Biological weapons: Preparing for the worst

Special note for Poohbah before we read the first article from Medical Laboratory Observer:

Not for commercial use. Solely to be used for the educational purposes of research and open discussion.

Medical Laboratory Observer
September 1, 2000
No. 9, Vol. 32; Pg. 26

Biological weapons: Preparing for the worst.
Leach, Donna L.; Ryman, Denny G.

Bioterrorism has been given significant attention during the past 2 years by the laboratory industry press and has been the subject of numerous seminars at national meetings of laboratory organizations. The likely precursors to this coverage were the discovery of a huge biological weapons program in Iraq after the Gulf War of 1991, the discovery of a major biological weapons program in the former Soviet Union called "Biopreparat," and the known recruitment of scientists from other rogue nations who worked on Biopreparat. [1,2] Terrorist attacks, such as the dispersal of sarin nerve gas in a Tokyo subway in 1995 by the Japanese cult Aum Shinrikyo, may also have contributed to the added attention bioterrorism has received. [3,4]

Many countries have biological weapons programs with virtually no safeguards against the transfer of weapons or the technology used to manufacture them to potential terrorist groups. These countries (many classified by the US State Department as supporting terrorism) include Syria, North Korea, Russia, Iran, Iraq, Libya, and China. [5] The threat of a terrorist action against the US that involves lethal biological weapons is not only possible but also probable, according to experts. In his congressional testimony before the Subcommittee on National Security, Veterans Affairs, and International Relations for the US House of Representatives on Oct. 20, 1999, Raymond Zalinskas, PhD, the Senior Scientist-in-Residence for the Chemical and Biological Weapons Nonproliferation Project at the Center for Nonproliferation Studies in Washington, DC, said that the most likely attacks would be on food or water supplies. He also predicted a substantial increase in the possibility of biological attacks using airborne pathogens between 2006 and 2010. [6]

Three major trends have been cited as responsible for the increased threat of biological weapons: the expertise needed to develop biological agents is rapidly proliferating, the technology needed to manufacture these agents is readily available, and the will to use these agents may be increasing among terrorist organizations. [1-4] Many toxins can be readily produced with minimal scientific knowledge, facilities, and financial support. Biological weapons are appealing to terrorists because they are both cheap to produce and capable of causing cause massive casualties. [2,7] Any "basement laboratory" can produce significant quantities of toxic substances. Advances in genetic engineering also mean that a microbiologist can engineer new organisms that are more lethal and resistant to known antibiotics. Because of this, the threat for bioterrorism is the greatest it has ever been. Terrorist groups with specific political goals may be unwilling to use biological agents out of fear of backlash, but the more fanati c ethnic and religious organizations whose motives cannot be understood in political terms may be more prone to experiment with agents of biological warfare.

The use of biological weapons is not new. Diseased corpses were catapulted into enemy cities in medieval times; and in the Eighteenth century, blankets infested with smallpox were distributed to certain Native American tribes, [8,9]

Attempts to control the use of biological weapons are almost as old as the weapons themselves. Most of the members of the League of Nations signed the 1925 Geneva Protocol renouncing the use of chemical or biological weapons. Later, the 1972 Biological Weapons Convention was signed by 118 countries, including China, Japan, all NATO members, and the former Warsaw Pact countries. [2] The BWC defined both biological and chemical weapons as instruments of biological warfare and prohibits the development, production, and stockpiling of biological and chemical weapons. Because no verification method exists, however, this pact remains largely unenforceable. [1]

Domestic defense

In 1996, the US government developed the Biological Warfare Defense Program. The purpose of the program was to develop broad-spectrum approaches to neutralizing biological agents (bacteria, viruses, bioengineered organisms, and toxins) used in biological attacks. [10] This program partners with universities and other organizations to perform research that creates fast, simple methods for detecting and identifying biological agents. It also develops protective gear and mechanisms to destroy organisms before they enter the body. Even though this program provides expertise for the Department of Defense in biological attacks, many innovations will be transferred to the civilian sector for use in a bioterrorism attack.

That same year, Congress passed the Defense Against Weapons of Mass Destruction Act, which mandated that the Secretary of Defense create a program to improve the responses of state and local agencies to emergencies involving biological and chemical weapons. As a result, the Department of Defense established the Biological Weapons Improved Response Program, which uses the resources of he US Army's Chemical and Biologic Defense Command, the Department of Health and Human Services, the Department of Energy, the Department of Agriculture, the Federal Emergency Management Agency, the Federal Bureau of Investigation, the Environmental Protection Agency, and the Centers for Disease Control and Prevention to develop the Biological Weapons Response Template, which will help city and state governments prepare their defenses for an attack. [11,12]

Most published government and military reports state that the nation's medical and government structures would be unable to effectively respond to such a catastrophic event. [13] The US, local, state, and federal public health infrastructure is already overburdened with other pressing public health issues. [13] A simulated biological attack staged in New York, Chicago, and Los Angeles in 1996 revealed just how vulnerable the US is to bioterrorism. [14] Firemen were reported to have rushed into the "contaminated" area without protective clothing, and hospitals reported they would have been overwhelmed in the event of an actual attack. The US government responded in several ways, including appropriating $ 800 million for chemical and biological weapons defense in fiscal year 1997. [2] These and other government actions indicate that the detection, deactivation, and containment of biological weapons are becoming priorities for the US.

The lab's response

The execution of 4 critical steps will determine the success of the medical community's response to a bioterrorist attack [15]:

* prompt lab identification of agents of biological warfare,

* notification of local, state, and federal health officials,

* notification of appropriate law enforcement agencies, and

* support of healthcare providers who may be faced with caring for large numbers of infected patients.

For their part, laboratory professionals must be aware of potential agents of biological warfare, know how to isolate and identify them, and know what precautions should be taken when handling such agents. Also important is having a procedure for notifying authorities of a suspected bioterrorist attack.

What are biological weapons?

Biological weapons include both biological agents, such as bacteria, protozoa, rickettsia, viruses, and fungi, as well as toxins, such as poison gas and chemicals. This article addresses the most commonly used biological weapons, most of which are biological agents.

Biological and chemical weapons are extremely pathogenic to both humans and animals. Their effects can include acute respiratory paralysis, central nervous system disorders, and organ failure, with death as the final outcome.

According to Zalinskas, the major biological threats to the US include emerging pathogens, reemerging pathogens, and transported infectious diseases. [11] Terrorist groups could use many different biological agents in a bioterrorism attack. The following biological agents are those put forth by the US Army Medical Research Institute of Infectious Diseases (USAMRIID) as those most likely to be used: Bacillus anthracis, Brucella sp., Burkbolderia mallei, Vibrio cholerae, Yersinia pestis, Francisella tularensis, Coxiella burnetii, Venezuelan equine encephalitis (VEE), viral hemorrhagic fevers, smallpox, botulinum toxin, staphylococcal enterotoxin B, ricin, and T-2 toxins. [8,16,17]

Anthrax

An aerobic, spore-forming, gram-positive rod called Bacillus anthracis causes anthrax. Anthrax is usually found in cattle, sheep, and horses, although other animals can also be infected. The infectious form of the organism is the spore, which remains viable for years in soil, water, and direct sunlight. The incubation period is 1-6 days.

Diagnosis. Initial symptoms include fever, malaise, fatigue, cough, and mild chest pain, which quickly progresses to severe respiratory distress, then shock and death within 24-36 hours after the initial symptoms. The gastrointestinal and cutaneous forms of anthrax are not lethal. A vaccine is available and is now required for all military members. Diagnosis usually comes late in the disease by blood culture or Gram stain of peripheral blood.

Treatment. Penicillin is effective before the symptoms appear, but high-dose antibiotic treatment with penicillin, ciprofloxicin, or doxycycline is recommended. [8,16,17]

Brucellosis

Brucellosis can be caused by Brucella abortus, Brucella melitensis, and Brucella suis, which are gram-negative coccobacilli. These organisms are highly infectious, and as few as 10-100 bacteria can produce disease after being inhaled. The incubation period is from 5-60 days, but large aerosol doses can shorten the incubation period. Brucellosis is an incapacitating disease, but the mortality rate is less than 5% of infected individuals. Brucellosis also occurs as a percutaneous or enteric infection, which is contracted by consuming unpasteurized dairy products (especially goat's milk and cheese).

Diagnosis. Brucellosis presents as a nonspecific febrile illness with headache, fever, myalgia, arthralgia, back pain, sweats, chills, and malaise. The bacteria may cause meningitis in 5% of the cases, and the organism can be cultured from cerebrospinal fluid. Patients may present with anemia and thrombocytopenia, and blood and bone marrow cultures may be positive during the acute febrile phase. Enzyme immunoassays are under development as is a polymerase chain reaction test using a protein from B. abortus.

Treatment. Treatment is doxycycline plus rifampin for 6 weeks. Ofloxacin plus rifampin can also be given. For patients with meningitis or endocarditis, rifampin, tetracycline, and an aminoglycoside are administered. [8,16,17]

Cholera

Cholera is caused by a short, curved, motile, anaerobic, gram-negative rod called Vibrio cholera. Vi cholerae produces an enterotoxin that inhibits water absorption in the small intestine. The organism is transmitted by contaminated water, food, flies, or soiled utensils and can be killed by drying, chlorinating, steaming, and boiling water. This organism can withstand freezing for 3-4 days.

Diagnosis. Diagnosis is performed clinically by observing "rice water" diarrhea and dehydration. Laboratory diagnosis is made by identifying the motile vibrio under phase-contrast microscopy in the field or by culture in clinical laboratories.

Treatment. Treatment with antibiotics will reduce shedding of the organism so that the infected person does not pass as many organisms into his or her body fluids. However, antibiotics will not kill the organism [8,16,17]

Glanders

Glanders is caused by a small, gram-negative rod called Burkholderia mallei (formerly known as Pseudomonas mallei). This organism usually produces disease in horses, mules, and donkeys, but may also infect humans. Infection occurs through inhalation or through cracks or sores in the skin. Laboratory cultures are considered extremely infectious and require biosafety level 3 practices.

Infections in patients can take 4 forms: acute localized, septicemia, acute pulmonary, or chronic cutaneous. The acute localized form can be either cutaneous or mucosal. In the cutaneous form, patients present with nodules and ulcerations. If the cutaneous form becomes systemic, a papular or pustular rash accompanies systemic invasion, and it can be mistaken for smallpox.

The septic form of this infection presents with a sudden onset fever, rigors, sweats, myalgia, chest pain, phototrophia, lacrimation, and diarrhea. The blood cultures are usually negative, and this form causes death quickly after onset.

The mucosal form involves infection of oral, nasal, and/or conjunctival mucosa, which causes mucopurulent, bloodstreaked discharged from the nose. Turbinate nodules and ulcerations are also present in the nose. Systemic invasion can occur from here.

The chronic form presents with cutaneous and intramuscular abscesses on the legs and arms. There is also enlargement and induration of the lymph glands. Patients with this form of the disease may still erupt into acute septicemia.

Diagnosis. Diagnosis is achieved through a Gram stain of exudates and routine culture. B. mallei takes 48 hours to grow on nutrient agar, but colony growth can be enhanced by the addition of meat infusion media. Antibody detection tests are not positive for 7-10 days and are difficult to interpret because of a high background titer. Complement fixation tests are more specific and are considered positive at a titer of 1:20.

Treatment. Most antibiotics have been tested only on animals, so each organism encountered must be tested to determine susceptibility to antibiotic agents. Experts expect high mortality despite antibiotic use. [8,16,17]

Smallpox

Smallpox is an orthopoxvirus. It has two forms: variola major and variola minor. Variola major produces more severe disease. The virus is highly infectious when transported by aerosols, is easy to make, and the world population does not have immunity to it. In 1980, the World Health Organization declared that smallpox was globally eradicated and approved CDC and the Institute for Viral Preparedness in Moscow to hold live cultures of smallpox. In the 1980s, children in the US stopped receiving smallpox vaccinations, and the military stopped vaccination programs in 1989. This means that a good part of the US population and its military force are now susceptible to variola major. This fact makes smallpox a choice biological agent because even though smallpox was "globally eradicated" and a vaccine exists, countries with live cultures can still use it in biological weapons. The incubation period for smallpox is around 12 days, but because it is extremely infectious as pustules, patients and contacts are quarantin ed for about 16 days after exposure.

Symptoms. The patient infected with variola major presents with malaise, fevers, rigors, vomiting, headache, and backache. After 48-72 hours, patients develop a rash on the face, hands, and forearms, which then extends to the legs and trunk over the next week. Lesions are plentiful on the face and extremities--this is called centrifugal distribution and is diagnostic. Approximately 2 weeks after onset of nonspecific symptoms, pustules form scabs, which then become depressed and depigmented. After healing, scars are left on the skin. Patients are considered infectious until all scabs disappear. Variola major can cause up to 30% mortality among the unvaccinated population.

The early stages of smallpox are indistinguishable from other diseases such as chicken pox or allergic-contact dermatitis. Particularly troubling is the fact that many vaccinated people could contract mild cases of the disease and spread it before they are quarantined.

Diagnosis. Smallpox is usually diagnosed by appearance of virions on electron microscopy of vesicular scrapings. Guarnieri's bodies in vesicular scrapings can be seen with Gispen's modified silver stain, but the inclusions do not differentiate between cowpox, monkeypox, and smallpox.

The problem with smallpox is that it is highly contagious. If a vesicular exanthem (eg, skin eruptions or vesicles on the lips, nose, or tongue) is discovered on a patient, physicians must suspect a biological attack and undertake appropriate quarantine measures. A confirmed case of smallpox is an international emergency and needs to be reported to public health officials immediately. One sobering thought: only persons vaccinated within the past 3 years are considered immune; however, if vaccination is given within 7 days of exposure to smallpox, the disease can be prevented.

Treatment. There are no effective antiviral drugs at this time. Variola immune globulin (VIG) does exist and can provide protection for people who cannot take the smallpox vaccine. [8,16,17]

Plague

A gram-negative, nonmotile, nonsporulating, aerobic bacteria named Yersinia pestis is responsible for the plague. Plague is a zoonotic infection that is passed onto humans by fleas. If a human is bitten by an infected flea, this person develops the bubonic form of plague, but the pneumonic form of plague is better suited for a biological weapon because all people are susceptible. The organism can remain alive in water, meals, and grains for weeks; but at near freezing, it can remain alive from months to years. It is killed when exposed to temperatures of 72[degrees]C for 15 minutes and several hours of sunlight exposure.

Diagnosis. The pneumonic plague presents with malaise, high fever, chills, headache, myalgia, cough with a bloody sputum, and toxemia. Patients have bronchopneumonia, which progresses rapidly to dyspnea, stridor, and cyanosis. They die from respiratory failure, circulatory collapse, and a bleeding diathesis. The typical incubation period for pneumonic plague is 2-3 days.

Diagnostic laboratory tests include CBC with a WBC of as high as 20,000/L with increased bands and [greater than] 80% polymorphonuclear cells on the differential. Patients experience a lowgrade disseminated intravascular coagulation (DIC) with a positive fibrin degradation product (FDP) and elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels. Presumptive diagnosis consists of finding gram-negative coccobacillus in lymph node aspirate, sputum, or CSF. The gram-negative coccobacillus exhibits safety-pin bipolar staining with Giemsa stain. Definitive diagnosis is made from culture of blood, sputum, bubo aspirates, and CSF. Yersinia pestis will grow on blood and MacConkey agars.

Treatment. Patients must be isolated for 72 hours after starting antibiotics. Antibiotics of choice include streptomycin, tetracycline, chloramphenicol, gentamicin, and ceftriaxone. A vaccine is available, but it is a 3-dose vaccine that requires boosters at 6, 12, and 18 months; then every 1-2 years after vaccination. People who need prophylaxis can take doxycycline to prevent infection in face-to-face encounters with infected people. [8,16,17]

Tularemia

Tularemia is caused by a small, nonmotile, aerobic, gramnegative coccobacillus called Francisella tularensis. This organism can survive in water, carcasses, hides, and for years in frozen rabbit meat. It also survives in soil or water at freezing temperatures and below. It is susceptible to heat and disinfectants.

Tularemia manifests itself in several forms in man: ulceroglandular, septicemic (typhoidal), and pneumonic. The most probable form of the disease caused by a bioterrorism attack would be septicemic tularemia. Septicemic tularemia occurs after intradermal, respiratory, or gastric inoculation of the organism. This is the presenting form of tularemia in 5-15% of cases. Pneumonic tularemia can be primary (inhaled bacteria) or secondary (produced after patient is septic).

Diagnosis. Acute onset of disease usually occurs from 2-10 days after exposure. Diagnosis of tularemia is difficult because signs and symptoms are nonspecific. The organism grows poorly on conventional media or is overgrown by normal flora. Direct Gram stains from ulcer fluids or sputums are usually not helpful.

Treatment. Tularemia is treated with intramuscular streptomycin for 10-14 days or gentamicin. Tetracycline and chloramphenicol are also used, but there are more relapses associated with these drugs. A new investigational drug was recently developed. [8,16,17]

Q fever

Q fever is caused by a rickettsia called Coxiella burnetii that usually infects sheep, cattle, and goats. Coxiella burnetii is extremely infective via the aerosol route. As few as 1-10 organisms can produce clinical disease when inhaled by a human. The incubation period for this disease is 10-20 days, after which the illness is usually self-limiting--lasting from 2 days to 2 weeks.

Diagnosis. The disease usually presents with headache, myalgia, and fatigue. About half of the patients develop pneumonia, but only 25% of those patients have a productive cough. About one-third of the patients have an elevated WBC, and most patients have an elevated ALT and AST.

Treatment. Tetracycline or doxycycline treatment will shorten the length of the illness, and the fever will disappear after 2 days of antibiotic treatment. A vaccine is available and provides at least 5 years of immunity against Q fever. Prophylaxis with doxycycline or tetracycline can prevent the disease if given 8-12 days after exposure and continued for 10 days. [8,16,17]

Venezuelan equine encephalitis

Venezuelan equine encephalitis (VEE) is caused by an alphavirus of the same name. This virus usually affects horses, mules, and donkeys and is usually carried by mosquitoes. Wet and dry forms are stable and can be released by aerosol or through water and food contamination. The virus can be inactivated with heat and disinfectants.

This virus causes an inflammation of the meninges and the brain, with fatality occurring in less than 1% of infected patients. The disease is usually acute and short-lived. Recovery from this disease produces lifelong immunity. The incubation period is usually 1-5 days before the onset of symptoms.

Diagnosis. Symptoms include malaise, fever, rigors, severe headache, photophobia, and myalgia of the legs and lower back. Secondary symptoms include nausea, vomiting, diarrhea, cough, and sore throat. The WBC differential shows leukopenia and lymphopenia. CSF may contain as many as 1,000 leukocytes/[mm.sup.3] and an elevated protein level. Serological tests such as IgM ELISA, IFA, and complement-fixation tests are available for this virus.

Treatment. Treatment of the symptoms is the only relief for patients infected with this virus. Recovery usually takes 1-2 weeks. There is no commercially available vaccine. [8,16,17]

Viral hemorrhagic fevers

This group of diseases is caused by RNA viruses from the Filoviridae (Ebola and Marburg), Arenaviridae (Lassa fever, Argentine and Bolivian hemorrhagic fever), and Bunyaviridae (Hantavirus, Congo-Crimean hemorrhagic fever, Rift Valley fever, and Yellow fever) families; the Dengue hemorrhagic fever virus; and others (see Table 1). Thankfully, aerosol biological weapons do not exist for some of these viruses, but the symptoms may confuse physicians treating infected people.

Viral hemorrhagic fevers target the vascular system and cause changes in vascular permeability, which then leads to microvascular damage. The initial symptoms include fever, myalgia, mild hypotension, flushing, and petechiae. These symptoms quickly evolve to shock with generalized mucous membrane hemorrhage. Renal failure accompanies the cardiovascular decline, and mortality can be 5-20% or higher. The fatality rates for Ebola are 50-90%.

Diagnosis. A detailed history is important because many of these viral hemorrhagic fevers are spread by mosquitoes or other arthropod vectors. Therefore, if a patient has visited a geographic location where the disease is endemic, a terrorist attack can probably be ruled out. When large numbers of cases are diagnosed in a nonendemic area, however, a biological attack should be suspected. A viral hemorrhagic fever should not be ruled out if the patient presents with hypotension, petechiae, and flushing of the face and chest. Other diseases that may be confused with viral hemorrhagic fevers include typhoid fever, rickettsial disease, relapsing fever, and leptospiral disease. Diseases that lead to DIC such as leukemias, lupus erythromatosus, idiopathic or thrombotic thrombocytopenic purpura, or hemolytic ureniic syndrome can also be confused with viral hemorrhagic fevers and must be ruled out.

Laboratory results include thrombocytopenia (except Lassa), leukopenia (except Lassa, hantaviral, and severe Crimean-Congo hemorrhagic fever), and proteinuria and/or hematuria (found in Argentine hemorrhagic fever, Bolivian hemorrhagic fever, and hantaviral infections). Serological tests for antibodies to Lassa, Argentine hemorrhagic fever, Rift Valley fever, Crimean-Congo hemorrhagic fever, yellow fever, and hantaviral disease may also be used to confirm viral hemorrhagic fevers. These viruses all require biosafety level 4 containment facilities.

Treatment. Supportive therapy is given to patients with viral hemorrhagic fevers. If DIC is present, heparin therapy should be given. Dengue and hantaviral infections should be managed differently than the rest of the viral hemorrhagic fevers because of the severe consequences of Dengue fever and the renal involvement of hantaviral infections. The antiviral drug ribavirin can reduce mortality in Lassa fever. Dengue fever, Yellow fever, Ebola, and Marburg fever are not responsive to ribavirin therapy. [8,6,7]

Botulinum toxin

Clostridium botulinum produces 7 neurotoxins, types A through G. All neurotoxins produce symptoms of botulism. These toxins are considered some of the most toxic substances in the world. (The botulinum toxins are 100,000 times more toxic than sarin nerve gas.) The toxins can be delivered as an aerosol, and people who inhale the toxins will become ill with symptoms of botulism. The toxins can produce paralysis in infected persons because they bind to the presynaptic nerve terminal at neuromuscular junctions and prevent release of acetyicholine and ultimately, neurotransmission.

Diagnosis. Patients can become ill in as little as one day after inhaling the toxins. The initial symptoms include blurred vision, diplopia, photophobia, dysarthria, dysphagia, and dysphonia. Next, skeletal muscles are affected, which causes a symmetrical, descending, progressive weakness that can result in respiratory failure. Patients may also experience dry and crusted mucous membranes--especially in the mouth--and can experience difficulty speaking and lose their gag reflex.

If many patients present with no fever, but exhibit a descending paralysis, botulism should be expected. This condition can be confused with Guillain-Barre syndrome, myasthenia gravis, or tick paralysis. Laboratory testing is not helpful in diagnosing this condition.

Treatment. Antitoxin is available from the CDC, but because it is equine-based, side effects may include anaphylaxis and serum sickness from the horse proteins. A toxoid made from Clostridium botulinum toxin types A, B, C, D, and E has been used on groups at high risk for inhalation of botulinum toxins. The toxoid induces antitoxin production that will protect against the adverse effects of the toxins. [8,6,7]

Staphylococcal enterotoxin B

Staphylococcal enterotoxin B is a pyrogenic toxin that is produced by Staphylococcus aureus and that causes food poisoning. In bioterrorism, this toxin would probably be introduced using an aerosol. It produces a different disease when inhaled as compared with ingestion. Although it would not cause high mortality if used in an attack, it would cause a great number of people to be incapacitated and to require medical treatment. This toxin causes disease by activating a nonspecific immune response from a person, and it induces T-cell proliferation that leads to increased interleukin-2 production, which produces severe nausea and vomiting. Inhalation of the toxin also causes production of tumor necrosis factor and interferon gamma.

Diagnosis. Symptoms begin 3-12 hours after inhalation. There is a sudden onset of fever, headache, chills, myalgias, and a nonproductive cough. Soon after the initial symptoms, nausea, vomiting, and diarrhea occur and lead to heavy fluid loss. The fever ranges from 103 to 106[degrees]F and may last up to 5 days. Severe cases can develop pulmonary edema and acute respiratory distress syndrome.

Laboratory tests are not useful in diagnosing staphylococcal enterotoxin B inhalation, so it must be diagnosed clinically and epidemiologically. This disease presentation is similar to anthrax, tularemia, Q fever, plague, adenovirus, influenzae, and mycoplasma infections. Epidemiologists should be concerned about a bioterrorist attack if large numbers of patients present with the initial symptoms in a short period of time.

Treatment. Treatment is limited to supportive care, no antitoxin or other specific treatment is available. There is also no vaccine on the market to prevent reaction to this toxin. [8,16,17]

Ricin

Ricin is a toxin that is derived from castor beans. After the oil is extracted from the beans, the waste product contains about 5% ricin. Ricin is easy and inexpensive to produce in large quantities and is toxic to cells because it inhibits protein synthesis. The amount of ricin inhaled determines the severity of disease produced. Sublethal doses will produce fever, chest tightness, cough, dyspnea, nausea, and arthralgias within 4-8 hours of exposure. If enough toxin is inhaled, severe damage occurs in the airways and alveoli, causing death in approximately 18-72 hours. If ricin is ingested, gastrointestinal hemorrhage and hepatic, splenic, and renal necrosis occurs.

Diagnosis. Because of the nonspecific symptoms, an aerosol attack would be diagnosed by clinical and epidemiological data. Ricin is immunogenic, so survivors will have antibody protection for a short period of time.

Treatment. Treatment is only supportive because no antitoxin is available. There is also no vaccine available, but gas masks can prevent inhalation of the toxin. [8,16,17]

T-2 toxins

Filamentous fungi, especially those of the Fusarium, Myrotecium, Trichoderma, and Stachybotrys genera, produce trichothecene mycotoxins. These mycotoxins are extremely heat stable and resist ultraviolet light inactivation. If the mycotoxins are ingested, they produce a lethal illness called alimentary toxic aleukia (ATA) with the following initial symptoms: abdominal pain, diarrhea, vomiting, and prostration. These progress into fever, chills, myalgias, and bone marrow depression causing granulocytopenia and sepsis. If the patient survives these initial stages, the next set of symptoms are painful pharyngeal/laryngeal ulceration and diffuse bleeding into the skin, bloody diarrhea, hematuria, hematemesis, epistaxis, and vaginal bleeding. Some believe that these mycotoxins were used in Southeast Asia and Afghanistan in the form of "yellow rain" to produce casualties and deaths among the civilian populations. [8]

Mycotoxins can enter the body through the skin, stomach, or lungs and inhibit protein and nucleic acid synthesis. The first cells attacked are the rapidly dividing cells such as bone marrow, skin, mucosal epithelia, and germ cells. When skin is exposed to mycotoxins, burning, redness, blistering, and skin necrosis occur. When nasal mucosa is exposed to mycotoxins, this produces nasal pain, sneezing, rhinorrhea, dyspnea, wheezing, cough, and blood tinged saliva and sputum. Exposure of the eyes to mycotoxins produces eye pain, tearing, redness, and blurred vision. Once the mycotoxins enter the system, symptoms include weakness, prostration, dizziness, ataxia, loss of coordination, and in fatal cases, tachycardia, hypothermia, and hypotension. Death may occur in minutes, hours, or days.

Diagnosis. Laboratory tests are not available to diagnosis exposure to T-2 toxins. Toxic exposure can only be confirmed when tissue samples taken at autopsy are tested using a mass spectrometer.

Treatment. Again, exposure can be prevented with a gas mask and protective chemical gear. All treatment is supportive because no antitoxins or antifungals are presently available. [8,16,17]

Bioterrorism readiness plan

In 1999, the Association of Professionals in Infection Control and Epidemiology's Bioterrorism Task Force and the CDC's Hospital Infections Program Bioterrorism Working Group collaborated to produce a reference document to help healthcare facilities develop readiness plans in case a bioterrorism attack occurs in their city. [18] This plan includes reporting requirements; detection of outbreaks; infection control practices for patient management; postexposure management; patient, visitor, and public information; and laboratory support and confirmation. When these agencies developed this initial template, only 4 diseases were considered potential biological agents: anthrax, botulinum toxin, plague, and smallpox. More recently, other agents have been added to the list by USAMRIID.

Reporting requirements. Because healthcare facilities will probably be the first to recognize a bioterrorism attack, they will be responsible for notifying local infection control personnel, administrators, public health facilities, FBI field offices, local police, the CDC, and emergency medical services. Every facility should have these phone numbers available.

Detection of outbreaks. Terrorist attacks using biological agents can occur as announced or unannounced events. Healthcare facilities must be able to deal effectively with both types of attacks. To do this, facilities should determine syndrome-based criteria and epidemiological features of the outbreak to determine if terrorists have used a biological agent.

Infection control practices for patient management. Healthcare facilities must determine what isolation procedures should be used for individual biological agents because some agents are not transmitted via person-to-person contact and others are. Patient placement and patient transport is important to avoid both exposure of the infected patient to other agents and exposure of unaffected patients to toxic agents. In addition, cleaning, disinfection, and sterilization of equipment and the environment are very important to prevent the spread of the agent to other healthy patients. Postexposure plans should include discharge management of patients to ensure reinfection does not occur. Clinical laboratories and pathology departments need to be informed of suspected agents so that extra biosafety precautions can be taken with bodies and bodily substances after postmortem examinations.

Postexposure management. Patients and the environment need to be decontaminated after release of a biological agent. People who were exposed or thought to have been exposed should be (1) given medication to prevent onset of the disease and its symptoms and (2) immunized against a particular biological agent. Healthcare facilities must develop plans for triage and management of large-scale exposure and suspected exposures without shutting down the hospital. Masses of people can overwhelm healthcare facilities, so this possibility should be dealt with up-front so that plans can be made to keep the system flowing. Finally, psychological aspects of bioterrorism must be taken into account and planned for. Mental health professionals need to be an integral patt of the response team.

Patient, visitor, and public information. All 3 audiences must be kept adequately informed to prevent widespread panic. The information given must be clear, concise, and understandable. Fact sheets can be prepared ahead of time and distributed to interested parties. All lines of communication with the outside world need to be coordinated in advance so that misunderstanding and anxiety can be minimized.

Laboratory support and confirmation. Clinical microbiology laboratories routinely identify infectious agents that cause disease in humans and animals. Laboratories provide 80% of objective data used to make a diagnosis; and in a bioterrorism attack, providers will expect the laboratory to identify the bioterrorism agent and its antimicrobial susceptibility pattern. Bioterrorism agents used can be categorized as biosafety level 2 pathogens such as salmonella, biosafety level 3 pathogens such as Venezuelan equine encephalitis, or biosafety level 4 pathogens such as smallpox (see Table 2). Most clinical laboratories routinely identify biosafety level 2 pathogens, and larger laboratories may identify biosafety level 3 pathogens; but only 2 labs in the US have the capability to identify biosafety level 4 pathogens--the CDC and USAMRIID. If an attack with a biosafety level 4 agent occurred anywhere in the country, clinical laboratories would be unable to identify the agent.

The CDC, USAMRIID, and the Association for Public Health Laboratories identified the need for a laboratory network for responding to bioterrorism and emerging infectious diseases. [19] This network is being developed and would consist of hospital clinical laboratories and physician office laboratories (level A), commercial reference laboratories (level B), public health and military laboratories (level C), and CDC and USAMRIID (level D). Hospital clinical and physician office laboratories would be first-response labs because patients would seek medical care at local facilities as soon as they became ill. (After a covert bioterrorism attack; the disease incubation period could be as short as 1 day or as long as 1 month before victims became symptomatic.) This period of time between exposure and developing symptoms would increase the difficulty of identifying a bioterrorism attack. The level A labs would be responsible for ruling out bioterrorism agents, referring suspected agents to level C labs, and evaluati ng specimens from patients.

The responsibilities of level B labs would be to confirm laboratory specimens referred from level A labs, to isolate and identify bioterrorism agents, to train and educate level A lab personnel, and to test for antimicrobial susceptibility of isolates. If an agent of biological warfare was suspected, commercial reference labs would refer the specimen to level C labs (public health and military labs).

Level C labs would have particular expertise in working with particular organisms, and specimens would be referred to those labs specializing in the characterization or molecular fingerprinting of that organism. This would be necessary to compare and identify isolates from other suspected victims of bioterrorism. These labs would also be responsible for evaluating and distributing devices or new rapid identification methods for identifying biological agents.

Level D labs would be responsible for developing new rapid identification tests for bioterrorism agents, testing all agents for chimeras (genetically altered organism that may not be detectable by current methods), and for culturing and performing antimicrobial susceptibility tests on all biosafety level 3 and 4 bioterrorism agents.

This laboratory network would rely heavily on information technology to provide timely identification and antimicrobial susceptibility of bioterrorism agents. The current vision shows level C and D labs developing new methods and procedures, then passing these newly developed tests to the level A and B labs. A central Web-based repository would be available to laboratories through a secure Internet site. Level D labs would also develop algorithms to aid level A and B labs in ruling out and identifying bioterrorism agents. CDC and APHL envision 2 parallel networks (civilian and military) that can be cross-linked so that both can retrieve relevant data. [20]

Even though some experts do not anticipate bioterrorism attacks in the next 5 years, the medical community must expect the unexpected. Plans should be developed that have criteria for determining exposure to biological agents, triaging thousands of patients, reducing risk for both unexposed and infected patients, and keeping the public from panicking. As one looks at all the potential biological agents and the similarities between the syndromes produced, detecting and identifying biological agents is a monumental task. The civilian community can look to the military for some answers, but the military detection and identification techniques for biological agents are still infantile--if they exist. When bioterrorist attacks occur in the US, we must be prepared or pay dearly for a lesson learned.

Donna Leach is associate professor and chair of the Clinical Laboratory Science Department and Denny G. Ryman is assistant professor in the Clinical Laboratory Science Department at Winston-Salem State University, Winston-Salem, NC.

References

(1.) Alibek K. Biohazard. New York: Random House.

(2.) Seldon Z. Assessing the biological weapons threat. Business Executives for National Security Special Report. www.bus.org/pubs/bwc.html. Accessed July 17, 2000.

(3.) Carus SW. The threat of bioterrorism. From the National Defense University's Institute for National Strategic Studies, Strategic Forum. Sept 1997. www.ndu.edu/niss/strforum/forum 127.html. Accessed July 21, 2000.

(4.) Tucker JB. Historical Trends Related to Bioterrorism: An Empirical Analysis. Emerging and Infectious Diseases. Vol. 5, no. 4, July-August, 1999. www.cdc.gov/ncidod/eid/vol5no4/tucker.html. Accessed on April 5, 2000.

(5.) Anderson JH. Microbes and Mass Casualties: Defending America Against Bioterrorism, The Backgrounder. The Heritage Foundation, www.heritage.org/library/backgrounder/bgl182es.html. Accessed on August 17, 2000.

(6.) Zalinskas R. (20 October 1999). Assessing the Threat of Bioterrorism: Congressional Testimony by Raymond Zalinskas. Center for Nonproliferation Studies, Monteray Institute of International Studies, National Defense University.

(7.) MacKenzie D. (September 19, 1998). Bioarmageddon. New Scientist 2000, Online conference reports, www.newscientist.com/nsplus/insight/ bioterrorism/bioarmageddon.html. Accessed on 4/5/00.

(8.) US Army Medical Research Institute of Infection Diseases. Medical Management of Biological Casualties. September 1999. www.nbcmed.org/SiteContent/HomePage/What'sNew/MedManual/Sep99/Current /Handbook.html. Accessed on April 15, 2000.

(9.) Kupperman RH, Smith DM. Coping with biological terrorism. In: Roberts B, ed. Biological Weapons: Weapons of the Future? Washington, DC: Center for Strategic and International Studies; 1993.

(10.) Kozaryn L. (February 9, 2000). Biological Defenses on the Horizon. American Forces Information Service. www.defenselink.mil/news/Feb2000/n02092000_20002092.html. Accessed on 4/5/00.

(11.) Boyce N. Nowhere to hide. New Scientist, Online Conference Reports. www.newscientist.com/nsplus/insight/bioterrorism/nowhere.html. March 21, 1998.

(12.) Hutchinson R. Improving Local and State Agency Response to Terrorist Incidents Involving Biological Weapons. Response to Nunn-Lugar-Domenici Domestic Preparedness Program by Department of Defense. August 1, 2000. dp.sbccom.army.mil/fr/dp_bwirp_interim_planning_guide_download.html. Accessed on August 16, 2000.

(13.) CDC Strategic Planning Workgroup. Biological and chemical terrorism: Strategic plan for preparedness and response. MMWR. April 21, 2000;49(RR04);1-14.

(14.) "US Cities Prepare to Deal with Terror Attacks, But Drills Point to Weankess in Rescue Plans." Wall Street Journal. Monday, June 3, 1996: A16.

(15.) Wilson ML. Bioterrorism Q&A. Laboratory Medicine. 1999;30(9):568.

(16.) Zajtchuk R. Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Published by the Office of the Surgeon General, Department of the Army; 1997.

(17.) Murray PR, Baron EJ, Pfsllor MA, et al, eds. Manual of Clinical Microbiology. 6th ed. Washington, DC: ASM Press; 1995.

(18.) APIC Bioterrorism Task Force and CDC Hospital Infections Program Bioterroism Working Group. Bioterrorism Readiness Plan: A Template for Healthcare Facilities. April 13, 1999. www.cdc.gov/ncidod/hip/bio/13apr99APIC-CDCBioterrorism.PDF. Accessed on April 5, 2000.

(19.) Gilchrist MJR. A national laboratory network for bioterrorism: Evolving from a prototype network of laboratories performing routine surveillance. Military Medicine. 2000;165(supplement 2:001):28-31.

(20.) Ascker MS. A civilian-military virtual public health laboratory network. Military Medicine. 2000;165(supplement 2:001):1-4.

CDC: Our national resource for responding to biological attacks

If the unthinkable happens and an attack on the US with biological weapons occurs, an immediate call would be placed to the Centers for Disease Control and Prevention, which has set up an office to coordinate a national response to bioterrorist attacks. The next step would depend on whether the event was a chemical or a biological episode, said Elaine Gunter, Chief, NHANES Laboratory (National Health and Nutrition Examination Survey), CDC. "With biological events, it may be 2 weeks before you know what people are exposed to. They are going to trickle into doctors, county health offices, and hospitals. When a chemical event occurs, people are going to drop like flies. You know something has happened right away," she explained.

"Seven of us in this laboratory are medical technologists. Two of us would be dispatched within 2 hours to help first responders with specimen collection. We would look primarily for certain groups of chemicals, such as organophosphate nerve agents, agents used in riot control, or ricin. We developed a rapid toxic screen that enables us to identify these chemicals with a very small amount of blood or urine." Within 24 hours, 75 chemical agents can be identified through the use of various tests conducted on very high level instruments such as mass spectrometers that are capable of measuring down to parts per trillion, noted Gunter. "In another year, we hope to be able to measure 150 chemical agents within 48 hours." The rapid toxic screen answers 3 critical questions: Which agents were used? Who was exposed? How much exposure occurred? "We're not only looking for the exotic agents. We're looking for agents that are commonly available," she said.

In addition to helping collect blood and urine from victims, the team helps first responders package and ship samples to the CDC. They establish a "really strict chain of custody in accordance with the FBI's guidance because these are forensic specimens that will be used in a criminal trial. We have to be extremely careful," added Gunter.

The CDC's Chemical Terrorism Laboratory Network is composed of the laboratory at CDC and five state laboratories in New York, California, Virginia, Michigan, and New Mexico. CDC provides training, technical assistance, and proficiency testing for the state labs. "We bring them on board basically one method at a time. Most of these methods didn't exist 18 months ago."

On the biological side, the network is a complex one that goes from level A (the physician or county hospital) to level D (the CDC and US Army Medical Research Institute of Infectious Diseases). On the chemical side, the division of laboratory sciences at the CDC is the reference laboratory and has close ties to US Army Medical Institute of Chemical Warfare Agents. The states applied for CDC grants in five areas: preparedness and prevention, detection and surveillance, diagnosis and characterization of biological and chemical agents, response, and communication systems.

The CDC received $ 178 million in fiscal year 1999 to prepare against bioterrorism and to establish this network of biological and chemical labs to assist with measurement. (In addition, the CDC received $ 52 million to establish a pharmaceutical stockpile, which will ensure the availability of drugs, vaccines, prophylactic medicines, chemical antidotes, medical supplies, and equipment that will be needed to support a medical response to a terrorist incident.)

The CDC is holding regional meetings with all the state labs--in Philadelphia, Atlanta, St. Louis, Denver, and San Francisco. "We are telling them who we are, what the CDC's response plan is, and how we can help them so that this becomes a partnership," Gunter explained.

Not for commercial use. Solely to be used for the educational purposes of research and open discussion.

The Middle East
Published monthly. United Kingdom
June 1, 2001

Pg. 18 ; 0305-0734

A BIO-TERRORIST THREAT UNMASKED;
Statistical Data Included
Venter, Al

Terrorist activity is completely international, but within the Unites States a fear of rogue Middle Eastern states pervades. Libya, Iran and Iraq are constantly under the microscope in Washington, along with the activities of organisations such as Hizbullah, Hamas as well as operatives aligned to public enemy number one, Osama bin Laden. Recent reports which warn of the potential use of smallpox as a terrorist weapon have started alarm bells ringing. Al Venter reports from the US capital.

Smallpox is in the news again. An American specialist in biological warfare has highlighted its possible use as a weapon of mass destruction. The US government is taking the threat seriously.

Dr Jonathan B Tucker, director of the Chemical and Biological Weapons Nonproliferation Programme at the Monterey Institute of International Studies in California, recently completed a book about the eradication and possible return of smallpox. In Scourge: The Once and Future Threat of Smallpox -- to be published shortly in the US -- he notes that thanks to a world-wide vaccination campaign, smallpox was vanquished as a human disease more than two decades ago. Laboratory stocks of the virus continue to exist, however, and may have fallen into the hands of rogue states. These could include several Middle East countries such as Syria, Iran and Iraq. Obviously the disease is tailor-made for use by terrorists as a weapon of mass destruction.

Tucker highlights an accident in 1978 -- a year after smallpox was eradicated worldwide -- when smallpox virus escaped from a research laboratory at the University of Birmingham Medical School in Britain. A medical photographer working on the floor above became infected and later died. The disease also spread to the photographer's mother, who survived. It was only a matter of luck that a major smallpox outbreak in Birmingham did not result.

Because of fears that smallpox could be used as a terrorist weapon, Washington recently announced that it is pouring money into developing new drug treatments for the virus and is also expanding its supply of smallpox vaccine. Unconfirmed reports state that the special forces of some western nations are being innoculated against the disease.

In an exclusive interview with The Middle East, Dr Tucker said there are currently only about 7.5 million doses of smallpox vaccine in the US stockpile, yet epidemiologists believe that at least 40 million vaccine doses would be needed to contain an outbreak resulting from a bio-terrorist attack. In view of this shortfall, Washington recently launched a programme to bolster the US civilian vaccine supply.

Last September, the US Center for Disease Control (CDC) in Atlanta awarded a contract to the pharmaceutical company OraVax of Cambridge, Massachusetts (owned by Britain's Peptide Therapeutics) for 40 million doses of smallpox vaccine, with anticipated delivery of the first batches in 2004.

The most feared of all infectious diseases, smallpox was first described in ancient Egypt and gradually spread throughout the world. Over the centuries, it caused hundreds of millions of deaths. Smallpox killed rich and poor, royalty as well as commoners, and repeatedly changed the course of history.

Highly contagious, the smallpox virus is spread through the air, and only a few particles are needed to infect. After a two-week incubation period, a patient develops fever and severe aches and pains. Then red spots appear on the skin and swell into painful, pus-filled boils the size of peas. The more potent form of the disease, called variola major, killed about 30 per cent of its victims, and the survivors were disfigured with ugly scars.

More than 20 years ago, a worldwide vaccination campaign organised by the World Health Organisation (WHO) successfully eradicated the disease. The last natural outbreak of smallpox occurred in Somalia in 1977. Three years later, the WHO declared the disease extinct and urged all member-countries to halt routine vaccination because it entailed a significant risk of complications.

The eradication of smallpox was a remarkable public health achievement that, at least in theory, freed the world from a terrible scourge.

Even after smallpox was eliminated from nature, however, some countries retained laboratory stocks of the virus for research purposes. Although Soviet leaders had been the driving force behind the WHO smallpox eradication campaign, they cynically exploited the world's new vulnerability to the disease by turning it into a strategic weapon.

During the 1980s, the Soviet army mass-produced the smallpox virus as a biological weapon. Tons of the virus in liquid suspension were stored in refrigerated tanks; in wartime, the agent could have been loaded into aerial bombs and warheads targeted on US and Chinese cities.

Dr Ken Alibek, who served as first deputy director of Biopreparat, a major component of the Soviet biological weapons programme, revealed Moscow's mass-production of smallpox to western intelligence agencies after his defection to the United States in 1992. He also claimed stocks of smallpox virus had been distributed "to places in Russia beyond the known laboratories -- possibly where there were less effective security controls". Alibek added that while smallpox was an effective weapon, Soviet scientists had attempted to make it even more deadly by adding foreign genes from other viruses such as ebola.

Specialists at a Johns Hopkins University conference on bio-terrorism last year said that much of Dr Alibek's information had been confirmed by other sources.

Dr Kathleen Vogel, a scientist at Cornell University who toured biological warfare facilities in the former Soviet Union, told a recent meeting of the American Association for the Advancement of Science that she suspected secret stocks of smallpox virus were still being held at Russian military microbiology facilities outside the WHO-approved repository in Novosibirsk.

Dr Vogel reported that scientists formerly employed by the Soviet bio-warfare programme had been offered lucrative jobs in countries categorised by the US State Department as supporting international terrorism. She also expressed concern that samples of smallpox virus might have been sold to such rogue states.

Dr Joshua Lederberg, a Nobel laureate in biology who advises Washington on germ warfare, commented: "We have no idea what may have been retained, maliciously or inadvertently, in the laboratories of a hundred countries from the time that smallpox was a common disease." These would be the most likely sources of supply for potential bio-warfare terrorists, he added.

Because of the Soviet betrayal of the smallpox eradication campaign, the potential use of the virus as an agent of bio-warfare or bio-terrorism continues to worry western governments. The possibility that a nation could use smallpox as a terrorist weapon has serious long-term implications for the international community.

Since the smallpox virus no longer exists in nature, the only way terrorists could acquire seed cultures would be on the international black market. For this reason, Dr Tucker believes that smallpox would be an unlikely weapon for ordinary terrorist groups, but it might be obtained by state-sponsored operatives or by wealthy doomsday cults such as Aura Shinrikyo, which released sarin nerve agent on the Tokyo subway in 1995.

Once terrorists managed to acquire and produce the virus in liquid form, it would be a relatively easy matter to disseminate it with a small aerosol device in an enclosed space such as the London underground or the New York City subway.

Two weeks later, the first victims would come down with fever, aches, and other nonspecific symptoms before developing the distinctive pustular rash. By the time the first patients were diagnosed, they would have already infected the next wave of cases.

Professor Vincent Fiscetti, head of the Department of Bacterial Pathogenesis and Immunology at the Rockefeller University, has observed that in a mass-transport environment, there are people from all over the world. "It takes several days for the symptoms to show, by which time they will have carried it back to their own countries," he said.

Professor Fiscetti maintains that an even more effective delivery method would be to use a low-flying aircraft to disperse an aerosol of the virus over an international event like the Olympics, a World Cup football game or even those making the Haj to Mecca. Geographically small countries such as Israel and Jordan would be especially vulnerable.

One of the reasons international terrorists might be tempted to use smallpox as a weapon is that the United States stopped vaccinating its civilian population in 1972 and all other nations followed suit by the early 1980s. Since smallpox vaccination provides full immunity for only about 10 years, nearly the entire US population is now susceptible to infection. At greatest risk would be the 120 million or more Americans -- roughly 45 per cent of the population -- born since routine vaccination ceased.

Given this vulnerability, the CDC has warned that even a limited terrorist release of emergency and -- in the absence of sufficient stocks of the vaccine world-wide -- could potentially result in the return of smallpox as a global health threat.

In 1996, the WHO agreed to destroy all of the stocks of smallpox virus stored in two official repositories, at the CDC in Atlanta and the Vector laboratory near Novosibirsk, Russia.

Because nobody was certain that other countries did not retain undeclared samples of the virus, however, the US persuaded the WHO in 1999 to delay destruction of the official stocks for another three years in order to conduct more research on the virus and to develop anti-smallpox drugs.

Mike Hammer, a spokesman for the US National Security Council, said that because of escalating concern about the threat of bioterrorism with smallpox, Washington didn't want to take any chances.

The most immediate defensive move that western nations could take would be to build up their stocks of smallpox vaccine, which is made from a distinct, relatively harmless virus known as vaccinia. Considering the numbers of people at risk -- the current US population, alone, is roughly 285 million -- producing more vaccine will be a formidable task.

In addition to acquiring 40 million doses, the CDC plans to continually replenish the vaccine stockpile as specific lots expire, resulting in the production of a total of about 168 million doses by the year 2020. The old lots will be retained because the shelf life of the vaccine is almost unlimited when it is stored in sealed vials at sub-zero temperatures.

Because the smallpox vaccination is associated with a significant risk of complications, particularly in people with eczema or a suppressed immune system caused by HIV infection, pregnancy, or cancer chemotherapy, the CDC does not intend to start vaccinating people except in the unlikely event that an actual case of smallpox is confirmed.

U.S. Department of Defense
News Briefing
Tuesday, September 4, 2001

Presenter: Victoria Clarke, ASD(PA)

[...]

Q: A different topic. Can you describe in any way the current efforts of the United States to conduct research into biological weapons and what the purpose of that research might be, and whether it falls within the confines of the Chemical -- Biological Weapons Convention?

Clarke: Again, we've said pretty consistently that we're very concerned about the threat of offensive biological weapons, of the proliferation of materials and technology that could enhance the proliferation of chemical and biological warfare. And we are doing work in places. All of the work is consistent with U.S. treaty obligations. All of the work is thoroughly briefed and gone through a heavy consultation process, both interagency and the appropriate legal reviews and the appropriate congressional briefings.

Q: What is the purpose of that research?

Clarke: The purpose is to protect the men and women in uniform and the American people from what we see is a real and growing threat.

Q: Does this research involve creating any germs in the laboratory?

Clarke: There has been, about 1997, I think it was, and what you're talking about, is some reporting about developing a strain, a new strain of anthrax. In 1997 there was a journal called "Vaccine" which reported on a new or modified anthrax strain that the Russians may have been developing. We have a vaccine that works against most of the known -- all of the known anthrax strains. What we want to do is make sure we are prepared for any surprises, we're prepared for anything else that might happen that might be a threat. So about in the early part of this year, the DIA started to look into the feasibility, and doing all the legal consultations, doing all the appropriate interagency consultations to look into how we could develop that modified anthrax strain so we could test our vaccines against it and make sure we prevent against any surprises, and make sure we could protect the men and women in uniform from potential threats.

Q: Are you growing it?

Clarke: Right now there is no work going on on the modified anthrax strain. The director --

Q: Is it going to go forward?

Clarke: The director has made it very clear that he wants further interagency consultation work done -- that's with the DoD and other agencies; that he wants the legal reviews to continue; and further congressional briefings.

Q: Director of DIA?

Clarke: Yes.

Q: Well what work has been done prior? You say no work is being done now. Was this strain actually developed prior to today?

Clarke: In the United States? No.

Q: By the U.S. government --

Clarke: No.

Q: -- it wasn't?

Clarke: Right.

Q: Was it worked with? Did you get a hold of agent? Were there other bio-agents that were created for these programs?

Clarke: No.

Q: No bio-agent of any kind was created for these programs?

Clarke: For this particular program that we're talking about, which is this modified anthrax strain that was reported on in 1997, I believe it was, in this magazine "Vaccine," we have had consultations with the Russians about this, we have had cooperative efforts with the Russians on biological warfare in the past. But on this particular strain, no work has been done.

Q: And the U.S. had asked for a sample of the Russian and that was not provided; is that correct?

Clarke: To date, it has not been provided. And I've asked, I don't yet have the answer; I know as early as '97 we started talking to them about providing a strain so our folks could take a look at it and test the vaccine and see what we can do to prepare against those sorts of threats.

Q: The U.S. then didn't attempt to simulate that vaccine or create its own version of -- not of the vaccine, but of the agent, rather?

Clarke: No, that's what I was trying to say. Earlier this year, the DIA started to look into what it would take to get the legal approvals, to get the interagency coordination, to do the congressional briefings, to look into developing that strain so they could test vaccines and they could see what we have to do to make sure we're protected against it.

Q: That appears to be the path that you're now headed down, is doing that interagency process, making sure it is legal, and then going ahead and developing or growing this strain?

Clarke: Correct.

Q: That is? Okay.

And secondly, on the issue of making bomblets, which are some of the pieces of technology that other countries have done to dispense biological weapons, has the United States made these small bomblets for experimenting or any other reason?

Clarke: That comes under the Clear Vision program, which is a CIA project, so you should direct your questions over there.

Yes. Second row.

Q: In the -- you say the Russians haven't provided samples of this strain of anthrax. Have they provided notes or research or anything? How would we know that we're going to get the same strain that they came up with?

Clarke: You know, that we'll have to get back to you with some information. I just know there's been ongoing work with them in a cooperative nature on other elements when it comes to biological warfare. There's been a fair amount of communication lab to lab, if you will. But I don't know about all those aspects of -- [Update: the Department of Defense Cooperative Threat Reduction Program is funding a collaborative research project on anthrax monitoring with the State Research Center for Applied Microbiology in Obolensk, Russia. In August 2001 the State Research Center applied to the Russian Export Control Commission for a license to transfer the anthrax strain to the U.S. Centers for Disease Control. The application is currently pending a decision of the Russian Export Control Commission, and the U.S. government will seek Russian approval of the export license.]

Q: To the best of your knowledge, has the United States developed other strains of biological warfare agents in an effort to study them, strains of basically banned biological agents?

Clarke: I'll have to take that question. [Update: no, we do not develop biological weapons within the DOD.]

Q: Do the Russians acknowledge that they have, in fact, produced this hybrid strain of anthrax?

Clarke: Not to my knowledge.

Yes.

Q: New subject?

Q: Can we please stick on this subject?

Clarke: I'm sorry. How about Pam, and then back to you?

Q: So far, what is the legal determination with regard to the Bio Weapons Convention? Does DIA think they're going to be able to push ahead with this with no problem?

Clarke: We're compliant.

Q: This -- right now you're compliant because you haven't done it yet. But if you do it, will --

Clarke: We're compliant, and the legal reviews that have been done to date indicate that the work would be compliant. The Biological Weapons Convention allows you to do work that is purely defensive in nature. It allows you to have small quantities of a known agent, limited quantities of an agent if you want to study it for the purpose of protecting people against that threat.

Q: And is -- does the United States consider what Russia did compliant with the Bio Weapons Convention?

Clarke: You know, we have, as I said at the start of this questioning, we have concerns about the spread of biological and chemical warfare-enabling technology whatever the source and whoever is engaged in those activities. We have raised these concerns about chemical and biological warfare with the Russians, and we will continue to do so.

Q: Victoria, in the New York Times article today, according to the Times, the Times and ABC News were given a tour of a germ warfare laboratory in Nevada. Can you explain what the purpose -- what that facility does and what the purpose of it is?

Clarke: The facility, the Battelle facility of one that looks at -- I'm sorry, it's not the Battelle facility, it's the DTRA facility. And they are looking at signatures -- and I'm clearly going to get beyond my level of knowledge here -- but looking at signatures which indicate biological activity. They're using commercially available equipment, using commercially available organisms.

Q: And did -- are there any germs or biological agents produced at that facility?

Clarke: You know, that -- I'm going to have to refer you to DTRA. But on this particular project that was referred to in the New York Times, again, they were using commercially available equipment and commercially available organisms to test again the signatures, which is your ability to -- the level of activity -- not the level, but the activities of organisms.

Q: Is that for detection purposes?

Clarke: I believe so.

Yes?

Q: What's the rationale for having kept this work a secret up to now?

Clarke: Which work are you referring to?

Q: The research that we've been talking about, these various projects --

Clarke: Well, the DIA, for instance, doing this work, is trying to protect us and protect the men and women in uniform against threats of chemical and biological warfare. There are certain countries that we know are trying to do very bad things out there. The less information we give them about it, the better. Intelligence activities tend to remain secret.

Q: This is going to sound a little cynical, but let me just ask, on behalf of the public, how can the American public be assured that as the United States government conducts this kind of research, which is aimed at protection, that in the process they don't -- they're not also at the same time developing some offensive capability or creating some new strain of dangerous bacterial agent?

Clarke: Well, for instance -- and I think we can provide you with a chronology of the activities that have to do with this modified anthrax strain -- the Jefferson project, as it's referred to. And you look at this -- there was a long litany of interagency coordination, legal reviews, congressional briefings, all of which are obviously to ensure the appropriate, you know, coordination. It's also to make sure that all the appropriate steps are taken to make sure we are compliant. This program's undergone serious, serious scrutiny by a number of people. We are compliant, and we will remain so. And the BWC does allow you to do these things, as Project Jefferson has done.

Q: Is it safe to say that -- as you said here, that the United States intends -- intends -- to go ahead and develop this strain of anthrax, unless something -- retain the interagency process, but you made pretty clear the United States feels that it would be legal, as of now, to do so, and you fully intend to do it?

Clarke: Yeah. And let me repeat, again, we take the threat of the spread of biological and chemical warfare very, very seriously. We have an obligation -- and it's an important obligation -- to make sure we protect, first and foremost, the men and women in uniform against those threats. There's absolutely an obligation and responsibility that we do so. So with all the appropriate legal reviews, with all the appropriate interagency coordination and congressional briefing, we plan to proceed.

Q: Just to be clear, we'd be talking about in this instance a minute quantity of bacterial agent, or how would you characterize how much of this anthrax variant should be produced?

Clarke: You know, the question I asked before I came down here, and gotten the answer back, was to actually define that a little more clearly. But the BWC does make clear "small, limited quantities" of a known agent. And I'll try to get a better definition of that for you.

Yes?

Q: Was the desire to maintain the confidentiality and details of these programs related in any way to the administration's decision not to participate in developing a verification and on-site inspection protocol for BWC?

Clarke: Absolutely not. I mean, remember, we are signatories to the Biological Weapons Convention. This administration has made clear one of its priorities is to work against the threat of biological warfare. That is one of our top priorities. Concerns with the protocol had to do, one, it couldn't really do what some said it might be able to do; two, the information that would be revealed about our biodefense capabilities, as well as confidential business information.

But I dare say almost every meeting of every high-level administration official over the last several months, as we've met with friends and allies on a variety of issues, this issue has been put on the table and said this is a concern; we want to do everything we can together around the world to reduce this threat.

Q: Nevertheless, the verification protocol would have allowed demand inspections by any party to the treaty. And had any party demanded inspection rights to these projects, the United States would have been obliged to provide those inspections.

Clarke: The protocol has lots of problems recognized by lots of people other than us. Foremost among them, it would make it very hard to do biodefense. It would make it very clear that some confidential commercial business information would be revealed. But again, I'd try to put the emphasis on what is really important, which is our commitment to the Biological Weapons Convention and the fact that we have made this issue and the priority of reducing the threat of chemical and biological warfare right front and center for this administration.

Q: Is it the intention of this administration to keep this kind of research as secret as the last administration did? Or is it the intention of this administration to be more forthcoming, to explain to the public what you are doing so there will be no misunderstandings about what the U.S. is doing behind closed doors?

Clarke: Let me clear up one thing and then come back.

No biological agents were produced, only simulants, as part of the research and the study in Nevada. So there were no biological agents used there, they were just simulants. I hope that clears that up.

And, I'm sorry, just do it one more time quickly.

Q: Is it the intention of this administration to continue the very extreme levels of secrecy surrounding all of these projects, which the administration says are benign and within the purview of the various conventions, or is it the intention of this administration, as has been indicated in a newspaper article today, to keep it even more secret than the previous administration?

Clarke: Well, I believe the intention will be to keep that information secret that we think by not doing so would have serious national security concerns. Giving those who have hostile intent information about what we can do to protect against the threats they might be carrying out against us is not a good thing.

Q: Does the revelation of these three projects threaten the United States?

Clarke: I feel pretty confident. You know, I've looked into this pretty hard for the last couple of days, and I feel pretty confident with the way this program is being run, the way it is being executed, the way it's being briefed throughout the interagency process and getting the appropriate legal consultations and doing the correct and appropriate congressional consultations, I feel confident that we're on a good path. And again, I go back to what I think is most important: the threat is real, it is growing, and it is the responsibility of the country, of the United States, the United States military and this administration to take steps to protect us against it.

Q: Let me try it again. Does the disclosure of these three projects threaten the United States? In other words, in the future, if the disclosure of this doesn't threaten the United States and letting the public know what you're doing doesn't threaten the United States, why not continue to follow that path in the months and years ahead? Or does this disclosure threaten the United States? Has it done harm?

Clarke: I don't think there is a level of detail that has been revealed that has done any harm to the program.

Q: So one might conclude then that it's okay to talk about this and other projects which are currently classified as secret or top secret. Or does the press have to rule it out?

Clarke: It's hard -- no, it's hard for me to make a blanket statement about all things going forward. But I will say this: if it's good and important that people know something about the level and the nature of the threat, absolutely. Is it good and important that people know what this administration is trying to do to protect them and their friends and colleagues and family members in uniform? Absolutely. But I just -- I can't help you on a blanket statement going forward.

Yes, sir.

Q: Another topic?

Q: One more.

Clarke: I'm sorry, one more.

Q: Just to pick up on the thread of Jack's question, do the scientists who are involved in this research, are they involved in any exchange programs with foreign counterparts, much like scientists at Los Alamos, where they might be susceptible to, you know, espionage or something like that? Do they come into contact with any of their counterparts overseas?

Clarke: There is cooperative work, yes.

Q: With which countries?

Clarke: You know, I'll have to take that question.

Q: But -- but their activities are monitored --

Clarke: (Inaudible due to cross talk) -- but they're -- yes, there are cooperative activities underway.

Q: And on the same subject, was the very existence of these programs classified as secret or top secret?

Clarke: What -- I'm sorry, what do you mean?

Q: Was the fact that there was work going on in this area classified as top secret? Was the name of these -- were the names of these projects classified? Were these things really kept so secret, or is it the details of what's going on in these projects that was categorized as secret or top secret?

Clarke: Well, I can speak to the Jefferson project, which has been going on since 1997. And the Jefferson project covers a variety of issues in terms of preventing surprise on biological and chemical warfare. They do the work such as we're talking about, or may do the work such as we're talking about on the modified anthrax strain. They study literature. They consult with others. The Jefferson project, for instance, is one that has been known. Now, the level of detail in some of these projects has not.

Q: So the existence of these -- of this project, at least, was not classified.

Clarke: The Jefferson project. That's correct.

Q: Right. But the details of the work that was going on under that project may have been classified.

Clarke: Yes.

Q: And you're not sure when it comes to the other projects.

Clarke: Right.

Q: Okay.

Clarke: If you want, we can get a more detailed list of the kinds of work that they do, because it's pretty extensive. And again, it's a broad range of work designed to prevent surprise and make sure we have the capabilities we need to protect us.

[...]

Source: Defenselink

Thanks for the nunya. Here's another one. Hey poohbah, you'll love this one. It has lots of references from the Army.

Not for commercial use. Solely to be used for the educational purposes of research and open discussion.

Inhalational anthrax: Threat, clinical presentation, and treatment

Journal of the American Academy of Nurse Practitioners
Vol. 13, Issue 4, p. 164
Apr 2001
Leslie Henry
PURPOSE
To provide nurse practitioners (NPs) with a basic understanding of clinical presentation, transmission, diagnosis, pharmacological treatment, and post-exposure prophylaxis of inhalational anthrax.

DATA SOURCES
Selected research and clinical articles and government guidelines.

CONCLUSIONS
Inhalational anthrax has an incubation period of 1 to 6 days and is very difficult to diagnose early. The chest radiograph consistently reveals a widened mediastinum and pleural effusion without infiltrates. Mortality for inhalational anthrax is high, despite aggressive treatment after onset of symptoms. Delays in diagnosis contribute to the high mortality rate.

IMPLICATIONS FOR PRACTICE
The potential use of aerosolized anthrax as a biological warfare weapon has renewed interest in inhalational anthrax. Primary care providers are cornerstones in the defense against biological weapons because they may be the first to recognize and report suspicious cases.

KEY WORDS
Anthrax; bacillus anthracis; biological warfare; woolsorter's disease.

SCOPE OF THE PROBLEM
An infectious disease of antiquity, anthrax has caused outbreaks and numerous fatalities in humans and animals as far back as 1500 BC (Cieslak, & Eitzen, 1999; Pile, Malone, Eitzen, & Friedlander, 1998). Anthrax is caused by Bacillus anthracis (B. anthracis), a large gram-positive spore-forming rod. In spore form, B. anthracis can survive for decades in the environment (Cieslak, & Eitzen, 1999; Penn, & Klotz, 1997).
The potential use of aerosolized anthrax as a biological weapon has renewed interest in this infectious disease. Aerosolized anthrax is lethal in an unprotected population and remains stable and virulent during storage, making it a manageable weapon (Zilinskas, 1999). The United States (U. S.) developed anthrax in the 1950s and 1960s as an offensive biological weapon before terminating its program in 1972 (Franz et al, 1997). Iraq admitted to conducting research on anthrax as a biological weapon during the Persian Gulf war (Franz et al., 1997). In response to this threat, U.S. troops have received the anthrax vaccine; however, the military's vaccination program remains controversial due to questions regarding the safety and efficacy of the vaccine (Shafazand, Doyle, Ruoss, Weinacker, & Raffin, 1999).
An epidemic of anthrax in Sverdlovsk, part of the former Soviet Union, occurred in 1979. Autopsies performed on 42 of the 66 patients who died documented inhalational anthrax. The possible source of the exposure was an accidental release of anthrax from a nearby military facility (Ibrahim, Brown, Wright, & Rotschafer, 1999; Pile et al, 1998; Penn, & Klotz, 1997).
Several bioterrorist threats in the U. S. alleging exposure to anthrax occurred in 1998. Decontamination and prophylaxis therapy was initiated until the threats were proven to be hoaxes (Centers for Disease Control and Prevention [CDC], 1999). As a result of these threats, the CDC developed recommendations for post-exposure prophylaxis and biological warfare response guidelines.
It is important for primary care nurse practitioners (NPs) and physicians to become familiar with anthrax ("Reporting of cluster," 2000). Primary care providers are cornerstones in the defense against biological weapons because they may be the first to recognize and report potential cases (Cieslak, & Eitzen, 1999). In the event of a covert or hidden release of anthrax, health care providers will be the front-line responders in the U. S. (Dixon, Meselson, Guillemin, & Hanna, 1999; "Reporting of cluster," 2000).
This article reviews the pathophysiology, clinical presentation, diagnosis, and treatment of inhalation anthrax and discusses vaccination and post-exposure prophylaxis. The purpose is to provide NPs with a basic understanding of inhalational anthrax, the deadliest form of the disease.
Anthrax most commonly occurs in nature in animals such as cattle, goats, and sheep (Pile et al, 1998). Humans become infected after close contact with infected animals or animal products. In humans, an infection with anthrax can take three forms: cutaneous, gastrointestinal, and inhalational.
Cutaneous anthrax is the most frequently occurring form of anthrax in humans, but it is rare in the U. S. A cut or abrasion of the skin is the usual site of entry for anthrax spores. A painless, pruritic papule will appear in 3 to 5 days. Cutaneous anthrax is recognized by the typical black eschar on the affected areas and is easily treated with antibiotics (Cieslak, & Eitzen, 1999; Dixon et al, 1999).
Gastrointestinal anthrax is usually caused by consuming contaminated meat. Although this form has not been reported in the U. S., it can be fatal (Dixon et al, 1999). Death occurs from blood loss, intestinal perforation, and shock.
Inhalational anthrax is also known as woolsorter disease (Pile et al, 1998). Wool handlers inhale the B. anthracis spores during early processing of animal hides and become deathly ill (Franz et al., 1997). Robert Koch discovered anthrax in 1876, demonstrating for the first time the origin of a specific bacterial disease (Pile et al, 1998). John Bell recognized B. anthracis as the cause of woolsorter disease and established disinfection procedures that became the standard for the British woolen industry. In 1880, William Greenfield developed an anthrax immunization for livestock; subsequently, Louis Pasteur developed a live vaccine for anthrax. In 1881, Pasteur tested the heat-cured vaccine on sheep.
As a result of animal immunization, anthrax has been virtually eliminated as an occupational hazard of textile workers and meat packers in the U. S. (Cieslak, & Eitzen, 1999). However, anthrax remains a problem in Asia, Africa, South America, and southern Europe where animal vaccination programs are sporadic (Pile et al, 1998). The last fatal case of inhalational anthrax in the U. S.occurred in 1976 (Penn & Klotz, 1997).

PATHOPHYSIOLOGY
Inhalational anthrax begins after spores, less than 5 microns in size, enter the body and reach the alveolar spaces (Dixon et al, 1999). The spores are transported by pulmonary macrophages, an antiphagocytic capsule is produced, and germination occurs within the macrophage (Cieslak, & Eitzen, 1999; Dixon et al, 1999; Friedlander, 1999). Macrophages transport the spores to the mediastinal and tracheobronchial lymph nodes where the bacilli cause a hemorrhagic lymphadenitis by growing in regional lymph nodes.
The bacillus produces at least three proteins, known as edema factors (EF), lethal factor (LF), and protective antigen (PA), that interfere with host defenses (Cieslak, & Eitzen, 1999; Friedlander, 1999; Ibrahim et al, 1999). The proteins form toxins called edema toxin and lethal toxin. Edema toxin is formed from EF and PA and produces excessive fluid accumulation. Lethal toxin is formed from a combination of LF and PA and releases cytokines such as interleukin -1 and tumor necrosis factor (Cieslak, & Eitzen, 1999; Dixon et al, 1999; Ibrahim, et al, 1999; Shafazand et al, 1999).
Edema toxin and lethal toxin interfere with host defenses, causing necrosis of lymphatic tissue and the release of high numbers of bacilli into the blood and lymph, which in turn leads to toxemia, septicemia, and in some cases meningitis (Cieslak, & Eitzen, 1999; Dixon et al, 1999). The hemorrhagic lymphadenitis of the mediastinal and tracheobronchial lymph nodes causes a hemorrhagic mediastinitis, which is pathognomonic for inhalational anthrax (Shafazand et al, 1999). Hemorrhagic mediastinitis results in pulmonary lymphatic blockage and pulmonary edema (Dixon et al, 1999). The overwhelming pulmonary edema and septicemia cause death in approximately 1 to 7 days after exposure.

CLINICAL PRESENTATION
Inhalational anthrax has a reported incubation period of one to six days and is very difficult to diagnose early (Cieslak, & Eitzen, 1999). After incubation, inhalational anthrax is biphasic in nature (Shafazand et al, 1999). The first phase, lasting an average of four days, is a non-- specific flu-like syndrome presenting with low-grade fever, non-- productive cough, myalgia, headache, malaise, and possibly mild chest pain (Cieslak, & Eitzen, 1999; Dixon et al, 1999; Franz et al., 1997; Shafazand et al, 1999). This initial phase, or prodrome, may be followed by a period of one to three days of symptomatic improvement.
The second phase presents with an abrupt onset of acute respiratory distress. Fever, severe dyspnea, cyanosis, and shock mark the rapid deterioration (Cieslak, & Eitzen, 1999; Penn & Klotz, 1997). The enlarged mediastinal lymph nodes may partially compress the trachea and cause stridor (Shafazand et al, 1999). Auscultation of lung sounds may be remarkable for crackles and signs of pleural effusion. Diaphoresis is often present, resulting in hypotension and chills ("U.S.Army," 1996). A decreased level of consciousness and possible coma may be symptoms of meningitis, which occurs when an overwhelming bacterial load is present (Shafazand et al, 1999; Penn & Klotz, 1997; "U.S.Army," 1996). After onset of respiratory distress, shock followed by death occurs within 24 to 36 hours (Franz et al., 1997; "U.S.Army," 1996).

DIAGNOSIS
The chest radiograph consistently reveals a widened mediastinum and pleural effusion without infiltrates, which is a hallmark of inhalational anthrax (a typical chest radiograph can be viewed on-line at http://phil.cdc.gov/public/1118.htm). This widened mediastinum is a result of mediastinitis and pleural effusion and may be present as early as the second day following exposure (Dixon, et al, 1999; Cieslak, & Eitzen, 1999; Franz et al., 1997; Ibrahim, et al, 1999; Penn & Klotz, 1997; Pile et al, 1998; Shafazand et al, 1999; "U.S.Army", 1996).
Blood cultures and a Gram stain should be obtained. Grampositive bacilli can be detected during the illness in blood smears; spores are not found in blood samples. Bacillus anthracis cultured from blood confirms the diagnosis (Cieslak, & Eitzen, 1999; "U.S.Army", 1996). A nasal swab, or environmental sample, containing gram-positive B. anthracis supports a diagnosis of anthrax due to intentional release as in war or terrorist activity (Cieslak, & Eitzen, 1999). Detecting circulating antibodies against the toxins with the enzyme-linked immunosorbent assay (ELISA) can help to confirm the diagnosis (Franz et al., 1997; Ibrahim, et al, 1999).
A confirmed or suspected case of anthrax must be reported to the CDC and local health and law enforcement authorities immediately (CDC, 1999). "Although inhalation anthrax in man is usually fatal, prompt recognition of disease may improve outcome and allow for immunization/prophylaxis for other individuals who may have been exposed" (Penn, & Klotz, 1997, p. 29). Immediate reporting may also deter further terrorist activity.

TREATMENT
Management Mortality for inhalational anthrax is high, despite aggressive treatment after onset of symptoms. Delays in diagnosis contribute to the high mortality rate. The Sverdlovsk outbreak reported 11 survivors of inhalation anthrax, suggesting that aggressive management and early diagnosis may optimize survival (Shafazand et al, 1999). Support in an intensive care unit is necessary due to severe respiratory distress in the second phase. Standard universal precautions are adequate since human-to-human transmission of anthrax has not been reported (Cieslak, & Eitzen, 1999; CDC, 2000).
Pharmacological therapy. Penicillin G has historically been the drug of choice for treating inhalational anthrax (Cieslak, & Eitzen, 1999; Franz et al., 1997; "U.S. Army", 1996). The recommended dose is 2 million units of penicillin G intravenously (IV) every 2 hours. Penicillin is still recommended in cases where the susceptibility of the organism is known. Adding streptomycin 30 mg/kg intramuscularly (IM) every day has demonstrated a synergistic effect in animal studies (Franz et al., 1997; Ibrahim, et al, 1999).
The possibility of an antibiotic-resistant strain of B.anthracis has prompted experts to recommend ciprofloxacin as the drug of choice until drug sensitivity reports confirm the sensitivity of the organism to penicillin (Cieslak, & Eitzen, 1999; Ibrahim, et al, 1999). Ciprofloxacin was recently approved to reduce the incidence and progression of inhalational anthrax following exposure to aerosolized B.anthracis (Food and Drug Administration [FDA], 2000). Ciprofloxacin also provides the convenience of twice-daily dosing. It is recommended to initiate treatment at the earliest signs of disease with ciprofloxacin 400 mg, IV every 12 hours (Cieslak, & Eitzen, 1999; Franz et al., 1997). An alternative regimen starts with a 200mg dose of doxycycline IV, followed by 100 mg IV every 12 hours (Franz, et al., 1997; Dixon et al, 1999; "U.S.Army", 1996). A 30-day or longer course of antibiotics may help to maintain long-term protection (Ibrahim, et al, 1999). The FDA (2000) recommends ciprofloxacin be administered for a total of 60 days. Cieslak and Eitzen note that these recommendations are based on animal studies and in vitro data: "...no human clinical experience with these regimens exists" (p. 4, 1999).
In children, penicillin G 100,000-150,000 U/kg/day in divided doses every 4-6 hours is preferred (Dixon et al, 1999). The FDA has approved the use of ciprofloxacin in pediatric patients for inhalational anthrax. The recommended pediatric dose of ciprofloxacin for post-exposure inhalational anthrax is 15mg/kg orally twice a day or 10mg/kg IV twice a day (FDA, 2000). Penicillin may also be the drug of choice during pregnancy, although the life-threatening nature of a biologically altered strain of B. anthracis may warrant the use of ciprofloxacin, despite adverse indication, until drug sensitivity is confirmed (Shafazand et al, 1999; "U.S. Army," 1996).
Corticosteroid therapy should be started in cases of meningitis, massive edema, and toxemia. Possible choices include dexamethasone, prednisone, and hydrocortisone (Dixon et al, 1999; Ibrahim, et al, 1999).
Post-exposure prophylaxis. Individuals exposed to anthrax who do not display symptoms will not require support with intensive care or IV antibiotic regimens (Ibrahim, et al, 1999). Post-exposure prophylaxis should be started at the earliest opportunity with ciprofloxacin 500 mg orally every 12 hours or doxycycline 100 mg orally every 12 hours (Cieslak, & Eitzen, 1999; Ibrahim, et al, 1999; FDA, 2000). In the event of an anthrax threat, drug therapy can be delayed 24-48 hours until evidence of release is verified (Cieslak, & Eitzen, 1999). Post-exposure chemoprophylaxis should continue for 4 to 6 weeks until anthrax vaccination provides antibodies or exposure can be excluded (Dixon et al, 1999; CDC, 1999). According to recent recommendations (FDA, 2000), ciprofloxacin prophylaxis should be administered for a total of 60 days.
Fluoroquinolones are not usually recommended for children or during pregnancy due to the risk of arthropathy (Shafazand et al, 1999). However, the CDC (1999) recommends weighing the adverse effects of ciprofloxacin against the potential life-threatening effects of inhalational anthrax. The FDA (2000) has approved the use of ciprofloxacin for prophylaxis in children who have been exposed as a result of an intentional release of inhalational anthrax. The prophylactic pediatric dose of ciprofloxacin is 15 mg/kg orally twice a day or 10 mg/kg twice a day IV (FDA, 2000). The CDC recommends ciprofloxacin in children and pregnant women until sensitivity to penicillin is known. Amoxicillin 40 mg/kg/day orally in divided doses every 8 hours is the recommended prophylactic dose in children once susceptibily to penicillin is determined (CDC, 1999).
Vaccination. Vaccination after a biological incident is recommended, in conjunction with post-exposure chemoprophylaxis (CDC, 1999). The anthrax vaccine can be obtained from the CDC and should be administered in a series of three doses. The first 0.5ml subcutaneous injection should be given as soon as possible after confirmed exposure and repeated at 2 weeks and 4 weeks (CDC, 1999; Ibrahim, et al, 1999). This vaccine has not been evaluated for efficacy and safety in the elderly or children. The anthrax vaccines developed for animals should not be administered to humans (CDC, 2000). Patients should be closely monitored for early symptoms of anthrax during prophylaxis and after antibiotic therapy is discontinued. In animal studies, relapse after antibiotics are discontinued occurred in unvaccinated subjects (Penn, & Klotz, 1997).
Decontamination. Decontamination of people potentially exposed to a biological release of anthrax may be appropriate (CDC, 1999; Cieslak, & Eitzen, 1999). Clothing and personal effects should be removed and sealed in plastic bags; a shower with soap and water is necessary to complete decontamination procedures (CDC, 1999; Cieslak, & Eitzen, 1999). Environmental surfaces can be cleaned with a hypochlorite solution of one part bleach to 10 parts water after an investigation of the release has been completed.

PREVENTION
Active immunization by vaccination is the key to prevention of inhalational anthrax in high-risk populations (Friedlander, 1997; Ibrahim, et al, 1999). The FDA approved an anthrax vaccine in 1970 for human use in the U. S. The vaccine has been referred to as MDPH-PA or Michigan Department of Public Health Protective Antigen (Pile et al, 1998; Ibrahim, et al, 1999).
The vaccine should be stored at 2 to 8 degrees Celsius. The schedule for vaccination is 0.5 ml subcutaneously at 0, 2, and 4 weeks, followed by boosters of the same dose given at 6, 12 and 18 months. An annual booster is recommended in the event of continued exposure (Friedlander, 1997). High-risk populations, such as workers who could be exposed to animal products from countries that lack adequate anthrax control or individuals working with anthrax in a laboratory setting, should be vaccinated. United States military at risk for exposure to biological weapons in the Persian Gulf region received the vaccine (Friedlander, 1997).
Reported side effects of the vaccine are local reactions and rare systemic reactions. Local reactions occur in about 30% of vaccine recipients and include edema, warmth, erythema, pruritis, and tenderness with a small painless nodule at the injection site (Ibrahim, et al, 1999; Pile et al, 1998). The most severe local reaction noted is edema from the injection site to the elbow or forearm (Friedlander, 1997). Local reactions have been noted after the first injection which increase with subsequent injections and subside by the 6th and 7th injections, suggesting an allergic reaction (Ibrahim, et al, 1999). Systemic reactions are reported in less than 0.2% of vaccine recipients. Symptoms include mild myalgia, malaise, and headache, which may last from 1 to 2 days (Friedlander, 1997).
New vaccines are being researched and developed that would provide a less frequent dosing schedule. A cost-effective vaccine available for public protection may be developed in the near future (Ibrahim, et al, 1999).

CONCLUSION
The potential use of anthrax as a biological weapon has renewed interest in the clinical presentation and treatment of this infectious disease. Recognizing the clinical presentation, diagnosing, reporting, and treating casualties of biological warfare are developing responsibilities for the NP It is important for NPs to stay informed of developing technology aimed at prevention and protection against anthrax, and the potential of terrorist activity in metropolitan areas, port cities, military installations, and rural communities. Knowledge of local emergency and disaster plans is important for prompt and efficient response to an intentional or unintentional release of B. anthracis. Methods for procurement of antibiotics and vaccines in case of mass casualties must be part of the disaster plan. Disease reporting protocols for suspected and diagnosed infectious disease should be readily available. Despite the best efforts of NPs and other health care providers, the consequences of an intentional release of anthrax could result in a public health disaster. The knowledgeable and immediate response of NPs in the event of an intentional release of aerosolized anthrax will control public panic and minimize morbidity and mortality.

[Reference List]
Centers for Disease Control and Prevention (CDC). (1999). Bioterrorism alleging use of anthrax and interim guidelines for management-United States, 1998. MMWR Morbidity and Mortality Weekly Report, 48(4), 69-74.
Centers for Disease Control and Prevention. (2000). Anthrax - General informaton. Division of Bacterial and Mycotic Diseases, April 5. Retrieved October 10, 2000 from World Wide Web: http://www.cdc.gov/incidod/dbmd/diseaseinfo/anthrax-g.htm
Cieslak, T. J., & Eitzen, E. M. (1999). Clinical and epidemiologic principles of anthrax. Emerging Infectious Diseases, 5(4). Retrieved March 24, 2000 from World Wide Web: http://www.cdc.gov/ncidod/EID/vol5no4/cieslak.htm
Dixon, T. C., Meselson, M., Guillemin, J., & Hanna, R C. (1999). Anthrax. The New England Journal of Medicine, 341(11), 815-826.

Food and Drug Administration (2000, August 31). Approval of Cipro for use after exposure to inhalational anthrax. FDA Talk Paper. Rockville, MD: Author. Retrieved September 5, 2000 from the World Wide Web: http://www.fda.gov/bbs/topics/ANSWERS/ANS01030.html
Franz, D. R., Jahrling, R B., Friedlander, A. M., McClain D. J., Hoover, D. L., Bryne, W. R., Pavin, J. A., Christopher, G. W., & Eitzen, E. M. (1997). Clinical recognition and management of patients exposed to biological warfare agents. Journal of the American Medical Association, 278(5), 399-411.
Friedlander, A. M. (1997). Anthrax. In F. R. Sidell, E. T. Takafuji & D. R. Franz (Eds.), Medical aspect of chemical and biological warfare (467-478). Washington, DC; TMM publications. Retrieved May 7, 2000 from the World Wide Web: http://www.nbc-med.org
Friedlander, A. M. (1999). Clinical aspects, diagnosis and treatment of anthrax. Journal of Applied Microbiology, 87, 303.
Ibrahim, K. H., Brown, G., Wright, D. H., & Rotschafer, J. C. (1999). Bacillus anthracis: Medical issues of biologic warfare. Pharmacotherapy, 19(6), 690-701.
Penn, C. C., & Klotz, S. A. (1997). Anthrax pneumonia. Seminars in Respiratory Infections, 12(1), 28-30.

Pile, J. C., Malone, J. D., Eitzen, E. M., & Friedlander, A. M. (1998). Anthrax as a potential biological warfare agent. Archives of Internal Medicine, 158, 429434.
Reporting of cluster of cases with possible public health significance including those that suggest a possible chemical bioterrorist incident (2000). Maine Epi-Gram, March 2000, 2-3.
Shafazand, S., Doyle, R., Ruoss, S., Weinacker, A., & Raffin, T. A. (1999). Inhalational anthrax: Epidemiology, diagnosis and management. Chest, 116 (5), 1369-1376.
U. S. Army Medical Research Institute of Infectious Diseases. (1996). Medical management of biological casualties handbook, August 1996 (Second edition). Frederick, MD: Author. Retrieved April 27, 1998 from the World Wide Web: http://www.nbc-med.org/FMs/medman/index.htm
Zilinskas, R. A. (1999). Iraq's biological warfare program: The past as future? In J. Lederberg (Ed.), Biological weapons (137-158). Cambridge, MA: MIT.

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