The lower respiratory tract is involved in 47-94% of patients. Approximately 30% of patients with ulceroglandular and 80% of patients with typhoidal tularemia have pneumonia. Patients present with productive or nonproductive cough and less commonly with pleuritic chest pain, shortness of breath, or hemoptysis. Fifty percent of patients have radiographic evidence of pneumonia, and 1% or fewer have hilar adenopathy. Pleural effusions are seen in 15% of patients with pneumonia.
DIAGNOSIS - TULAREMIA
Tularemia can be diagnosed by recovery of F tularensis in culture. Although difficult to culture, it can be recovered from blood, ulcers, sputum, conjunctival exudate, pharyngeal exudates, and gastric washings. On media containing cysteine, F tularensis appears as small, smooth, opaque colonies after 24-48 hours of incubation at 37°C. Identification of the organism is made on the basis of its growth characteristics and bacterial agglutination or fluorescent stain using antiserum specific for F tularensis.
Most diagnoses of tularemia are made serologically using bacterial agglutination or ELISA. The serologic response may be blunted by the use of antibiotics and may not appear for more than 2 weeks.
Patients usually do not have abnormalities in the hemoglobin, hematocrit, or platelet count. The peripheral white blood cell count usually is elevated only mildly and often shows a lymphocytosis late in the disease. Patients may have microscopic pyuria, which may lead to erroneous diagnosis of urinary tract infection. Some patients show mild elevations in lactic dehydrogenase, serum transaminases, and alkaline phosphatase. CSF is usually normal.
TREATMENT - TULAREMIA
Patients with tularemia who do not receive appropriate antibiotic therapy may have a prolonged illness characterized by malaise, weakness, and weight loss. With appropriate therapy, tularemia has a mortality rate of only 1-2.5%.
Streptomycin (30 mg/kg/d IM divided bid for 10-14 d) is the drug of choice for tularemia. Gentamicin (3-5 mg/kg/d parenterally for 10-14 d) is also effective. Tetracycline and chloramphenicol are effective as well but have been associated with significant relapse rates. Although laboratory-related infections with this organism are common, human-to-human spread is unusual, and respiratory isolation is not required.
PROPHYLAXIS/PREVENTION - TULAREMIA
Antibiotic prophylaxis after exposure to tularemia is difficult, because the ideal drug, streptomycin, must be administered parenterally. Tetracycline is effective after exposure to an aerosol of tularemia if administered within 24 hours of the exposure at an oral dose of 2 g/d for 14 days.
A live attenuated vaccine has been developed and used in humans since 1940. In the 1960s, a further purified derivative was introduced and called live vaccine strain (LVS). Extensive studies have demonstrated that the LVS vaccine protected humans against an aerosol challenge with virulent F tularensis. Evidence indicates that immunization with the LVS vaccine prevents the typhoidal and ameliorates the ulceroglandular forms of tularemia.
INTRODUCTION
Brucellosis is a zoonotic infection of domesticated and wild animals caused by an organism of the genus Brucella. The organism infects mainly cattle, sheep, goats, and other ruminants, causing abortion, fetal death, and genital infection. Humans, who usually are infected incidentally by contact with infected animals, may develop numerous symptoms in addition to the usual ones of fever, malaise, and muscle pain. The disease often becomes chronic and may relapse, even with appropriate treatment. The ease of transmission by aerosol suggests that Brucella species may be useful as a BW agent.
PATHOPHYSIOLOGY - BRUCELLOSIS
Brucella species are small, nonmotile, nonsporulating, aerobic, gram-negative coccobacilli that may represent a single species. However, they are classified into 6 species. Each species has a characteristic predilection to infect certain animal species. Only Brucella melitensis, Brucella suis, Brucella abortus, and Brucella canis cause disease in man. Infection of humans with Brucella ovis and Brucella neotomae has not been described.
Animals may transmit Brucella organisms during septic abortion, at the time of slaughter, and in their milk. Brucellosis is rarely, if ever, transmitted from human to human. Brucella species can enter mammalian hosts through skin abrasions or cuts, the conjunctiva, the respiratory tract, and the GI tract. Organisms are ingested rapidly by polymorphonuclear leukocytes, which generally fail to kill them. Organisms also are phagocytized by macrophages, which traffic to lymphoid tissue and eventually localize in lymph nodes, liver, spleen, joints, kidneys, and bone marrow.
Brucellosis also can replicate extracellularly in host tissue. The host cellular response may range from abscess formation to granuloma formation with caseous necrosis.
CLINICAL FEATURES - BRUCELLOSIS
Clinical manifestations of brucellosis are diverse, and the course of the disease varies. Patients may present with an acute, systemic, febrile illness; an insidious chronic infection; or a localized inflammatory process. The disease may be abrupt or insidious in onset, with an incubation period of 3 days to several weeks. Patients usually have nonspecific symptoms such as fever, sweats, fatigue, anorexia, and muscle or joint aches. Neuropsychiatric symptoms such as depression, headache, and irritability occur frequently. In addition, focal infection of bones, joints, or the genitourinary tract may cause local pain. Cough and pleuritic chest pain also may be noted.
Symptoms often last 3-6 months and occasionally for longer than a year. Brucellosis usually does not cause leukocytosis, and patients may be neutropenic. B melitensis tends to cause more severe, systemic illness than the other Brucella species. B suis is more likely to cause localized suppurative disease.
Infection with B melitensis leads to bone or joint disease in approximately 30% of patients. Sacroiliitis develops in 6-15%, particularly in young adults. Arthritis of large joints occurs with about the same frequency as sacroiliitis. In contrast to septic arthritis caused by pyogenic organisms, joint inflammation observed with B melitensis is mild, and erythema of overlying skin is uncommon. Synovial fluid is exudative, with cell counts in the low thousands, predominantly mononuclear. In both sacroiliitis and peripheral joint infections, destruction of bone is unusual. Organisms can be cultured from fluid in approximately 20% of patients. Spondylitis tends to affect middle-aged or elderly patients, causing back (usually lumbar) pain, local tenderness, and occasionally radicular symptoms.
Radiographic findings, similar to those of tuberculous infection, include disk space narrowing and epiphysitis. Paravertebral abscesses occur rarely. In contrast to frequent infection of the axial skeleton, osteomyelitis of long bones is rare.
Infection of the genitourinary tract, an important target in ruminant animals, also may lead to signs and symptoms of disease in humans. Pyelonephritis, cystitis, and, in males, epididymo-orchitis may occur. Both diseases may mimic their tuberculous counterparts with sterile pyuria on routine bacteriologic cultures.
Lung infections also have been described. Although up to 25% of patients may complain of respiratory symptoms (mostly cough, dyspnea, or pleuritic pain), chest radiographic examinations usually are normal. Diffuse or focal infiltrates, pleural effusions, abscesses, and granulomas may be seen.
Hepatitis and, rarely, liver abscess also occur. Mild elevations of serum lactase dehydrogenate and alkaline phosphatase are common. Biopsy may show well-formed granulomas or nonspecific hepatitis with collections of mononuclear cells.
Other sites of infection include the heart, central nervous system (CNS), and skin. Brucella endocarditis, a rare but feared complication, accounts for 80% of deaths from brucellosis. CNS infection usually manifests itself as chronic meningoencephalitis, but subarachnoid hemorrhage and myelitis also occur. Cases of skin abscess also have been reported.
DIAGNOSIS - BRUCELLOSIS
A thorough history eliciting details of appropriate exposures (animals, animal products, environmental exposures) is the most important diagnostic tool. Strongly consider brucellosis in the differential diagnosis when military troops exposed to a biological attack have febrile illnesses. PCR and antibody-based antigen detection systems may demonstrate the presence of organisms in environmental samples collected from attack areas.
When the disease is considered, diagnosis usually is made by serology. The tube agglutination test remains the criterion standard. This test reflects the presence of anti-O-polysaccharide antibody. Most patients already have high titers at the time of clinical presentation. Serum testing always should include dilution to at least 1:320. The tube agglutination test does not detect antibodies to B canis, because this organism does not have O-polysaccharide on its surface.
In addition to serologic testing, pursue diagnosis by microbiologic cultures of blood or body fluid samples. Hold cultures for at least 2 months. The reported frequency of isolation from blood varies widely, from less than 10% to 90%. B melitensis is said to be cultured more readily than B abortus. Culture of bone marrow may increase the yield.
TREATMENT - BRUCELLOSIS
Therapy with a single drug has resulted in a high relapse rate, so use combined antibiotic regimens whenever possible. A 6-week regimen of doxycycline 200 mg/d PO with the addition of streptomycin 1 g/d IM for the first 2 weeks is effective in most adults with most forms of brucellosis. Patients with spondylitis may require longer treatment. A 6-week oral regimen with both rifampin 900 mg/d and doxycycline 200 mg/d is effective. Several studies have demonstrated that treatment with a combination of streptomycin and doxycycline may result in less frequent relapse than treatment with the combination of rifampin and doxycycline.
Endocarditis likely is best treated with a combination of rifampin, streptomycin, and doxycycline for 6 weeks. Replace infected valves early. CNS disease responds to a combination of rifampin and trimethoprim/sulfamethoxazole but may need prolonged therapy. The latter combination is also effective for children younger than 8 years. Rifampin is recommended for pregnant women.
PREVENTION/PROPHYLAXIS - BRUCELLOSIS
Animal handlers should wear appropriate protective clothing when working with infected animals. Meat should be well cooked and milk should be pasteurized. Laboratory workers should culture the organism only with appropriate Biosafety level 2 or 3.
In the event of a biological attack, the standard gas mask should protect personnel adequately from airborne Brucella species. No commercially available vaccine exists for humans.
INTRODUCTION
Q fever is a zoonotic disease caused by Coxiella burnetii, a rickettsialike organism of low virulence but remarkable infectivity. A single organism may initiate infection. In addition, despite the fact that C burnetii is unable to grow or replicate outside host cells, a sporelike form of the organism is extremely resistant to heat, pressure, and many antiseptic compounds. This allows C burnetii to persist in the environment for long periods under harsh conditions. In contrast to this high degree of inherent resilience and transmissibility, the acute clinical disease associated with Q fever is usually a benign, although temporarily incapacitating, illness in humans. Even without treatment, most patients recover.
The primary reservoir for natural human infection is livestock, particularly parturient females, and the distribution is worldwide. Humans who work in animal husbandry, especially those who assist during parturition, are at risk for acquiring Q fever.
The potential of C burnetii as a BW agent is related directly to its infectivity. It has been estimated that 50 kg of dried C burnetii would produce casualties at a rate equal to that of similar amounts of anthrax or tularemia organisms.
The causative agent of Q fever was designated Coxiella burnetii to recognize the outstanding contribution of both Harold Cox and MacFarlane Burnet in the isolation and characterization of the pathogen. The disease now has been identified in at least 51 countries and on 5 continents.
PATHOPHYSIOLOGY - Q FEVER
The genus Coxiella has only 1 species. C burnetii is extremely infectious. Under experimental conditions, a single organism is capable of producing infection and disease in humans.
The host range of C burnetii is diverse and includes a large number of mammalian species and arthropods. Among these, man is the only host identified that experiences an illness as a result of infection. A number of different strains of C burnetii have been identified worldwide, and different clinical manifestations and complications may be associated with the various strains.
Humans have been infected most commonly by contact with domestic livestock, particularly goats, cattle, and sheep. The risk of infection is increased substantially if humans are exposed to these animals at parturition. During gestation, the proliferation of C burnetii in the placenta facilitates aerosolization of large numbers of the pathogen during parturition. Survival of the organism on inanimate surfaces, such as straw, hay, or clothing, allows for transmission to individuals who are not in direct contact with infected animals.
Human infection with C burnetii is usually the result of inhalation of infected aerosols. Following this, host cells phagocytize the organisms. After phagocytosis by host cells, dissemination of the pathogen occurs as a result of circulation of organism free in the plasma, on the surface of the cells, and carried by circulatory macrophages.
Little host reaction occurs at the initial portal of entry, either in the lung following inhalation of aerosol or in the skin following a tick bite. Q fever develops without formation of a primary infectious focus in the area of the tick bite, and the organism does not infect the vascular endothelium, as do other rickettsial pathogens. The presence of a lipopolysaccharide on the cell surface of C burnetii protects the pathogen from host microbicidal activity.
CLINICAL FEATURES - Q FEVER
Humans are the only hosts that commonly develop an illness as a result of the infection. Incubation varies from 10-40 days. The duration of the incubation period is correlated inversely with the magnitude of the inoculum. A higher inoculum also increases the severity of the disease. Q fever in humans may be manifested by asymptomatic seroconversion, acute illness, or chronic disease. The frequency of chronic disease (usually endocarditis) is probably less than 1% of the total infected population.
No characteristic illness is described for acute Q fever, and manifestations may vary considerably between locations where the disease is acquired. The onset of symptomatic Q fever may be abrupt or insidious. Fever, chills, and headache are the most common signs and symptoms. Diaphoresis, malaise, myalgias, fatigue, and anorexia are also common. Arthralgias are relatively uncommon. Cough often occurs later in the illness. Chest pain occurs in a minority of patients. Although nonspecific, evanescent skin eruptions have been reported. No characteristic rash results.
Most patients appear mildly to moderately ill. The temperature tends to fluctuate, with peaks at 39-40°C, and is biphasic in approximately 25% of patients. The fever generally lasts less than 13 days but has been reported to last longer in older adults.
Encephalopathic symptoms, headache, hallucinations (visual, auditory), expressive dysphasia, facial pain resembling trigeminal neuralgia, diplopia, and dysarthria have been reported.
Physical findings in acute Q fever are as nonspecific as the clinical symptomatology. Rales are probably the most commonly observed physical finding; evidence of pleural effusion and consolidation also may be noted but not in most infections.
Reports of abnormalities on chest radiographic examination vary with locale, but abnormalities probably are seen 50-60% of the time. The most common abnormality reported is a unilateral, homogenous infiltrate involving 1 or 2 lobes. Rounded opacities and hilar adenopathy are not uncommon. Consider the diagnosis of Q fever when these abnormalities are observed in the setting of acute pneumonia.
Patients with acute Q fever may present with a clinical picture of acute hepatitis with elevations of aminotransferases that are 2- to 3-fold higher than the upper limit of normal. The total bilirubin can be expected to be elevated in 10-15% of patients with acute Q fever. The white blood cell count is usually normal. The erythrocyte sedimentation rate is elevated in 33% of patients. Mild anemia or thrombocytopenia also may be observed.
Chronic infection with C burnetii usually is manifested by infective endocarditis, which also is the most severe complication of Q fever. In addition, hepatitis, infected vascular prostheses, aneurysms, osteomyelitis, pulmonary infection, cutaneous infection, and an asymptomatic form have been reported.
In Q fever endocarditis, fever has been recorded in 85% of patients, along with other systemic symptoms (eg, chills, headache, myalgias, weight loss). Other frequently reported clinical features of Q fever endocarditis include heart failure, splenomegaly, hepatomegaly, clubbing, and cutaneous signs. Routine blood cultures in Q fever endocarditis are negative, and Q fever should be considered when culture-negative endocarditis is encountered. The diagnosis of infective endocarditis secondary to Q fever is confirmed by serologic testing.
DIAGNOSIS- Q FEVER
Diagnosis of Q fever usually is accomplished by serologic testing; the most common methods are complement fixation, indirect fluorescent antibody, and ELISA. Significant antibody titers usually are not identifiable until 2-3 weeks into the illness.
Of the methods currently used for the diagnosis of Q fever, ELISA is the most sensitive and easiest to perform. This assay can establish a diagnosis of Q fever from a single serum specimen with a sensitivity of 80-84% in early convalescence and 100% in intermediate and late convalescence.
TREATMENT – Q FEVER
Tetracycline has been the mainstay of therapy since the 1950s. When initiated within the first few days of the illness, treatment significantly shortens its course. Macrolide antibiotics, such as erythromycin and azithromycin, are also effective.
When chronic Q fever infection is manifested by infective endocarditis, the mortality is 24% even when patients receive appropriate treatment. At least 2 years of therapy are required, usually with a tetracycline combined with rifampin or a quinolone, although trimethoprim-sulfamethoxazole also has been used.
PREVENTION/PROPHYLAXIS - Q FEVER
Although an effective vaccine (Q-Vax) is licensed in Australia, all Q fever vaccines used in the US are investigational. Q fever can be prevented by immunization.
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VIRAL AGENTS | Section 5 of 8 |
INTRODUCTION
Variola, the causative agent of smallpox, is the most notorious of the poxviruses (family Poxviridae). Smallpox was an important cause of morbidity and mortality in the developing world until recent times. In 1980, the World Health Organization (WHO) declared endemic smallpox eradicated, with the last occurrence in Somalia in 1977.
Variola represents a significant threat as a BW agent. Variola is highly infectious and is associated with a high mortality rate and secondary spread. Currently, the majority of the US population has no immunity, little vaccine is readily available, and no effective treatment exists for the disease. Currently, 2 WHO-approved and inspected repositories remain: the CDC in the US and Vector Laboratories in Russia; however, clandestine stockpiles may exist.
PATHOPHYSIOLOGY - SMALLPOX
Variola virus is highly infectious by aerosol, environmentally stable, and can retain infectivity for long periods. Infection throughcontaminated fomites is infrequent. After exposure to aerosolized virus, the virus multiplies locally in the respiratory tract. After an incubation period of 7-17 days, variola is spread hematogenously (primary viremia) to regional lymph nodes, where additional replication occurs. Subsequently, variola is spread hematogenously (secondary viremia) to small dermal blood vessels, where skin inflammatory changes (pox) occur. Two types of smallpox generally are recognized. Variola major, the most severe form, has a fatality rate of 30% in unvaccinated individuals and 3% in those previously vaccinated. Variola minor, a more mild form of smallpox, produces lethality in only 1% of unvaccinated individuals.
CLINICAL MANIFESTATIONS - SMALLPOX
After a 7- to 17-day incubation period, symptoms begin acutely with high fever, headache, rigors, malaise, myalgias, vomiting, and abdominal and back pain. During the initial phase, 15% of patients develop delirium, and 10% of light-skinned patients may develop a fleeting erythematous exanthem. After 2-3 days, an exanthem develops on the face, hands, and forearms and extends gradually to the trunk and lower extremities. The lesions progress synchronously from macules to papules to vesicles to pustules that often are umbilicated, such as in molluscum contagiosum. Centrifugal distribution of the rash is an important diagnostic feature, with a greater number of lesions on the face and extremities compared to the trunk. Patients are most infectious on days 3-6 after the onset of fever. Virus is shed from oropharyngeal and respiratory secretions.
The above-described manifestations are known as variola major. In variola minor (ie, alastrim), cutaneous lesions are similar but smaller and fewer in number. Patients are not as ill as those who have variola major are. Small numbers (3%) of patients develop hemorrhagic lesions, and these patients typically die of disease before papules develop. Flat smallpox with macular, soft, velvety lesions develops in 4% of patients and forebodes a poor prognosis. Modified smallpox occurs in those who have been vaccinated and develop a mild prodrome with rapid development of lesions and crusting by day 7. Frequently patients with modified disease form no pustules.
DIAGNOSIS - SMALLPOX
The most difficult aspect of diagnosing smallpox is the current lack of familiarity with the disease for most physicians. Other viral exanthems, such as chicken pox, erythema multiforme with bullae, or allergic contact dermatitis, can look similar. Smallpox is distinguished from chicken pox by the centrifugal distribution of its rash and the presence of lesions at the same stage of development everywhere on the body. The failure to recognize mild cases of smallpox in persons with partial immunity permits rapid person-to-person transmission. Exposed people may shed virus from the oropharynx without ever manifesting disease.
The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of vesicular scrapings. Gispen modified silver stain is rapid but relatively insensitive. When microscopy is unavailable, the gel diffusion test, in which vesicular fluid antigen from a pus lesion is incubated with vaccine hyperimmune serum, may be used. However, none of the above tests differentiate smallpox from monkeypox or cowpox. PCR techniques have been developed and may provide for more accurate diagnosis in the near future.
TREATMENT - SMALLPOX
It is critical for medical personnel to recognize a vesicular exanthem in possible terrorist areas or warfare theaters as possible smallpox. Immediate reporting of all possible cases must be made to public health authorities and to the chain of command. Strict quarantine with respiratory isolation for 17 days is applied to all people in direct contact with the index case or cases. All personnel exposed to either weaponized variola or clinical cases must be vaccinated immediately. Immediate vaccination is effective at ameliorating or preventing illness if accomplished within a few days of exposure. Give vaccinia immune globulin (VIG) to patients who cannot receive the vaccine. Treatment of smallpox is mainly supportive. The antiviral agent, cidofovir, is effective in vitro and may be involved in treatment of symptomatic illness.
PREVENTION/PROPHYLAXIS - SMALLPOX
Smallpox vaccine (attenuated vaccinia virus) is administered by intradermal inoculation with a bifurcated needle. The permanent scar results from a process known as scarification. A vesicle usually appears 5-7 days after inoculation; scabbing over and healing of the site occur over the next 1-2 weeks. Common adverse effects include low-grade fever and axillary lymphadenopathy. The most frequent complication is inadvertent inoculation to other skin or mucous membrane sites or to other people.
The absolute contraindication to vaccination is significant impairment of systemic immunity. Other relative contraindications include immunosuppression, HIV, pregnancy, and history or evidence of eczema. Evidence exists that VIG is of value in postexposure prophylaxis when administered within several days following smallpox exposure and concurrently with vaccination. VIG can be obtained from the CDC and is administered at a dose of 0.6 mL/kg IM.
MONKEYPOX
The monkeypox virus is a naturally occurring relative of variola, which is formed in Africa. The first case of human monkeypox was identified in 1970, with subsequently confirmed cases totaling less than 400. Some concern exists that monkey pox may be weaponized; however, human monkeypox is less virulent than smallpox. Monkeypox has a case-fatality rate of 11% in humans not vaccinated against smallpox. However, pneumonia due to monkeypox has about a 50% mortality rate. The secondary attack rate is only 9%, far lower than the rates of 25-40% observed in smallpox.
The clinical picture of monkeypox is clinically indistinguishable from smallpox with the exception of enlarged cervical and inguinal lymph nodes. The virus is transmitted by respiratory aerosol or direct contact with an infected individual or fomites. Immunization to vaccinia virus provides protection to 85% of individuals exposed to monkeypox. The treatment for monkeypox remains supportive.
INTRODUCTION
The viral encephalitides, Venezuelan equine encephalitis (VEE) virus, western equine encephalitis (WEE) virus, and eastern equine encephalitis (EEE) virus, are members of the Alphavirus genus and regularly are associated with encephalitis. These viruses first were recovered from horses during the 1930s. VEE was isolated in the Guajira peninsula of Venezuela in 1930, WEE in the San Joaquin Valley of California in 1930, and EEE in Virginia and New Jersey in 1933.
Although natural infections with these viruses occur following bites from mosquitos, the viruses also are highly infectious by aerosol. Alphaviruses replicate readily to very high titers and are relatively stable. They once were used as model systems by which to study different aspects of viral replication genesis and vector relationships. These characteristics and the familiarity of the virus lend it to weaponization. The intentional release as a small particle aerosol may be expected to infect a high percentage of individuals within an area of a least 10,000 km.
PATHOPHYSIOLOGY - VIRAL ENCEPHALITIDES
After exposure to these viruses, the tissues of the CNS and reticuloendothelial and/or lymphoid systems most commonly are affected in both humans and animals. A systemic viral febrile syndrome characterizes most infections. The severity of response is highly dependent upon host and viral factors, including the species and immune response of the host, route of infection, and strain and dose of the virus. VEE virus has the capacity to produce large human epidemics. Outcomes are significantly worse for young and elderly patients, with case fatalities ranging from 4-35%. WEE and EEE typically produce less fulminant and widespread disease but are associated with case-fatality rates of 50-75% in those with severe illness.
CLINICAL MANIFESTATIONS - VIRAL ENCEPHALITIDES
After an incubation period of 2-6 days, patients with VEE develop fevers, chills, headache, malaise, myalgias, sore throat, and photophobia. CNS manifestations range from mild confusion and lethargy to seizures, paralysis, and coma. For those that survive, CNS recovery usually is complete.
The incubation period for EEE varies from 5-15 days. Adults may exhibit a viral prodrome of up to 11 days before the onset of CNS manifestations. Signs and symptoms include fever, chills, vomiting, muscle rigidity, lethargy, paresis, excess salivation, and impaired respiratory regulation. Children frequently develop facial and periorbital edema. CNS effects range from mild confusion to seizures and paralysis. Up to 30% of survivors of severe disease have permanent neurologic sequelae, which include seizures and various degrees of dementia.
WEE has an incubation period of 5-10 days. Most patients are asymptomatic or have a nonspecific febrile illness/aseptic meningitis picture. Manifestations include fever, nausea, vomiting, malaise, headache, nuchal rigidity, and lethargy. The severity of CNS involvement is inversely proportional to age. Up to 90% of patients younger than 1 year exhibit seizure activity. Typically, adults recover completely. Children have a higher incidence of persistent neurologic sequelae, which ranges from 50% in newborns to 1% in those older than 1 year.
DIAGNOSIS - VIRAL ENCEPHALITIDES
Laboratory evaluation may reveal leukopenia with all 3 viruses. CSF analysis demonstrates from 10 to thousands of white blood cells per microliter with a lymphocyte pleocytosis. Specific diagnosis depends on virus isolation, serology, or both. Virus may be collected from the nasopharynx for 3 days after the onset of symptoms.
TREATMENT - VIRAL ENCEPHALITIDES
No specific treatment is available for the viral encephalitides. Supportive care may include aggressive airway management and antipyretic and anticonvulsant drug administration.
PREVENTION/PROPHYLAXIS - VIRAL ENCEPHALITIDES
TC-83 is a live attenuated vaccine for VEE. It is administered as 0.5-mL subcutaneous injection for those at high risk, such as laboratory field personnel. Approximately 20% of those who receive the vaccine fail to make a minimum neutralizing antibody response. An additional 25% of those vaccinated develop high fever, chills, and malaise that require bed rest. D-84 is a vaccination developed for those with incomplete inactivation from the TC-83 vaccine. It is an inactivated vaccine, which produces only mild tenderness at the injection site. It also is a 0.5-mL subcutaneous injection, administered at 2- and 4-week intervals until a satisfactory antibody response is measured.
The EEE vaccine is inactivated and administered in a 0.5-mL subcutaneous injection on days 0 and 28. Minimal side effects are noted, and no long-term problems have occurred. Boosters are required to maintain neutralizing titers. Like the EEE vaccine, the VEE vaccine is inactivated, produces no adverse effects, and requires boosters. The vaccine is administered on days 0, 7, and 28.
INTRODUCTION
Viral hemorrhagic fevers are caused by 4 families of viruses, which include the Arenaviridae (Lassa, Argentine, Bolivian, Brazilian, Venezuelan hemorrhagic fevers), Bunyaviridae (Rift Valley, Crimean-Congo, Hantaan), Filoviridae (Marburg, Ebola 4 Fs), and Flaviviridae (Yellow, Dengue, Kyasanur Forest, Omsk HFs). The best known of the viral hemorrhagic fever agents is Ebola virus. First recognized in Zaire in 1976, the virus has been linked to 3 outbreaks in Africa and is associated with a 53-92% mortality rate. A related virus was discovered in Reston, VA, in 1989 in association with an outbreak of illness among cynomolgus monkeys imported from the Philippines. No human cases occurred with this latter outbreak.
These viruses each are characterized by an acute generalized illness that includes malaise, prostration, increased vascular permeability, and abnormalities of circulatory regulation. All agents are highly infectious via the aerosol route, and most are stable as respiratory aerosols. Thus, they possess characteristics ideal for use by terrorists.
PATHOPHYSIOLOGY - VIRAL HEMORRHAGIC FEVERS
The agents that produce viral hemorrhagic fever are all simple RNA viruses with lipid envelopes. They are stable at a neutral pH and able to survive in blood for long periods, which leads to their infectivity of patients around domestic animal slaughters. These viruses are linked to the ecology of their vector, whether rodent or arthropod, which helps in searching for a diagnosis.
The specific viral hemorrhagic fever syndrome that develops in patients depends on numerous factors such as viral virulence and strain characteristic, routes of exposure, dose, and host factors.
CLINICAL MANIFESTATIONS - VIRAL HEMORRHAGIC FEVERS
All viral hemorrhagic fevers primarily target vascular beds. They produce microvascular damage and enhance vascular permeability. Clinical manifestations include fever, myalgia, prostration, conjunctival injection, mild hypotension to severe shock, and mucosal and petechial hemorrhages. Neurologic, hematopoietic, hepatic, and pulmonary involvement can be found with more severe disease.
Among the arenaviruses, Lassa fever is not associated with hemorrhagic or neurologic manifestations, but deafness is common. It causes the most severe capillary leak syndrome among hemorrhagic fever viruses and causes massive edema. Argentine and Bolivian hemorrhagic fevers have much more pronounced hemorrhagic and neurologic manifestations.
Rift Valley fever virus is primarily hepatatrophic; a small portion of patients demonstrates hemorrhagic signs. Crimean-Congo virus commonly is associated with severe DIC and the most severe hemorrhaging among the viral hemorrhagic fevers. Hantaan virus is associated with pulmonary and renal failure. A sunburn flush on the head, neck, and upper back is somewhat characteristic.
Limited clinical data are available on Marburg and Ebola hemorrhagic fevers. A nonpruritic, centripetal, pinhead-sized papular erythematous exanthem (visible primarily in fair-skinned patients) and DIC are prominent manifestations of illness.
Of the flaviviruses, yellow fever virus is primarily hepatatrophic. Black vomit caused by hematemesis is common, and patients usually develop clinical jaundice and die from hepatorenal syndrome.
DIAGNOSIS - VIRAL HEMORRHAGIC FEVERS
A high index of suspicion and detailed travel history are the most important steps in making the diagnosis of viral hemorrhagic fever. These agents are linked tightly with their natural geographic area and ecology of the reservoir species and vectors. Patients often recall exposures to rodents (Arenavirus, Hantavirus), mosquitoes (Rift Valley fever virus, yellow and dengue fever viruses), or even slaughtered horses (Rift Valley fever virus, Crimean-Congo virus). Suspect viral hemorrhagic fever in patients with fever, diffuse mucosal and dermal bleeding, and known travel to an endemic area for the illness.
Laboratory tests may be helpful. Leukopenia and thrombocytopenia are common, except in Lassa fever and Hantavirus. Proteinuria and hematuria are both common, but their absence rules out Hantavirus and Argentine and Bolivian hemorrhagic fevers.
Definitive diagnosis requires specific virologic diagnosis. ELISA can detect early immunoglobulin antibody responses during the acute illness; however, results may take 3-10 days. Reverse transcriptase PCR also may be used to identify a specific RNA virus. Testing can be conducted at the CDC in Atlanta or the US Army Medical Research Institute of Infectious Disease in Frederick, Maryland.
TREATMENT - VIRAL HEMORRHAGIC FEVERS
Treatment for a viral hemorrhagic fever is largely supportive. Patients benefit from rapid nontraumatic hospitalization to prevent damage to the capillary bed. Air transport is contraindicated. Sedative and pain-relieving medications are helpful, but aspirin and other antiplatelet agents should be avoided.
Avoid intravenous lines and catheters unless absolutely necessary. Secondary infections should be sought and aggressively treated.
Immunosuppressive agents such as steroids are contraindicated. The treatment for bleeding is controversial. Generally, mild bleeding should not be treated, whereas severe hemorrhage requires appropriate replacement therapy. Fluid infusions are typically safe for severe volume depletion except in the setting of pulmonary edema.
Specific treatment with ribavirin has been used and currently is being investigated as therapy for Lassa fever, Hantavirus, Crimean-Congo, and Rift Valley Fever. The dosage is 130 mg/kg IV followed by 15 mg/kg q6h for 4 days, then 7.5 mg/kg q8h for 6 days. Treatment is most effective if begun within 7 days. Ribavirin has poor activity against the filoviruses and flaviviruses.
PREVENTION/PROPHYLAXIS - VIRAL HEMORRHAGIC FEVERS
The only established and licensed virus-specific vaccine against any of the VHF viruses is the yellow fever vaccine. It is mandatory for those traveling into endemic areas of Africa and South America. Current trials are underway for further vaccines and antibody therapies.
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BIOLOGICAL TOXINS | Section 6 of 8 |
INTRODUCTION
Staphylococcal enterotoxin B (SEB) is one of the best-studied and, therefore, best-understood toxins. Staphylococcal enterotoxin is one of the most common causes of food poisoning. Nausea, vomiting, and diarrhea normally occur following ingestion of contaminated foodstuffs. The toxin causes a markedly different clinical syndrome when exposure is through a nonenteric route. In a BW or terrorist situation, the toxin is likely to be acquired through inhalation of an SEB aerosol. SEB is stable as an aerosol, and the inhaled dose necessary to incapacitate individuals is small (0.004 mcg/kg). Within 24 hours of inhalation of SEB toxin, exposed individuals are likely to be incapacitated by systemic illness created by the toxin.
PATHOPHYSIOLOGY - STAPHYLOCCOCAL ENTEROTOXIN B
SEB is an extracellular product produced by coagulase-positive staphylococci. The toxin is heat stable and generally forms in the presence of overgrowth of staphylococcal organisms, as occurs with poorly handled food. The effects of the enterotoxin are mediated by its interactions with the host's own immune system. The toxin binds directly to the major histocompatibility complex and subsequently stimulates large numbers of T lymphocytes. These activated T lymphocytes then stimulate the release of various cytokines, which are thought to mediate the toxic effects of SEB.
CLINICAL MANIFESTATIONS - STAPHYLOCOCCAL ENTEROTOXIN B
After exposure, signs and symptoms begin in 2-12 hours. Mild-to-moderate exposure to SEB produces nonspecific systemic illness that is characterized by fever, chills, headache, nausea, vomiting, dyspnea, chest pain, myalgias, and a nonproductive cough. Severe exposures can lead to a toxic shocklike picture and even death.
In mild-to-moderate cases, the physical examination is typically unremarkable. In severe instances, rales are common from pulmonary edema. Depending on the severity of exposure, duration of illness varies from 3-10 days.
DIAGNOSIS - STAPHYLOCOCCAL ENTEROTOXIN B
Diagnosis of SEB intoxication can be difficult and is made primarily by clinical and epidemiologic methods. Laboratory studies may show a nonspecific neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate. In severe exposures with significant pulmonary symptoms, a chest radiograph may show interstitial edema.
Enterotoxin is a stable protein that can be collected from serum if performed quickly. However, by the time symptoms are noted, the detection of toxin is unlikely. SEB accumulates in urine and may be detected for several hours following exposure. If the source of infection is from an inhalation injury, the toxin may be isolated from nasal swabs for up to 12-24 hours.
TREATMENT - STAPHYLOCOCCAL ENTEROTOXIN B
Supportive care is the mainstay of treatment. Close attention to oxygenation and hydration are important. Patients with severe SEB may need ventilator support and diuretics. Most patients are expected to do well after the initial phase, but the time to full recovery may be prolonged.
PREVENTION/PROPHYLAXIS - STAPHYLOCOCCAL ENTEROTOXIN B
No approved human vaccine exists for SEB, although human trials are ongoing. Passive immunotherapy agents have demonstrated some promise when given within 4 hours of exposure, but such therapy is still investigational.
INTRODUCTION
Ricin, a plant protein toxin derived from the beans of the castor plant, is one of the most toxic and easily produced of the plant toxins. Although the lethal toxicity of ricin is approximately 1000-fold less than botulinum toxin, the worldwide ready availability of castor beans and the ease with which toxin can be produced give it significant potential as a biological weapon.
Since ancient times, more than 750 cases of ricin intoxication have been described. Ricin may have been used in the highly published assassination of Bulgarian exile Georgi Markov in London in 1978. He was attacked with a device that implanted a ricin-containing pellet into his thigh.
PATHOPHYSIOLOGY - RICIN
The toxicity of ricin varies greatly with the route of administration. Ricin is extremely toxic to cells and acts by inhibiting protein synthesis. Inhalation exposure causes primarily pulmonary symptoms, ingestion causes GI symptoms, and intramuscular exposure results in a localized reaction.
CLINICAL MANIFESTATIONS - RICIN
Following inhalation exposure of ricin, toxicity is characterized by the sudden onset of nasal and throat congestion, nausea and vomiting, itching of the eyes, urticaria, and tightness in the chest. If exposure is significant, pulmonary manifestations occur after 12-24 hours and include airway lesions, alveolar flooding, and severe respiratory distress. In animal studies, death occurs 36-48 hours after severe exposure.
Ingestion of ricin is generally less toxic because of its poor absorption and enzymatic degradation in the digestive tract. Out of 751 ingestions recorded, only 14 resulted in a fatality. Clinical manifestations occur rapidly and are characterized by nausea, vomiting, abdominal pain and cramping, diarrhea, fever and chills, hematochezia, and eventually, shock and vascular collapse. Autopsy findings have revealed significant hepatic, splenic, and renal necrosis.
At low doses, intramuscular exposures produce flulike symptoms, myalgias, nausea, vomiting, and localized pain and swelling at the injection site. Severe intoxication results in local lymphoid necrosis and GI hemorrhage, as well as diffuse hepatic, splenic, and renal necrosis.
DIAGNOSIS - RICIN
The diagnosis of ricin poisoning is made on the basis of clinical and epidemiologic factors. In a BW or terrorist situation, exposure is likely to occur by inhalation of a toxin aerosol. Thus, consider ricin poisoning when patients experience upper airway and pulmonary symptoms in the setting of a known or suspected mass casualty incident.
Patients may have neutrophilic leukocytosis, hypoxemia, and bilateral infiltrates on chest radiograph. Confirmation of ricin exposure can be made by ELISA analysis of a swab sample from nasal mucosa. Ricin can be identified for up to 24 hours after exposure.
TREATMENT - RICIN
Treatment is supportive. Determine specific treatment largely by the route of exposure and clinical manifestations. Inhalation injury may require treatment of pulmonary edema, with respiratory support as indicated. Early following ingestion, patients should undergo GI decontamination with gastric lavage and the administration of activated charcoal. Intravenous crystalloid infusion and pressor support may be necessary for patients with hypotension.
PREVENTION/PROPHYLAXIS - RICIN
Currently, no vaccine is available for ricin exposure. Investigational vaccines have proven effective in animals. Some chemotherapeutic agents are being studied as well.
INTRODUCTION
The anaerobic, spore-forming, gram-positive bacillus, Clostridium botulinum, produces botulinum toxins. Botulinum toxins are the most lethal toxins known, with an estimated lethal dose to 50% of the exposed population (LD50) of 0.001 mcg/kg in humans. Since botulinum toxin is so lethal and easy to manufacture and weaponize, it represents a credible threat as a BW agent. When used as a BW or terrorist agent, exposure is likely to occur following inhalation of aerosolized toxin or ingestion of food contaminated with the preformed toxin or microbial spores. Recently, Iraq admitted to active research on the offensive use of botulinum toxins and to weaponizing and deploying more than 100 munitions with botulinum toxin in 1995.
PATHOPHYSIOLOGY - BOTULINUM TOXIN
All 7 subtypes (A-G) of botulinum toxin act by similar mechanisms. The toxin produces similar effects whether ingested or inhaled. The time course and severity of illness vary with route of exposure and dose received. Symptom onset is slower after inhalation exposure.
Botulinum toxins bind to the presynaptic nerve terminal at the neuromuscular junction and cholinergic autonomic sites. This prevents the presynaptic release of acetylcholine and blocks neurotransmission. Interruption of neurotransmission produces muscular weakness and paralysis.
CLINICAL MANIFESTATIONS - BOTULINUM TOXIN
Symptom onset may occur hours to several days after exposure. Initial signs and symptoms include blurred vision, mydriasis, ptosis, dysphagia, dysarthria, dysphonia, and muscle weakness. After 24-48 hours, neuromuscular manifestations progress to symmetric descending paralysis and respiratory failure. Varying degrees of muscular weakness may occur. Patients may become cyanotic or exhibit narcosis from carbon dioxide retention secondary to respiratory failure. Postural hypotension may occur from autonomic insufficiency. Deep tendon reflexes may be depressed or absent on physical examination. Cranial nerve palsies often are present.
DIAGNOSIS - BOTULINUM TOXIN
The occurrence of multiple related cases of descending and progressive bulbar and skeletal paralysis in afebrile patients should suggest the diagnosis of botulinum toxicity. Laboratory tests, including CSF studies, generally are not helpful. Oral exposure can be detected by analyzing serum or gastric contents with a mouse neutralization assay. Intoxication by inhalation can be diagnosed by ELISA identification from nasal swabs up to 24 hours after exposure.
TREATMENT - BOTULINUM TOXIN
The most serious complication of toxicity is respiratory failure. With supportive care and ventilatory assistance, fatalities should be less than 5%. For confirmed exposures, a trivalent equine antitoxin is available from the CDC. This antitoxin has all of the disadvantages of horse serum products, including the risks for anaphylaxis and serum sickness. Skin testing is performed by injecting 0.1 mL of a 1:10 dilution of antitoxin intradermally and monitoring the patient for 20 minutes. After a negative skin test, administer the antitoxin at a dose of 10 mL IV over 20 minutes, which is repeated until improvement ceases. With a positive skin test, administer 0.01-0.1 mL of antitoxin subcutaneously, gradually increasing the dose every 20 minutes until 2 mL can be sustained without reaction.
PREVENTION/PROPHYLAXIS - BOTULINUM TOXIN
A toxoid for C botulinum, which has been used in volunteers and occupationally at-risk workers, is available through the CDC. It was used to immunize US military troops in the Persian Gulf War. The current schedule for immunization is at 0, 2, and 12 weeks with an annual booster. Currently, no indication exists for prophylactic use of the antitoxin except under specialized circumstances.
INTRODUCTION
The trichothecene mycotoxins are highly toxic compounds produced by certain species of filamentous fungi (Fusarium, Myrotecium, Cephalosporium, Trichoderma, Verticimonosporium, Stachybotrys species). These mycotoxins (eg, T2, nivalenol) cause multiple organ effects, which include emesis, diarrhea, weight loss, nervous disorders, cardiovascular alterations, immunosuppression, hemostatic derangements, skin toxicity, and bone marrow damage.
Because of their antipersonnel properties, ease of large-scale production, and amenability to dispersal by various methods (dusts, droplets, aerosols, smoke, rockets, artillery mines, portable sprays), mycotoxins have an excellent potential for weaponization.
Strong evidence suggests that trichothecenes ("yellow rain") have been used as a BW agent in Southwest Asia and Afghanistan. From 1974-1981, numerous attacks resulted in a minimum of 6310 deaths in Laos, 981 deaths in Cambodia, and 3042 deaths in Afghanistan.
PATHOPHYSIOLOGY - MYCOTOXIN
These toxins are nonvolatile, low molecular weight compounds that are highly soluble in acetone, ethyl acetate, chloroform, ethanol, methanol, and propylene glycol. The trichothecenes vaporize when heated in organic solvents. Extraction of the mycotoxin from fungal cultures yields a yellow-brown liquid that evaporates into a yellow crystalline product (thus, the "yellow rain" appearance). These toxins require a 3-5% sodium hydroxide solution and heating at 900°F for 10 minutes or 500°F for 30 minutes for complete inactivation.
The trichothecene mycotoxins are cytotoxic to most eukaryotic cells by way of inhibiting protein synthesis and electron transport. Rapid absorption from the gut or pulmonary mucosa can produce initial symptoms in 5 minutes and maximal effects by 60 minutes. Peak tissue levels occur 1-4 hours following exposure. These toxins are absorbed slowly through intact skin.
CLINICAL MANIFESTATIONS - MYCOTOXIN
After exposure to the mycotoxins, early symptoms begin within minutes. Cutaneous manifestations include burning, tender erythema, edema, and blistering with progression to dermal necrosis and sloughing of large skin areas in lethal cases. Respiratory exposure results in nasal itching, pain, sneezing, epistaxis, rhinorrhea, dyspnea, wheezing, cough, and blood-tinged saliva and sputum.
GI toxicity consists of anorexia, nausea and vomiting, abdominal cramping, and watery and/or bloody diarrhea. Following entry into the eyes, pain, tearing, redness, and blurred vision occurs. Systemic toxicity may occur and includes weakness, prostration, dizziness, ataxia, tachycardia, hyperthermia or hypothermia, diffuse bleeding, and hypotension. Death may occur within minutes to days depending on the dose and route of exposure.
DIAGNOSIS - MYCOTOXIN
Diagnosis of an attack of trichothecene mycotoxin depends on clinical observations and identification of the toxin from biological and environmental samples. Many patients presenting with the above symptoms and reporting a yellow rain or smoke attack lend support to the diagnosis. Initial laboratory studies are nonspecific. Elevations of serum creatinine, potassium, and phosphorus may occur, as well as abnormalities of coagulation parameters. An initial rise in absolute neutrophils can be seen. Leukopenia, thrombocytopenia, and anemia may occur 2-4 weeks following initial exposure.
Currently, a rapid identification kit for any of the trichothecene mycotoxins does not exist. Gas-liquid chromatography has been used in the past with great success. However, chromatographic methods lack great sensitivity, and presently alternative methods of detection are under investigation (eg, radioimmunoassay, ELISA, mass-spectometry).
TREATMENT - MYCOTOXIN
Treatment is supportive. The immediate use of protective clothing and mask during a mycotoxin aerosol attack should prevent illness. If a soldier is unprotected during an attack, the outer clothing should be removed within 4-6 hours and decontaminated with 5% sodium hydroxide for 6-10 hours. The skin should be washed with copious amounts of soap and uncontaminated water. The eyes, if exposed, should be irrigated with copious amounts of normal saline or sterile water. A skin decontamination kit (M291) currently is fielded to all US military personnel and is efficacious against most chemical warfare agents, including the mycotoxins.
No specific therapy exists for a trichothecene exposure. After appropriate skin decontamination, give victims of inhalation and oral exposures superactivated charcoal orally. Activated charcoal binds mycotoxins. Treat severe respiratory distress with endotracheal intubation and mechanical ventilation as needed. Early use of systemic steroids increases survival time by decreasing the primary injury and shocklike state that follows significant poisoning.
PREVENTION/PROPHYLAXIS - MYCOTOXIN
No vaccine exists for trichothecene mycotoxin exposure. Currently, 2 topical skin protectants as well as vaccines are in advanced development but have not been approved yet for use in humans.
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PICTURES | Section 7 of 8 |
Caption: Picture 1. Al Hakam Single-Cell Protein Plant. Iraq's major facility for the production of biological warfare agents. Under the watchful eye of the United Nations Special Commission, this plant was destroyed by Iraqi workers in May and June 1996. (Photo courtesy of David Franz, DVM, PhD)
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Caption: Picture 2. The "eight ball" one million liter test sphere at Fort Detrick, Maryland. This aerobiology chamber was used before 1969 when the US was performing offensive biological warfare research. Animals were tethered within the sphere while aerosolized agents were aerosolized.
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Caption: Picture 3. The "eight ball" one million liter test sphere at Fort Detrick, Maryland. This aerobiology chamber was used before 1969 when the US was performing offensive biological warfare research. Animals were tethered within the sphere while aerosolized agents were aerosolized.
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Caption: Picture 4. Anthrax pilot plant used to produce billions of anthrax spores at Fort Detrick, Maryland, before the US unilaterally ended offensive biological warfare research in 1969. Spores were sent to other military sites where they were placed in weapons. The building is entirely free of anthrax spores and on the National Register of Historic Places. Tours frequently take visitors through this old production facility.
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Caption: Picture 5. Entrance to Fort Detrick with headquarters building in background.
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Caption: Picture 6. Front of main building at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) on the grounds of Fort Detrick, Maryland.
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Caption: Picture 7. A suppurative bubo of the femoral lymph node (a), the most common site of erythematous, tender, swollen nodes in a plague victim. The next most common lymph node regions involved are the inguinal, axillary (b), and the cervical areas. The child in (b) has an erythematous, eroded, crusting necrotic ulcer at the presumed primary inoculation site on the left upper quadrant. This type of lesion is uncommonly found in patients with plague. Bubo location is primarily a function of the region of the body in which an infected flea inoculates plague bacilli.(Photos courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention, Fort Collins, CO)
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Caption: Picture 8. A suppurative bubo of the femoral lymph node (a), the most common site of erythematous, tender, swollen nodes in a plague victim. The next most common lymph node regions involved are the inguinal, axillary (b), and the cervical areas. The child in (b) has an erythematous, eroded, crusting necrotic ulcer at the presumed primary inoculation site on the left upper quadrant. This type of lesion is uncommonly found in patients with plague. Bubo location is primarily a function of the region of the body in which an infected flea inoculates plague bacilli.(Photos courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention, Fort Collins, CO)
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Caption: Picture 9. Small femoral bubo and presumed inoculation site (inferior thigh) in a patient with tularemia. This gram-negative bacterial infection (Francisella tularensis) may closely mimic bubonic plague and is successfully treated with the same antibiotics. (Photo courtesy of Dermatology Service, Fitzsimons Army Medical Center, Aurora, CO)
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Caption: Picture 10. Vesicles and erosions on the back of hairless guinea pigs at (a) 1 day, (b) 2 days, (c) 7 days, and (d) 14 days after application of (bottom to top) 25 ng, 50 ng, 100 ng, or 200 ng of T-2 mycotoxin in 2mcL of methanol. (Reprinted from Wannamacher RW Jr, Wiener SL. Trichothecene mycotoxins. In: Zajtchuk R, Bellamy RF, eds. Medical Aspects of Chemical and Biological Warfare- Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute; 1997: 666.)
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Caption: Picture 11. Adult with variola major with hundreds of pustular lesions distributed centrifugally. (Fitzsimons Army Medical Center Slide File)
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Caption: Picture 12. Boy with monkeypox in Democratic Republic of the Congo in 1996. Note the (a) centrifugal distribution and (b) synchronicity of lesions as was typical for smallpox. (Courtesy of William Clemm)
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Caption: Picture 13. Boy with monkeypox in Democratic Republic of the Congo in 1996. Note the (a) centrifugal distribution and (b) synchronicity of lesions as was typical for smallpox. (Courtesy of William Clemm)
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Caption: Picture 14. Bunyavirus infection - CCHF Virus. Ecchymoses encompassing left upper extremity one week after onset of CCHF. Ecchymoses often are accompanied by hemorrhage in other locations: epistaxis, puncture sites, hematemesis, melena, and hematuria. (Photo courtesy of Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.)
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Caption: Picture 15. Bunyavirus Infection - Hantaan Virus. Patient with Korean Hemorrhagic Fever caused by Hantaan virus demonstrating typical sunburn flush of cheeks, chin, and base of neck. (Photo courtesy of John Huggins, PhD)
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Caption: Picture 16. Ulceroglandular tularemia demonstrating inoculation site on check and cervical lymphadenopathy (Fitzsimons Army Medical Center Dermatology Slide File)
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Caption: Picture 17. Typical heaped up ulcer of tularemia. (Reprinted from Evans ME, Friedlander AM. Tularemia. Chapter 24 In: Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare. In: Zajtchuk R, Bellamy RF, eds. Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute; 1997:505.)
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BIBLIOGRAPHY
Section 8 of 8
Nuclear, Biological, & Chemical Warfare- Survival Skills, Pt. II
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