Examples of Biological Warfare Agents (With Treatment) | Toxicology

Biological warfare (BW), also known as germ warfare, is the use of any pathogen (bacterium, virus or other disease-causing organism) or toxin found in nature, as a weapon of war. BW may be intended to kill, incapacitate or seriously impede an adversary. It may also be defined as the material or defense against such employment.

The creation and stockpiling of biological weapons (offensive BW) was outlawed by the 1972 Biological Weapons Convention (BWC), signed by over 100 countries. The rationale behind the agreement is to avoid the devastating impact of a successful biological attack which could conceivably result in thousands, possibly, even millions, of deaths and cause severe disruptions to societies and economies.

Oddly enough, the convention prohibits only creation and storage, but not usage, of these weapons. However, the consensus among military analysts is that, except in the context of bioterrorism, BW is of little military use. Many countries pursue “defensive BW” research (defensive or protective applications) which is not prohibited by the BWC.

Biological weapons are the most horrifying tools today. The Biological Weapons Convention (BWC) of 1975 instructs all signatories to forego any biological weapon program. They are relatively cheap, inconspicuous and anonymous. A small private airplane with 100 kilograms of anthrax can kill a million people on a day with moderate wind.

A short description of biological warfare agents is given below:

Example # 1. Anthrax:

Anthrax is a zoonotic disease caused by Bacillus anthraces. There are three types of this disease: cutaneous anthrax, inhalation anthrax, and gastrointestinal anthrax. About 95% of the human anthrax cases in the United States have been related to the former category.

Cutaneous anthrax develops when a bacterial organism from infected animal tissues becomes deposited under the skin. When a patient contracts cutaneous anthrax, he develops a small elevated lesion on his skin which becomes a skin ulcer, frequently surrounded by swelling or edema.

Inhalation anthrax develops when the bacterial organism is inhaled into the lungs. A progressive infection follows. Since inhalation anthrax is usually not diagnosed in time for treatment, the mortality rate in the United States is 90-100%. A biological attack with anthrax spores delivered by aerosol would cause inhalation anthrax, an extraordinarily rare form of the naturally occurring disease.

A lethal dose of anthrax is considered to be 10,000 spores; 80 percent of a population that inhaled such a dose would die. Less than one millionth of a gram is invariably fatal within five days to a week after exposure. According to an estimate by the U.S. Congress’s Office of Technology Assessment, 100 kilograms of anthrax, released from a low-flying aircraft over a large city on a clear, calm night, could kill one to three million people.

Vaccines are available against some forms of anthrax, but their efficacy against abnormally high concentrations of the bacteria is uncertain. A licensed, alum-precipitated preparation of purified B.anthracis protective antigen (PA) has been shown to be effective in preventing or significantly reducing the incidence of inhalation anthrax.

Example # 2. Botulism:

Botulism is caused by intoxication with any of the seven distinct neurotoxins produced by the bacillus, Clostridium botulinum. In humans, disease results from only four (A, B, E, and F) of those seven types of neurotoxins. The toxins are proteins with molecular weights of approximately 150,000, which bind to the presynaptic membrane of neurons at peripheral cholinergic synapses to prevent release of acetylcholine and block neurotransmission.

The blockade is most evident clinically in the cholinergic autonomic nervous system and at the neuromuscular junction. A biological attack with botulinum toxin delivered by aerosol would be expected to cause symptoms similar in most respects to those observed with food-borne botulism.

In pure form, the toxin is a white crystalline substance that is readily soluble in water, but decays rapidly in the open air. Symptoms of inhalation botulism may begin as early as 12-36 hours following exposure or as late as several days. Initial signs and symptoms include ptosis, generalized weakness, lassitude, and dizziness.

Diminished salivation with extreme dryness of the mouth and throat may cause complaints of a sore throat. Urinary retention or ileus may also occur. Motor symptoms usually are present early in the disease; cranial nerves are affected first with blurred vision, diplopia, ptosis, and photophobia.

Development of respiratory failure may be abrupt. Mucous membranes of the mouth may be dry and crusted. Neurological examination shows flaccid muscle weakness of the palate, tongue, larynx, respiratory muscles, and extremities. Deep tendon reflexes vary from intact to absent.

A Pentavalent toxoid of Clostridium botulinum types A, B, C, D, and E is available under IND status. This product has been administered to several thousand volunteers and occupationally at-risk workers and induces serum antitoxin levels that correspond to protective levels in experimental animal systems. The currently recommended schedule (0, 2, and 12 weeks, then a 1 year booster) induces solidly protective antitoxin levels in greater than 90 percent of those vaccinated after 1 year.

Example # 3. Brucellosis:

Brucellosis is a systemic zoonotic disease that, in humans, is caused by one of four species of bacteria: Brucella melitensis, B. abortus, B. suis, and B. canis; virulence for humans decreases somewhat in the order given. These bacteria are small gram-negative, aerobic, non-motile coccobacilli that grow within monocytes and macrophages. They reside quiescently in tissue and bone-marrow, and are extremely difficult to eradicate even with antibiotic therapy.

Their natural reservoir is domestic animals, such as goats, sheep, and camels (B. melitensis); cattle (B. abortus); and pigs (B. suis). Brucella canis is primarily a pathogen of dogs, and only occasionally causes disease in humans upon contact with an infected dog’s blood, semen, or placenta. Humans are infected when they ingest raw (unpasteurized), infected milk or meat, inhale contaminated aerosols, or have abraded skin or conjunctiva surfaces that come in contact with the bacteria.

Laboratory infections are quite common, but human-to- human transmission is rare and occurred through breastfeeding. Therefore, isolation of infected patients is not required. Brucella species long have been considered potential candidates for use in biological warfare.

The organisms are readily lyophilized, perhaps enhancing their infectivity. Under selected environmental conditions (for example, darkness, cool temperatures, high CO₂), persistence for up to 2 years has been documented. When used as a biological warfare agent, Brucellae would most likely be delivered by the aerosol route; the resulting infection would be expected to mimic natural disease.

The initial symptoms of brucellosis are usually nonspecific, and the differential diagnosis is therefore very broad and includes bacterial, viral, and mycoplasmal infections. The systemic symptoms of viral and mycoplasmal illnesses, however, are usually present for only a few days, while they persist for prolonged periods in brucellosis. Brucellosis may be indistinguishable clinically from the typhoidal form of tularemia or from typhoid fever itself.

The disease in humans is characterized by a multitude of somatic complaints, including fever, sweats, anorexia, fatigue, malaise, weight loss, and depression. Localized complications may involve the cardiovascular, gastrointestinal, genitourinary, hepatobiliary, osteoarticular, pulmonary and nervous systems. Without adequate and prompt antibiotic treatment, some patients develop a ‘chronic’ brucellosis syndrome with many features of the ‘chronic fatigue’ syndrome.

The recommended treatment is doxycycline (200 mg/day) plus rifampin (900 mg/day) for 6 weeks. Alternative effective treatment consists of doxycycline (200 mg/day) for 6 weeks plus streptomycin (1 gm/day) for 3 weeks. Trimethoprimsulfamethoxazole given for 4-6 weeks is less effective. In 5-10% of cases, there may be relapse or treatment failure. Laboratory infections with brucellosis are quite common, but there is no human-to-human transmission and isolation is not required.

Example # 4. Cholera:

Cholera is a diarrheal disease caused by Vibrio cholera, a short, curved, gram-negative bacillus. Humans acquire the disease by consuming water or food contaminated with the organism. The organism multiplies in the small intestine and secretes an enterotoxin that causes a secretory diarrhea.

When employed as a BW agent, cholera will most likely be used to contaminate water supplies. It is unlikely to be used in aerosol form. Without treatment, death may result from severe dehydration, hypovolemia and shock. Vomiting is often present early in the illness and may complicate oral replacement of fluid losses. There is little or no fever or abdominal pain.

Watery diarrhea can also be caused by enterotoxigenic E. coli, rotavirus or other viruses, noncholera Vibrios, or food poisoning due to ingestion of preformed toxins such as those of Clostridium perfringens, Bacillus cereus, or Staphylococcus aureus.

Treatment of cholera depends primarily on replacement of fluid and electrolyte losses. This is best accomplished using oral dehydration therapy with the World Health Organization solution (3.5 g NaCl, 2.5 g NaHCO₃, 1.5 g KCl and 20 g glucose per liter). Intravenous fluid replacement is occasionally needed when vomiting is severe, when the volume of stool output exceeds 7 liters/day, or when severe dehydration with shock has developed. Antibiotics will shorten the duration of diarrhea and thereby reduce fluid losses.

Improved oral cholera vaccines are presently being tested. One vaccine, which has been discontinued in the U.S., is a killed suspension of V. cholera provided about 50% protection that lasts for no more than 6 months. The initial dose is two injections given at least 1 week apart with booster doses every 6 months.

Example # 5. Gas Gangarene:

Clostridium perfringens is a common anaerobic bacterium associated with three distinct disease syndromes; gas gangrene or clostridial myonecrosis; enteritis necroticans (pig-bel); and perfringens food poisoning. Each of these syndromes has very specific requirements for delivering inocula of C. perfringens to specific sites to induce disease, and it is difficult to imagine a general scenario in which the spores or vegetative organisms could be used as a biological threat agent.

There are, however, at least 12 protein toxins elaborated, and one or more of these could be produced, concentrated, and used as a weapon. Waterborne disease is conceivable, but unlikely. The alpha toxin would be lethal by aerosol. This is a well characterized, highly toxic phospholipase C. Other toxins from the organism might be co-weaponized and enhance effectiveness. For example, the epsilon toxin is neurotoxic in laboratory animals.

Gas gangrene is a well-recognized, life-threatening emergency. Symptoms of the disease may be subtle before fulminant toxemia develops, and the diagnosis is often made at postmortem examination. The bacteria produce toxins that create the high mortality from clostridia myonecrosis, and which produce the characteristic intense pain out of proportion to the wound. Within hours, signs of systemic toxicity appear, including confusion, tachycardia, and sweating.

Most Clostridia species produce large amounts of CO₂ and hydrogen that cause intense swelling, hence the term “gas” gangrene, resulting in gas in the soft tissues and the emission of foul-smelling gas from the’ wound. Clinical features include necrosis, dark red serous fluid, and numerous gas filled vesicles.

The infection may progress up to 10 cm per hour, and early diagnosis and therapy are essential to prevent rapid progression to toxemia and death. Pulmonary findings might lead to confusion with staphylococcal enterotoxin B (SEB) initially. Liver damage, hemolytic anemia, and thrombocytopenia are not associated with SEB and the pulmonary findings should be reversible in SEB.

No specific treatment is available for C. pefringens intoxication. Early antibiotic treatment is effective, if undertaken before significant amounts of toxins have accumulated in the body. If not treated the bacteria enter the bloodstream causing fatal systemic illness. The organism itself is sensitive to penicillin, and consequently, this is the current drug of choice.

Recent data indicate that clindamycin or rifampin may suppress toxin production and provide superior results in animal models. Prompt surgical debridement and broad spectrum, intravenous antibiotics are the mainstay of therapy. Hyperbaric oxygen has been seen as effective in prolonging survival in animal studies when coupled with other treatments.

Example # 6. Crimean-Congo Hemorrhagic Fever:

Crimean-Congo hemorrhagic fever (CCHF) is a viral disease caused by the Nairovirus. The virus, first characterized in the Crimea in 1944, is transmitted by ticks, principally of the genus Hyalomma, with intermediate vertebrate hosts varying with tick species. In 1969 it was recognized that the pathogen causing Crimean hemorrhagic fever was the same as that responsible for an illness identified in 1956 in the Congo, and linkage of the two place-names resulted in the current name for the disease and the virus.

The disease, next found in the Congo, occurs also in the Middle East, the Balkans, the former USSR, and eastern China. Little is known about variations in the virus properties over the huge geographic area involved. Humans become infected through tick bites, crushing an infected tick, or at the slaughter of viremic livestock. Even in epidemics, cases do not show narrow clustering and person-to-person spread is rare, though possible through contact with infectious blood or bodily fluids. CCHF would probably be delivered by aerosol if used as a BW agent.

Diagnosis of suspected CCHF is performed in specially-equipped, high biosafety level laboratories. Other viral hemorrhagic fevers, meningococcemia, rickettsia diseases, and similar conditions may resemble full-blown CCHF. Most fatal cases and half the others will have detectable antigen by rapid enzyme-linked immunosorbant assay (ELISA) testing of acute serum samples. IgM ELISA antibodies occur early in recovery. Polymerase chain reaction has recently been used in diagnosing CCHF.

Supportive therapy with replacement of clotting factors is indicated. Crimean- Congo hemorrhagic fever virus is sensitive to ribavirin in vitro and clinicians have been favorably impressed in uncontrolled trials. Immune sera have also been used for therapeutic purposes several times, but its value has not been demonstrated.

Example # 7. Ebola Hemorrhagic Fever:

Ebola hemorrhagic fever is one of the most virulent viral diseases known to humankind, causing death in 50-90% of all clinically-ill cases. Consequently, it has figured prominently in popular discussions of biological weapons, although its practical applications as a biological threat agent remain speculative. The disease has its origins in the jungles of Africa and Asia and several different forms of Ebola virus have been identified and may be associated with other clinical expressions, on which further research is required.

The Ebola virus is transmitted by direct contact with the blood, secretions, organs or semen of infected persons. Transmission through semen may occur up to 7 weeks after clinical recovery, as with Marburg hemorrhagic fever. Health care workers have frequently been infected while attending patients. In the 1976 epidemic in Zaire, every Ebola case caused by contaminated syringes and needles died.

After an incubation period of 2 to 21 days, Ebola is often characterized by the sudden onset of fever, weakness, muscle pain, headache and sore throat. This is followed by vomiting, diarrhea, rash, limited kidney and liver functions, and both internal and external bleeding. Specialized laboratory tests on blood specimens (which are not commercially available) detect specific antigens or antibodies and/or isolate the virus. These tests present an extreme biohazard and are only conducted under maximum containment conditions.

No specific treatment or vaccine exists for Ebola hemorrhagic fever. Severe cases require intensive supportive care, as patients are frequently dehydrated and in need of intravenous fluids. Experimental studies involving the use of hyper-immune sera on animals demonstrated no long-term protection against the disease after interruption of therapy.

Suspected cases should be isolated from other patients and strict barrier nursing techniques practiced. All hospital personnel should be briefed on the nature of the disease and its routes of transmission. Particular emphasis should be placed on ensuring that high-risk procedures such as the placing of intravenous lines and the handling of blood, secretions, catheters, and suction devices are done under barrier nursing conditions.

Hospital staff should have individual gowns, gloves, and masks. Gloves and masks must not be reused unless disinfected. Patients who die from the disease should be promptly buried or cremated.

Different hypotheses have been developed to try to uncover the cycle of Ebola. Initially, rodents were suspected, as is the case with Lassa fever whose reservoir is a wild rodent (Mastomys). Another hypothesis is that a plant virus may have caused the infection of vertebrates. Laboratory observation has shown that bats experimentally infected with Ebola do not die and this has raised speculation that these mammals may play a role in maintaining the virus in the tropical forest.

Example # 8. Melioidosis:

Melioidosis is an infectious disease of humans and animals caused by Burkholderia pseudomallei (formerly Pseudomonas pseudomallei), a gram-negative bacillus. It is especially prevalent in Southeast Asia but has been described in many countries around the world. The disease has a variable and inconstant clinical spectrum. A biological warfare attack with this organism would most likely be by the aerosol route.

Infection by inoculation results in a subcutaneous nodule with acute lymphangitis and regional lymphadenitis, generally with fever. Pneumonia may occur after inhalation or hematogenous dissemination of infection. It may vary in intensity from mild to fulminant, usually involves the upper lobes, and often results in cavitation. Pleural effusions are uncommon. An acute fulminant septicemia may occur characterized by rapid appearance of hypotension and shock. A chronic supportive form may involve virtually any organ in the body.

Antibiotic regimens that have been used successfully include tetracycline, 2-3 g/day; chloramphenicol, 3 g/day; and trimethoprim-sulfamethoxazole, 4 and 20 mg/kg per day. Ceftazidine and piperacillin have enjoyed success in severely ill patients as well. In patients who are toxic, a combination of two antibiotics, given parenterally, is advised.

There are no means of immunization. Vigorous cleansing of abrasions and lacerations may reduce the risk of disease after inoculation of organisms into the skin. There is no information available on the utility of antibiotic prophylaxis after potential exposure, but before the onset of clinical symptoms.

Example # 9. Plague:

Plague is a zoonotic disease caused by Yersinia pestis. Under natural conditions, humans become infected as a result of contact with rodents, and their fleas. The transmission of the gram-negative coccobacillus is by the bite of the infected flea, Xenopsylla cheopis, the oriental rat flea, or Pulex irritans, the human flea.

Under natural conditions, three syndromes are recognized: bubonic, primary septicemia, or pneumonic. In a biological warfare scenario, the plague bacillus could be delivered via contaminated vectors (fleas) causing the bubonic type or, more likely, via aerosol causing the pneumonic type.

In bubonic plague, the incubation period ranges from 2 to 10 days. The onset is acute and often fulminant with malaise, high fever, and one or more tender lymph nodes. Inguinal lymphadenitis (bubo) predominates, but cervical and axillary lymph nodes can also be involved. The involved nodes are tender, fluctuant, and necrotic.

Bubonic plague may progress spontaneously to the septicemia form with organisms spread to the central nervous system, lungs (producing pneumonic disease), and elsewhere. The mortality is 50 percent in untreated patients with the terminal event being circulatory collapse, hemorrhage, and peripheral thrombosis.

In primary pneumonic plague, the incubation period is 2 to 3 days. The onset is acute and fulminant with malaise, high fever, chills, headache, myalgia, cough with production of a bloody sputum, and toxemia. The pneumonia progresses rapidly, resulting in dyspnea, strider, and cyanosis. In untreated patients, the mortality is 100 percent with the terminal event being respiratory failure, circulatory collapse, and a bleeding diathesis.

In cases where bubonic type is suspected, tularemia adenitis, staphylococcal or streptococcal adenitis, meningococcemia, enteric gram negative sepsis, and rickettsiosis need to be ruled out. In pneumonic plague, tularemia, anthrax, and staphylococcal enterotoxin B (SEB) agents need to be considered. Continued deterioration without stabilization effectively rules out SEB.

Plague may be spread from person to person by droplets. Strict isolation procedures for all cases are indicated. Streptomycin, tetracycline, and chloramphenicol are highly effective if begun early. Significant reduction in morbidity and mortality is possible if antibiotics are given within the first 24 hours after symptoms of pneumonic plague develop.

A formalin-killed Y. pestis vaccine that was produced in the United States and extensively used is no longer manufactured. Efficacy against flea-borne plague was inferred from population studies, but the utility of this vaccine against aerosol challenge was unknown. Immunity was maintained through boosters every 1-2 years. Live-attenuated vaccines are available elsewhere but are highly reactogenic and without proven efficacy against aerosol challenge.

Example # 10. Q Fever:

Q fever is a zoonotic disease caused by a rickettsia, Coxiella burnetii. The most common animal reservoirs are sheep, cattle and goats. Humans acquire the disease by inhalation of particles contaminated with the organisms. A biological attack would cause disease similar to that occurring naturally.

Following an incubation period of 10-20 days, Q fever generally occurs as a self- limiting febrile illness that includes headache, fatigue, and myalgias and lasts from 2 days to 2 weeks. Pneumonia occurs frequently, usually manifested only by an abnormal chest x-ray. A nonproductive cough and pleuritic chest pain occur in about one-fourth of patients with Q fever pneumonia. Patients usually recover uneventfully.

Q fever usually presents as an undifferentiated febrile illness, or a primary atypical pneumonia, which must be differentiated from pneumonia caused by mycoplasma, Legionnaire’s disease, psittacosis or Chlamydia pneumonia. More rapidly progressive forms of pneumonia may look like bacterial pneumonias including tularemia or plague.

Tetracycline (250 mg every 6 hr) or doxycycline (100 mg every 12 hr) for 5-7 days is the treatment of choice. A combination of erythromycin (500 mg every 6 hr) plus rifampin (600 mg per day) is also effective.

Vaccination with a single dose of a killed suspension of C. burnetii provides complete protection against naturally occurring Q fever and >90% protection against experimental aerosol exposure in human volunteers. Protection lasts for at least 5 years.

However, neither this vaccine nor any other is commercially available in the U.S. Administration of this vaccine in immune individuals may cause severe cutaneous reactions including necrosis at the inoculation site. Newer vaccines are under development. Treatment with tetracycline during the incubation period will delay but not prevent the onset of illness.

Example # 11. Ricin:

Ricin is a glycoprotein toxin (66,000 Daltons) from the seed of the castor plant. It blocks protein synthesis by altering the rRNA, thus killing the cell. Ricin’s significance as a potential biological threat agent relates to its availability worldwide, ease of production, and extreme pulmonary toxicity when inhaled.

Overall, the clinical picture seen depends on the route of exposure. All reported serious or fatal cases of castor bean ingestion have taken approximately the same course: rapid onset of nausea, vomiting, abdominal cramps, and severe diarrhea with vascular collapse; death has occurred on the third day or later.

Following inhalation, one might expect nonspecific symptoms of weakness, fever, cough, nausea, and hypothermia followed by hypotension and cardiovascular collapse. High doses by inhalation appear to produce severe enough pulmonary damage to cause death.

In oral intoxication, fever, gastrointestinal involvement, and vascular collapse are prominent, the latter differentiating it from infection with enteric pathogens. With regard to inhalation exposure, nonspecific findings of weakness, fever, vomiting, cough, hypothermia, and hypotension in large numbers of patients might suggest several respiratory pathogens.

Therapy is supportive and should include maintenance of intravascular volume. Standard management for poison ingestion should be employed if intoxication is by the oral route. There is presently no antitoxin available for treatment.

There is currently no prophylaxis approved for human use. Active immunization and passive antibody prophylaxis are under study, as both are effective in protecting animals from death following exposure by intravenous or respiratory routes.

Example # 12. Rift Valley Fever:

Rift Valley Fever (RVF) is a viral disease caused by RVF virus. The virus circulates in sub-Saharan Africa as a mosquito-borne agent. Epizootics occur when susceptible domestic animals are infected, and because of the large amount of virus in their serum, amplify infection to biting arthropods. Deaths and abortions among susceptible species such as cattle and sheep constitute a major economic consequence of these epizootics, as well as providing a diagnostic clue and a method of surveillance.

Humans become infected through the bite of mosquitoes, contact with infected blood, bodily fluids, or organs, or exposure to virus-laden aerosols or droplets. The human disease appears to be similar whether acquired by aerosol or by mosquito bite.

A biological attack, most likely delivered by aerosol, would be expected to elicit the rather specific spectrum of human clinical manifestations and to cause disease in sheep and cattle in the exposed area. If disease occurred in the absence of heavy vector populations or without domestic animals as amplifiers of mosquito infection, a BW attack would also be a likely cause.

The occurrence of an epidemic with febrile disease, hemorrhagic fever, eye lesions, and encephalitis in different patients would be characteristic of RVF. Demonstration of viral antigen in blood by ELISA is rapid and successful in a high proportion of acute cases of uncomplicated disease or hemorrhagic fever. Other methods of diagnosis include polymerase chain reaction and virus propagation.

In hemorrhagic fever, supportive therapy may be indicated for hepatic and renal failure, as well as replacement of coagulation factors. The virus is sensitive to ribavirin in vitro and in rodent models. No studies have been performed in human or the more realistic monkey model to ascertain whether administration to an acutely ill patient would be of benefit.

Avoidance of mosquitoes and contact with fresh blood from dead domestic animals and respiratory protection from small particle aerosols are the mainstays of prevention. An effective inactivated vaccine for humans is not licensed for public use, but is available in limited quantities, particularly to laboratory and veterinary personnel.

Example # 13. Saxitoxin:

Saxitoxin is the parent compound of a family of chemically related neurotoxins. In nature they are predominantly produced by marine dinoflagellates, although they have also been identified in association with such diverse organisms as blue-green algae, crabs, and the blue-ringed octopus. Human intoxications are principally due to ingestion of bivalve mollusks which have accumulated dinoflagellates during filter feeding.

The resulting intoxication, known as paralytic shellfish poisoning (PSP), is known throughout the world as a severe, life-threatening illness requiring immediate medical intervention. In a BW scenario, the most likely route of delivery is by inhalation or toxic projectile. In addition, saxitoxin could be used in a confined area to contaminate water supplies.

After oral exposure, absorption of toxins from the gastrointestinal tract is rapid. Onset of symptoms typically begins 10-60 minutes after exposure, but may be delayed several hours depending upon the dose and individual idiosyncrasy. Initial symptoms are numbness or tingling of the lips, tongue and fingertips, followed by numbness of the neck and extremities and general muscular incoordination.

Nausea and vomiting may be present, but typically occur in a minority of cases. Respiratory distress and flaccid muscular paralysis are the terminal stages and can occur 2-12 hours after intoxication. Death results from respiratory paralysis. Clearance of the toxin is rapid and survivors for 12-24 hours will usually recover. There are no known cases of inhalation exposure to saxitoxin in the medical literature, but data from animal experiments suggest the entire syndrome is compressed and death may occur in minutes.

Management is supportive and standard management of poison ingestion should be employed if intoxication is by the oral route. Toxins are rapidly cleared and excreted in the urine, so diuresis may increase elimination. Incubation and mechanical respiratory support may be required in severe intoxication. Timely resuscitation would be imperative, albeit very difficult, after inhalation exposure on the battlefield.

No vaccine against saxitoxin exposure has been developed for human use.

Example # 14. Smallpox:

Smallpox virus, an orthopoxvirus with a narrow host range confined to humans, was an important cause of morbidity and mortality in the developing world until recent times. Although the World Health Organization declared the virus eradicated in 1980, eradication of the natural disease was completed in 1977 and the last human cases, associated with laboratory infections, occurred in 1978.

The virus exists today in only 2 laboratory repositories, one in the U.S. and the other in Russia. Appearance of human cases outside the laboratory would signal use of the virus as a biological weapon. Under natural conditions, the virus is transmitted by direct (face-to face) contact with an infected case, by fomites, and occasionally by aerosols.

Smallpox virus is highly stable and retains infectivity for long periods outside of the host. A related virus, monkeypox, clinically resembles smallpox and causes sporadic human disease in West and Central Africa.

The incubation period is typically 12 days (range, 10-17 days). The illness begins with a prodrome lasting 2-3 days, with generalized malaise, fever, rigors, headache, and backache. This is followed by defervescence and the appearance of a typical skin eruption characterized by progression over 7-10 days of lesions through successive stages, from macules to papules to vesicles to pustules.

The latter finally form crusts and, upon healing, leave depressed depigmented scars. The case fatality rate is approximately 30% in unvaccinated individuals. Permanent joint deformities and blindness may follow recovery. Vaccine immunity may prevent or modify illness.

The eruption of chickenpox (varicella) is typically centripetal in distribution (worse on trunk than face and extremities) and characterized by crops of lesions in different stages of development. Chickenpox papules are soft and superficial, compared to the firm, shotty, and deep papules of smallpox. Chickenpox crusts fall off rapidly and usually leave no scar. Monkeypox cannot be easily distinguished from smallpox clinically.

Monkeypox occurs only in forested areas of West and Central Africa as a sporadic, zoonotic infection transmitted to humans from wild squirrels. Person-to- person spread is rare and ceases after 1-2 generations. Mortality is 15%.

Other diseases that are sometimes confused with smallpox include typhus, secondary syphilis, and malignant measles. Skin samples (scrapings from papules, vesicular fluid, pus, or scabs) may provide a rapid identification of smallpox by direct electron microscopy, agar gel immunoprecipitation, or immunofluorescence.

There is no specific treatment available although some evidence suggests that vaccinia-immune globulin is of some value in treatment if given early in the course of the illness.

Patients with smallpox should be treated by vaccinated personnel using universal precautions. Objects in contact with the patient, including bed linens, clothing, ambulance, etc.; require disinfection by fire, steam, or sodium hypochlorite solution.

Example # 15. Staphylococcal Enterotoxin B:

Staphylococcal Enterotoxin B (SEB) is one of several exotoxins produced by Staphylococcus aureus, causing food poisoning when ingested. A BW attack with aerosol delivery of SEB to the respiratory tract produces a distinct syndrome causing significant morbidity and potential mortality.

The disease begins 1-6 hours after aerosol exposure with the sudden onset of fever, chills, headache, myalgia, and nonproductive cough. In more severe cases, dyspnea and retrosternal chest pain may also be present. Fever, which may reach 103-106° F, can last 2-5 days, but cough may persist 1-4 weeks.

In many patients nausea, vomiting, and diarrhea will also occur. In moderately severe laboratory exposures, lost duty time has been <2 weeks, but, based upon animal data, it is anticipated that severe exposures will result in fatalities.

In foodborne SEB intoxication, fever and respiratory involvement are not seen, and gastrointestinal symptoms are prominent. The nonspecific symptoms of fever, nonproductive cough, myalgia, and headache occurring in large numbers of patients in an epidemic setting would suggest any of several infectious respiratory pathogens, particularly influenza, adenovirus, or mycoplasma. In a BW attack with SEB, cases would likely have their onset within a single day, while naturally occurring outbreaks would present over a more prolonged interval.

Treatment is limited to supportive care; humidified oxygen and steroids for pain control. No specific antitoxin for human use is available. There currently is no prophylaxis for SEB intoxication. Experimental immunization has protected monkeys, but no vaccine is presently available for human use.

Example # 16. Mycotoxicoses:

The trichothecene mycotoxins are a diverse group of more than 40 compounds produced by fungi. They strongly inhibit protein synthesis, impair DNA synthesis, alter cell membrane structure and function, and inhibit mitochondrial respiration. Secondary metabolites of fungi, such as T-2 toxin and others, produce toxic reactions called mycotoxicoses upon inhalation or consumption of contaminated food products by humans or animals. Naturally occurring trichothecenes have been identified in agricultural products and have been implicated in the animal disease moldy corn toxicosis, or poisoning.

There are no well-documented cases of clinical exposure of humans to trichothecenes. However, strong circumstantial evidence has associated these toxins with alimentary toxic aleukia (ATA), the fatal epidemic seen in Russia during World War II, and with alleged BW incidents (“yellow rain”) in Cambodia, Laos, and Afghanistan.

Consumption of these mycotoxins results in weight loss, vomiting, skin inflammation, bloody diarrhea, diffuse hemorrhage, and possibly death. The onset of illness following acute exposure to T-2 (intravenously or through inhalation) occurs in hours, resulting in the rapid onset of circulatory shock characterized by reduced cardiac output, arterial hypotension, lactic acidosis and death within 12 hours.

Clinical signs and symptoms of ATA were hemorrhage, leukopenia, ulcerative pharyngitis, and depletion of bone marrow. The purported use of T-2 as a BW agent resulted in acute exposure via inhalation and/or dermal routes, as well as oral exposure upon consumption of contaminated food products and water. Alleged victims reported painful skin lesions, lightheadedness, dyspnea, and a rapid onset of hemomhage, incapacitation and death. Survivors developed a radiation-like sickness including fever, nausea, vomiting, diarrhea, leukopenia, bleeding, and sepsis.

Specific diagnostic modalities are limited to reference laboratories. Because of their long “half-life” the toxic metabolites can be detected as late as 28 days after exposure.

Ascorbic acid (400-1200 mg/kg, inter-peritoneal (ip)) works to decrease lethality in animal studies, but has not been tested in humans. While not yet available for humans, administration of large doses of monoclinal antibodies directed against T-2 and other metabolites have shown prophylactic and therapeutic efficacy in animal models.

Example # 17. Tularemia:

Tularemia is a zoonotic disease caused by Francisella tularensis, a gram-negative bacillus. Humans acquire the disease under natural conditions through inoculation of skin or mucous membranes with blood or tissue fluids of infected animals, or bites of infected deerflies, mosquitoes, or ticks. A BW attack with F. tularensis delivered by aerosol would primarily cause typhoidal tularemia, a syndrome expected to have a case fatality rate which may be higher than the 5-10% seen when disease is acquired naturally.

A variety of clinical forms of tularemia are seen, depending upon the route of inoculation and virulence of the strain. In humans, as few as 10-50 organisms will cause disease if inhaled or injected intradermally, whereas 10⁸ organisms are required with oral challenge. Under natural conditions, ulceroglandular tularemia generally occurs about 3 days after intradermal inoculation (range 2-10 days), and manifests as regional lymphadenopathy, fever, chills, headache, and malaise, with or without a cutaneous ulcer.

Gastrointestinal tularemia occurs after drinking contaminated ground water, and is characterized by abdominal pain, nausea, vomiting, and diarrhea. Bacteremia may be common after primary intradermal, respiratory, or gastrointestinal infection with F. tularensis and could result in septicemia or “typhoidal” tularemia.

The typhoidal form also may occur as a primary condition in 5-15% of naturally- occurring cases; clinical features include fever, prostration, and weight loss, but without adenopathy. Diagnosis of primary typhoidal tularemia is difficult, as signs and symptoms are nonspecific and there frequently is no suggestive exposure history. Pneumonic tularemia is a severe atypical pneumonia that may be fulminant, and can be primary or secondary.

Primary pneumonia may follow direct inhalation of infectious aerosols, or may result from aspiration of organisms in cases of pharyngeal tularemia. Pneumonic tularemia causes fever, headache, malaise, substernal discomfort, and a non-productive cough; radiologic evidence of pneumonia or mediastinal lymphadenopathy may or may not be present.

A biological warfare attack with F. tularensis would most likely be delivered by aerosol, causing primarily typhoidal tularemia. Many exposed individuals would develop pneumonic tularemia (primary or secondary), but clinical pneumonia may be absent or non-evident. Case fatality rates may be higher than the 5-10% seen when the disease is acquired naturally.

The clinical presentation of tularemia may be severe, yet nonspecific. Differential diagnoses include typhoidal syndromes (e.g., salmonella, rickettsia, malaria) or pneumonic processes (e.g., plague, mycoplasma, SEB). A clue to the diagnosis of tularemia delivered as a BW agent might be a large number of temporally clustered patients presenting with similar systemic illnesses, a proportion of whom will have a nonproductive pneumonia. Identification of organisms by staining ulcer fluids or sputum is generally not helpful. Routine culture is difficult, due to unusual growth requirements and/or overgrowth of commensal bacteria.

Streptomycin (1 gm every 12 hours intramuscularly (IM) for 10-14 days) is the treatment of choice. Gentamicin also is effective (3-5 mg/kg/day parenterally for 10-14 days). Tetracycline and chloramphenicol treatment are effective as well, but are associated with a significant relapse rate. Although laboratory-related infections with this organism are very common, human-to-human spread is unusual and isolation is not required.

A live, attenuated tularemia vaccine is available as an investigational new drug (IND). This vaccine has been administered to more than 5,000 persons without significant adverse reactions and is of proven effectiveness in preventing laboratory- acquired typhoidal tularemia. Its effectiveness against the concentrated bacterial challenge expected in a BW attack is unproven. The use of antibiotics for prophylaxis against tularemia is controversial.