Marek T. Greer, MD, MPH
Richard Lewis, MD, MPH
Chemical, biological, radiological, nuclear, and explosive (CBRNE) agents present a growing threat to businesses and communities around the world. Occupational health professionals are in the unique position to contribute to the overall preparedness strategy. The attributes that the occupational health professional brings to this challenge include
• Expertise in toxicology, infectious disease, and physical trauma
• Training in epidemiology and emergency response
• Experience in health and safety program planning and training
• Familiarity with outreach to businesses and medical facilities
The 2010 United States National Security Strategy stated that there is no greater danger to the nation than a terrorist attack with a weapon of mass destruction. The real nature of these threats was recently highlighted with the mailing of ricin toxin to the White House and the bombings in Boston in 2013. The Bacillus anthracis attacks of 2001 and the release of sarin gas in a Tokyo subway demonstrated the tremendous direct and indirect impact these events can have on communities, the workplace, and the health care system.
Current national security efforts include planning and exercises, research and development, and educational outreach. Professionals from diverse backgrounds working in public and private partnerships have come together to address the CBRNE threat. What had been an area limited to specialized military units has evolved to include first responders, police, firefighters, emergency medical services, hazardous materials (Hazmat) response units, and bomb squads. Preparation for potential bioterrorist acts shares much in common with preparation for natural occurring pandemics from influenza or other novel viral threats, like the SARS virus in 2004. Ultimately, a coordinated, methodical approach will result in the nations being prepared to recognize, respond, and contain a terrorist event.
CHEMICAL AGENTS
Chemical weapons were used during World War I leading to extensive morbidity. The agents consisted primarily of chlorine, mustard agent, and phosgene. Nerve agents were developed by Germany during World War II although they were never deployed. In the 1950s and 1960s, both the United States and the former Soviet Union developed large stockpiles of both nerve agents and mustard agents. After signing the Chemical Weapons Convention in 1996, both nations pledged to destroy their arsenals of these compounds. As of 2013, the United States is still in the process of destroying stockpiles and closing arsenals.
Chemical weapons (nerve agents and mustard) were used in the Iran-Iraq war resulting in over 100,000 casualties. These have also been used by terrorist groups, the most notable being the release of Sarin on a subway in Tokyo by a cult terrorist group. There were 12 casualties and some impacted were medical responders. In addition, over 5000 persons sought care, most having no evidence of exposure or toxicity. The Tokyo event demonstrated the need for preparedness at emergency medical facilities, both to protect themselves from secondary exposure and to be able to effectively triage large numbers of persons presenting after an incident. Table 37–1 lists chemical agents that might be used as weapons. The toxic industrial compounds listed are covered elsewhere in this text.
Table 37–1. Substances that may be used as agents of chemical terrorism.
Nerve agent
Tabun (ethyl N,N-dimethylphosphoramidocyanidate)
Sarin (isopropyl methylphosphonofluoridate)
Soman (pinacolyl methyl phosphonofluoridate)
GF (cyclohexylmethylphosphonofluoridate)
VX (o-ethyl-[S]-[2-diisopropylaminoethyl]methylphosphonothiolate)
Blister agents
Lewisite (an aliphatic arsenic compound, 2-chlorovinyldichloroarsine)
Nitrogen and sulfur mustards
Phosgene oxime
Pulmonary agents
Phosgene
Chlorine
Explosive nitro compounds and oxidizers
Ammonium nitrate combined with fuel oil
Flammable industrial gases and liquids
Gasoline
Propane
Poison industrial gases, liquids, and solids
Cyanides
Nitriles
Corrosive industrial acids and bases
Nitric acid
Sulfuric acid
NERVE AGENTS
ESSENTIALS OF DIAGNOSIS
Miosis (ocular contact or systemic toxicity).
Localized muscle twitching (skin contact).
Salivation and nasal secretions (vapor or systemic).
Bronchorrhea, wheezing (vapor or systemic).
Diffuse muscle twitching.
Gastrointestinal symptoms (cramping diarrhea).
Urinary urgency.
Disorientation, seizures.
Flaccid paralysis, respiratory arrest.
Toxicity
Nerve agents are considered some of the most toxic materials made by man. G series agents tabun, sarin, sonam, and GF are non-persistent, while the V series agents such as VX, are persistent. The LCt50(vapor or aerosol exposure lethal to 50% of the population exposed) of V agents is approximately 50 mg-min/m3 and that of the G agents ranges from 70 to 400 mg-min/m3. Dermal LD50 is estimated to be 10 mg/kg or less for V agents and for G agents ranges from 30 to 1000 mg. Exposure risk for the G agents is primarily inhalation while the V agents are primarily a dermal hazard.
General Considerations
Nerve agents exert toxicity through inhibition of the enzyme acetylcholinesterase (AChE) at synaptic endings within the cholinergic nervous system, preventing the hydrolysis of acetylcholine (ACh). The accumulation of ACh at nerve endings causes repeated stimulation and continued propagation of the neurotransmitter signal and cholinergic over activity. Acetylcholine is found in both the central and peripheral nervous systems. Muscarinic receptors are found in the autonomic nervous system and impact internal organs such as the heart, lungs, gut, and bladder, along with sweat glands in the skin. The nicotinic receptors are typically found in autonomic ganglia and skeletal muscles.
Use
Initially, these agents were developed as insecticides but due to their extreme toxicity their only considered use is for chemical warfare or terrorism. While nerve agents were not used during World War II, Iraq used tabun and sarin against Iran in the 1980s. Iraq also used these weapons against a subpopulation of Kurds. In 2004, two American soldiers were exposed to sarin while in Baghdad. Sarin has also been used by a Japanese cult, Aum Shinrikyo, as a weapon of terror twice, once in Matsumoto and the other with the Tokyo subways. Nerve agents are considered a real threat, emphasizing the importance of early recognition of this characteristic toxidrome.
Absorption, Metabolism, & Excretion
Nerve agent may be absorbed after inhalation, skin contact or ingestion. The rate of absorption is fastest after inhalation and contact with mucosal surfaces or warm, moist skin surfaces. Inhalation may cause symptoms within minutes, while skin contact may result in toxicity being delayed from 4 to 18 hours. The agents vary in the binding to AChE, some “aging” immediately (irreversible) while others may be released. In general, recovery requires cessation of exposure and replenishment of AChE stores.
Clinical Findings
A. Symptoms and Signs
Nerve agent toxicity may be triaged as mild, moderate or severe based on clinical presentation. This is summarized in Table 37–2. The key to clinical management is to recognize that vapor exposure results in immediate effects at points of contact (eye, mucosa) while skin contact may present with variable effects, delayed by hours.
Table 37–2. Nerve agent vapor exposure—clinical signs developing early or immediately.
Ocular effects include miosis, lacrimation, conjunctival injection, pain, and blurred or dim vision. Miosis may take up to 60 days to resolve. This is a prominent vapor sign, but may not be seen until late after skin contact. Extreme rhinorrhea and salivation are prominent findings with both inhalational and dermal exposures. Careful and repeated respiratory assessment is critical, with wheezing and bronchorrhea being ominous signs requiring aggressive treatment and monitoring. Impact on pulse and blood pressure is variable and cannot be used as a reliable indicator of exposure. Signs and symptoms of gastrointestinal and urinary stimulation are signs of serious systemic toxicity. Sweating and localized muscle twitching may be seen at the site of liquid exposure.
As the dose increases more muscle fibers and muscle groups become involved, leading to full body fasciculations and jerking movements. As the brain is impacted confusion and generalized seizures occur. If the victim recovers, persistent neurologic effects have been observed, such as difficulty in concentration, sleep disturbances, mood changes, and fatigue.
B. Laboratory Findings
Nerve agents inhibit AChE measured red blood cell cholinesterase activity. In acute intoxication this must be a clinical diagnosis. After skin contact, determination of serial RBC cholinesterase activity may be useful since inhibition occurs before clinical signs. Other laboratory tests include arterial blood gases or pulse oximetry to assess respiratory status.
Prevention
For research laboratory workers or at demilitarization sites appropriate chemical agent safety practices include material containment and proper respiratory and skin protection.
Antidote kits should be immediately available and emergency medical staff trained in their use. Medical responders must consider using respiratory and skin protection until they can assure that victims have been adequately decontaminated.
Treatment
Treatment involves elimination of exposure, decontamination, basic/advanced life support and use of antidotes. Atropine will block ACh at the muscarinic sites, leading to drying of secretions. In severe cases large amounts of atropine may be required. Pralidoxime is used to remove the nerve agent from AChE restoring normal enzyme activity. Benzodiazepines (diazepam and midazolam) are used as anticonvulsants. These medications are available as autoinjectors for emergency use. DuoDote is a combination of 2 mg of atropine and 600 mg of pralidoxime. Diazepam (10 mg intramuscular dose) is also available as an autoinjector. Emergency treatment recommendations are shown in Tables 37–2 and 37–3.
Table 37–3. Nerve agent skin exposure—clinical signs may be variable and delayed.
Prognosis
Prognosis is dependent on quick recognition, prompt decontamination and administration of antidote. Mild to moderate cases should recover completely. After severe poisoning, there may be long-term neurologic sequelae present for many months.
MUSTARD VESICANT
ESSENTIALS OF DIAGNOSIS
Ocular irritation, blurred vision.
Skin blistering.
Respiratory irritation/bronchospasm.
Delayed respiratory effects (pneumonia, bronchiectasis).
Bone marrow suppression.
Acute pain/arsenic toxicity (HL, Lewisite).
Toxicity
Mustard has been used as a chemical warfare agent on multiple occasions causing significant morbidity. The LCt50 (vapor or aerosol exposure lethal to 50% of the population exposed) is approximately 1500 mg-min/m3. The LD50 of a liquid dose is estimated to be about 100.0 mg/kg. Exposure pathways are inhalational, dermal and ingestion.
General Considerations
Mustard has a low volatility and is persistent. Mustard gas is five times denser then air and settles in low areas. Volatility is increased in warmer weather and this becomes a major hazard with temperatures above 100°F. Mustard is a highly reactive molecule and acts as an alkylating agent to cause cellular tissue damage. Mustard also has mild cholinergic activity.
Use
The potential effectiveness of mustard on the battlefield was recognized early and used by Germany, the Allies, and Italy in World War I. This has also been used by Japan against the Chinese, Egypt in Yemen, and most recently by Iraq in the Iran-Iraq war. Of note, during World War I, this agent was not used until around the last year of the conflict but is considered responsible for 70% of all of the chemical casualties and responsible for 1.5 million of the 5 million casualties during this war. Due to the past extensive stockpiling of Mustard, it is still considered a threat.
Absorption, Metabolism, & Excretion
Mustard is highly reactive and penetrates the dermis and mucosal membranes. It rapidly reacts with cellular DNA to disrupt function and cause damage. Once reacted, it is no longer actively available and not found in fluids such as blister fluids or other biological fluids.
Clinical Findings
A. Symptoms and Signs
The eyes are the most sensitive to mustard exposure, with effects seen at a much lower doses than those required to damage the skin and airways. Conjunctivitis or injection, lacrimation, edema and a feeling of sandy grit in the eyes has been observed. Blepharospasm, corneal haziness and hemorrhage may be seen as well, with blindness a potential complication. Vapor also affects warm, moist skin areas such as arm pits, groin, and the antecubital fossae. Symptoms initially are similar to sunburn with erythema occurring after several hours. Vesicles later develop and coalesce into large bullae over the next 24–36 hours.
Pulmonary involvement results from direct tissue injury from the upper airway through the bronchi. Symptoms include hoarseness, sneezing, rhinorrhea, sore throat, and cough. As dose increases erythema, mucosal edema, rhonchi, and crackles are observed. High levels of exposure can cause laryngospasm, chemical pneumonitis and acute respiratory distress. Following acute symptoms, pseudomembranes may form causing mechanical obstruction. Rarely, systemic absorption may cause bone marrow suppression. Complications of less intense exposure include bacterial bronchitis and/or pneumonia.
B. Laboratory Findings
Basic laboratory measurements include a complete blood count, arterial blood gases and a chest x-ray. Urine, blister fluid, and plasma may be tested for thiodiglycol, SBMTE, or thiodiglycol protein adducts for post-exposure confirmation. Information on how to request this type of laboratory testing from the Centers for Disease Control is found at http://emergency.cdc.gov/chemical/lab.asp.
Prevention
For research laboratory workers and at demilitarization sites appropriate chemical agent safety practices include containment and personal protective equipment.
Treatment
Decontamination is the most important step in patient treatment. If decontamination occurs within two minutes of exposure, it is unlikely any damage may occur at all. Eye exposures are medical emergencies and require immediate irrigation with copious amounts of isotonic sterile fluids or water. A Morgan lens may be used for continuous copious irrigation. Immediate ophthalmologic consultation is warranted.
Skin contact with the mustard agents usually does not exhibit immediate symptoms. Cellular interaction can occur within 1–2 minutes with visible clinical effects 2–48 hours later (usually within 4–8 hours). Even if decontamination has not occurred within 2 minutes, decontamination still should be performed with copious amounts of soap and water. Reactive skin decontamination lotion is available for localized skin decontamination but there are no specific antidotes for mustard exposure. Over time, the area of chemical burn may require debridement or skin grafting.
Prognosis
With immediate decontamination prognosis is excellent. Chemical tissue injuries from mustard are slow to heal. Severe eye injuries may take up to 2 months to heal or be permanent. Pulmonary injuries may take weeks or months to stabilize. The impact of skin injuries will depend on the extent and severity of the damage and the need for skin grafts.
BIOLOGICAL AGENTS AND TOXINS
Following World War II, the United States, Russia, and other nations began to investigate the potential use of biological warfare agents, including Bacillus anthracis, Francisella tularensis, botulinum toxin, and others. While the international Biological Weapons Convention of 1975 stated that these nations would never “develop, produce, stockpile or otherwise acquire or retain microbiological agents or toxins, whatever their origin … for hostile purposes or in armed conflict” various forms of research continued into the 1990s. The widespread availability of biological agents makes them a major terrorist threat. The past two decades have seen the actual use of anthrax, ricin toxin, salmonella, and other agents by terrorist groups. The following is a discussion of the key biological agents and toxins of concern.
ANTHRAX (BACILLUS ANTHRACIS)
ESSENTIALS OF DIAGNOSIS
Cutaneous: serosanguinous papule that becomes necrotic.
Inhalational: dyspnea, chest pain, widening mediastinum.
Gastrointestinal: nonspecific pain, discomfort.
Infectivity
• Cutaneous: estimated to be 10 or less spores
• Inhalational: median lethal dose (LD50) = 2500–50,000 spores
• Person-to-person transmission is unlikely
• Vaccine: Biothrax (Anthrax Vaccine Adsorbed) is effective
General Considerations
Anthrax is an infectious disease that affects animals and humans. It is caused by Bacillus anthracis, a gram-positive, spore forming, rod-shaped, aerobic and/or facultative anaerobic bacterium. Spores are hardy and persist in soil and B anthracis has commonly infected grazing ruminants. “Wool sorters disease” was a term used to describe both cutaneous and inhalational anthrax occurring in the early twentieth century from handling contaminated hair. Infection with B anthracis begins when the spores are ingested by macrophage cells and become vegetative. The dividing bacteria create both a protective capsule and cellular toxins, causing tissue destruction and swelling. The clinical disease takes on different characteristics based on the route of exposure.
Use
Due to their environmental persistence, B anthracis spores were weaponized by several nations prior to this being banned by international treaties. In 1979, a release from a biological weapons facility in the former Soviet Union caused over 70 deaths from inhalational anthrax. Anthrax spores were mailed to governmental officials in the United States in 2001 causing 22 cases of disease (11 cutaneous, 11 inhalational with 5 deaths) and led to prophylactic treatment of nearly 10,000 persons. B anthracis is a select agent that requires CDC registration prior to possession, use, storage or transfer.
Clinical Findings
A. Signs and Symptoms
Inhalational anthrax begins with nonspecific symptoms of malaise, fatigue, myalgia, and fever. Mild chest pain/discomfort and a nonproductive cough may be present. Following 2–3 days of these symptoms, there may be a short period of improvement. This period of improvement is followed by the sudden onset of increasing respiratory distress with dyspnea, stridor, cyanosis, increased chest pain, and diaphoresis. Pneumonia has not been a consistent finding but can occur in some patients. Meningitis is present in up to 50% of cases, and some patients may present with seizures.
Cutaneous anthrax first appears as a small papule that progresses to a vesicle containing serosanguinous fluid. The fluid may contain many organisms and a paucity of leukocytes. The vesicle typically ruptures leaving a necrotic ulcer. The lesion is usually painless. Edema may be present and can occasionally be massive, encompassing the entire face or limb. Patients usually have fever, malaise, and headache. There may also be local lymphadenitis (enlarged lymph glands).
Gastrointestinal anthrax is rare and occurs after ingestion. It presents with nonspecific symptoms of nausea, vomiting, and fever. This is followed in most cases by severe abdominal pain, vomiting of blood, and bloody diarrhea. Patients with oropharyngeal disease present with severe sore throat or a local oral or tonsillar ulcer, usually associated with fever, toxicity, and swelling of the neck due to cervical or submandibular lymphadenitis and edema. Dysphagia and respiratory distress may also be present.
B. Laboratory
Diagnosis depends on identification of bacteria on culture or gram stain. Lesions may also be tested for organisms using polymerase chain reaction (PCR) assays or immunofluorescence. Lymphadenopathy with a widening of the mediastinum may be present on chest x-ray.
Prevention
There is a licensed vaccine available (BioThrax). For workers at risk of airborne exposure, the vaccine is administered intramuscularly (0.5 mL) in a primary series at 0, 1, and 6 months followed by boosters at 12 and 18 months. Annual boosters are recommended thereafter. Individuals are considered to have adequate immunity 4 weeks after the second dose of vaccine. Anthrax vaccine is not currently recommended for the general public in a pre-event setting. Post event considerations include accelerated vaccination programs and antibiotics.
For researchers, biosafety level 2 or level 3 practices, containment, and facilities are recommended for activities using cultures, clinical materials and potential aerosols. Sodium hypochlorite (bleach) has a high level of disinfection against B anthracis when used at a concentration of 0.79% with a minimum contact time of 20 minutes.
Treatment
For effective treatment, antibiotics should be given as soon as possible following suspicion of exposure. Current CDC recommendations for postexposure prophylaxis (PEP) following an inhalational exposure to B anthracis is 60 days of oral antibiotics using either ciprofloxacin (500 mg twice per day) or doxycycline (100 mg twice per day). Nonvaccinated persons should also receive a 3-dose series of the current anthrax vaccine. Antibiotic choice should be based on information pertaining to bacterial resistance, if known. Transition to amoxicillin is recommended in cases when the bacterium is susceptible to penicillin. This use is considered “off-label.” Ciprofloxacin and doxycycline are recommended to treat uncomplicated cutaneous anthrax.
Prognosis
Untreated, inhalational anthrax is estimated to result in 100% mortality. This emphasizes the importance of containment, respiratory protection and prompt medical treatment. Vaccination is effective in preventing disease in laboratory animals. Prompt antibiotic treatment has resulted in survival rate over 55% in the recent outbreaks reported.
BURKHOLDERIA MALLEI & PSEUDOMALLEI
ESSENTIALS OF DIAGNOSIS
Fever, malaise, myalgia.
Ulcerating, granulomatous lesions of the skin and mucous membranes.
Relapse and/or reactivation of disease process many years later.
Infectious Dose
General Considerations
Burkholderia mallei (glanders) and pseudomallei (melioidosis) are very closely related zoonotic diseases with natural reservoirs in horses, mules, donkeys and goats. B pseudomallei also occurs in swine, monkeys, rodents, cats, and birds. These organisms can infect humans with B pseudomallei being the more likely of the two to do so. Spread to humans occurs after inhalation, skin contact (through microabrasions) or contact with mucosal surfaces. Both diseases have variable incubation periods ranging from 1 to 21 days. Treatment is difficult requiring multiple antibiotics and the untreated case fatality rate is high. Persons with impaired immunity (diabetics, alcoholics, chronic renal disease, cystic fibrosis and steroid use) are at increased risk.
The severe course of infection, aerosol infectivity and worldwide availability of this pathogen has resulted in B pseudomallei’s inclusion as a potential agent of biological warfare or bioterrorism and is listed on the Centers for Disease Control list as a select agent.
Use
B mallei has been used as a biological warfare agent during the Civil War, World War I, World War II, and Afghanistan.
The agent was used by Germany in World War I to disrupt troop transport. B pseudomallei infected forces during the French Indochina conflict, and the Vietnam War. Several countries have shown interest in these agents in biological warfare programs. The former Soviet Union developed and may have used B mallei in Afghanistan. Bioterrorists may be able to readily gain access to these agents and cause significant numbers of casualties.
Clinical Findings
A. Symptoms and Signs
Each disease can produce an acute localized infection, acute septicemic infection, acute pulmonary infection and chronic suppurative infection. Disease severity depends on route of exposure, virulence, inoculum, and host health.
B pseudomallei and B mallei primarily cause an acute pulmonary infection after inhalational exposure or hematogenous spread from septicemia. Clinical presentation is nonspecific, including fever, cough, chest pain, hemoptysis, tachypnea or pharyngitis. A more chronic form of pulmonic infection can also present with weight loss, cavitary lesions in the upper lobes, hemoptysis and infiltrations, similar to tuberculosis.
The acute localized infection stems from exposures to mucous membranes, percutaneous injection, or skin contact where microabrasions might be present. The incubation period at the site is typically less than 6 days and will result in localized abscesses, cellulitis, and lymphadenitis. Fever, malaise, and septicemia may subsequently develop. The acute septicemic infection can include symptoms of fever, myalgia, pneumonitis, hepatosplenomegaly, and shock. A chronic suppurative infection can cause cutaneous lesions or internal abscesses.
With B mallei, an acute pulmonary infection can be more intense and include fever, malaise, myalgia, rigor, and chest pain. B pseudomallei has a more variable incubation period and is much more likely to relapse after treatment and become chronic.
B. Laboratory Findings
Laboratory results consist of a nonspecific leukocytosis. Chest x-ray findings include infiltrates, cavitations, and/or miliary lesions. Abscesses can be seen on CT and ultrasound. The definitive diagnosis requires isolation and positive identification of the organism. While there is no validated in vitro diagnostic test, agglutination/complement fixation as well as PCR have been used on an experimental basis. Table 37–4 lists criteria proposed for the diagnosis of acute pulmonary glanders in humans.
Prevention
Both B mallei and B pseudomallei are considered hazardous to laboratory workers with potential exposures from aerosolization or cutaneous exposures. Working with this agent requires biosafety level 3 containment if aerosols or droplets are a risk. Respirators and skin protection are important. Decontamination using sodium hypochlorite (bleach) is effective with a concentration of 0.79% and a contact time of 20 minutes.
Table 37–4. Diagnostic criteria for pulmonary glanders.
1. Constitutional symptoms (fever, rigors, myalgias, fatigue, headache, pleuritic chest pain)
2. Chest x-ray infiltrates (either segmental or lobar, or nodular opacities)
And either
• Positive isolation of B mallei organism from blood or sputum
OR
• Positive Burkholderia species nonspecific IHA titer with fourfold titer increase
Treatment
Limited information exists regarding the use of antibiotics for the treatment of infected humans. The treatment of choice for oral antibiotic therapy options are sulfamethoxazole in combination with trimethoprim (TMP-SMX), with or without a secondary oral medication of doxycycline. Dosing recommendations are shown in Table 37–5.
Table 37–5. Treatment recommendations for melioidosis and glanders.
Prognosis
Due to the rarity of glanders, it is difficult to determine prognosis as opposed to the more common melioidosis. With acute pulmonary infection and sepsis case fatality rates can approach 90%. Even after treatment, case fatality rate can still approach 40%. Localized infections are typically much less severe with a case fatality rate of less than 20% with treatment. Chronic suppurative infections can last many years requiring multiple rounds of treatment.
PLAGUE (YERSINIA PESTIS)
ESSENTIALS OF DIAGNOSIS
Swollen lymph nodes (bubonic).
Fever, cough, rapidly progressive pneumonia, hemoptysis (pneumonic).
Fever, chills, prostration, abdominal pain, shock (septicemic).
Infectivity
General Considerations
Plague is caused by the bacterium Yersinia pestis, a gram-negative, nonmotile coccobacilli. This bacterium is found naturally in wild rodents and fleas. Plague is endemic in many areas of the world, including the Western United States. Natural plague outbreaks are still prevalent with up to 4500 cases with 300 deaths reported to the World Health Organization annually. Y pestis is a Tier 1 Select Agent that requires CDC registration prior to possession, use, storage or transfer.
Use
Y pestis remains a biological agent of concern for terrorist use due to its wide availability and natural vectors for disease spread. Pneumonic plague may be spread from person to person with close contact. To date there has been no documented outbreak from intentional release of the organism.
Clinical Findings
A. Signs and Symptoms
Pneumonic plague presents with fever, headache, weakness, and rapidly developing pneumonia. Victims develop shortness of breath, chest pain, productive cough, and bloody or watery sputum. The pneumonia progresses for 2–4 days and may cause respiratory failure, shock, and death without treatment. Pneumonic plague may be spread from person to person due to inhalation of infectious secretions with close contact.
Bubonic plague presents with sudden onset of fever, headache, chills, weakness, and swollen, tender lymph glands (“buboes”) in the area draining the site of a bite or percutaneous exposure. Without proper treatment sepsis may develop.
Septicemic plague produces fever, chills, prostration, abdominal pain, shock, bleeding into skin and other organs, and can lead to rapid death. Disseminated intravascular coagulation may cause the skin and other tissues to blacken, especially the fingers, toes, and nose. Septicemic plague can occur as the first symptom of plague, or may develop secondary to untreated bubonic or pneumonic plague. Blood and other bodily fluids are infectious and can cause secondary exposure.
B. Laboratory
Laboratory testing will correlate with the nature and severity of the illness. Disseminated intravascular coagulation is an ominous development. Gram-negative, coccobacilli may be identified on Gram stain of sputum or bubo aspirate. A Wayson stain reveals a light blue bacillus with dark blue polar bodies. A definitive diagnosis is made by culturing the organism from blood, sputum, or bubo aspirates.
Treatment
For effective treatment, broad spectrum antibiotics must be given within 24 hours of the onset of symptoms. Streptomycin is FDA-approved to treat plague, however many antibiotics may be effective, including aminoglycosides, tetracycline, chloramphenicol, and fluoroquinolones. Prophylactic antibiotics such as doxycycline 100 mg po bid or ciprofloxacin 500 mg po bid for 10 days will protect persons who have had direct contact with infected victims, aerosols, or other materials suspected or known to contain Y pestis.
Prevention
There is no vaccine for plague. Wearing appropriate personal protective equipment is essential when working with the organism in the laboratory. Working with Y pestis cultures, samples, and other potentially infectious specimens should be conducted in a biological safety cabinet by trained personnel wearing appropriate PPE within a BSL-3 laboratory. Sodium hypochlorite (bleach) is an effective disinfectant for Y pestis when used at concentrations of 0.79% with a minimum contact time of 20 minutes.
Prognosis
Early recognition and prompt treatment should result in complete recovery. Once septicemic complications develop, the fatality rate is 30–50% despite treatment.
TULAREMIA (FRANCISELLA TULARENSIS)
ESSENTIALS OF DIAGNOSIS
Ulcerative skin lesion, lymphadenopathy (ulceroglandular).
Fever, prostration (typhoidal).
Subclinical pneumonitis.
Infectivity
General Considerations
Francisella tularensis causes tularemia in humans and animals. F tularensis is a small, aerobic, nonmotile, nonsporulating, gram negative, coccobacillus. The bacteria is harbored by a wide variety of animals including rabbits, muskrats, beavers, deerfly, mosquito, rodents, and arthropods such as ticks. F. tularensis is also resistant to lower temperatures and is able to survive for weeks in water, soil, and carcasses. This is a Select Agent and any work with F tularensis requires special security considerations and licensing through the CDC.
Use
Environmental hardiness and low infective dose have made F tularensis a candidate for use as a biological weapon. While outbreaks have occurred during wartime, there is no evidence this has ever been specifically used as a weapon. Prior to the institution of modern Biosafety containment practices, tularemia was one of the most common forms of laboratory-acquired infections in researchers. Approximately 100–200 cases of naturally occurring tularemia are reported in the United States each year.
Clinical Findings
A. Signs and Symptoms
F tularensis can infect humans through the skin, mucous membranes, gastrointestinal tract, and lungs. The disease has an incubation period of 2–10 days. As few as 10–50 organisms will cause disease in humans by aerosol or cutaneous route. The initial tissue reaction to infection is a focal, intensely suppurative lesions and ulcers.
Ulceroglandular disease is the most common form, presenting as an ulcerative lesion accompanied by regional lymphadenopathy and systemic symptoms. Typhoidal tularemia presents with fever, chills, myalgias, and prostration. Subclinical pneumonitis is commonly present. An intentional release of F tularensis would lead to hemorrhagic inflammation of the airways early in the course of illness. This may progress to pneumonia and systemic illness. The onset of tularemia is usually abrupt, with fever, headache, chills and rigors, generalized body aches, dry cough, and sore throat. Nausea, vomiting, and diarrhea may occur. Typhoidal tularemia may have a fatality rate as high as 70% if untreated.
B. Laboratory
White blood cell counts may be normal or elevated. Lymphocytosis may be seen later in the course of disease. Chest x-rays may reveal a pneumonitis; although, lobar consolidation and hilar adenopathy may also occur. Diagnosis depends on isolation of the organism from blood or lesions. Clinical laboratories should be alerted if tularemia is suspected and a culture is grown using Biosafety level 3 practices. Tularemia can be diagnosed using serology by microagglutination assay or enzyme-linked immunosorbent assay (ELISA) with a rise in titer developing 2 or more weeks after infection.
Treatment
F tularensis is susceptible to aminoglycocides and other antibiotics. Streptomycin (1 g IM twice daily for 10 days) or gentamicin (5 mg/kg IM or IV once daily for 10 days) are the preferred treatment for clinical disease. Doxycycline (100 mg twice daily for 14 days) or ciprofloxacin (500 mg twice daily for 14 days) may be used for postexposure prophylaxis.
Prevention
Documented laboratory acquired infections have resulted from accidental inoculation with cultures or from inhalation of infectious aerosols. F tularensis live vaccine strain is available only as an investigational new drug from the United States Army Medical Research Institute for Infectious Diseases (USAMRIID). Laboratory work with cultures or contaminated materials should be performed using Biosafety level 3 containment practices. Sodium hypochlorite (bleach) has a high level of disinfection. Heat sterilization, autoclaving, 70% ethanol, and formaldehyde gas can also be used for decontamination.
Prognosis
With prompt treatment complete recovery should occur. Delay in diagnosis can result in a more chronic illness with symptoms that persist for months.
BOTULINUM TOXIN
ESSENTIALS OF DIAGNOSIS
Weakness, lassitude, and dizziness followed by descending paralysis.
Diplopia.
Dysphagia.
Neck weakness.
Respiratory difficulties then paralysis.
Full motor paralysis.
Toxicity
General Considerations
Clostridium botulinum produces botulinum toxins (types A–G), all producing botulism. The microorganism is a gram-positive, rod-shaped, spore former and is a strict anaerobe. Botulism cases occur naturally due to ingestion of contaminated food, wound infection and infantile consumption. All forms of botulism can be fatal and are considered medical emergencies.
Use
Botulinum toxin is one of the most toxic substances known to man. It is considered a candidate for bioterror because of the potential for contamination of food or water supplies. There have not been any reported outbreaks due to intentional poisoning.
Absorption, Metabolism, & Excretion
Botulinum toxin is readily absorbed after ingestion or inhalation. It may also be absorbed through nonintact skin or injection. Botulinum toxins attack the presynaptic terminal of the peripheral nerves blocking the release of acetylcholine and inhibiting muscle contraction. The calculated lethal dose for humans is approximately 1 μg by ingestion and 1 ng by injection. Lethal doses by aerosol delivery are 20–80 times greater than those measured by injection (based on animal studies). Intact skin provides an effective barrier against systemic absorption.
Clinical Findings
A. Symptoms and Signs
Symptoms begin 12–36 hours following ingestion of the toxin, but may be delayed as long as 8 days after. Weakness, lassitude and dizziness are early complaints. Other symptoms are double vision, difficulty swallowing, dilated pupils and a dry tongue. Fever is rarely observed. As the disease progresses, muscles weaken (particularly the neck, proximal extremities, and respiratory musculature) leading to respiratory paralysis, airway obstruction and death. Severe nausea and vomiting are frequently observed with type E intoxication.
B. Laboratory Findings
Botulism is a clinical diagnosis. There are no laboratory findings specific for the illness. Culture methods for C. botulinum are poorly developed, and efficient isolation and identification tools are lacking.
Prevention
An investigational vaccine was used over the past 50 years but is no longer available. Next generation botulinum vaccines are actively being investigated. Research handling of botulinum toxin should be conducted by trained personnel in a class II cabinet in a biosafety level 2 or 3 laboratory. Aerosol exposure and percutaneous injection are serious potential hazards for research personnel. Sodium hypochlorite (bleach) has a high level of disinfection against botulinum toxin when used at a concentration of 0.1–5% with a minimum contact time of 30 minutes.
Treatment
Severe cases require prolonged assisted ventilation and other systemic support. Heptavalent botulinum antitoxin (HBAT) is available as an investigational new drug from the Centers for Disease Control (CDC, 770-488-7100). This may prevent or decrease respiratory failure and aid in recovery.
Prognosis
Persons provided ventilator support should survive and recover completely. The main risk during the illness is the development of complications during the 3–6 week period of paralysis.
RICIN
ESSENTIALS OF DIAGNOSIS
Tracheobronchitis, pneumonitis, pulmonary edema.
Gastrointestinal disturbances (nausea, vomiting, hemorrhage, hepatotoxicity).
Systemic toxicity (liver, kidney, bone marrow, cardiac).
Toxicity
The reported estimated lethal dose of ricin in humans is 1–25 μg/kg when inhaled or injected, and 2–20 mg/kg when ingested.
General Considerations
Ricin is a phytotoxic poison that is derived from processing the castor bean plant, Ricinus communis. Active toxin can be in the form of a powder, a mist, or a pellet and can be dissolved in water. It is environmentally stable and is not affected by extreme weather conditions, such as very hot or very cold temperatures. Ricin is a cellular toxin that inhibits protein synthesis by binding to and catalytically modifying ribosomes. This material is highly toxic if inhaled, ingested or injected. The clinical manifestations of ricin poisoning depend on the route of exposure. Affected individuals could be a threat to treating personnel if they are not properly decontaminated.
Use
Ricin was investigated as a possible warfare toxin by the United States in World War II. Subsequent research for this intent was banned in 1975. Because castor beans are readily available, this remains a potential terror agent of concern. Ricin is a select agent that requires CDC registration prior to possession, use, storage or transfer of quantities greater than 100 mg.
Absorption, Metabolism, & Excretion
Ricin is more toxic after inhalation or injection than ingestion. It is not absorbed through the skin.
Clinical Findings
A. Symptoms and Signs
The toxicity, symptoms, onset, and outcome depend on both the dose and the route of exposure. After inhalation, symptoms occur within 4–8 hours and the primary organ system affected is the respiratory tract. Symptoms include shortness of breath, cough, and chest tightness, along with systemic symptoms. Hemoptysis (coughing up blood) and pulmonary edema may develop over the next 18–36 hours leading to respiratory failure and death.
Ingestion of ricin may cause localized symptoms of gastrointestinal discomfort but usually results in delayed symptoms of nausea, vomiting, diarrhea and gastrointestinal bleeding within 1 to 3 days. Systemic absorption can lead to failure of major organs (liver, spleen, and kidneys) and death.
Topical contact with powder or mist forms of ricin could cause immediate (hours) local irritation of the eyes and skin, though should not result in systemic toxicity. Percutaneous exposure, however, can cause serious systemic toxicity affecting the nervous system (seizures) and cardiovascular system (hypotension) within hours. In general, if a lethal exposure has occurred, death will result within 36–72 hours from exposure. If the exposure does not result in death within 3–5 days, the victim should expect to recover.
B. Laboratory Findings
Leukocytosis with counts as high as five times normal have been reported. Other findings will reflect organ damage based on the site of exposure. Lung damage is not a prominent feature after ingestion or injection.
There are tests available to potentially confirm the presence of ricin toxin in biological tissues. These include a time-resolved fluorescence immunoassay and a polymerase chain reaction assy. These are available in the United States through state health departments.
Prevention
For research laboratory workers, BSL-2 safety practices, containment equipment, and facilities are recommended for work with ricin. Laboratory coat, gloves, and full-face respirator should be worn if there is any potential for creating a toxin aerosol.
Treatment
There are no vaccines or antidotes available to prevent or treat ricin toxicity. Recognition of potential exposure, rapid decontamination of the toxin and supportive medical interventions are the only available options. Eye or skin contact should be irrigated immediately with copious amounts of water. After ingestion, gastric lavage, catharsis, and activated charcoal may reduce absorption and systemic toxicity. Any case, in which ricin exposure is considered probable, should be hospitalized for observation. Supportive care would be based upon the clinical findings and organ systems impacted.
Prognosis
If the victim can be supported for 3–5 days after poisoning there is a good chance of survival.
BIOLOGICAL PREPAREDNESS
The primary defense against a biological terror event is the ability to respond. Public health programs developed to respond to natural pandemics, such as influenza, provide many of the elements necessary to respond to a bioterrorist event. Rapid detection and diagnosis with triage and delivery of appropriate medical supplies (including mass vaccination and prophylactic medications) are critical. A Bio-Response Report Card from the WMD Center, released in 2011, reported an evaluation of the United States capabilities in eight categories of bio-response. Occupational health providers have the unique training necessary to integrate into community preparedness planning to assist in education, response, and recovery.
RADIATION AND ENERGETICS
There are as many as 225 explosive device detonations each week in the United States which are classified as criminal in nature. Between 1983 and 2002, there were a total of 36,110 incidents causing 5931 injuries and 699 deaths. Bullets and bombs are still the most common threat of various terrorist organizations.
The radiological threat from a “dirty bomb” is likely to be small scale but can still cause significant physical illness and death, as well as large-scale psychological illness. These devices are not technologically challenging (as compared to a nuclear device). The utilization of a radiological device could produce major economic, social, and psychological disruptions.
The nuclear threat from a terrorist organization is difficult to assess. Three known groups, though, have actively tried to acquire these capabilities which include Aum Shinrikyo (Japan), Chechen rebels (Russia), and Al Qaeda. If these or other organizations were to acquire nuclear capabilities then the result of a nuclear detonation would be catastrophic in terms of lives lost, structural damage, and social impact.
Occupational health providers should understand the acute effects of exposure as well as what to recommend for mitigation of potential ionizing radiation effects after an event. The effects of a nuclear event range from prompt effects, which occur within the first minute of the explosion, and delayed effects (“fallout”) which occur over weeks.
Prompt effects, in the high damage zone, are due to damaged and collapsed structures as well as very high radiation levels. The moderate damage zone may extend out to about a mile and include structural damage, downed utility poles, overturned vehicles, collapsed buildings and fires. The light damage zone starts outside the moderate damage zone and consists of broken windows and damage to less stable structures.
Prompt radiation exposure can be the most hazardous. Thermal radiation will also result in those persons in “line-of-sight” exposures. Flash blindness occurs from the initial brilliant blast and can last up to several minutes. This can occur out to 12 miles from the initial blast.
Delayed effects from fallout come from contact with contaminated debris. Over a distance these particles tend to settle out and radiation levels tend to drop-off promptly with an estimated amount of 55% within the first hour and around 80% within the first day. The pattern seen with fallout is dependent on meteorological conditions. The highest doses most dangerous to people are typically found within 20 miles downwind. The various particles, particularly gamma particles, are the most dangerous. For this reason, sheltering in place is recommended. For a detailed view of radiation sickness please see Chapter 11. General guidelines for the public in the event of a radiation event are shown in Table 37–6.
Table 37–6. Public guidelines for actions after a radiation event.
1. Shelter in the most protective building or structure possible and plan to stay there at least 12–24 h. During this time, the fallout will dissipate greatly. This allows for safer egress.
2. Duck and cover. Avoid windows. The blast wave can take more than 10 s to reach a distance of 3 mi.
3. Tune-in to local radio stations and listen for instructions from authorities.
4. Vehicles do not offer protection. If in a vehicle, use it only to find more permanent shelter.
5. Particles of fallout come from the initial blast. Decontaminating the skin or removing the outer layer of clothing in a controlled manner will help mitigate the effects of radiation.
OPPORTUNITIES FOR OCCUPATIONAL HEALTH PROFESSIONALS
Support for Research Operations
Research on detection, prevention, and treatment of chemical and biological terror agents remains a priority in the United States and other nations. This work invariably requires the handling of small amounts of the actual agents, placing researchers at risk. Research work with conventional chemical weapons in the United States is under the jurisdiction of the Department of Defense, as are the continuing efforts to destroy remaining chemical weapon stockpiles. Surety programs ensure the reliability and medical fitness of persons conducting this work, as well as work with nuclear materials and biological select agents. Occupational health professionals must evaluate research staff for substance abuse, physical capabilities, and both medical and psychological fitness. The medical team also plays a critical role in medical response to a release or exposure incident. Unlike planning for a hypothetical community event, the occupational health professional must prepare protocols and conduct drills to react to an actual occupational mishap.
The Centers for Disease Control has also initiated a suitability program for researchers working with select agents. While not as defined or rigorous as the surety program, the concepts are similar. Occupational health professionals at universities, public agencies, and private laboratories must participate in both medical and psychological fitness assessments and emergency planning. Links to program descriptions are contained in the reference section.
Medical Preparedness Training
As demonstrated over the past two decades, terrorist events may occur anywhere, anytime. Emergency medicine may be on the frontlines in responding to a major chemical event; however, a more subtle biological event could present to various primary care providers across a region. Occupational health professionals can assist their communities in being prepared to identify and respond to such events.
Since the Oklahoma City bombing and 9-11, training opportunities are continuing to be developed to assist physicians in emergency planning and preparedness. Most of these courses provide attendees with a skill set which will help them integrate into a real event. Courses are generally set-up to provide an all-hazards approach and deliver basic information regarding each CBRNE or natural disaster component. Objectives are general and help promote recognition of an event, activation of appropriate response systems, and delivery of care.
CBRNE Preparedness represents a new frontier for occupational physicians. Threats are very real and the need for preparedness is critical. The skill set of the occupational physician provides a solid foundation to effectively support these programs for employers, academia, and government. This should become an integral part of future training programs in occupational and environmental medicine.
REFERENCES
CDC. Biosafety in microbiological and biomedical laboratories. http://www.cdc.gov/biosafety/publications/bmbl5/.
CDC. Emergency preparedness and response. http://www.bt.cdc.gov/.
Department of Homeland Security. Preparedness, response and recovery. http://ipv6.dhs.gov/files/prepresprecovery.shtm.
OSHA. Emergency preparedness. http://www.osha.gov/SLTC/emergencypreparedness/index.html.
US Army. Medical aspects of chemical and biological warfare, 2012. http://www.au.af.mil/au/awc/awcgate/medaspec/CWBWFMelectrv699.pdf.
USAMRIID. Occupational Health Manual for Laboratory Exposures to Select (BSL-3 & BSL-4) and Other Biological Agents, 2011. http://www.acoem.org/uploadedFiles/What_is_OEM/Occupational%20Health%20Manual%20for%20Laboratory%20Exposures.pdf
SELF-ASSESSMENT QUESTIONS
Select the one correct answer to each question.
Question 1: Nerve agent
a. vapor exposure results in immediate effects on the eye, mucosa, and skin
b. ocular effects include miosis, lacrimation, conjunctival injection, pain, and blurred or dim vision
c. miosis resolves rapidly
d. effects on pulse and blood pressure are reliable indicators of exposure
Question 2: Mustard
a. has a high volatility and is persistent
b. is a highly reactive molecule and acts as an alkylating agent to cause cellular tissue damage
c. has a pronounced cholinergic activity
d. is found in fluids such as blister fluids or other biological fluids
Question 3: Anthrax
a. is an infectious disease that affects animals and humans
b. spores are hardy but do not persist in soil
c. infection begins when the spores are ingested by lymphocytes and become vegetative
d. clinical disease has the same characteristics regardless of the route of exposure
Question 4: Inhalational anthrax
a. begins with nonspecific symptoms of malaise, fatigue, myalgia, and fever
b. invariably causes chest pain and a nonproductive cough
c. symptoms persist and steadily become more severe
d. leads to pneumonia in most patients
Question 5: Cutaneous anthrax
a. first appears as a small papule that progresses to a vesicle containing serosanguinous fluid
b. lesions are very painful
c. patients seldom have fever, malaise, and headache
d. always causes local lymphadenitis
Question 6: Gastrointestinal anthrax
a. is the most common form of infection
b. presents with nonspecific symptoms of nausea, vomiting, and fever
c. rarely causes severe abdominal pain, vomiting of blood, and bloody diarrhea
d. would very likely cause dysphagia
Question 7: Botulinum toxin
a. is considered a candidate for bioterror because of the potential for contamination of food or water supplies
b. is slowly absorbed after ingestion or inhalation
c. is readily absorbed through skin
d. attacks the presynaptic terminal of the peripheral nerves blocking the release of acetylcholine and inhibiting muscle contraction
Question 8: Ricin is
a. absorbed through the skin
b. unstable and is affected by extreme weather conditions
c. a cellular toxin that inhibits protein synthesis by binding to and catalytically modifying ribosomes.
d. less toxic after inhalation or injection than ingestion
Question 9: After inhalation of ricin
a. symptoms occur immediately
b. the primary organ affected is the central nervous system
c. there are no systemic symptoms
d. hemoptysis and pulmonary edema may develop over the next 18–36 hours leading to respiratory failure and death