arsenal in the 1950s and 1960s, and was weaponized by Iraq in the 1980s The Aum Shinrikyo cult in Japan tried unsuccessfully to disseminate botulinum toxin before deciding to release sarin in the Tokyo subway system Pathophysiology Botulinum toxins are produced by certain strains of Clostridium botulinum, a strictly anaerobic spore-forming gram-positive rod commonly found in soil Most cases of naturally occurring botulism result from ingestion of preformed toxin (food poisoning) or intestinal toxin formation (infant form) Infant botulism has additional unique epidemiologic considerations; more extensive discussion of this disease, and of botulism in general, may be found elsewhere in this text (see Chapters 82 Weakness and 97 Neurologic Emergencies ) The botulinum neurotoxins are the most toxic substances known to man These toxins function at the peripheral cholinergic presynaptic nerve terminals, principally the neuromuscular junction, by preventing the release of acetylcholine and thereby leading to a generalized flaccid paralysis and autonomic symptoms In keeping with the fact that toxins are chemical poisons produced by biologic organisms, it is important to keep in mind that cases of botulism arising from a terrorist attack represent intoxication rather than infection caused by replicating C botulinum organisms Clinical Manifestations Following a latent period ranging from 24 hours to several days, victims begin to experience cranial nerve dysfunction, manifesting as bulbar palsy, ptosis, photophobia, and blurred vision owing to difficulty in accommodation Symptoms progress to include dysarthria, dysphonia, and dysphagia Ultimately, a descending, symmetric, flaccid paralysis ensues, although sensorium and sensation are not affected primarily The mucous membranes are dry; this fact, along with mydriasis, the nature of the paralysis (lack of initial fasciculations), and the latent period, all differentiate botulism from nerve-agent intoxication A solitary case of botulism must also be differentiated from myasthenia gravis, Guillain–Barré syndrome, tick paralysis, and a few other uncommon neurologic disorders The presence of multiple casualties with similar symptoms should raise the concern for botulism Management Supportive care, with meticulous attention to ventilatory support, remains the mainstay of botulism management Patients may require such support for several months, making the management of a large-scale botulism outbreak especially problematic in terms of medical resources A heptavalent (types A to G) despeciated (Fab2) equine botulinum antitoxin was licensed in 2013 for the management of noninfant botulism and is available through the CDC Although administration of antitoxin is unlikely to reverse disease (the antitoxin is most effective when given during the clinically asymptomatic, or latent, period), it may be useful in preventing progression when administered to exposed persons In addition, a licensed human botulinum immunoglobulin is available to treat infant botulism While the product (BabyBIG) contains antibody against botulinum toxin types A to E, it has only been studied, and is thus only licensed, to treat type A and B intoxication Botulism is not contagious, and standard precautions are adequate for patient care Tularemia Tularemia is a highly infectious plague-like disease caused by the gram-negative coccobacillus Francisella tularensis Several clinical forms of naturally occurring tularemia are known, but pneumonic tularemia would presumably be the most likely clinical presentation in the event of an intentional aerosol release of F tularensis The onset of symptoms may be abrupt and include fever, nonproductive cough, substernal tightness, pleuritic chest pain, occasional hemoptysis, chills, headache, malaise, anorexia, and fatigue Chest radiographs may show infiltrates, hilar adenopathy, pleural effusion, or miliary infiltrates (may mimic tuberculosis) Tularemia is not contagious, and standard precautions are adequate in patient care However, because of the very low infectious dose by aerosol, processing tularemia bacterial cultures is an extreme health risk to laboratory staff, who therefore must be notified of a suspected case, and special precautions are warranted See Table 132.3B for detailed treatment recommendations for children VIRAL HEMORRHAGIC FEVERS The viral hemorrhagic fevers are a heterogeneous group of illnesses caused by infection with lipid-enveloped RNA viruses belonging to the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae These viruses may cause deadly, fulminant illnesses with fever, hypotension, and bleeding diatheses A high mortality rate, with a capacity for human-to-human transmission by direct contact with body fluids makes the filoviruses (e.g., Ebola and Marburg viruses) and arenaviruses (e.g., Lassa fever virus) particularly concerning Bunyaviridae such as Crimean-Congo Hemorrhagic Fever virus can also be transmitted to healthcare providers Supportive care remains the cornerstone of therapy for most of the viral hemorrhagic fevers Intravenous ribavirin appears somewhat efficacious in treating disease due to the Arenaviridae To date, the most severe Ebola outbreak in history began in Guinea in 2013 and spread to West African neighbors Liberia and Sierra Leone Before being declared extinguished in 2016, over 28,000 cases and 11,000 deaths occurred A few cases were imported to the United States, revealing issues with medical readiness for imported viral hemorrhagic fevers Ebola, depending on the strain, typically has a case fatality rate of 50% to 80% in African nations, raising concerns regarding its intentional release by terrorists A recombinant Ebola vaccine tested in Guinea during the outbreak has shown great promise in preventing spread of disease to close contacts Ricin The distinction between biologic agents, which are living organisms capable of causing infections, and chemical agents, which are nonliving poisons, is obvious Toxins such as ricin, however, are chemical poisons produced by biologic organisms and occupy a somewhat nebulous niche between chemical and biologic (infectious) agents Although discussed with biologic agents, it should be kept in mind that they cause intoxication (poisoning) rather than infection, not replicate in hosts, and not produce communicable, or contagious, conditions Ricin is a toxin derived from the castor bean, and its production is not technologically challenging It is quite toxic if ingested, and far more so if injected or inhaled It is infamous as a homicidal weapon of espionage used by the Bulgarian secret service in London during the Cold War against defector Georgi Markov More recently, in February 2004, it was discovered in a U.S Senate office building, apparently having been delivered through the mail At least 16 persons required decontamination, although no one became ill Ricin is an inhibitor of cellular protein synthesis via enzymatic attack on the 28S ribosomal subunit The clinical presentation of ricin intoxication depends on the route of exposure Exposures due to aerosols produce dose-dependent symptoms Four to hours after inhalation, fever, chest tightness, cough, dyspnea, nausea, and arthralgias can occur, followed within 36 hours by progressive cough, dyspnea, cyanosis, and pulmonary edema resulting in respiratory failure If ingested, necrosis of the GI epithelium, local hemorrhage, and hepatic, splenic, and renal necrosis can be expected followed by vascular collapse and death If injected, severe local necrosis of muscle and regional lymph nodes with moderate visceral organ involvement are seen Patients with ricin poisoning are not contagious Establishing a diagnosis of ricin intoxication may be challenging: Early postexposure (0 to 24 hours) nasal or throat swabs and respiratory secretions may be submitted for toxin assay for epidemiologic purposes, although positive nasal swabs not prove penetration of toxin to the lungs, and negative swabs not exclude exposure in any given patient In addition, assays for the presence of toxin, as well as measurement of an antibody response, can be performed on serum Management is primarily supportive, although the U.S military has found that postexposure prophylaxis with an investigational toxoid is efficacious in animal trials OTHER AGENTS Numerous other agents may present bioterrorist threats of varying degrees In addition to previously discussed incidents, terrorists and belligerents have attempted to use Salmonella, Shigella, glanders, cholera, typhus, and probably many other organisms or toxins to induce disease Many of these agents are discussed adequately elsewhere in this and other texts; a few warrant additional comment here Venezuelan equine encephalitis makes an attractive weapon because of its high infection-to-disease ratio; virtually all those who are not immune become symptomatic In infants and young children the disease can be severe, with as many as 4% developing overt encephalitis, often leading to permanent sequelae or death Staphylococcal enterotoxin B (SEB) is a bacterial toxin that has been weaponized in the past Although familiar to many clinicians as a common cause of food poisoning, SEB would also be a potent incapacitating toxin if delivered by aerosol Symptoms produced in this manner would begin to 12 hours after exposure and consist of fever, headache, chills, myalgias, and nonproductive cough Dyspnea and chest pain accompany the inhalation of high dosages of inhaled toxin Nausea, vomiting, and diarrhea may occur as a result of inadvertently swallowed toxin Treatment is supportive; meticulous attention should be paid to fluid management Patients may be ill for as long as weeks with aerosol exposure Various fungal toxins, such as the trichothecene mycotoxins, have been mentioned in a biowarfare or bioterrorism context After the Vietnam War, the U.S government accused the Soviets of using a trichothecene toxin, T-2 mycotoxin (otherwise known as “yellow rain”), against Hmong tribesmen The Iraqis are known to have weaponized another fungal toxin, aflatoxin, which in addition to acute clinical effects, is a potent hepatic carcinogen Symptoms produced by various mycotoxins are variable and depend on the route of exposure The trichothecene mycotoxins are different from virtually all other bioterrorist agents in that they are dermally active Treatment is supportive